Interrater agreement in classifying infections during extracorporeal membrane oxygenation

Infectious complications are common during extracorporeal membrane oxygenation (ECMO) and may negatively impact outcomes. However, there is considerable variation in the reported rates of incidence, which hampers the use of infections as a quality benchmark for ECMO centers. To assess the contributing role of poor interrater agreement, three independent raters reviewed medical records from all intensive care unit (ICU) patients who received ECMO for &gt;24 h in our tertiary center between October 2019 and October 2021 for suspected episodes of infection, which were rated based on their date of onset and presumed site/diagnosis. To establish a gold standard, any discrepancies were resolved using an expert panel consisting of two intensivists/infectious disease specialists. During 83 ECMO-runs in 77 patients, we observed a total of 62 adjudicated infectious episodes (incidence rate 62, 95% CI: 48–80, per 1000 days at risk). Among 81 episodes suspected by at least one observer, 66 (81%) were identified by two, and only 44 (54%) by all three raters, resulting in Fleiss’ kappa of 0.10 (95% CI: 0.00–0.19; slight agreement). However, if raters concurred regarding infection onset, subsequent agreement on infection site was good (concordance 89%; kappa 0.85, 95% CI: 0.72–0.98; near perfect agreement). In conclusion, adjudication of infectious episodes during ECMO is associated with poor interrater agreement regarding occurrence—but not site—of infection. This finding might partially explain the significant disparities observed in reported infection rates during ECMO, emphasizing the need for caution when interpreting infection data in this particular population due to the potential for inherent measurement error.</p

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma:prospective real-world data from the DRUG Access Protocol

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.</p

Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer:Results from the drug rediscovery protocol (DRUP)

Background: In 2–5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort ‘trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)’. Methods: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. Results: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9–10.3) and 8.2 months (95% CI 7.2–14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. Conclusions: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.</p

A new variant in the ZCCHC8 gene:diverse clinical phenotypes and expression in the lung

Introduction:Pulmonary fibrosis is a severe disease which can be familial. A genetic cause can only be found in ∼40% of families. Searching for shared novel genetic variants may aid the discovery of new genetic causes of disease. Methods:Whole-exome sequencing was performed in 152 unrelated patients with a suspected genetic cause of pulmonary fibrosis from the St Antonius interstitial lung disease biobank. Variants of interest were selected by filtering for novel, potentially deleterious variants that were present in at least three unrelated pulmonary fibrosis patients. Results:The novel c.586G&gt;A p.(E196K) variant in the ZCCHC8 gene was observed in three unrelated patients: two familial patients and one sporadic patient, who was later genealogically linked to one of the families. The variant was identified in nine additional relatives with pulmonary fibrosis and other telomererelated phenotypes, such as pulmonary arterial venous malformations, emphysema, myelodysplastic syndrome, acute myeloid leukaemia and dyskeratosis congenita. One family showed incomplete segregation, with absence of the variant in one pulmonary fibrosis patient who carried a PARN variant. The majority of ZCCHC8 variant carriers showed short telomeres in blood. ZCCHC8 protein was located in different lung cell types, including alveolar type 2 (AT2) pneumocytes, the culprit cells in pulmonary fibrosis. AT2 cells showed telomere shortening and increased DNA damage, which was comparable to patients with sporadic pulmonary fibrosis and those with pulmonary fibrosis carrying a telomere-related gene variant, respectively. Discussion:The ZCCHC8 c.586G&gt;A variant confirms the involvement of ZCCHC8 in pulmonary fibrosis and short-telomere syndromes and underlines the importance of including the ZCCHC8 gene in diagnostic gene panels for these diseases.</p

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma:prospective real-world data from the DRUG Access Protocol

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC).Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS).Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice.Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.</p

Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer:Results from the drug rediscovery protocol (DRUP)

Background: In 2–5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort ‘trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)’. Methods: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. Results: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9–10.3) and 8.2 months (95% CI 7.2–14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. Conclusions: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.</p

Mutation in the AP4M1 Gene Provides a Model for Neuroaxonal Injury in Cerebral Palsy

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography