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Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12–16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m2) or doxorubicin alone (75 mg/m2) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% CI 4·1–8·3) with olaratumab plus doxorubicin and 4·1 months (2·8–5·4) with doxorubicin (stratified hazard ratio [HR] 0·67; 0·44–1·02, p=0·0615). Median overall survival was 26·5 months (20·9–31·7) with olaratumab plus doxorubicin and 14·7 months (9·2–17·1) with doxorubicin (stratified HR 0·46, 0·30–0·71, p=0·0003). The objective response rate was 18·2% (9·8–29·6) with olaratumab plus doxorubicin and 11·9% (5·3–22·2) with doxorubicin (p=0·3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26·2) to 487 μg/mL (CV% 33·0) and from 123 μg/mL (CV% 31·2) to 156 μg/mL (CV% 38·0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. Eli Lilly and Company.

BackgroundAnti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.MethodsPatients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome.Results249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24–43), and median treatment duration was 2.8 months (range 0.5–42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses.ConclusionsAfter ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

After an initial safety study in 7 normal volunteers, a randomized double-blind comparison was made between 3,5-diiodothyropropionic acid (DITPA) and placebo in 19 patients with moderately severe congestive failure. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Systolic cardiac function was unchanged but isovolumetric relaxation time was decreased significantly, suggesting improvement in diastolic function. Total serum cholesterol (p = 0.005) and triglycerides (p = 0.01) also were decreased significantly. DITPA could represent a useful new agent for treatment of congestive heart failure.

Background: The discoid lateral meniscus (DLM) is a common congenital abnormality of the meniscus. Tears are common, and initial treatment is often not definitive, leading to a spectrum of complications, including persistent symptoms, meniscal insufficiency, osteochondral defects, and recurrent tears potentially requiring reoperation. Purpose: To determine demographic, injury, and perioperative risk factors that increase the likelihood of complications and reoperation after treatment in patients with DLM. Study Design: Case series; Level of evidence, 4. Methods: Patients surgically treated for DLM from 9 institutions between 2000 and 2020 were reviewed. Data on demographics, presenting symptoms and signs, surgical findings and treatments, complications, and reoperations were collected and analyzed using a 2-level generalized linear mixed model. The conditional probability of complications was predicted using logistic regressions. Odds ratios were calculated to identify findings associated with an increased likelihood of postoperative complications and reoperations. Results: In total, 867 knees in 784 patients were surgically treated for DLM. There were 175 complications in 139 knees (16%); reoperations were performed in 110 knees (13%). Complication rates varied among institutions, ranging from 0% to 29%. The most common complication was retear of the meniscus (12%). Female patients were more likely to have complications and reoperations than male patients. Patients with a meniscus tear were 74% less likely to have a complication than those without tears, although patients with a complex meniscal tear were 3.4 times more likely to have a complication and 4.4 times more likely to have a reoperation than those without. Horizontal tears, as well as the open repair technique, had an increased risk of reoperation. Other tear types, tear locations, repair techniques, the presence of rim instability, age, and preoperative symptoms were not significantly associated with complications. Conclusion: Of the patients, 17% (16% of knees) had postoperative complications after DLM treatment, of whom 17% had more than 1 complication. Additionally, 13% underwent reoperation. Complications were less likely in those treated for their DLM who had a meniscus tear and more likely in female patients and those with complex meniscus tears. Reoperation was more likely in female patients, those with a horizontal or complex tear, and those who had an open meniscus repair.

We evaluated 48 patients with chronic obstructive pulmonary disease by means of pulmonary-function and exercise testing to determine whether any tests of pulmonary function could predict the development of arterial desaturation during exercise. We found that only two indexes — diffusing capacity and forced expiratory volume in one second (FEV 1 ) — were predictive of desaturation. The diffusing capacity was more specific and sensitive than FEV 1 . A diffusing capacity above 55 per cent of predicted was 100 per cent specific in excluding desaturation, as compared with an 82 per cent specificity for an FEV 1 above 55 per cent of predicted. With this cutoff point, the sensitivity of the diffusing capacity was 68 per cent, as compared with 46 per cent for the FEV 1 . Both the frequency and the magnitude of arterial desaturation increased substantially when the diffusing capacity was below 55 per cent of predicted. Testing the diffusing capacity should be useful in identifying which patients with chronic obstructive lung disease are likely to become desaturated during exercise and may therefore benefit from oxygen therapy. (N Engl J Med 1984; 310:1218–21.) OXYGEN therapy decreases pulmonary-artery pressure 1 and hematocrit, 2 improves psychological function, 3 and decreases mortality 4 in patients with severe chronic obstructive pulmonary disease. It is generally recommended that patients with a resting arterial oxygen tension of less than 55 mm Hg, as well as patients with arterial desaturation during exercise, should receive oxygen therapy. 5 Some studies have suggested that patients with the \"emphysematous\" type of chronic obstructive pulmonary disease are more likely to have arterial desaturation with exercise. 6 , 7 However, there have been no studies of large groups of patients with the disease to determine whether arterial desaturation during exercise can be reliably . . .