Long-term functional outcome after dorsal capsular imbrication for post-traumatic dorsal instability of the distal radioulnar joint.

PURPOSE: The goal of this study was the assessment of long-term outcome of dorsal capsular imbrication of the distal radioulnar joint (DRUJ) in dorsal instability. METHODS: The study included ten patients (mean 38.7 years of age) with a mean follow-up time of 11.2 years (9.3 years to 14.3 years). Examination parameters included Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, modified Mayo Wrist Score (MMWS), determination of range of motion in comparison with the healthy extremity, pre- and post-operative pain level assessment, and examination of DRUJ stability. RESULTS: Eight of ten DRUJs proved to be stable after the above-mentioned follow-up. Mean MMWS was 92.5 (65-100; SD: 11.1). Mean DASH Score was 8.8 (0-60; SD: 18.4). Grip strength reached 93.5% of the contralateral unaffected hand. Range of motion did not differ significantly in comparison with the healthy contralateral extremity. Nine of ten patients regarded pain level reduction as excellent. Eight of ten patients regarded DRUJ stability as excellent after surgery. CONCLUSION: Dorsal capsular imbrication of the DRUJ is an efficacious surgical technique for post-traumatic dorsal instability in the long-term.

[Corrective osteotomy of the hand]. / Korrekturosteotomie an der Hand.

Fractures of fingers and metacarpals are among the most frequent injuries. Many fractures can be successfully treated conservatively. Nevertheless, various malformations, such as malrotation, spur development, bone shortening, deviation of the axis and combinations of these individual deformities may appear in the course of time. Corrective osteotomy can correct these deformities with clinically impaired function and improve/optimize hand function. Prerequisites for corrective osteotomy are a precise analysis of the deformity, precise osteotomy, exercise stable osteosynthesis and intensive follow-up treatment of the hand. Complications, such as implant failure, postoperative tendon and joint adhesions, joint contracture and nonunion are however possible.

Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia.

BACKGROUND: Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML. METHODS: We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML. RESULTS: AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival. CONCLUSIONS: PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.

Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax.

The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. SIGNIFICANCE: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.

Long-term results of more than 13 years after arthroscopic repair of triangular fibrocartilage complex (TFCC) Palmer 1B tears: a comparison with short- and mid-term results.

PURPOSE: Goal of this study was the assessment of long-term outcome of arthroscopically assisted repair of Palmer 1B/Atzei 1 triangular fibrocartilage complex tears and the comparison with short- and mid-term results. METHODS: The study included nineteen patients (mean 49.2 years of age) with a mean follow-up time of 13.6 years (13.1-14.3 years). Examination parameters included disabilities of arm, shoulder, and hand (DASH) questionnaire, modified Mayo Wrist Score (MMWS), Krimmer Score, determination of range of motion in comparison to the contralateral extremity. Grip and pinch grip strength measurement and pain level assessment was performed, as well. RESULTS: The mean MMWS after at least 13.1 years was 95.8 (85-100, SD 5.6). Mean DASH Score was 10.2 (0-55.8, SD 13.6). Mean Krimmer Score was 97.2 (85-100, SD 4.8). Grip strength reached 101% of the contralateral unaffected hand. Range of motion did not differ significantly in comparison to the healthy contralateral extremity. None of the patients suffered from major complications. Fourteen of nineteen patients regarded pain level reduction as excellent. Five patients reported a relevant pain level reduction. Sixteen of nineteen patients regarded functional outcome as excellent, the other three patients reported on a pleasing improvement of the functional outcome. CONCLUSION: Arthroscopically assisted repair of Palmer 1B/Atzei 1 triangular fibrocartilage complex tears may be an efficacious and safe surgical technique for ulnar-sided TFCC tears in the long term.