Hamiltonkronborg0214

The patients with PRKN variants showed specific symptoms dependent on the number of mutated alleles.

ABP 501 (European Union, adalimumab; United States, adalimumab-atto) is a biosimilar to the adalimumab reference product (RP). A model was developed characterizing population pharmacokinetic (PK) variables of ABP 501 and adalimumab RP to include the impact of antidrug antibodies (ADAs).

Data were retrospectively analyzed from a single-dose, parallel-group bioequivalence study in healthy adults who received a single 40-mg SC injection of ABP 501 or adalimumab RP. Modeling was performed by using NONMEM 7.2. The impact of ADAs on PK similarity was assessed from population model-based AUC

values using ANCOVA.

Linear compartment models with various clearance pathways were compared with a one-compartment distribution, first-order subcutaneous absorption model. The final model, a one-compartment model with first-order subcutaneous absorption and linear clearance from the central compartment with an additional time-dependent linear clearance for ADA-positive subjects, described ABP 501 and adalimumab RP population PK variables. Model-derived estimates confirmed PK similarity for ABP 501 and adalimumab RP despite the impact of ADAs.

A traditional approach for evaluating bioequivalence based on noncompartmental analysis may be inappropriate for drugs with a high incidence of ADAs because accounting for the effect of ADAs on noncompartmental analysis parameters is challenging. Use of a population PK model to discern the effect of ADAs on drug PK variables allows for assessment of PK similarity accounting for the presence or absence of ADAs.

A traditional approach for evaluating bioequivalence based on noncompartmental analysis may be inappropriate for drugs with a high incidence of ADAs because accounting for the effect of ADAs on noncompartmental analysis parameters is challenging. Use of a population PK model to discern the effect of ADAs on drug PK variables allows for assessment of PK similarity accounting for the presence or absence of ADAs.

Many regulators offered new ways of working to help combat the COVID-19 pandemic, and the rolling review procedure is an important and successful example. In rolling reviews, data are submitted and reviewed as they become available before the full data package is available. This approach is resource intensive but faster than standard review processes and therefore of benefit to society and patients during a health emergency. In this study, we analyze the European Medicines Agency (EMA) rolling review process and extract learning, based on the vaccines and treatments that have been approved to date (November 2021), and formulate 3 suggestions for the future.

Data and information on rolling reviews and similar related processes were collected from health authority websites across the globe with a focus on the EMA. Literature searches in PubMed and checking company websites for additional information were conducted to complement and corroborate findings as required.

The duration of a rolling review cycle aing a health emergency, such as the COVID-19 pandemic, to meet an unmet medical need. Other critical conditions or life-threatening diseases with unmet needs exist and may be suitable to be addressed by a rolling review process to accelerate patient access to life-changing treatments. Indeed, we call for an evaluation of the rolling review process, its use, and its efficiency to capture learning with the aim of building a new, lean, and effective expedited review procedure that could be institutionalized and added to the regulatory toolbox.Over the past couple of decades, the life expectancy of patients with multiple myeloma (MM) has progressively increased, however, the disease per se remains incurable. This has resulted in a subset of the patient population who have progressed despite multiple standard treatment options but remain amenable for novel therapies to achieve durable remission. With the discovery of the role of B-Cell Maturation Antigen (BCMA) in the pathogenesis of MM, strategies targeting the BCMA have been the focus of many treatment modalities in development. Although autologous CAR-T cell therapy has shown an overall efficacy of >80% across various phases of studies, it has its own set of limitations and challenges. There is now an increasing focus on identifying novel therapeutic targets for multiple myeloma and developing "off-the-shelf" immunotherapeutic approaches for treatment of MM. This review discusses and highlights the emerging data from various ongoing trials on "off-the-shelf" approaches like antibody-drug conjugates, bispecific antibodies, and allogeneic cellular therapies demonstrating feasibility, acceptable safety, and promising preliminary efficacy. Ongoing and future efforts will need to focus on comparative effectiveness of these different approaches, possible combination strategies, and ensuring equitable and affordable access to these therapies globally.

Cold-stored low titer group O whole blood (LTOWB) is increasingly utilized in the initial resuscitation of exsanguinating trauma patients. We report on our early experience with LTOWB, focusing on logistics, implementation challenges, and outcomes.

In February, 2019, LTOWB was incorporated into the massive transfusion protocol (MTP) activated for trauma patients in the emergency department (ED.) Up to 4 units of LTOWB were included in the MTP cooler, depending on availability, and were transfused prior to transfusion of any other blood products from the MTP cooler. Demographics, injury characteristics, and outcomes were obtained, and the logistics of LTOWB availability were reviewed.

Over a 12-month period, MTP was activated for 74 trauma patients. Of those, 38 (51%) MTP included at least one unit of LTOWB, with 19/38 (50%) including 4 LTOWB units. A total of 177 units of LTOWB were purchased during the study period, and of those, 74 (42%) expired before use. Patients who received LTOWB had a similar mortality compared to those who received component therapy (39% vs. 47%; Odds Ratio [95% CI] 0.7 [0.3, 2.0]; p=0.72,) however, they were able to achieve a significantly higher plasmapRBC ratio during the duration of MTP activation (mean [SD] 0.8 [0.2] vs. 0.4 [0.4]; mean difference [95% CI] 0.4 [0.2, 0.5]; p<0.01.) CONCLUSIONS Our early experience with LTOWB transfusion demonstrates feasibility, but also highlights challenges with inventory management. These findings triggered changes to our protocol aiming at minimizing wastage. The use of LTOWB may yield a higher plasmapRBC ratio early during the resuscitation period. Further investigation is required to explore whether this may yield a survival advantage.

