Moving Forward on Tumor Pathology Research Reporting: A Guide for Pathologists From the World Health Organization Classification of Tumors Living Evidence Gap Map by Tumour Type Group.

Evidence-based medicine (EBM) can be an unfamiliar territory for those working in tumor pathology research, and there is a great deal of uncertainty about how to undertake an EBM approach to planning and reporting histopathology-based studies. In this article, reviewed and endorsed by the Word Health Organization International Agency for Research on Cancer's International Collaboration for Cancer Classification and Research, we aim to help pathologists and researchers understand the basics of planning an evidence-based tumor pathology research study, as well as our recommendations on how to report the findings from these. We introduce some basic EBM concepts, a framework for research questions, and thoughts on study design and emphasize the concept of reporting standards. There are many study-specific reporting guidelines available, and we provide an overview of these. However, existing reporting guidelines perhaps do not always fit tumor pathology research papers, and hence, here, we collate the key reporting data set together into one generic checklist that we think will simplify the task for pathologists. The article aims to complement our recent hierarchy of evidence for tumor pathology and glossary of evidence (study) types in tumor pathology. Together, these articles should help any researcher get to grips with the basics of EBM for planning and publishing research in tumor pathology, as well as encourage an improved standard of the reports available to us all in the literature.

Improvement of differential diagnosis of lung cancer by use of multiple protein tumor marker combinations.

BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of serum tumor markers (STMs) and their combinations for the differentiation of NSCLC and SCLC subtypes. METHODS: Between 2000 and 2003, 10 established STMs were assessed retrospectively in 311 patients with NSCLC, 128 with SCLC prior systemic first-line therapy and 51 controls with benign lung diseases (BLD), by automatized electrochemiluminescence immunoassay technology. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic efficacy of both individual and multiple STMs with corresponding sensitivities at 90% specificity. Standards for Reporting of Diagnostic Accuracy (STARD guidelines) were followed. RESULTS: CYFRA 21-1 (cytokeratin-19 fragment), CEA (carcinoembryonic antigen) and NSE (neuron specific enolase) were significantly higher in all lung cancers vs BLD, reaching AUCs of 0.81 (95% CI 0.76-0.87), 0.78 (0.73-0.84), and 0.88 (0.84-0.93), respectively. By the three marker combination, the discrimination between benign and all malignant cases was improved resulting in an AUC of 0.93 (95% CI 0.90-0.96). In NSCLC vs. BLD, CYFRA 21-1, CEA and NSE were best discriminative STMs, with AUCs of 0.86 (95% CI 0.81-0.91), 0.80 (0.74-0.85), and 0.85 (0.79-0.91). The three marker combination also improved the AUC: 0.92; 95% CI 0.89-0.96). In SCLC vs. BLD, ProGRP (pro-gastrin-releasing peptide) and NSE were best discriminative STMs, with AUCs of 0.89 (95% CI 0.84-0.94) and 0.96 (0.93-0.98), respectively, and slightly improved AUC of 0.97 (95% CI 0.95-0.99) when in combination. Finally, discrimination between SCLC and NSCLC was possible by ProGRP (AUC 0.86; 95% CI 0.81-0.91), NSE (AUC 0.83; 0.78-0.88) and CYFRA 21-1 (AUC 0.69; 0.64-0.75) and by the combination of the 3 STMs (AUC 0.93; 0.91-0.96), with a sensitivity of 88% at 90% specificity. CONCLUSIONS: The results confirm the power of STM combinations for the differential diagnosis of lung cancer from benign lesions and between histological lung cancer subtypes.

Serum tumor markers for response prediction and monitoring of advanced lung cancer: A review focusing on immunotherapy and targeted therapies.

BACKGROUND: The value of serum tumor markers (STMs) in the current therapeutic landscape of lung cancer is unclear. OBJECTIVE: This scoping review gathered evidence of the predictive, prognostic, and monitoring value of STMs for patients with advanced lung cancer receiving immunotherapy (IT) or targeted therapy (TT). METHODS: Literature searches were conducted (cut-off: May 2022) using PubMed and Cochrane CENTRAL databases. Medical professionals advised on the search strategies. RESULTS: Study heterogeneity limited the evidence and inferences from the 36 publications reviewed. While increased baseline levels of serum cytokeratin 19 fragment antigen (CYFRA21-1) and carcinoembryonic antigen (CEA) may predict IT response, results for TT were less clear. For monitoring IT-treated patients, STM panels (including CYFRA21-1, CEA, and neuron-specific enolase) may surpass the power of single analyses to predict non-response. CYFRA21-1 measurement could aid in monitoring TT-treated patients, but the value of CEA in this context requires further investigation. Overall, baseline and dynamic changes in individual or combined STM levels have potential utility to predict treatment outcome and for monitoring of patients with advanced lung cancer. CONCLUSIONS: In advanced lung cancer, STMs provide additional relevant clinical information by predicting treatment outcome, but further standardization and validation is warranted.

