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.

     

Measurement of alveolar derecruitment in patients with acute lung injury: computerized tomography versus pressure–volume curve

Introduction  

Positive end-expiratory pressure (PEEP)-induced lung derecruitment can be assessed by a pressure–volume (P–V) curve method or by lung computed tomography (CT). However, only the first method can be used at the bedside. The aim of the study was to compare both methods for assessing alveolar derecruitment after the removal of PEEP in patients with acute lung injury or acute respiratory distress syndrome.     

Influence of Lung Aeration on Pulmonary Concentrations of Nebulized and Intravenous Amikacin in Ventilated Piglets with Severe Bronchopneumonia

Background: Pulmonary concentrations of aminoglycosides administered intravenously are usually low in the infected lung parenchyma. Nebulization represents an alternative to increase pulmonary concentrations, although the obstruction of bronchioles by purulent plugs may impair lung deposition by decreasing lung aeration.

Methods: An experimental bronchopneumonia was induced in anesthetized piglets by inoculating lower lobes with a suspension of 106 cfu/ml Escherichia coli. After 24 h of mechanical ventilation, 7 animals received two intravenous injections of 15 mg/kg amikacin, and 11 animals received two nebulizations of 40 mg/kg amikacin at 24-h intervals. One hour following the second administration, animals were killed, and multiple lung specimens were sampled for assessing amikacin pulmonary concentrations and quantifying lung aeration on histologic sections.

Results: Thirty-eight percent of the nebulized amikacin (15 mg/kg) reached the tracheobronchial tree. Amikacin pulmonary concentrations were always higher after nebulization than after intravenous administration, decreased with the extension of parenchymal infection, and were significantly influenced by lung aeration: 197 +/- 165 versus 6 +/- 5 [mu]g/g in lung segments with focal bronchopneumonia (P = 0.03), 40 +/- 62 versus 5 +/- 3 [mu]g/g in lung segments with confluent bronchopneumonia (P = 0.001), 18 +/- 7 versus 7 +/- 4 [mu]g/g in lung segments with lung aeration of 30% or less, and 65 +/- 9 versus 2 +/- 3 [mu]g/g in lung segments with lung aeration of 50% or more.     

Poor Intraoperative Blood Glucose Control Is Associated with a Worsened Hospital Outcome after Cardiac Surgery in Diabetic Patients

Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity.

Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity.

Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0).     

Incidence of Chest Tube Malposition in the Critically Ill: A Prospective Computed Tomography Study

Background: Malposition of percutaneously inserted chest tubes is considered as a rare complication in critically ill patients. Its incidence, however, remains uncertain. The aims of the study were to assess the true incidence of chest tube malposition in critically ill patients and to identify predicting factors.

Methods: The authors prospectively studied 122 chest tubes percutaneously inserted in 75 consecutive critically ill patients. For clinical reasons independent of the study, thoracic computed tomography scanning was performed in 63 patients, allowing direct visualization of 106 chest tubes. Based on these findings, chest tube position was classified as intrapleural, intrafissural, or intraparenchymal. Factors predicting chest tube malposition were analyzed by univariate and multivariate analysis.

Results: The mean delay between chest tube placement and thoracic scan was 3.5 +/- 2.9 days. Twenty-two chest tubes were diagnosed as being intrafissural (21%), and 10 were diagnosed as being intraparenchymal (9%). The only predicting factor associated with the risk of malposition was the use of a trocar for the percutaneous insertion of the chest tube (P = 0.032).     

Assessment of myocardial viability in rats: Evaluation of a new method using superparamagnetic iron oxide nanoparticles and Gd-DOTA at high magnetic field.

The aim of this study was to detect salvageable peri-infarction myocardium by MRI in rats after infarction, using with a double contrast agent (CA) protocol at 7 Tesla. Intravascular superparamagnetic iron oxide (SPIO) nanoparticles and an extracellular paramagnetic CA (Gd-DOTA) were used to characterize the peri-infarction zone, which may recover function after reperfusion occurs. Infarcted areas measured from T1-weighted (T1-w) images post Gd-DOTA administration were overestimated compared to histological TTC staining (52% +/- 3% of LV surface area vs. 40% +/- 3%, P=0.03) or to T2-w images post SPIO administration (41% +/- 4%, P=0.04), whereas areas measured from T2-w images post SPIO administration were not significantly different from those measured histologically (P=0.7). Viable and nonviable myocardium portions of ischemically injured myocardium were enhanced after diffusive Gd-DOTA injection. The subsequent injection of vascular SPIO nanoparticles enables the discrimination of viable peri-infarction regions by specifically altering the signal of the still-vascularized myocardium.     