III (Therapeutic/Care Management).

III (Therapeutic/Care Management).

Treatment of high-risk extremity soft tissue sarcomas remains widely varied. Despite growing support for a multimodal approach for treatment of these rare and aggressive neoplasms, its dissemination remains underused. This national study aimed to evaluate variations in treatment patterns and uncover factors predictive of underuse of multimodal therapy in high-risk extremity soft tissue sarcomas.

The 2010 to 2015 National Cancer Database was used to evaluate trends in 3 common treatment patterns surgery alone, surgery+ adjuvant therapy, and neoadjuvant therapy+ surgery. Demographic-, sarcoma-, hospital-, and treatment-level factors of 6,725 surgically treated patients with stage II or III intermediate- to high-grade extremity soft tissue sarcomas were evaluated by types of treatment modality. Stepwise multivariable logistic regression was performed to identify factors predictive of each treatment modality.

When compared to surgery alone (34.6%) and adjuvant therapy (41.2%), use of neoadjuvant therapy+ suy therapy for high-risk extremity soft tissue sarcomas remains low and gradual in the United States. Dissemination of multimodality therapy will require attention to access and hospital factors to maximize these therapies for high-risk extremity soft tissue sarcomas.

The management of complications after major hepatectomy in perihilar cholangiocarcinoma may not always be successful, leading to failure to rescue. The present study seeks to identify independent risk factors for failure to rescue after major hepatectomy in perihilar cholangiocarcinoma.

We retrospectively analyzed the postoperative course of all consecutive patients who underwent major hepatectomy in a curative intent for perihilar cholangiocarcinoma between 2005 and 2019 at our department. DZD9008 ic50 A multivariate logistic regression analysis was performed to identify independent risk factors for failure to rescue.

Of 287 patients, 186 (65%) had major complications (Dindo-Clavien grade ≥IIIa), of which 142 (76%) were grade IIIa to IVb (rescue group). Failure to rescue (FTR group, Dindo-Clavien grade V) occurred in 44 of 186 patients (24%). Age >65 years (odds ratio= 4.001, 95% confidence interval 1.025-15.615, P= .046) and right-sided resection (odds ratio= 17.040, 95% confidence interval 1.926 - 150.782, P= .011) were independently associated with failure to rescue. Preoperative carbohydrate antigen 19-9 levels >100 kU/mL as well as preoperative chemotherapy appear to increase odds for failure to rescue as well; however, the association was short of statistical significance (P= .070 and .079, respectively).

Elderly patients as well as patients undergoing right-sided hepatectomy for perihilar cholangiocarcinoma with high preoperative carbohydrate antigen 19-9 levels are at high risk for failure to rescue. Thus, patients should be assessed critically preoperatively. Postoperatively, close monitoring, especially of patients who are at risk, is mandatory.

Elderly patients as well as patients undergoing right-sided hepatectomy for perihilar cholangiocarcinoma with high preoperative carbohydrate antigen 19-9 levels are at high risk for failure to rescue. Thus, patients should be assessed critically preoperatively. Postoperatively, close monitoring, especially of patients who are at risk, is mandatory.

Evaluation of donor renal function as glomerular filtration rate (GFR) is a crucial part of pretransplant workup. Most guidelines recommend measured GFR (mGFR) using exogenous markers with creatinine clearance (CrCl) as an alternative. However, exogenous markers are difficult to obtain and perform, and CrCl may overestimate GFR.

We explore the use of CrCl and combined urea and creatinine clearance as an alternative for GFR assessment.

A retrospective study involving 81 kidney donors from 2007 to 2020, with mGFR collected by chromium 51-labeled ethylenediaminetetraacetic acid (

Cr-EDTA) and CrCl and combined urea and creatinine clearance. We analyzed the performance of CrCl and combined urea and creatinine clearance against

Cr-EDTA. Adequacy of urine volume was taken into consideration.

A total of 81 candidates with a mean age of 44.80 ± 10.77 years were enrolled. Mean mGFR from

Cr-EDTA was 123.66 ± 26.91 mL/min/1.73 m

, and combined urea and creatinine clearance and CrCl were 122.13 ± 47.07 and 133.40 ± 36.32 mL/min/1.73 m

, respectively. CrCl overestimated

Cr-EDTA. Though combined urea and creatinine clearance had minimal bias, it had a lower correlation coefficient (0.25 vs 0.43), lower precision (49.51 vs 38.10), and slightly lower accuracy within 30% of

Cr-EDTA (74.07% vs 76.54%).

Combined urea and creatinine clearance did not improve the performance of CrCl. Nevertheless, it can potentially be used as first-line GFR assessment, followed by mGFR in selected donors, to ascertain threshold of safe kidney donation. A stringent urine collection method is essential to ensure accurate measurement.

Combined urea and creatinine clearance did not improve the performance of CrCl. Nevertheless, it can potentially be used as first-line GFR assessment, followed by mGFR in selected donors, to ascertain threshold of safe kidney donation. A stringent urine collection method is essential to ensure accurate measurement.