2 Minute Medicine Rewind April 1, 2019

Outcomes of Extremely Preterm Infants With Birth Weight Less Than 400 g

Little is known about the survival and neurodevelopmental outcomes of extremely preterm infants with low birth weight. More data is needed to facilitate decisions regarding the initiation of treatment and resuscitation in this population. In this retrospective cohort study, 205 infants born between 22 and 26 weeks gestational age (GA) with a birth weight of less than 400 grams and with no major birth defects were studied to assess survival to discharge home or to 1 year (if still hospitalized) among infants who received active treatment. Active treatment was defined as the provision of any potentially lifesaving intervention after birth. Of the 205 infants, 49.3% received active treatment at birth; infants were more likely to have been exposed to antenatal steroids (93.1% of infants who received active treatment vs. 42.3% of infants who did not, p<0.001). At baseline, 59.0% of infants were female, 64.9% were singletons, and 86.8% were small for GA. Researchers found that overall, 26 of 205 infants (12.7%, 95% CI 8.5% to 18.0%) survived to discharge (n=25) or remained hospitalized (n=1) at 1 year. Of these, 19 infants were known to have survived to 18 to 26 months corrected age, and 74% of these infants had moderate or severe neurodevelopmental impairment. All infants who survived received active treatment at birth, and 25.7% of infants who received active treatment at birth survived (95% CI 17.6% to 35.4%). Increased survival was associated with advancing GA, from 16.7% (95% CI 6.4% to 32.8%) at 22 to 23 weeks GA to 32.4% (95% CI 18.0% to 49.8%) at 25 to 26 weeks GA (p< 0.001). Nearly all infants that did not receive active treatment died within 12 hours of birth. The leading causes of death were immaturity, respiratory distress syndrome, and severe intracranial hemorrhage. This study was limited by the small number of survivors with follow-up to toddlerhood, which may preclude generalizability of the study. Overall, this study illustrates the significant mortality and morbidity of preterm infants with low birth weight.

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial

Intravenous thrombolytic therapy with alteplase (recombinant human tissue plasminogen activator) is approved for the treatment of acute ischemic stroke. However, whether it is efficacious in the treatment of lacunar infarcts remains unclear. In this secondary post-hoc analysis of the WAKE-UP randomized controlled trial, 108 patients with acute lacunar stroke from the original study population of 503 patients with an acute stroke of unknown onset time were studied to determine the efficacy and safety of intravenous thrombolysis with alteplase as compared to placebo among patients with lacunar infarcts. The primary endpoint was a favorable outcome defined as a score of 0 or 1 point on the modified Rankin Scale (mRS) at 90 days after stroke, adjusted for age and severity of symptoms. Compared to patients with non-lacunar infarcts, patients with lacunar infarcts were more likely to be male (68.5% vs. 63.5%), younger (mean age 63 years vs. 66 years, p=0.003), and to have a lower median National Institutes of Health Stroke Scale (NIHSS) score on admission (5 vs. 6, p<0.001). In total, 55 of the 108 patients with a lacunar infarct (50.9%) were assigned to receive alteplase, and 49.1% were assigned to receive placebo. Among all 503 patients, alteplase treatment was associated with higher odds of favorable outcome, with no differences observed between lacunar infarcts and non-lacunar infarcts (OR 1.68 vs.1.62, respectively, test for interaction, p=0.94). In patients with lacunar stroke, there was no significant difference in the proportion of patients achieving a favorable outcome in the alteplase group as compared to the placebo group (59% vs. 46%, respectively, OR 1.67, 95% CI 0.77 to 3.64, p=0.20). At 90 days, there was a non-significant difference in outcomes based on the distribution of mRS scores at 90 days (OR 1.94, 95% CI 0.95 to 3.93, p=0.07). In terms of safety, there was 1 death and 1 symptomatic intracranial hemorrhage in the alteplase group; neither of these outcomes occurred in the placebo group. Importantly, the WAKE-UP trial was not powered to show a significant treatment outcome in patient subgroups. Nonetheless, this study does show that the association of intravenous alteplase with functional outcome does not differ in patients with lacunar infarcts as compared to those experiencing other stroke subtypes.

