Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors.

BACKGROUND: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938). PATIENTS AND METHODS: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt. RESULTS: Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease. CONCLUSIONS: The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.

Ponseti casting for club foot - above- or below-knee?: A prospective randomised clinical trial.

We undertook a randomised clinical trial to compare treatment times and failure rates between above- and below-knee Ponseti casting groups. Eligible children with idiopathic clubfoot, treated using the Ponseti method, were randomised to either below- or above-knee plaster of Paris casting. Outcome measures were total treatment time and the occurrence of failure, defined as two slippages or a treatment time above eight weeks. A total of 26 children (33 feet) were entered into the trial. The above-knee group comprised 17 feet in 13 children (ten boys and three girls, median age 13 days (1 to 40)) and the below-knee group comprised 16 feet in 13 children (ten boys and three girls, median age 13 days (5 to 20)). Because of six failures (37.5%) in the below-knee group, the trial was stopped early for ethical reasons. The rate of failure was significantly higher in the below-knee group (p = 0.039). The median treatment times of six weeks in the below-knee and four weeks in the above-knee group differed significantly (p = 0.01). This study demonstrates that the use of a below-knee plaster of Paris cast in conjunction with the Ponseti technique leads to unacceptably high failure rates and significantly longer treatment times. Therefore, this technique is not recommended.

Outcome of meniscal repair prior compared with concurrent ACL reconstruction.

Meniscal tears are commonly associated with traumatic rupture of the anterior cruciate ligament (ACL). At our centre, if a patient presents with locked knee in conjunction with an ACL injury we perform an initial arthroscopy to remove the cause of locking and schedule ACL reconstruction once a full range of motion has returned. The aim of this study was to assess the outcome of meniscal tears stabilised prior to ACL reconstruction. We identified 24 patients who underwent repair of a torn meniscus before having their ACL reconstruction (group 1). As a comparison group we identified 148 patients who underwent meniscal repair at the time of ACL reconstruction (group 2). Twelve of the patients in group 1 underwent meniscectomy, seven at the time of reconstruction and five subsequently. This gives a success rate of 50% (12/24) in the ACL deficient patients. In comparison forty two of the patients in group 2 went on to have a meniscectomy representing a success of 72% (106/148). The odds ratio for meniscectomy in an ACL deficient meniscal repair is 2.52 (95% CI 1.07-5.97) and there is a relative risk of 1.76 (95% CI 1.05-2.63). The difference in success of the meniscal repair between the groups was significant (Fisher's exact test p=0.05). Meniscal repair and delayed ACL reconstruction is more likely to fail than a combined repair and ACL reconstruction.

White on white meniscal tears to fix or not to fix?

The mechanical disadvantage to articular cartilage following meniscectomy has been well documented in the literature. Meniscal repair in the avascular (white on white) is controversial and would be deemed inappropriate by many. We have developed criteria for repair in all meniscal tears. These are: The meniscus 1. must not be degenerated 2. must be reducible, without a rolled edge 3. the fixation must be considered sound. Between 1999 and 2008 our department prospectively collected data on meniscal repairs as part of a sports database. Four hundred and twenty three patients underwent repair during this time period. We identified 87 patients with no co existent ACL injury or instability. There were 73 males and 14 females with a mean age of 26 years (13-54). All tears were in the non peripheral (white on white) area. The criterion for failure was reoperation on the same meniscus requiring excision or re fixation. The mean follow up was 49 months (10-112). Twenty eight patients required further surgery on their repaired meniscus. There were eight re-repairs and 20 partial menisectomies. This represents a success rate of 68% (59/87). The mean pre operative Lysholm score was 61 (4-88) which rose to 75 (12-100) postoperatively, p=0.002. The mean pre op Tegner score was 6 (3-10) and this did not change significantly post operatively, mean 6 (0-10) p=0.4. Isolated white on white avascular meniscal tears can be successfully repaired in the majority of cases with a good clinical and functional result.