Characteristics and associations of high-mitotic-rate melanoma.

IMPORTANCE: Mitotic rate is now recognized as having independent prognostic significance in melanoma survival. However, its clinicopathologic associations have not been the focus of any previous study. OBJECTIVE: To identify a set of patient and tumor characteristics associated with high-mitotic-rate melanoma with the aim of facilitating the earlier detection of aggressive primary invasive melanoma. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of patients from a multidisciplinary melanoma clinic based in a public hospital. A total of 2397 cases from January 2006 to December 2011 were reviewed by the Victorian Melanoma Service, and 1441 patients with 1500 primary invasive melanomas were included in the study. MAIN OUTCOMES AND MEASURES: Mitotic rate was measured as number of mitoses per mm2 and analyzed as ordered categories (0, <1, 1 and <2, 2, 3-4, 5-9, and ≥10) according to patient demographics, phenotypic markers, historical data, tumor presentation, and histopathologic features. RESULTS: Melanomas with higher mitotic rates were more likely to occur in men (odds ratio [OR], 1.5; 95% CI, 1.3-1.8), patients 70 years or older (OR, 2.1; 95% CI, 1.7-2.8), and those with a history of solar keratosis (OR, 1.3; 95% CI, 1.1-1.6). These melanomas occurred more frequently on the head and neck (OR, 1.4; 95% CI, 1.0-1.9) and presented more often as amelanotic (OR, 1.9; 95% CI, 1.4-2.5) and rapidly growing (≥2 mm/mo) lesions (OR, 12.5; 95% CI, 8.4-18.5). An association was seen with the nodular melanoma subtype (vs superficial spreading [reference]) (OR, 2.5; 95% CI, 1.8-3.4), greater tumor thickness (vs ≤1 mm [reference]) (>1-4 mm: OR, 4.5; 95% CI, 3.2-6.1; >4 mm: OR, 12.6; 95% CI, 7.5-21.1), and ulceration (OR, 2.0; 95% CI, 1.5-2.7). These histopathologic features, along with amelanosis and rate of growth, remained as significant associations with high mitotic rate in the overall multivariate analysis. CONCLUSIONS AND RELEVANCE: High-mitotic-rate primary cutaneous melanoma is associated with aggressive histologic features and atypical clinical presentation. It has a predilection for the head and neck region and is more likely to be seen in elderly men with a history of cumulative solar damage who present clinically with rapidly developing disease.

Neuropathy in a patient with lymphocytic thrombophilic arteritis.

A 35-year-old Lebanese woman presented with a 3-year history of persistent, localized livedo racemosa over her feet, distal legs and forearms that was associated with the development of lower limb sensorimotor neuropathy. Investigations revealed the patient was heterozygous for prothrombin gene mutation and was also found to have a T-cell receptor gamma chain gene rearrangement. Histological examination revealed a mid-lower dermal medium vessel lymphocytic vasculitis with prominent fibrinoid ring within its wall. These findings are consistent with a recently described condition known as lymphocytic thrombophilic arteritis. This has so far been considered to be a benign clinical condition not associated with extra cutaneous manifestations. The novel findings in the present case are the associated sensorimotor neuropathy and the characteristic fibrin ring appears to be intramural rather intraluminal in location. The findings of a T cell gene rearrangement and a prothrombin gene mutation suggest that both immunological and thrombophilic factors might contribute to the development of this condition.

IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress.

When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this "terminal UPR." TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing microRNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1ß (IL-1ß) secretion. Txnip gene deletion reduces pancreatic ß cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1α RNase inhibitors suppress TXNIP production to block IL-1ß secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death and may be targeted to develop effective treatments for cell degenerative diseases.

The use of methotrexate in dermatology: a review.

Methotrexate is a synthetic folic acid analogue valued for both its anti-proliferative and anti-inflammatory properties. Considered one of the original immune-modifying agents, it is used widely for the treatment of steroid-recalcitrant inflammatory diseases. While there are abundant studies documenting its efficacy in rheumatic diseases, the use of methotrexate for dermatological conditions, with the exception of psoriasis, has yet to be comprehensively explored. This two-part review firstly outlines current data concerning the pharmacology of methotrexate, including its mechanism of action, side-effect profile and recommended therapeutic approach, and, secondly, examines the emerging evidence for methotrexate's efficacy in a wide range of cutaneous disorders.

