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Background: The quality of evidence of the orthopedic literature has been often called into question. The fragility index (FI) has emerged as a means to evaluate the robustness of a significant result. Similarly, reverse fragility index (RFI) can be used for nonsignificant results to evaluate whether one can confidently conclude that there is no difference between groups. The analysis of FI and RFI in proximal humerus fracture (PHF) management is of particular interest, given ongoing controversy regarding optimal management and patient selection. The aim of this study was to report the FI, RFI and quality of the evidence in the proximal humerus fracture literature., Methods: A systematic review was conducted based on the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines, which utilized EMBASE, MEDLINE and Cochrane Library databases. Inclusion criteria included randomized controlled clinical trials related to the management of proximal humerus fractures, published from 2000 to 2020 with dichotomous outcome measures and 1:1 allocation. The FI and RFI were calculated by successively changing one nonevent to an event for each outcome measure until the result was made nonsignificant or significant, respectively. The fragility quotient, (FQ), calculated by dividing the FI by the total sample size, was calculated as well., Results: There were 25 studies that met our criteria with 48 outcome measures recorded. A total of 21 studies had at least one fragile result, with ten studies including a fragile result in the conclusion of the abstract. A total of 31 outcome measures had nonsignificant results and the median RFI was found to be 4, with 71% greater than number of patients lost to follow up. Seventeen outcomes had significant results, with a median FI of 1, with 65% greater than or equal to the number patients lost to follow up. A total of 18 of 25 studies (72%) included a power analysis. In particular, ten studies reported a statistical analysis of complication rates, 90% of which were fragile. The median FQ was found to be 0.037., Conclusions: The literature on PHF management is frequently fragile. Outcome measures are often fragile, particularly with regards to comparing complication rates and reoperation rates in treatment arms. Comparing to the studies in other subspecialties PHF RCTs are relatively more fragile and underpowered. Standardized reporting of FI, FQ and RFI can help the reader to reliably draw conclusions based on the fragility of outcome measures., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4 + cells into cytotoxic effectors required the presence of CD8 + cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma.

Cancer biology relies on intrinsic and extrinsic deregulated pathways, involving a plethora of intra-cellular and extra-cellular components. Tyrosine kinases are frequently deregulated genes, whose aberrant expression is often caused by major cytogenetic events (e.g. chromosomal translocations). The resulting tyrosine kinase fusions (TKFs) prompt the activation of oncogenic pathways, determining the biological and clinical features of the associated tumors. First reported half a century ago, oncogenic TKFs are now found in a large series of hematologic and solid tumors. The molecular basis of TKFs has been thoroughly investigated and tailored therapies against recurrent TKFs have recently been developed. This review illustrates the biology of oncogenic TKFs and their role in solid as well as hematological malignancies. We also address the therapeutic implications of TKFs and the many open issues concerning their clinical impact., Competing Interests: CONFLICTS OF INTERESTS We declare no competing interests.