Current systemic therapies for melanoma.

BACKGROUND: Systemic agents are used in melanoma for adjuvant therapy and to treat metastatic disease. Currently, interferon-α is the only agent approved for adjuvant therapy. Six drugs are FDA approved for metastatic disease: dacarbazine, interleukin-2 (IL-2), vemurafenib, ipilimumab, dabrafenib, and trametinib. Vemurafenib and ipilimumab were approved in 2011, whereas dabrafenib and trametinib were approved in 2013. OBJECTIVE: This review will update the practicing dermatologist on the differences in efficacy, adverse events, and cost of systemic therapies available for the treatment of melanoma. MATERIALS AND METHODS: This article is a review of the current literature on systemic therapies for advanced melanoma. Key search words included "advanced melanoma," "systemic therapy," and "adjuvant therapy" with particular focus on the past 20 years. RESULTS: Before 2011, dacarbazine and IL-2 were the only FDA approved therapies for metastatic melanoma, and IFN-α is the only approved agent for adjuvant therapy. The new agents vemurafenib, ipilimumab, dabrafenib, and trametinib are the first to have improved overall survival in Phase III studies in comparison with other systemic therapies. CONCLUSION: Despite new developments, there remains a significant need for better therapies with improved long-term efficacy and decreased toxicity.

In vitro biomechanical testing of anterior cruciate ligament reconstruction: traditional versus physiologically relevant load analysis.

Various anterior cruciate ligament (ACL) graft-fixation devices exist. In this in vitro study a comparison of biomechanical characteristics of the cross-pin and button type fixation devices under practical rehabilitation loads was done. Forty bovine knees and hoof extensor tendons were harvested. After disarticulation, the femoral end of an ACL was prepared with either fixation, using the extensor tendon as graft. The mechanical test was either a single load to failure or load to failure after cycling loads. Twenty specimens were loaded to failure at a rate of 1mm/s, remaining specimens were cycled between 50 and 250 N for 1000 cycles then failure tested in a similar manner. Results show that both forms of fixation are able to withstand loads that exceed those observed in performing functional activities. Activity-specific stiffness (loads comparable to walking, jogging and stair descent) was lower than linear stiffness for both endobutton and cross-pin, without prior cycling. After cycling, activity-specific stiffness increased to linear stiffness values for the cross-pin for all activities. Thus, suggesting that the cross-pin provides a more rigid fixation after initial implantation over a wider range of activities, which would theoretically permit a more aggressive rehabilitation protocol and possibly an earlier return to regular activity. In contrast, activity-specific stiffness increased above linear stiffness values for the endobutton only under heavier loads (jogging and stair descent). Dynamic stiffness was higher and displacement lower for cross-pin throughout the cycle test. These results indicate, in ACL reconstruction, that graft complex stiffness should be considered at relevant loads only.

Dependence on extracellular Ca2+/K+ antagonism of inspiratory centre rhythms in slices and en bloc preparations of newborn rat brainstem.

The pre-Bötzinger Complex (preBötC) inspiratory centre remains active in isolated brainstem-spinal cords and brainstem slices. The extent to which findings in these models depend on their dimensions or superfusate [K(+)] and [Ca(2+)] (both of which determine neuronal excitability) is not clear. We report here that inspiratory-related rhythms in newborn rat slices and brainstem-spinal cords with defined boundaries were basically similar in physiological Ca(2+) (1.2 mm) and K(+) (3 mm). Hypoglossal nerve rhythm was 1 : 1-coupled to preBötC activity in slices and to cervical nerve bursts in en bloc preparations lacking the facial motonucleus (VII). Hypoglossal rhythm was depressed in brainstems containing (portions of) VII, while pre/postinspiratory lumbar nerve bursting was present only in preparations with > 79% VII. preBötC-related slice rhythms were inhibited in 1.5 mm Ca(2+) solution, whereas their longevity and burst rate were substantially augmented in 1 mm Ca(2+). Ca(2+) depression of slice rhythms was antagonized by raising superfusate K(+) to 8-10 mm. This strong extracellular Ca(2+)/K(+) antagonism of inspiratory (motor) rhythms was also revealed in brainstem-spinal cords without VII, while the inhibition was progressively attenuated with increasing amount of rostral tissue. We hypothesize that depression of hypoglossal rhythm and decreased Ca(2+) sensitivity of preBötC rhythm are probably not related to an increased content of rostral respiratory structures, but rather to larger brainstem dimensions resulting in interstitial gradients for neuromodulator(s) and K(+), respectively. We discuss whether block of pre/postinspiratory activity in preparations with < 79% VII is due to impairment of the pathway from preinspiratory interneurons to abdominal muscles.