Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

Cold atmospheric plasma modulates endothelial nitric oxide synthase signalling and enhances burn wound neovascularisation

Treatment with cold atmospheric plasma (CAP) has been reported to promote wound healing in animals. However, how this process is mediated remains unclear. In this study we examined the mechanisms which underlie the improved wound healing effects of CAP and the roles of associated reactive oxygen and nitrogen species (RONS), which are generated by plasma. By using in vitro models which mimicked various steps of angiogenesis, we demonstrated that CAP triggered the production of nitric oxide (NO), and enhanced cell migration and the assembly of endothelial cells into vessel-like structures. These are both hallmarks of the proliferative phase of wound healing. Using a mouse model of a third-degree burn wound, we went on to show that CAP treatment was associated with enhanced angiogenesis, characterised by accelerated in vivo wound healing and increased cellular proliferation. Here, CAP significantly increased the in vivo production of endothelial NO synthase (eNOS), an enzyme that catalyses NO synthesis in endothelial cells, and significantly increased the expression of pro-angiogenic PDGFRβ and CD31 markers in mouse wounds. Mechanistically, we showed that CAP induced eNOS phosphorylation and activation, thereby increasing the levels of endogenous NO in endothelial cells. Increased NO generation facilitated by CAP further stimulated important pro-angiogenic VEGFA/VEGFR2 signalling in vitro. This proof-of-concept study may guide future efforts aimed at addressing the use of physical plasma and its therapeutic applications in a variety of pathological scenarios. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Effect of indomethacin on bone destruction during experimental periodontal disease in the hamster

A major event in periodontitis is the destruction of alveolar processes. It is demonstrated that indomethacin (IND), an inhibitor of prostaglandin synthesis, can inhibit bone resorption in vitro . The aim of this study was to test the effect of IND on bone destruction in hamster periodontal disease. Its action was compared to calcitonin (CT), an inhibitor of osteoclastic resorption. IND decreased the macroscopic bone loss by 28% and the number of osteoclasts per mm by 55% in diseased animals but not significantly. Conversely CT reduced significantly bone loss (p<0.05) and decreased the number of osteoclasts to the control level (p<0.01). The combination of the two drugs had the same effect than CT alone on the two parameters. These results show an effect of IND on bone destruction but an inhibitory action on prostaglandin synthesis can only be hypothesized. In this model of periodontitis CT appears more effective than IND.     

Unusual in vivo extensive corrosion of a low-silver amalgam restoration involving galvanic coupling: a case report.

The basic mechanism of dental amalgam corrosion has been thoroughly studied during the last 50 years by various experimental techniques, most often carried out in vitro. Electrochemical methods were extensively employed, and it was recognized that a gradual dealloying of the more electroactive components, Zn, Sn, and to a lesser extent Cu, contributed to change the surface composition. It is also well known that, in all circumstances, galvanic coupling threatens the longevity of the restoration. Among the patients examined at the hospital attached to the Department of Dental Surgery of the Paris 5 University, the authors observed, in a few exceptional circumstances of defective restorations, a release of liquid metal droplets in the surrounding tissue. These particles were identified as elemental mercury. This unexpected phenomenon was the result of the use of a low-silver-content alloy, combined with an enhanced corrosion process due to galvanic coupling with a silver alloy crown and brass screw-posts. In the described clinical case, the tooth, which had to be extracted, was axially sliced for observation by scanning electron microscopy coupled with elemental analysis by X-ray fluorescence energy dispersive spectroscopy. The observations showed a dramatic corrosion of the amalgam matrix with the formation of porosity even in the bulk of the material. Superposition of the element mappings proved (1) the electrochemical coupling of the amalgam with the silver-based crown, (2) the decalcification of the dentin, and (3) the formation of tin oxychloride precipitates in the matrix porosities and the interfacial gaps. These experimental results corroborate the corrosion mechanisms described hereupon. They support the current national and international recommendations for the dental amalgam formulation and for a rigorous professional practice.     

