ObjectivesThere is little evidence guiding the management of grade I–II traumatic splenic injuries with contrast blush (CB). We aimed to analyze the failure rate of nonoperative management (NOM) of ...grade I–II splenic injuries with CB in hemodynamically stable patients.MethodsA multicenter, retrospective cohort study examining all grade I–II splenic injuries with CB was performed at 21 institutions from January 1, 2014, to October 31, 2019. Patients >18 years old with grade I or II splenic injury due to blunt trauma with CB on CT were included. The primary outcome was the failure of NOM requiring angioembolization/operation. We determined the failure rate of NOM for grade I versus grade II splenic injuries. We then performed bivariate comparisons of patients who failed NOM with those who did not.ResultsA total of 145 patients were included. Median Injury Severity Score was 17. The combined rate of failure for grade I–II injuries was 20.0%. There was no statistical difference in failure of NOM between grade I and II injuries with CB (18.2% vs 21.1%, p>0.05). Patients who failed NOM had an increased median hospital length of stay (p=0.024) and increased need for blood transfusion (p=0.004) and massive transfusion (p=0.030). Five patients (3.4%) died and 96 (66.2%) were discharged home, with no differences between those who failed and those who did not fail NOM (both p>0.05).ConclusionNOM of grade I–II splenic injuries with CB fails in 20% of patients.Level of evidenceIV.
Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20
B cells. Single-agent epcoritamab previously ...demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes.
In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20
large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee.
As of January 31, 2022, 157 patients were treated (median age, 64 years range, 20-83; median of three range, 2-11 prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event.
Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
In this cohort study, we investigated whether monitoring blood levels of immature neutrophils (myelocytes, metamyelocytes and band cells) differentiated patients with sepsis from those with the ...non-infectious (N-I) systemic inflammatory response syndrome (SIRS). We also ascertained if the appearance of circulating immature neutrophils was related to adverse outcome.
Blood samples were routinely taken from 136 critically ill patients within 48 hours of ICU entry and from 20 healthy control subjects. Clinical and laboratory staff were blinded to each other's results, and patients were retrospectively characterised into those with SIRS (n = 122) and those without SIRS (n = 14). The patients with SIRS were further subdivided into categories of definite sepsis (n = 51), possible sepsis (n = 32) and N-I SIRS (n = 39). Two established criteria were used for monitoring immature white blood cells (WBCs): one where band cells >10% WBCs and the other where >10% of all forms of immature neutrophils were included but with a normal WBC count. Immature neutrophils in blood smears were identified according to nuclear morphology and cytoplasmic staining.
With the first criterion, band cells were present in most patients with SIRS (mean = 66%) when compared with no SIRS (mean = 29%; P <0.01) and with healthy subjects (0%). The prevalence of band cells was higher in definite sepsis (mean = 82%) than in patients with possible sepsis (mean = 63%; P <0.05) or with N-I SIRS (mean = 39%; P <0.001), and they had a sensitivity of 84% and a specificity of 71% for the detection of definite sepsis. With the second criterion (that is, patients with normal WBC counts), we noted that immature neutrophils did not differentiate any of the patient groups from one another. Patients who died within 1 week of blood sample provision had higher levels of myelocytes and metamyelocytes (median = 9%; P <0.05) than patients who died at 2 to 4 weeks (median =0.5%).
Raised blood levels of band cells have diagnostic significance for sepsis, provided that measurements are not confined to patients with normal WBC counts, whereas an increased prevalence of myelocytes and metamyelocytes may have prognostic application.
There are significant challenges and opportunities in deploying and utilizing advanced information technology (IT) within pharmacovigilance (PV) systems and across the pharmaceutical industry. ...Various aspects of PV will benefit from automation (e.g., by improving standardization or increasing data quality). Several themes are developed, highlighting the challenges faced, exploring solutions, and assessing the potential for further research. Automation of the workflow for processing of individual case safety reports (ICSRs) is adopted as a use case. This involves a logical progression through a series of steps that when linked together comprise the complete work process required for the effective management of ICSRs. We recognize that the rapid development of new technologies will invariably outpace the regulations applicable to PV systems. Nevertheless, we believe that such systems may be improved by intelligent automation. It is incumbent on the owners of these systems to explore opportunities presented by new technologies with regulators in order to evaluate the applicability, design, deployment, performance, validation and maintenance of advanced technologies to ensure that the PV system continues to be fit for purpose. Proposed approaches to the validation of automated PV systems are presented. A series of definitions and a critical appraisal of important considerations are provided in the form of use cases. We summarize progress made and opportunities for the development of automation of future systems. The overall goal of automation is to provide high quality safety data in the correct format, in context, more quickly, and with less manual effort. This will improve the evidence available for scientific assessment and helps to inform and expedite decisions about the minimization of risks associated with medicines.
Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody ...that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells.
For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128–60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing.
Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128–60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients 69%), primarily associated with cytokine release syndrome (CRS; 40 59%, all grade 1–2), and injection site reactions (32 47%; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45–86), with 45% achieving a complete response at full doses of 12–60 mg. At 48 mg, the overall response rate was 88% (47–100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55–100), with 50% achieving a complete response at full doses of 0·76–48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels.
Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies.
Genmab and AbbVie.
Designed for students and teachers of Ancient History or Classical Civilisation at school and in early university years, this series provides a valuable collection of guides to the history, art, ...literature, values and social institutions of the ancient world. "Early Greek Lawgivers" examines the men who brought laws to the early Greek city states, as an introduction both to the development of law and to the basic issues in early legal practice. The lawgiver was a man of special status, who could resolve disputes without violence, and who brought a sense of order to his community. Figures such as Minos of Crete, Lycurgus of Sparta and Solon of Athens resolved the chaos of civil strife by bringing comprehensive norms of ethical conduct to their fellows, and establishing those norms in the form of oral or written laws. Arbitration, justice, procedural versus substantive law, ethical versus legal norms, and the special character of written laws, form the background to the examination of the lawgivers themselves. Crete, under king Minos, became an example of the ideal community for later Greeks, such as Plato.The unwritten laws of Lycurgus established the foundations of the Spartan state, in contrast with the written laws of Solon in Athens. Other lawgivers illustrate particular issues in early law; for instance, Zaleucus on the divine source of laws; Philolaus on family law; Phaleas on communism of property; and Hippodamus on civic planning. This is an ideal first introduction to the establishment of law in ancient Greece. It is written for late school and early university students.
In this paper, the controlled production of high-quality metal-free diamond nanoparticles is demonstrated. Milling with tempered steel is shown to leave behind iron oxide contamination which is ...difficult to remove. Milling with SiN alleviates this issue but generates more nondiamond carbon. Thus, the choice of milling materials is critically determined by the acceptable contaminants in the ultimate application. The removal of metal impurities, present in all commercially available nanoparticles, will open new possibilities toward the production of customized diamond nanoparticles, covering the most demanding quantum applications.
CNS diseases are often accompanied by changes in the protein composition of cerebrospinal fluid (CSF). SELDI‐TOF‐MS provides an approach for identifying specific protein markers of disease in ...biological fluids. We compared the CSF proteomes from patients with neoplastic and reactive/inflammatory CNS diseases to identify potential biomarkers. SELDI‐TOF‐MS was performed on CSF derived from lumbar puncture of 32 patients, including 10 with CNS malignancies, 12 with inflammatory or reactive conditions, and 10 with unknown CNS disease. Using the SAX‐2 (strong anionic exchange) chip, we uncovered three conserved protein peak ranges within each disease category. For neoplastic diseases, we identified conserved peaks at 7.5–8.0 kDa (9/10 samples), 15.1–15.9 kDa (8/10 samples), and 30.0–32.0 kDa (5/10 samples). In reactive/inflammatory diseases, conserved peaks were found at 6.7–7.1 kDa (10/12 samples), 11.5–11.9 kDa (12/12 samples), and 13.3–13.7 kDa (9/12 samples). A protein from the 30.0 to 32.0 kDa peak range found in neoplastic CSF was identified by MALDI analysis as carbonic anhydrase, a protein overexpressed in many malignancies including high‐grade gliomas. Similarly, cystatin C was identified in the 13.3–13.7 kDa peak range in non‐neoplastic CSF and was most prominent in inflammatory conditions. Our approach provides a rational basis for identifying biomarkers that could be used for detection, diagnosis, and monitoring of CNS diseases.
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