Peritoneal oleogranulomatosis after laparoscopic gastric banding.

Laparoscopic adjustable gastric banding is one of the most frequently performed bariatric operations worldwide owing to its low incidence of iatrogenic complications. Peritoneal oleogranulomatosis, a sequelae of mineral oil contact with tissues, has not been reported in the context of bariatric surgery. We present the case of a 52-year-old woman with an incidental finding of peritoneal oleogranulomatosis at laparoscopic cholecystectomy, who had previously undergone laparoscopic gastric banding. A potential mechanism linking the two is postulated and the importance of histological diagnosis highlighted, given the macroscopic resemblance to carcinomatosis peritonei.

The arterial supply of the patellar tendon: anatomical study with clinical implications for knee surgery.

The middle-third of the patellar tendon (PT) is well-established as a potential graft for cruciate ligament reconstruction, but there is little anatomical basis for its use. Although studies on PT vascular anatomy have focused on the risk to tendon pedicles from surgical approaches and knee pathophysiology, the significance of its blood supply to grafting has not been adequately explored previously. This investigation explores both the intrinsic and extrinsic arterial anatomy of the PT, as relevant to the PT graft. Ten fresh cadaveric lower limbs underwent angiographic injection of the common femoral artery with radio-opaque lead oxide. Each tendon was carefully dissected, underwent plain radiography and subsequently schematically reconstructed. The PT demonstrated a well-developed and consistent vascularity from three main sources: antero-proximally, mainly by the inferior-lateral genicular artery; antero-distally via a choke-anastomotic arch between the anterior tibial recurrent and inferior medial genicular arteries; and posteriorly via the retro-patellar anastomotic arch in Hoffa's fat pad. Two patterns of pedicles formed this arch: inferior-lateral and descending genicular arteries (Type-I); superior-lateral, inferior-lateral, and superior-medial genicular arteries (Type-II). Both types supplied the posterior PT, with the majority of vessels descending to its middle-third. The middle-third PT has a richer intrinsic vascularity, which may enhance its ingrowth as a graft, and supports its conventional use in cruciate ligament reconstruction. The pedicles supplying the PT are endangered during procedures where Hoffa's fat pad is removed including certain techniques of PT harvest and total knee arthroplasty.

A rare case of bilateral variations of upper limb arteries: brief review of nomenclature, embryology and clinical applications.

We present a rare case of bilateral variations of upper limb arteries, namely, the superficial brachioulnoradial artery and the superficial brachioradial artery in a female cadaver. The superficial brachioulnoradial artery presented here is a variant of classical accounts. The superficial arteries replaced the typical arteries and were not additional vessels.

A comparative anatomical study of brachioradialis and flexor carpi ulnaris muscles: implications for total tongue reconstruction.

BACKGROUND: Total or subtotal glossectomy following resection of intraoral tumors causes significant morbidity. Recent surgical endeavors have focused on the creation of a neotongue with both sensory and motor innervation. Although various local or regional free flaps have been used for this purpose, the optimal donor site remains undecided. The authors compared the neurovascular anatomy of the brachioradialis and flexor carpi ulnaris to assess their suitability as donor muscles together with overlying skin for functional total or subtotal tongue reconstruction. METHODS: Eighty-eight brachioradialis and 80 flexor carpi ulnaris muscles were studied, comprising 120 dissected specimens, 18 arterial studies, two venous studies, 20 histologic studies, and eight neurovascular studies. RESULTS: The dominant vascular pattern of the brachioradialis varied. The major pedicle arose from the radial (38 percent), radial recurrent (42 percent), and brachial arteries (20 percent). The muscle also lacked a single neurovascular pedicle. The vasculature of the flexor carpi ulnaris was consistent. The ulnar artery supplied the dominant pedicle in 86 percent of cases. The entry point of motor innervation is near that of the vascular pedicles. A minor distal nerve accompanied the main vascular pedicle in 65 percent of cases. The overlying skin was supplied by musculocutaneous perforators. The lower lateral cutaneous nerve of the arm supplied the skin over the brachioradialis, and the medial cutaneous nerves of the arm and forearm provided sensation over the flexor carpi ulnaris. CONCLUSION: The authors delineated the anatomical advantages of the flexor carpi ulnaris over the brachioradialis for total or subtotal tongue reconstruction.