Dento-facial orthopedics and osteopathy

Osteopathy has grown rapidly. Given their common action on children and adolescents, the collaboration between dentofacial orthopedics and osteopathy is increasingly common. It therefore becomes necessary and urgent to investigate whether, based on data acquired from science, there is evidence of possible interrelations between the two disciplines. After reviewing the literature, very few scientific publications demonstrate the utility of osteopathy and its relationships with other disciplines. However, the relationship between occlusion and posture seem relatively proven, especially in the sagittal direction. On the other hand, although the mobility of the cranial bones is established, the primary respiratory motion is still subject to controversy, even among osteopaths. This, even as orthodontics has long been accused of countering the primary respiratory motion of cranial bones (PRM). Today osteopaths do not reject orthodontics anymore, because the return to a physiological bite situation is considered beneficial. According to expert opinion (without proof, however), some orthodontic devices (like headgears) which block the sutures are still to be avoided and require appropriate monitoring osteopathy. The controversy over the adverse effects of orthodontic treatment is becoming more nuanced by osteopaths, and modern orthodontics claiming a ?global? approach of patient, collaboration may be possible in future year.     

High Vitamin D Deficiency Rate in Metabolic Inpatients: Is Bariatric Surgery Planning Found Guilty?

Background

High rates of vitamin D insufficiency are usually found in obese patients, even before any malabsorptive bariatric surgery. It is not clear whether they lack vitamin D because of different food intake, different solar exposure, or different storage pathways or bioavailability in adipose tissue. To better understand vitamin D deficiency, we studied different categories of inpatients.

Methods

We collected clinical and biological data from 457 consecutive inpatients during a year: 217 nonobese diabetic patients, 159 obese nonsurgical diabetic patients, 46 obese surgical nondiabetic patients, and 35 obese surgical diabetic patients. Statistically significant differences between two mean 25-hydroxyvitamin D (25(OH)D) levels were defined at the 5 % level using a Z-test.

Results

Vitamin D deficiency was found in 69 % of the patients, while 24 % had a normal level and 7 % an optimal level. A significant difference was found between obese (25(OH)D?=?40.3 nmol/l) and nonobese patients (25(OH)D?=?46.8 nmol/l). Patients undergoing bariatric surgery were not different from the other obese patients.

Conclusion

No significant difference in 25(OH) vitamin D level could be demonstrated between obese patients before bariatric surgery and obese patients with no obesity surgery project. No difference was found between our Parisian obese population and a Spanish obese population, which benefits from a better solar exposure. Both findings suggest that obesity itself is the link with vitamin D deficiency, independently from behavioral differences.     

Disclosure of Funding Sources and Conflicts of Interest in Phase III Surgical Trials: Survey of Ten General Surgery Journals

Background

Discussions regarding disclosure of funding sources and conflicts of interest (COI) in published peer-reviewed journal articles are becoming increasingly more common and intense. The aim of the present study was to examine whether randomized controlled trials (RCTs) published in leading surgery journals report funding sources and COI.

Methods

All articles reporting randomized controlled phase III trials published January 2005 through December 2010 were chosen for review from ten international journals. We evaluated the number of disclosed funding sources and COI, and the factors associated with such disclosures.

Results

From a review of 657 RCT from the ten journals, we discovered that presence or absence of a funding source and COI was disclosed by 47 % (309) and 25.1 % (165), respectively. Most articles in “International Committee of Medical Journal Editors (ICMJE)-affiliated journals” did not disclose COI. Disclosure of funding was associated with a journal impact factor >3 (51.7 vs 41.6 %; p < 0.01), statistician/epidemiologist involvement (64.2 vs 43.7 %; p < 0.001), publication after 2008 (52.9 vs 41.1 %; p < 0.01), and the journal being ICMJE-affiliated (49.3 vs 40 %; p < 0.05). Conflict of interest disclosure was associated with publication after 2008 (38.7 vs 11.3 %; p < 0.001), and with the journal not being affiliated with ICMJE (36.9 vs 21.3 %; p < 0.001).

Conclusions

Of the published studies we investigated, over half did not disclose funding sources (i.e., whether or not there was a funding source), and almost three quarters did not disclose whether COI existed. Our findings suggest the need to adopt best current practices regarding disclosure of competing interests to fulfill responsibilities to readers and, ultimately, to patients.     

Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful?

Objective

To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management.

Methods

We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick’s classification.

Results

Before TMT, thrombus level was staged I for 1 (7 %), II for 10 (72 %) and III (21 %) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1–5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43 %) patients had a measurable decrease, 6 (43 %) had no change, and 2 (14 %) had an increase in the thrombus. One patient (7 %) had a downstage of thrombus level, 12 (85 %) had stable thrombi, and 1 (7 %) had an upstage. Regarding primary tumor, 7 (50 %), 5 (36 %) and 2 (14 %) patients had a decrease, stabilization and an increase in tumor size, respectively.

Conclusion

Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.