A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan.

Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks. Results 34 patients were enrolled in Part I (seribantumab/cetuximab) and 14 patients were enrolled in Part II (seribantumab/cetuximab/irinotecan). Common toxicities of seribantumab/cetuximab included acneiform rash, diarrhea, stomatitis, and paronychia. The MTD of Part I was seribantumab 40 mg/kg bolus, then 20 mg/kg weekly combined with cetuximab 400 mg/m2 bolus, then 250 mg/m2 IV weekly. Common toxicities reported in the seribantumab/cetuximab/irinotecan combination were similar to the Part I portion. However, toxicities were more frequent and severe with the triplet combination. There was one treatment-related death in Part II secondary to Grade 4 neutropenia and grade 3 diarrhea. Other dose-limiting toxicities in Part II were Grade 3 mucositis and Grade 3 diarrhea. A cholangiocarcinoma patient, previously untreated with EGFR-directed therapy, had a confirmed partial response (PR). One colorectal cancer patient, previously treated with EGFR-directed therapy, had an unconfirmed PR. Conclusions Seribantumab/cetuximab was well tolerated and patients experienced toxicities typical to EGFR inhibition. Unlike the seribantumab/cetuximab doublet, seribantumab/cetuximab/irinotecan was difficult to tolerate in this heavily pretreated population. There was limited efficacy of the combination therapy.

Viability of Structured Gait Retraining for Improving Clinical Outcomes Following Running-related Injury in Active Duty Service Members.

INTRODUCTION: All branches of the U.S. Military have a running component of their physical readiness testing battery. Running-related musculoskeletal injuries affect 20 to 40% of DoD Service Members each year. Running form has not historically been addressed with military running-related injuries. To assess the utility of a structured gait retaining protocol designed to treat the onset of running-related pain and/or injury by correcting identified biomechanical risk factors for injury and improve clinical outcomes. STUDY DESIGN: Case series. MATERIALS AND METHODS: A total of 160 Active Duty Service Members (ADSMs) with running-related lower-body musculoskeletal injuries were referred by a physical therapist for a multisession gait retraining program termed "Run with CLASS" (Cadence, Lean, Alignment, Soft-landing, Strike). Run with CLASS utilized various drills to emphasize impact progression, proximal strengthening, and proprioception and spatial awareness. RESULTS: Results revealed that the implemented gait retraining protocol significantly improved running parameters following lower-body injury as evidenced by increased cadence, improved functional assessment scores, and a marked transition from predominantly heel strike to forefoot strike patterns during running. CONCLUSIONS: A 3-week supervised gait retraining program focused on the gait retraining program termed "Run with CLASS" (Cadence, Lean, Alignment, Soft-landing, Strike) was successful in altering biomechanics of self-selected running gait by increasing cadence and transitioning ADSMs to a forefoot foot strike. Additionally, ADSMs reported significant improvements on the self-reported functional scores on the University of Wisconsin Running Injury and Recovery Index and Single Assessment Numerical Evaluation. LEVEL OF EVIDENCE: 4.

Association of serum ferritin with severity and clinical outcome in COVID-19 patients: An observational study in a tertiary healthcare facility.

Background: Ferritin, an intracellular protein, has a pivotal role in immune dysregulation. Hyperferritinemia has been associated with higher disease severity and adverse clinical outcomes in COVID-19, including mortality. We aimed to study the association of serum ferritin levels with disease severity and clinical outcomes and its severity prediction potential in COVID-19 patients. Methods: This retrospective study included 870 adult patients with symptomatic COVID-19 infection hospitalized between July 1, 2020 to December 21, 2020. All the patients had a positive polymerase chain reaction test result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: The median age was 55 (IQR:40, 65) years with a male predominance [66.32% (n = 577)], among 870 COVID-19. Of these, 413 (47.47%) had mild COVID-19, and 457 (52.53%) had moderate plus severe COVID-19 disease. Median ferritin levels were significantly high in moderate to severe COVID-19 infection compared to mild [545.8 (326.0, 1046.0) vs 97.3 (52.65-155.5) (p = 0.001)], and in patients who developed a complication compared to without complications [380 (177.05, 863.15) vs 290 (110.9, 635) (p = 0.002). A slight elevation in median ferritin levels was observed in patients who had an ICU stay than non-ICU [326 (129.8, 655) vs 309 (119.1, 684) (p = 0.872)]. The cut-off for ferritin was identified at >287.4 ng/ml for mild versus moderate plus severe COVID-19 infections. Conclusion: Moderate to severe COVID-19 patients have elevated ferritin levels. Patients with more than 287.4 ng/ml ferritin value would have greater chances of developing moderate to severe COVID-19 infections.

Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121).

The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1), human EGFR 2 (HER2/ErbB2), ErbB3/HER3, and ErbB4/HER4. The first two members of this family, EGFR and HER2, have been implicated in tumorigenesis and cancer progression for several decades, and numerous drugs have now been approved that target these two proteins. Less attention, however, has been paid to the role of this family in mediating cancer cell survival and drug tolerance. To better understand the complex signal transduction network triggered by the ErbB receptor family, we built a computational model that quantitatively captures the dynamics of ErbB signaling. Sensitivity analysis identified ErbB3 as the most critical activator of phosphoinositide 3-kinase (PI3K) and Akt signaling, a key pro-survival pathway in cancer cells. Based on this insight, we designed a fully human monoclonal antibody, seribantumab (MM-121), that binds to ErbB3 and blocks signaling induced by the extracellular growth factors heregulin (HRG) and betacellulin (BTC). In this article, we present some of the key preclinical simulations and experimental data that formed the scientific foundation for three Phase 2 clinical trials in metastatic cancer. These trials were designed to determine if patients with advanced malignancies would derive benefit from the addition of seribantumab to standard-of-care drugs in platinum-resistant/refractory ovarian cancer, hormone receptor-positive HER2-negative breast cancer, and EGFR wild-type non-small cell lung cancer (NSCLC). From preclinical studies we learned that basal levels of ErbB3 phosphorylation correlate with response to seribantumab monotherapy in mouse xenograft models. As ErbB3 is rapidly dephosphorylated and hence difficult to measure clinically, we used the computational model to identify a set of five surrogate biomarkers that most directly affect the levels of p-ErbB3: HRG, BTC, EGFR, HER2, and ErbB3. Preclinically, the combined information from these five markers was sufficient to accurately predict which xenograft models would respond to seribantumab, and the single-most accurate predictor was HRG. When tested clinically in ovarian, breast and lung cancer, HRG mRNA expression was found to be both potentially prognostic of insensitivity to standard therapy and potentially predictive of benefit from the addition of seribantumab to standard of care therapy in all three indications. In addition, it was found that seribantumab was most active in cancers with low levels of HER2, consistent with preclinical predictions. Overall, our clinical studies and studies of others suggest that HRG expression defines a drug-tolerant cancer cell phenotype that persists in most solid tumor indications and may contribute to rapid clinical progression. To our knowledge, this is the first example of a drug designed and clinically tested using the principles of Systems Biology.

Pasteurized whole milk confers reduced susceptibilities to the antimicrobial agents trimethoprim, gatifloxacin, cefotaxime and tetracycline via the marRAB locus in Escherichia coli.

We inoculated pasteurized whole milk with Escherichia coli strains GC4468 (intact marRAB locus), JHC1096 (Delta marRAB), or AG112 (Delta marR), and incubated each overnight at 37 degrees C. All strains were then recovered from the milk cultures, and susceptibilities to antimicrobial agents were determined by the E-test strip method (CLSI). Cells of strain GC4468, prior to culturing in milk, were susceptible to trimethoprim, gatifloxacin, cefotaxime and tetracycline. After culturing GC4468 in pasteurized milk, however, the minimal inhibitory concentrations (MICs) increased 1.4-fold for trimethoprim (P0.05), 1.5-fold for gatifloxacin (P0.05), 2.0-fold for cefotaxime (P=0.008), and 1.4-fold for tetracycline (P0.05). After culturing GC4468 on milk count agar the MICs were enhanced 3.4-fold for trimethoprim (P0.05), 10-fold for gatifloxacin (P=0.001), 7.1-fold for cefotaxime (P=0.011), and 40.5-fold for tetracycline (P=0.074), but exhibiting tetracycline resistance with a mean MIC of 74.7+/-18.47 microg/ml (CLSI). The MICs of the antimicrobial agents for JHC1096 cells after culturing in pasteurized whole milk were indistinguishable (P0.05) from baseline MICs measured before culturing in the same type of milk. Thus, Esch. coli cells harbouring the marRAB locus exhibit reduced susceptibilities to multiple antimicrobial agents after culturing in pasteurized whole milk.