Prophylactic Irradiation of Tracts in Patients With Malignant Pleural Mesothelioma: An Open-Label, Multicenter, Phase III Randomized Trial

Malignant pleural mesothelioma is a devastating cancer, with survival rates ranging from as low as 17% to 46%. Diagnosis and/or treatment usually involves an invasive chest wall procedure, however, this carries the risk of tumor-cell seeding at the site of the procedure and subsequent development of metastases. Due to this risk, prophylactic radiotherapy is commonly delivered to the site of the chest wall procedure. However, past studies assessing the efficacy and safety of this approach have been underpowered and have produced conflicting results. In this randomized controlled trial, 375 patients with malignant pleural mesothelioma (MPM) were assigned to receive prophylactic radiotherapy or no prophylactic radiotherapy after a diagnostic or therapeutic chest wall procedure to study the impact on incidence of metastases on the ipsilateral chest wall (chest wall metastases, CWM) 6 months after randomization. There was a similar proportion of patients receiving chemotherapy in the two groups (66.7% in the prophylactic radiotherapy group, 60.3% in the no-radiotherapy group). Researchers found that there was no difference in the proportion of CWM 6 months after randomization between the two groups (3.2% in the prophylactic radiotherapy group vs. 5.3% in the no-radiotherapy group, OR 0.60, 95% CI 0.17 to 1.86, p=0.44). There was also no difference at 12 months (8.1% vs. 10.1%, respectively, OR 0.79, 95% CI 0.36 to 1.69, p=0.59). Skin toxicity was the most common radiotherapy-related adverse event, and occurred in 116 of 186 patients in the prophylactic radiotherapy group. A limitation of this study was the absence of blinding of the participants and investigators. In summary, results from this study do not support the routine use of prophylactic radiotherapy after a chest wall procedure in patients with malignant pleural mesothelioma.

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease: an international, randomised, double-blind, phase 3 non-inferiority study

Anti-tumor necrosis factor (TNF) therapies are commonly used in the treatment of patients with moderate to severe Crohn’s disease. However, due to the high costs of anti-TNF medications, biosimilar medications are being developed. These drugs have high likeness to already licensed biological therapies and are subject to strict approval criteria by regulatory authorities. CT-P13 is a biosimilar version of infliximab, an anti-TNF monoclonal antibody, and has been approved based on randomized controlled trials in patients with ankylosing spondylitis and rheumatoid arthritis. However, CT-P13 has not yet been studied in patients with Crohn’s disease. In this randomized controlled phase III non-inferiority study, 220 patients with active Crohn’s disease with no response or intolerance to non-biological treatments were assigned in a 1:1:1:1 ratio to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. The primary outcome was the proportion of patients with a decrease of at least 70 points in the Crohn’s Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was used. Overall, 166 patients completed the study, with lack of response at week 14 being the most common reason for discontinuation. Researchers found that, in the intention-to-treat population, CT-P13 was noninferior to infliximab in the achievement of a CDAI-70 response at week 6 (69.4% of patients who received CT-P13 first vs. 74.3% of patients who received infliximab first, difference -4.9%, 95% CI -16.9% to 7.3%). Similarly, CT-P13 was found to be noninferior to infliximab in terms of the CDAI-70 response at weeks 14 and 30, and also in terms of the proportion of patients achieving clinical remission at weeks 6,14, and 30. The proportion of patients with at least one treatment-emergent adverse event was similar between all groups. In conclusion, results from this study show that CT-P13 has a similar efficacy and safety profile to infliximab in the treatment of patients with active Crohn’s disease.

Combined Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery Alone for Treatment of Locally Advanced Gastric Cancer: The SEIPLUS Randomized Clinical Trial

Gastric cancer is typically treated with surgical resection followed by chemotherapy. Peritoneal metastasis, caused by direct cancer cell dissemination, is the most common pattern of postoperative recurrence; the prognosis of patients with peritoneal metastasis is very poor. Extensive intraoperative peritoneal lavage (EIPL) is one strategy that has been developed to prevent peritoneal dissemination. Currently, three studies are ongoing to assess the efficacy and safety of prophylactic EIPL for peritoneal recurrence of locally advanced gastric cancer. In this ongoing randomized controlled trial, 662 patients with locally advanced gastric cancer receiving open D2 gastrectomy were assigned to receive surgery alone or surgery plus EIPL to study short-term postoperative complications and mortality. Researchers found that there were significantly more deaths in the surgery alone group than in the surgery plus EIPL group (difference 1.9%, 95% CI 0.3% to 3.4%, p=0.02). Postoperative complications were more frequent in the surgery alone group than in the surgery plus EIPL group (17.0% vs. 11.1%, difference 5.9%, 95% CI 0.1% to 11.6%, p=0.04). Additionally, postoperative pain was more common in the surgery alone group than in the surgery plus EIPL group (17.7% vs. 10.8%, respectively, difference 7.0%, 95% CI 0.8% to 13.1%, p=0.02). Notably, 112 patients (16.9%) were excluded after randomization due to the finding of T1, T2, or M1 disease on histopathology, which may reduce the quality of the study. Overall, this trial supports the use of EIPL as a therapeutic strategy for patients with advanced gastric cancer. Future analysis will study the primary endpoint of 3-year overall survival.

Image: PD

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