Aortic prosthetic ring annuloplasty: a useful adjunct to a standardized aortic valve-sparing procedure?

OBJECTIVE: Dilation of aortic annulus, sinuses of Valsalva, and sinotubular junction (STJ) diameters are the characteristic lesions of aortic root aneurysm. The remodeling technique reduces STJ diameter and creates three neosinuses of Valsalva. Alternatively, the reimplantation technique reduces both annulus and STJ diameters to the detriment of aortic root dynamics. Although the remodeling technique is recognized as the most physiological valve-sparing procedure, aortic annulus dilation may jeopardize its results. A standardized approach that combines an external subvalvular aortic prosthetic ring annuloplasty with the remodeling technique is suggested. METHODS: Eighty-three patients underwent an elective aortic root remodeling procedure, either isolated (group 1, n=34) or combined with an external subvalvular aortic prosthetic ring annuloplasty (group 2, n=49). Preoperative aortic regurgitation was 1.59+/-1.1 (group 1) and 1.97+/-1.3 (group 2) (NS). The aortic annulus was more dilated in group 2 than in group 1 (27+/-2.77 mm vs 26.4+/-2.3 mm, p<0.01). Residual aortic regurgitation > or =grade II was the conversion criteria for aortic valve replacement. RESULTS: Operative mortality was 3.6% (n=3). Intraoperative conversion for valve replacement was 32.7% in group 1 (n=11) versus 4.2% in group 2 (n=2) (p<0.001). In group 1, preoperative annulus diameter was larger for converted than for valve-spared patients (27.6+/-1.7 mm vs 25.2+/-1.5 mm, p<0.02). In group 2, implanted aortic ring significantly reduced annulus diameter (20.6+/-1.8 mm) without significant aortic valve gradient (8.3+/-3 mmHg). Follow-up was 17.2+/-13.4 months (group 1) and 10.41+/-7.95 months (group 2). Reoperation for recurrent aortic regurgitation was 13% in group 1 (n=3) versus 4.2% in group 2 (n=2). Echocardiographic follow-up found residual aortic regurgitation < or =grade I in 17 patients in group 1 (90%) versus 43 patients in group 2 (95.5%) and of grade II in two patients in group 1 (10%) and two patients in group 2 (4.5%). CONCLUSION: The addition of external aortic prosthetic ring annuloplasty improves the remodeling technique's operative reproducibility and short-term results. Therefore, its use as a systematical adjunct to the remodeling procedure is suggested. However, further long-term evaluation comparing this valve-sparing procedure to composite graft replacement should define the best surgical strategy for aortic root aneurysm.     

Radiation therapy in proliferative vitreoretinopathy

In a prospective study of the effect of postoperative radiation therapy for the prevention of reproliferation of membranes and recurrent proliferative vitreoretinopathy (PVR) two similar groups of patients with retinal detachment and PVR grade D1 to D3 in one eye were compared. Half the eyes (30) received a total dose of 3000 cGy after surgery; the other half remained untreated. After a followup of 6 months and 14 months or more (maximum 36 months) the anatomical and functional results of each group were compared. After 6 months in the unirradiated group 57% (17/30) remained attached and 43% (13/30) had detached again. In the irradiated group 63% (19/30) were attached and 37% (11/30) had detached. However, there was no statistically significant difference between the two groups (P=0.479, Fisher's Exact Test). After 14 months the number of cured and uncured eyes remained the same in the unirradiated group, while in four of the eyes in the irradiated group a later onset of reproliferation and detachment occurred (after 7, 8, 12 and 14 months, respectively). A final cure rate of 57% (17/30) was achieved in the unirradiated group and a 50% (15/30) cure rate in the irradiated group. Thus the failure rate was 43% (13/30) in the unirradiated group and 50% (15/30) in the irradiated group (P=0.473, Fisher's Exact Test). No side effects from the radiation were observed in any case and no radiation retinopathy occurred during an observation period of up to 3 years. The visual acuity of the cured treated and cured untreated eyes was similar in the two groups. From these results we conclude that immediate radiation treatment does not improve the long-term results and does not reduce the number of reoperations. In a considerable number of treated eyes the onset of reproliferation was delayed from 7 to 14 months, whereas in the untreated group reproliferation was always observed during the first 6 months. A combination of various antiproliferative and antiinflammatory therapies are needed to suppress recurrent PVR after succesful vitreoretinal surgery and to minimize the side effects of these treatments.Presented in part at the XVIIth Meeting of the Club Jules Gonin, 1–6 September 1990, Lausanne