A New Hierarchy of Research Evidence for Tumor Pathology: A Delphi Study to Define Levels of Evidence in Tumor Pathology

The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.The overall project, International Agency for Research on Cancer, and beneficiaries (German Heart Centre Munich, Maria Sklodowska-Curie National Research Institute of Oncology, and Instituto de Salud Carlos III) are funded by the European Commission (HORIZON grant no. 101057127). R.C. and F.C. are funded by UK Research and Innovation. S.H. has received research funding or honoraria from Roche, BMS, Merck, Sysmex, Thermo, Volition, Trillium, Medica, and Instand and is a founder of SFZ BioCoDE and CEBIO. P.H.T. has received honoraria from AstraZeneca.S

Rotational Stability of Scaphoid Osteosyntheses: An In Vitro Comparison of Small Fragment Cannulated Screws to Novel Bone Screw Sets

<div><p>Background</p><p>The current standard of care for operative repair of scaphoid fractures involves reduction and internal fixation with a single headless compression screw. However, a compression screw in isolation does not necessarily control rotational stability at a fracture or nonunion site. The single screw provides rotational control through friction and bone interdigitation from compression at the fracture site. We hypothesize that osteosyntheses with novel bone screw sets (BSS) equipped with anti-rotational elements provide improved rotational stability.</p><p>Methods</p><p>Stability of osteosynthesis under increasing cyclic torsional loading was investigated on osteotomized cadaveric scaphoids. Two novel prototype BSS, oblique type (BSS-obl.) and longitudinal type (BSS-long.) were compared to three conventional screws: Acutrak2^®mini, HCS^®3.0 and Twinfix^®. Biomechanical tests were performed on scaphoids from single donors in paired comparison and analyzed by balanced incomplete random block design. Loading was increased by 50 mNm increments with 1,000 cycles per torque level and repeated until a rotational clearance of 10°. Primary outcome measure was the number of cycles to 10° clearance, secondary outcome measure was the maximum rotational clearance for each torque level.</p><p>Findings</p><p>BSS-obl. performed significantly better than Acutrak2^®mini and HCS^® (p = 0.015, p<0.0001). BSS-long. performed significantly better than HCS^® (p = 0.010). No significant difference in performance between BSS-obl. and BSS-long. (p = 0.361), between BSS obl. and Twinfix^® (p = 0.50) and BSS long. and Twinfix^® (p = 0.667) was detected. Within the torque range up to 200 mNm, four of 21 (19%) BSS-long. and four of 21 (19%) BSS-obl. preparations showed early failure. The same loading led to early failure in four (29%) Twinfix^®, seven (50%) Acutrak2^®mini and 10 (71%) HCS^® of 14 screw samples, respectively.</p><p>Conclusions</p><p>For both BSS and to a lesser extent for Twinfix^® (as dual-component screw), higher rotational stabilities were identified in comparison to single component headless compression screws.</p></div

Statistics for secondary outcome by implant.

<p>Adjustment for Multiplicity: Holm- Simulated.</p

primary outcome (Least squares means estimates for screw comparisons): dataset on cycles until failure with reference to torque loads (restricted to load range, where majority of failures occurred); N stands for number of screws which didn’t fail at a previous torque level and a further tested in the indicated load range.

<p>primary outcome (Least squares means estimates for screw comparisons): dataset on cycles until failure with reference to torque loads (restricted to load range, where majority of failures occurred); N stands for number of screws which didn’t fail at a previous torque level and a further tested in the indicated load range.</p

Primary outcome.

<p>Observed Cycles until failure by Implant. Median of maximum attained cycles of the respective screw models with average parameter and standard deviation. Box plot of maximum cycles per screw type. Median, 25% and 75% percentiles, the points correspond to the individual results per screw.</p

a-e. Screw types.

<p>The shown screws were used for the test series: Acutrak^®2mini (Acumed) (Fig 1a), Twinfix^® (Stryker) (Fig 1b), HCS^® 3.0 (Synthes) (Fig 1c), and prototypes of the two new BSS sets with an additional crosswise drill hole with an inner thread in oblique type (BSS-obl.) (Fig 1d) and with a longitudinal groove with an inner thread and longitudinal screw as a longitudinal type (BSS-long.) (Fig 1e).</p

a-d. Sample of a force/angle diagram.

<p>Force/angle diagrams of the cyclic load of a scaphoid bone with a torque load from 150 to 300 mNm and resulting loss of stability. In Fig 4d loosening of the screw fastening is clearly visible by the curves which run out to the right and the line up to 10°.</p

Test array.

<p>Draft of the test array for cyclic load to the scaphoid bone osteosyntheses, which were clamped into the holder.</p