Prognostic value of blood-based protein biomarkers in non-small cell lung cancer: A critical review and 2008-2022 update.

BACKGROUND: Therapeutic possibilities for non-small cell lung cancer (NSCLC) have considerably increased during recent decades. OBJECTIVE: To summarize the prognostic relevance of serum tumor markers (STM) for early and late-stage NSCLC patients treated with classical chemotherapies, novel targeted and immune therapies. METHODS: A PubMed database search was conducted for prognostic studies on carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA 21-1), neuron-specific enolase, squamous-cell carcinoma antigen, progastrin-releasing-peptide, CA125, CA 19-9 and CA 15-3 STMs in NSCLC patients published from 2008 until June 2022. RESULTS: Out of 1069 studies, 141 were identified as meeting the inclusion criteria. A considerable heterogeneity regarding design, patient number, analytical and statistical methods was observed. High pretherapeutic CYFRA 21-1 levels and insufficient decreases indicated unfavorable prognosis in many studies on NSCLC patients treated with chemo-, targeted and immunotherapies or their combinations in early and advanced stages. Similar results were seen for CEA in chemotherapy, however, high pretherapeutic levels were sometimes favorable in targeted therapies. CA125 is a promising prognostic marker in patients treated with immunotherapies. Combinations of STMs further increased the prognostic value over single markers. CONCLUSION: Protein STMs, especially CYFRA 21-1, have prognostic potential in early and advanced stage NSCLC. For future STM investigations, better adherence to comparable study designs, analytical methods, outcome measures and statistical evaluation standards is recommended.

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.

Method Comparison and Clinical Performance of Breast Cancer Tumor Markers on Novel Multiplex Immunoassay and Automatized LOCI Technology Platforms.

Tumor marker determinations are valuable tools for the guidance of breast cancer patients during the course of disease. They are assessed on diverse analytical platforms that may be associated with differences according to the methods applied and the clinical performance. To investigate the method dependency and clinical significance of breast cancer protein tumor markers, CEA, CA 15-3, CA 125, CA 19-9 and AFP were measured in a total of 154 biobanked samples from 77 patients with breast cancer, 10 with DCIS, 31 with benign breast diseases and 36 healthy controls using a Millipore multiplex biomarker panel (MP) and an automized version of the routinely used Vista LOCI technology. The markers were compared between methods and investigated for diagnostic performance. CEA, CA 15-3 and AFP showed good correlations between both platforms with correlation coefficients of R = 0.85, 0.85 and 0.92, respectively, in all samples, but similarly also in the various subgroups. CA 125 and CA 19-9 showed only moderate correlations (R = 0.71 and 0.56, respectively). Absolute values were significantly higher for CEA, CA 15-3, CA 125 and AFP in the Vista LOCI as compared with the MP method and vice versa for CA 19-9. The diagnostic performance for discrimination of breast cancer from healthy controls was similar for both methods with AUCs in ROC curves for CEA (MP 0.81, 95% CI 0.72-0.91; LOCI 0.81; 95% CI 0.72-0.91) and CA-15-3 (MP 0.75, 95% CI 0.65-0.86; LOCI 0.67, 95% CI 0.54-0.79). Similar results were obtained for the comparison of breast cancer with benign breast diseases regarding CEA (AUC MP 0.62, 95% CI 0.51-0.73; LOCI 0.64, 95% CI 0.53-0.74) and CA-15-3 (MP 0.70, 95% CI 0.6-0.81; LOCI 0.66, 95% CI 0.54-0.77). Both platforms show moderate to good method comparability for tumor markers with similar clinical performance. However, absolute levels in individual patients should be interpreted with care.

Cell-Free DNA in Plasma and Serum Indicates Disease Severity and Prognosis in Blunt Trauma Patients.

Background: Trauma is still a major cause of mortality in people < 50 years of age. Biomarkers are needed to estimate the severity of the condition and the patient outcome. Methods: Cell-free DNA (cfDNA) and further laboratory markers were determined in plasma and serum of 164 patients at time of admission to the emergency room. Among them were 64 patients with severe trauma (Injury Severity Score (ISS) ≥ 16), 51 patients with moderate trauma (ISS < 16) and 49 patients with single fractures (24 femur neck and 25 ankle fractures). Disease severity was objectified by ISS and Glasgow Coma Scale (GCS). Results: cfDNA levels in plasma and serum were significantly higher in patients with severe multiple trauma (SMT) than in those with moderate trauma (p = 0.002, p = 0.003, respectively) or with single fractures (each p < 0.001). CfDNA in plasma and serum correlated very strongly with each other (R = 0.91; p < 0.001). The AUC in ROC curves for identification of SMT patients was 0.76 and 0.74 for cfDNA in plasma and serum, respectively-this was further increased to 0.84 by the combination of cfDNA and hemoglobin. Within the group of multiple trauma patients, cfDNA levels were significantly higher in more severely injured patients and patients with severe traumatic brain injury (GCS ≤ 8 versus GCS > 8). Thirteen (20.3%) of the multiple trauma patients died during the first week after trauma. Levels of cfDNA were significantly higher in non-surviving patients than in survivors (p < 0.001), reaching an AUC of 0.81 for cfDNA in both, plasma and serum, which was further increased by the combination with hemoglobin and leukocytes. Conclusions: cfDNA is valuable for estimation of trauma severity and prognosis of trauma patients.

Assessment of Complication Risk in the Treatment of Proximal Humerus Fractures: A Retrospective Analysis of 4019 Patients.

(1) Background: The treatment of proximal humeral fractures (PHFs) is debated controversially. Current clinical knowledge is mainly based on small single-center cohorts. The goal of this study was to evaluate the predictability of risk factors for complications after the treatment of a PHF in a large clinical cohort in a multicentric setting. (2) Methods: Clinical data of 4019 patients with PHFs were retrospectively collected from 9 participating hospitals. Risk factors for local complications of the affected shoulder were assessed using bi- and multivariate analyses. (3) Results: Fracture complexity with n = 3 or more fragments, cigarette smoking, age over 65 years, and female sex were identified as predictable individual risk factors for local complications after surgical therapy as well as the combination of female sex and smoking and the combination of age 65 years or older and ASA class 2 or higher. (4) Conclusion: Humeral head preserving reconstructive surgical therapy should critically be evaluated for patients with the risk factors abovementioned.

Pull-out forces of headless compression screws in variations of synthetic bone models imitating different types of scaphoid fractures in good bone quality.

Screw osteosynthesis using headless compression screws has become the accepted gold standard for the surgical treatment of scaphoid fractures. Optimal screw specifications remain controversially discussed. We aimed to investigate the influence of bone model composition on screw stability tests using headless compression screws in different scaphoid fracture models. We conducted pull-out tests using Acutrak2®mini, HCS®, HKS®, HBS®, Herbert/Whipple® and Twinfix® screws. To imitate cortical and cancellous bone, two-layer polyurethane (PU) models with two distinct densities were produced. The cylinders were cut at different positions to replicate fracture localisations at increasing distances. The maximum pull-out force required to achieve up to 1 mm of pull-out distance (Nto 1 mm) was measured. Acutrak2®mini and HCS® followed by Twinfix® showed the greatest average pull-out forces. Nto 1 mm was, on average, greater in the cortico-cancellous model than in the cancellous cylinder with the Acutrak2®mini and the Herbert/Whipple® screws, while it was the least with the HBS® and the Twinfix® screws; there were also differences between the HCS® and HKS®. There were no differences between the different fracture simulations in the synthesis strength using either the HKS® or HBS®. The pull-out forces of the HCS® and Twinfix® remained high also in simulations with the smaller screw base fragments. Varying imitations of cancellous and cortico-cancellous bone and fracture localisation reveal important information about the ex vivo strength of screw syntheses. The grip of the cortical structure should be used with the screws that fit more firmly in cortico-cancellous bone.

Associated abdominal injuries do not influence quality of care in pelvic fractures-a multicenter cohort study from the German Pelvic Registry.

Background: Pelvic fractures are rare but serious injuries. The influence of a concomitant abdominal trauma on the time point of surgery and the quality of care regarding quality of reduction or the clinical course in pelvic injuries has not been investigated yet. Methods: We retrospectively analyzed the prospective consecutive cohort from the multicenter German Pelvic Registry of the German Trauma Society in the years 2003-2017. Demographic, clinical, and operative parameters were recorded and compared for two groups (isolated pelvic fracture vs. combined abdominal/pelvic trauma). Results: 16.359 patients with pelvic injuries were treated during this period. 21.6% had a concomitant abdominal trauma. The mean age was 61.4 ± 23.5 years. Comparing the two groups, patients with a combination of pelvic and abdominal trauma were significantly younger (47.3 ± 22.0 vs. 70.5 ± 20.4 years; p < 0.001). Both, complication (21.9% vs. 9.9%; p < 0.001) and mortality (8.0% vs. 1.9%; p < 0.001) rates, were significantly higher.In the subgroup of acetabular fractures, the operation time was significantly longer in the group with the combined injury (198 ± 104 vs. 176 ± 81 min, p = 0.001). The grade of successful anatomic reduction of the acetabular fracture did not differ between the two groups. Conclusion: Patients with a pelvic injury have a concomitant abdominal trauma in about 20% of the cases. The clinical course is significantly prolonged in patients with a combined injury, with increased rates of morbidity and mortality. However, the quality of the reduction in the subgroup of acetabular fractures is not influenced by a concomitant abdominal injury. Trial registration: ClinicalTrials.gov, NCT03952026, Registered 16 May 2019, retrospectively registered.

[Quality of operative treatment of pelvic fractures is not influenced by an additional abdominal injury : A monocentric registry study]. / Die Qualität der operativen Versorgung von Beckenfrakturen wird durch eine zusätzliche Abdominalverletzung nicht beeinflusst : Eine monozentrische Registerstudie.

BACKGROUND: Pelvic fractures are rare but severe injuries. The influence of a concomitant abdominal trauma on the quality of care regarding operative parameters, such as reduction quality and the clinical course in pelvic injuries has not yet been sufficiently investigated. METHODS: This study retrospectively analyzed the prospective consecutive data of patients with pelvic injuries treated at the BG Trauma Center in Tübingen in the years 2003-2017. Demographic, clinical and operative parameters were recorded and compared between two groups (isolated pelvic fracture vs. combined abdominal/pelvic trauma). RESULTS: A total of 1848 patients with pelvic injuries were treated during this period and 18.6% had a concomitant abdominal trauma. The mean age was 62.3 ± 23.1 years. Comparing the two groups, patients with a combination of pelvic and abdominal trauma were significantly younger (46.3 ± 20.3 years vs. 70.6 ± 20.8 years; p < 0.001). Both the overall complication rate (31.2% vs. 9.4%; p < 0.001) and mortality (5.0% vs. 1.7%; p = 0.001) were significantly higher in the group with a combination of injuries. The time until definitive surgery of the pelvis was significantly longer in the group with combined injuries (6.0 ± 6.4 days vs. 4.5 ± 4.4 days; p = 0.002). The results of postoperative reduction did not differ between the two groups. CONCLUSION: Patients with a pelvic injuries have a concomitant abdominal trauma in approximately 20% of the cases. The clinical course is significantly prolonged in patients with a combined injury and morbidity and mortality rates are increased; however, the quality of the postoperative results is not influenced by a concomitant abdominal injury.

EASY (endoscopic approach to the symphysis): a new minimally invasive approach for the plate osteosynthesis of the symphysis and the anterior pelvic ring-a cadaver study and first clinical results.

BACKGROUND: Minimally invasive surgical approaches to reduce approach-associated morbidity are an interdisciplinary goal in surgery. In principle, the endoscopic approach for the extraperitoneal repair of groin hernias is the minimally invasive variant of the modified Stoppa-approach, which is used for the treatment of pelvic ring injuries in traumatology. METHOD: Anatomical feasibility study regarding the plate osteosynthesis of the anterior pelvic ring via a minimally invasive variant of the modified Stoppa-approach. RESULTS: We present the minimally invasive variant of the modified Stoppa-approach in a human cadaver step by step, both photographically and radiologically. Feasibility of the plate osteosynthesis of the symphysis is presented in a patient with open book injury via the minimally invasive approach using standard laparoscopic instruments. CONCLUSION: The plate osteosynthesis of the anterior pelvic ring via the minimally invasive variant of the modified Stoppa-approach is feasible with existing standard laparoscopic instruments.

Endoscopic Approach to the Quadrilateral Plate (EAQUAL): a New Endoscopic Approach for Plate Osteosynthesis of the Pelvic Ring and Acetabulum - a Cadaver Study. / Endoscopic Approach to the Quadrilateral Plate (EAQUAL): ein neuer endoskopischer Zugang für die Plattenosteosynthese des Beckenringes und Azetabulums ­ eine anatomische Machbarkeitsstudie.

BACKGROUND: Dislocated pelvic fractures which require surgical repair are usually operated on via open surgery. Approach-related morbidity is reported with a frequency of up to 30%. The aim of this anatomical study was to prove the feasibility of endoscopic visualisation of the relevant anatomical structures in pelvic surgery and to perform completely endoscopic plate osteosynthesis of the acetabulum with available standard laparoscopic instruments. METHOD: In four human cadavers, we established an endoscopic preparation of the complete pelvic ring, from the symphysis to the iliosacral joint, including the quadrilateral plate and the sciatic nerve, and performed endoscopic plate osteosynthesis along the iliopectineal line. RESULTS: The endoscopic preparation of the complete pelvic ring and the quadrilateral plate was demonstrated step-by-step, followed by completely endoscopic plate osteosynthesis along the pelvic brim. Endoscopic, radiographic, and schematic pictures are used to illustrate the technique. CONCLUSION: The completely endoscopic preparation of the pelvic brim and the quadrilateral plate is feasible with available standard laparoscopic instruments. Moreover, plate osteosynthesis could be performed endoscopically. Further research on reduction techniques is necessary when planning to implement this technique into a clinical scenario.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. CONCLUSIONS: 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.