Reinterventions after dynamic intraligamentary stabilization in primary anterior cruciate ligament repair.

BACKGROUND The goal of this study was to perform an in-depth analysis of the frequency and cause of secondary interventions subsequent to primary anterior cruciate ligament (ACL) repair with dynamic intraligamentary stabilization (DIS). METHODS Between July 2009 and June 2014, 455 patients underwent DIS treatment. The minimum follow-up was 21months (mean 28months, range 21-64months). RESULTS A total of 215 (48.2%) reinterventions were performed in 190 (42.6%) patients. One-hundred and seventy-six (39.4%) were non-revision reinterventions, and 39 (8.7%) were revision ACL reconstructions. Re-arthroscopies included 26 (5.8%) scar tissue debridements with hardware removal due to range of motion deficits, 14 (3.1%) partial meniscectomies, four (0.9%) meniscal sutures, and four (0.9%) arthroscopies due to crepitation or knee pain. Minor non-revision reinterventions performed under analgosedation consisted of 97 (21.7%) hardware removals, 20 (4.5%) hardware removals with manipulations under anesthesia, and four manipulations under anesthesia alone (0.9%). CONCLUSIONS In our study, the revision rate was within the range of published results after ACL reconstructions. In over 90% of patients, the native ACL was preserved with no need for a secondary reconstruction. Most of the non-revision reinterventions were minor and included hardware removals and manipulations under anesthesia. The re-arthroscopy rate was lower than that after ACL reconstruction with fewer secondary meniscal sutures and partial meniscectomies. Early treatment of meniscal tears may be one crucial benefit of ACL repair with DIS

Developments in targeted therapy in melanoma

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF- and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy

MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. RESULTS: Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. CONCLUSIONS: Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance

Prognostic value of N-terminal pro-B-type natriuretic peptide in patients with acute coronary syndromes undergoing left main percutaneous coronary intervention

BACKGROUND: Patients undergoing acute left main (LM) coronary artery revascularization have a high mortality and natriuretic peptides such as N-terminal pro-B-type (NT-proBNP) have been shown to have prognostic value in patients with acute coronary syndromes. The present study looked at the prognostic value of NT-proBNP in these patients. METHODS AND RESULTS: We studied all consecutive patients undergoing acute LM coronary artery percutaneous coronary intervention between January 2005 and December 2008 in whom NT-proBNP was measured (n=71). We analyzed the clinical characteristics and the short- and long-term outcomes in relation to NT-proBNP level at admission. Median NT-proBNP was 1,364 ng/L, ranging from 46 to 70,000 ng/L. NT-proBNP was elevated in 63 (89%) patients and was ≥1,000ng/L in 42 (59%). Log NT-proBNP (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.55-7.97, P=0.003) and left ventricular ejection fraction (HR 0.95, 95%CI 0.91-0.99, P=0.007) were predictors for all-cause mortality. Log NT-proBNP was the only independent significant predictor of cardiovascular mortality. In-hospital mortality was 0% for patients with NT-proBNP <1,000, but 17% for those with NT-proBNP ≥1,000 (P=0.036). Conclusions: NT-proBNP is a strong predictor of outcome in patients undergoing acute LM coronary artery stenting. Mortality in such patients is high, but those with NT-proBNP < 1,000ng/L may have a favorable short- and long-term prognosis. Further research, including a larger patient population, is needed to determine the optimal cut-off value for NT-proBNP in patients undergoing acute LM coronary artery intervention

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An exploratory study investigating the metabolic activity and local cytokine profile in patients with melanoma treated with pazopanib and paclitaxel.

There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity. The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings. Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m &lt;sup&gt;-2&lt;/sup&gt; body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry (CD68, CD163) evaluation, and blood samples were taken at the same time points. Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17). In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines