Ab) and GPC3 aptamer (GPC3Apt), an “H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab” sandwich complex was formed with peroxidase-like properties which enhanced H2O2 to reduce the silver (Ag) ions in solution to metallic Ag, resulting in the deposition of silver nanoparticles (Ag NPs) on the surface of the biosensor. The amount of deposited Ag, which was derived from the amount of GPC3, was quantified by the differential pulse voltammetry (DPV) method. Under ideal circumstances, the response value was linearly correlated with GPC3 concentration at 10.0–100.0 μg/mL with R2 of 0.9715. When the GPC3 concentration was in the range from 0.01 to 10.0 μg/mL, the response value was logarithmically linear with the GPC3 concentration with R2 of 0.9941. The limit of detection was 3.30 ng/mL at a signal-to-noise ratio of three and the sensitivity was 1.535 μAμM−1cm−2. Furthermore, the electrochemical biosensor detected the GPC3 level in actual serum samples with good recoveries (103.78–106.52%) and satisfactory relative standard deviations (RSDs) (1.89–8.81%), which confirmed the applicability of the sensor in practical applications. This study provides a new analytical method for measuring the level of GPC3 in the early diagnosis of HCC.Glypican-3 (GPC3), as an emerging biomarker, has been shown to be beneficial for the early diagnosis and treatment of hepatocellular carcinoma (HCC). In this study, an ultrasensitive electrochemical biosensor for GPC3 detection has been constructed based on the hemin-reduced graphene oxide-palladium nanoparticles (H-rGO-Pd NPs) nanozyme-enhanced silver deposition signal amplification strategy. When GPC3 specifically interacted with GPC3 antibody (GPC3 Globally, hepatocellular carcinoma (HCC) has been evaluated as one of the most common malignant malignancies with high prevalence and fatality rates . The surImmunoassay detection of serum biomarkers including enzyme-linked immunoassay (ELISA) and bioluminescence enzyme immunoassay (BLIEA) has been widely used in clinical practice for the diagnosis of HCC ,5,6. GlyELISA serum kits are widely used to detect antigens or antibodies in clinical practice by using double antibodies and labeled-horseradish peroxidase (HRP) to form sandwich-type structures . On the In recent years, electrochemical detection has alternatively been used as a powerful technique for many point-of-care (POC) sensors due to its inherent advantages of low cost, portability, and fast response ,16. For Nanozymes are simulated enzymes composed of nanomaterials, which have two characteristics of nanomaterials and enzyme-like activities. Nanozymes can solve the shortcomings of the natural enzyme such as high cost and variability, but the activity is slightly lower than that of the natural enzyme. Nanozymes and reaction substrates are accompanied by electron transfer and valence changes, showing REDOX enzyme activities. Compared with ordinary bio-signal, the electrochemical signal generated by nanozyme-catalyzed amplification technique can be enhanced by the reaction of the chromogenic substrate ,20. AmonApt) and GPC3 antibody (GPC3Ab) as recognition elements. GPC3Apt was labelled on the binding sites of H-rGO-Pd NPs nanozyme through π-π action and Pd-N coordination interaction. The H-rGO-Pd NPs-GPC3Apt signal probe not only improves the electron transfer rate but also enhances the number of fixed biomolecules. GPC3Ab, as a capture probe, was adsorbed on the surface of a Au NPs@rGO-modified screen-printed electrode (SPE). In the presence of GPC3, an “H-rGO-Pd NPs-GPC3Apt-GPC3-GPC3Ab” sandwich-structure complex with peroxide properties was formed by specific binding, and further catalyzed the reaction of H2O2 with AgNO3 to deposit Ag NPs on the sensor surface. The dissolution current of Ag NPs could be measured using differential pulse voltammetry (DPV). The analytical performance in terms of working curve, linear range, sensitivity, specificity, reproducibility, and stability of the proposed GPC3 electrochemical nanobiosensor was discussed. Given the above considerations, our study aimed to generate a novel sandwich-structure electrochemical biosensor for GPC3 detection based on hemin-reduced graphene oxide-palladium nanoparticles (H-rGO-Pd NPs) nanozyme peroxidase-like catalytic silver deposition for signal amplification, combining GPC3 aptamer (GPC3Apt) and the GPC3 antibody (GPC3Ab) as recognition elements. Firstly, the H-rGO-Pd NPs nanozyme with good peroxidase-like catalytic properties was prepared by a two-step reduction method, and the H-rGO-Pd NPs-GPC3Apt detection probe was prepared through π-π action, and Pd-N coordination interaction. Then, the Au NPs@rGO was modified on the surface of pretreated SPE by electrodeposition, leading to the formation of Au NPs@rGO/SPE. After that, GPC3Ab was immobilized on Au NPs@rGO/SPE by Au-N bonding as well as physical adsorption. When the GPC3 was added, the specific recognition reaction between the GPC3Ab and GPC3 produced an antibody–antigen complex and arranged on the electrode surface. Next, the H-rGO-Pd NPs-GPC3Apt detection probe was fixed on the electrode surface by π-π bond and electrostatic adsorption. Both GPC3Ab and H-rGO-Pd NPs-GPC3Apt specifically bonded with GPC3 to form the H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab sandwich-structure complex with a stable spatial structure as well as catalytic performance, which could induce the reduction in the Ag ions in the solution containing H2O2 and AgNO3 solution for the deposition of Ag NPs on the surface of Au NPs@rGO/SPE. The metallic Ag NPs deposited on Au NPs@rGO/SPE could produce detectable anodic stripping signals, which can be determined by DPV. Since the amount of H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab affects the Ag NPs deposition which further leads to the change of the sensor response current, the standard curve was determined by studying the relationship between the sensor response current and GPC3 concentration.Herein, H-rGO-Pd NPs revealed good conductivity, nontoxicity, and high peroxidase-like catalytic properties because of the peroxidase properties of Hemin, good catalyst-supporting material of rGO, and the efficient catalytic synergies of Pt NPs.2O2 was able to react with AgNO3 slowly without catalytic substances, which left a small amount of deposited Ag on the electrode surface. Under the catalysis of H-rGO-Pd NPs peroxidase-like activity, the GPC3 nanobiosensor detected a significant current response (curve c and curve d). Moreover, the current response significantly increased when the concentration of GPC3 went up from 10.0 to 50.0 μg/mL. It was positively correlated with GPC3 concentrations. The feasibility analysis suggested that the “H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab” sandwich complex can effectively catalyze the reaction of H2O2 and AgNO3 on the surface of electrodes. Being heavily coated with Ag NPs amplified the current signal of the sensor, further indicating that the electrochemical nanobiosensor was capable of detecting GPC3.By using the DPV method, the feasibility of the GPC3 electrochemical nanobiosensor was determined under the potential voltage range of (−0.2–0.4 V) B. In theThe UV-vis spectra of rGO, hemin, and H-rGO-Pd NPs were shown in −1, a constriction vibration peak of C-H at 2918 cm−1, a vibration peak of C=O at 1630 cm−1, and a vibration peak of C-O at 1384 cm−1. H-rGO-Pd NPs and hemin have a common asymmetric stretching peak at 850 cm−1 which is from the formation of Fe-O bond in hemin 3−/4−, derived from Randles–Sevcik’s formula 3−/4− (6.70 × 10−6 cm2 s−1), n is the number of electrons involved ([Fe(CN)6]3−/4−, n = 1), v represents the scanning rate (0.1 V/s), and C represents the concentration of redox medium (5 mM/L). The surface area of different electrodes was calculated in square measure and placed in the following order: SPE (0.0555 cm2) < H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab/Au NPs@rGO/SPE (0.1006 cm2) < GPC3/GPC3Ab/Au NPs@rGO/SPE (0.1085 cm2) < GPC3Ab/Au NPs@rGO/SPE (0.1088 cm2) < Au NPs@rGO/SPE (0.1187 cm2) < Ag NPs/H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab/Au NPs@rGO/SPE (0.1670 cm2). These results confirmed that both H-rGO-Pd NPs nanozyme-catalyzed silver deposition and SPE deposition of Au NPs@rGO significantly increased the conductivity of the electrode, further facilitating electron transfer. In this formula, 6]3−/4− solution mixed with 1 M of KCl as the electrolyte solution, every electrode in the sensor construction process underwent an EIS scan at a constant voltage of 5 mV. As shown in Ab hindered electron transfer, and the impedance became larger . After GPC3 was incubated, the binding of GPC3 and GPC3Ab hindered electron transfer , H-rGO-Pd NPs-GPC3Apt was dropped on the electrode, the impedance increased  because of the presence of the aptamer hindering the electron transfer. Finally, after silver particles were deposited on the surface of the sensor, the electrode impedance decreased sharply , indicating that H-rGO-Pd NPs effectively catalyzed the reaction of H2O2 and AgNO3. It was concluded that the electrode impedance was significantly reduced by depositing a large amount of Ag NPs on its surface.EIS could be an effective tool for characterizing the properties of electron switches in a range of electrode modifications. Thus, 5 mM of [Fe(CN)Ab, the GPC3Ab/Au NPs@rGO/SPE , or a mixture  was mixed with GPC3 in a 1:1 ratio with the same concentration (1.0 μg/mL), for which the results are shown in To detect the GPC3 protein (1.0 µg/mL) and analyze its stability by using the DPV technique, the GPC3 electrochemical nanobiosensor was kept at 4 °C in a refrigerator, and would be taken out at various intervals  D. The reTo verify that the nanobiosensor would be applied in actual serum detection, GPC3 in human serum samples was detected by standard addition methods under optimal conditions. The approval was first received from the Ethics Committee of the Guangxi Key Laboratory of Metabolic Disease Research of the 924th Hospital of the Chinese People’s Liberation Army Joint Logistic Support Force . Three kinds of serum samples were prepared and detected with the same process instead of GPC3 standard solution and the results are shown in 2PdCl4), chloroauric acid (HAuCl4·4H2O), silver nitrate (AgNO3), Sodium chloride (NaCl), hydrogen peroxide (H2O2), ascorbic acid (AA), and ethylene glycol (EG) were obtained from Xilong Scientific Co., Ltd. . Human serum albumin (HSA), Sodium hydroxide (NaOH), and bovine serum albumin (BSA) were obtained from Macklin Biochemical Co., Ltd. . GPC3 antibody (GPC3Ab) and GPC3 aptamer  [Graphene oxide (GO) was obtained from Xianfeng Nano Co., Ltd. . Hemin, GPC3, Sodium tetrachloropalladate (NaCC A-3’) , Polydia2, Φ = 3 mm), and the reference electrode was Ag/AgCl inert.All electrochemical experiments were conducted on the electrochemical workstation  at room temperature. Electrochemical measurements were performed with conventional screen-printed electrodes , one of the carbon paste electrodes served as an auxiliary electrode, the other as a working electrode . A DXR Raman microscope  was used to measure Raman spectra between 200 and 3500 cm−1. The wavelength range of the ultraviolet-visible spectroscopy (UV-vis)  was 200–600 nm.Transmission electron microscopy (TEM) was performed with a JEM-2100F electron microscope  at 100 kV accelerating voltage. A Quanta 200 Fifield scanning electron microscope  was used for scanning electron microscopy (SEM). It was measured at 400–4000 cm3·H2O) and 100.0 μL hydrazine hydrate (NH2-NH2) were added. After mixing, the solution was centrifugally cleaned in a water bath at 60 °C for 4 h to obtain the H-rGO solution. Second, 2.0 mL of PDDA (ω = 0.2%) and 5.0 mL of NaCl (0.2 M) were added into the 10.0 mL of H-rGO solution (0.5 mg/mL) and stirred for 12 h to form PDDA-modified H-rGO solution. Then, 2.0 mL of Na2PdCl4 (20 mM) and 10.0 mL of EG were added into the PDDA-modified H-rGO solution. After being stirred overnight, the pH of the solution was adjusted to 12 with 1.0 M of NaOH. Furthermore, the above solution was refluxed for 4 h at 140 °C. Finally, the H-rGO-Pd NPs were obtained by centrifuging and drying.H-rGO-Pd NPs nanozymes were prepared by a two-step reduction method. First, well-dispersed hemin-reduced graphene oxide (H-rGO) solution was prepared as described in our earlier study . BrieflyApt detection probe was prepared through π-π action and Pd-N coordination interaction. A total of 100.0 μL of GPC3Apt solution (5 μM) and 200.0 μL of H-rGO-Pd NPs (0.5 mg/mL) were sonically mixed overnight at room temperature. Then, the solution was centrifuged at 12,000 rpm for 20 min to remove free aptamers. Thereafter, the H-rGO-Pd NPs-GPC3Apt detection probe (1.0 mg/mL) was obtained after the residue was dispersed in Tris-EDTA buffer.H-rGO-Pd NPs-GPC32SO4 solution (0.5 M) and activated by an electrochemical cyclic scanning method with a scanning speed of 0.5 V/s and a scanning voltage between 0.4 and 1.2 V for 20 cycles. Secondly, the activated SPE was placed in a 5 mL mixed aqueous solution of HAuCl4  solution and GO solution , and electrodeposited under cyclic voltammetry (CV) strategy for 120 s under magnetic stirring in the voltage range of −0.5–1.0 V. The scanning rate was 0.4 V/s and the scanning period was 10 cycles. After electrodeposition, the SPE was rinsed with water several times and dried to get Au NPs@rGO/SPE [Ab was dropped on the surface of Au NPs@rGO/SPE electrode and incubated for 30 min at 25 °C. Lastly, 6.0 μL of 1% BSA solution was added dropwise to GPC3Ab/AuNPs@rGO/SPE and incubated for 30 min at 25 °C to block non-specific active sites [Firstly, the SPE was immersed in 5 mL of H@rGO/SPE ,39,40,41ve sites , After eAb/AuNPs@rGO/SPE surface and incubated at 25 °C for 30 min. Secondly, 4.0 μL of H-rGO-Pd NPs-GPC3Apt (1.0 mg/mL) solution was added dropwise onto the surface of GPC3/GPC3Ab/AuNPs@rGO/SPE and incubated at 25 °C for 60 min. Thirdly, 6.0 μL of H2O2 (100 mmol/L) and 3.0 μL of AgNO3 (6.0 mmol/L) solution were added dropwise onto the surface of H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab/Au NPs@rGO/SPE and kept in the dark at 25 °C for 30 min. The electrode was rinsed three times with water. Lastly, the electrode was inserted into a 4.0 mL glycine-NaOH buffer solution  containing 0.1 M HNO3 and 0.6 M KNO3 solution and recorded the electrochemical responses with differential pulse voltammetry (DPV) method with scanning range from −0.4 to 1.0 V with a 0.1 V/s scanning rate. Each sample was detected three times, and the results were calculated as mean ± RSD.Firstly, 1.0 μL GPC3 standard solution (different concentration) was added dropwise onto the GPC3To verify that the developed electrochemical nanobiosensor would be applied in serum detection, GPC3 in human serum samples was detected by standard addition methods under optimal conditions. Firstly, the human serum samples were obtained after approval from the Ethics Committee of Guangxi Key Laboratory of Metabolic Disease Research, 924th Hospital of the People’s Liberation Army Joint Logistics Support Force . Three kinds of serum samples were prepared for determination by mixing 1.5 μL of normal serum with 1.5 μL of GPC3 solution . The serum samples were detected as the above process instead of the GPC3 standard solution. The DPV of the electrochemical workstation was used for the determination. The measured concentration of GPC3 in human serum samples was calculated by the calibration line. Each sample was detected three times, and the results were calculated as mean ± RSD. Apt and GPC3Ab as recognition elements. In the presence of GPC3, both GPC3Ab and H-rGO-Pd NPs-GPC3Apt specifically bonded with GPC3 to form the H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab sandwich-structure complex with a stable spatial structure as well as catalytic performance, which could enhance H2O2 to reduce the Ag ions in solution to metallic Ag, resulting in the deposition of Ag NPs on the surface of the biosensor. The amount of deposited Ag, which was derived from the amount of GPC3, was quantified by the DPV method. The developed nanobiosensor was able to determine GPC3 with the LOD of 3.30 ng/mL and showed good specificity, short-term stability, and recovery rates. Although the LOD value of the designed sensor was slightly higher, the GPC3 nanobiosensor can be an ideal solution for designing high-sensitivity clinical tests. We believe that this method may be an effective strategy for the determination of GPC3 with potential clinical applications and can be used to build accurate and simple sensors for other biomarkers. In this study, one novel electrochemical nanobiosensor was constructed for the quantitative analysis of GPC3 based on H-rGO-Pd NPs nanozyme for signal amplification, combining GPC3


Reliable tools for prognosis prediction are crucially needed by oncologists so they can tailor individual treatments. However, the wide spectrum of histologies and prognostic behaviors of sarcomas challenges their development. In this field, nomograms could definitely better account for their granularity compared to the more widely used AJCC/UICC TNM staging system. Nomograms are predictive tools that incorporate multiple risk factors and return a numerical probability of a clinical event. Since the development of the first nomogram in 2002, several other nomograms have been built, either general, site-specific, histology-specific, or both. Recently, some new “dynamic” nomograms and prognostic tools have been developed, allowing doctors to “recalculate” a patient’s prognosis by taking into account the time since primary surgery, the event history, and the potential time-dependent effect of covariates. Due to these new tools, prognosis prediction is no longer limited to the time of the first computation but can be adapted and recalculated based on the occurrence (or not) of any event as time passes from the first computation. In this review, we aimed to give an overview of the available nomograms for STS and to help clinicians in the process of selecting the best tool for each patient. Reliable tools for prognosis prediction in cancer patients are used by clinicians to set up adequate management of the disease. The more accurate the prediction, the more specific and tailored the treatment we might propose. Furthermore, these tools might help healthcare professionals address the need for awareness that cancer patients might express, possibly reducing the stress related to the unpredictability of their condition.Soft tissue sarcomas constitute a heterogeneous family of tumors comprised of >70 histological types arising in nearly any site of the body and with a wide spectrum of prognostic behaviors that goes from indolent entities, such as dermatofibrosarcoma protuberans, to extremely aggressive tumors with a high risk of relapse and death, such as leiomyosarcoma (LMS) or pleomorphic sarcomas.The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system, based on tumor size, nodal involvement, and presence of metastases, represents the most widely used tool for prognosis prediction in several cancers. However, as will be later discussed, even the recently updated version  carries important limitations in the field of sarcomas. To overcome the limitations of the AJCC/UICC TNM staging system, newer tools for individualized prognosis prediction were developed, i.e., nomograms. The 8th edition of the AJCC manual system endorsed a validated nomogram for retroperitoneal sarcoma that met all 16 AJCC inclusion/exclusion criteria listed by the AJCC Precision Medicine Core to identify reliable and valid prognostic tools . NomograWith this review, we aim to review the recent 8th edition of the AJCC/UICC staging system and give an overview of the available nomograms for STS, helping clinicians in the process of selecting the best tool for each patient.The 7th edition of the AJCC/UICC TNM staging system (2010) classified STS patients into four stages of disease according to malignancy grade, tumor dimension, tumor depth, lymph node involvement, and distant metastasis . AlthougFor these reasons, a new version of the AJCC/UICC TNM staging system was released in 2017 (8th edition) and includes four different site-specific staging systems for STS: trunk and extremities, retroperitoneum, head and neck, and abdomen and thoracic visceral organs. Other changes were also introduced: 1. in light of the correlation between size and the risk of distant relapse observed by some authors, tumor dimension (T) is considered a 4-tier categorical variable (compared to > vs. ≤5 cmused in the previous edition), ; 2. giveDespite these changes, several studies demonstrated the suboptimal performance of the 8th edition of the AJCC/UICC TNM staging system both for sarcomas of the retroperitoneum and the extremities. The prognostic performance of the 8th edition of the AJCC/UICC TNM staging system in RPS and ESTS was evaluated by Cates using data extracted from the Surveillance, Epidemiology, and End Results (SEER) database and by Fisher et al. using the National Cancer Database (NCDB) ,8,9.For RPS, both authors found that size was a weaker prognostic factor compared with grade, histology, and incomplete resection ,8. IndeeIn light of these observations, Cates proposed two new staging systems (Vanderbilt staging systems), one for RPS using size , histologic grade, histologic type, and presence of distant non-nodal metastasis, and one for ESTS based on histologic grade, tumor size, and depth. The Vanderbilt staging systems were compared to the 8th and 7th editions of the AJCC Cancer Staging Manual. At the internal validation, Vanderbilt staging systems performed better than both editions of the AJCC Cancer Staging Manual, and the 8th edition showed a worse discriminative ability compared to the 7th in RPS, while it was not better than the 7th in ESTS.The prognostication ability of the TNM staging system remains limited by the disproportioned importance attributed to anatomic variables and the penalization of pathological or patient-related variables. Furthermore, in the AJCC/UICC TNM staging system, patients are forced into a limited number of stages that are supposed to reflect their risk of recurrence or relapse, even though this risk would be better expressed as a continuous one.Nomograms are predictive tools that incorporate multiple risk factors and return a numerical probability of a clinical event. The computation might be performed through a simple graphical representation or, when available, through web-based calculators. Of note, risk calculation through nomograms accounts for the mutual influence of each prognostic variable on the others. In this way, the relative weight of every variable is not static, as in TNM, but changes according to the case, with the resulting computation giving a more accurate estimation of the real risk.In addition, nomograms find an application in the field of clinical research and were used to perform risk stratification of patients ,11.Still, some limitations do exist and are mainly related to the fact that the prognosis can change over time, thus making the prediction less reliable as one moves away from the time it was computed, usually after surgery. In fact, the risk of recurrence or of tumor-related death can change over time, generally being higher in the first years of follow-up and decreasing as time goes by after surgery. Furthermore, the occurrence of an event or the lack of events does affect prognosis, e.g., DM affects prognosis unfavorably, and vice versa, the lack of events affects prognosis favorably. Moreover, some prognostic factors might have a time-dependent effect . For these reasons, some new “dynamic” nomograms and prognostic tools were developed ,13,14, aNomograms can be site-specific, histology-specific, or both. According to this classification, we aimed to give an overview of the available nomograms for STS.https://www.mskcc.org/nomograms/sarcoma) (accessed on 9 March 2023), sarcoma-specific death predictions are also computed at 4 and 8 years. Nomogram predictor variables include age at diagnosis, tumor size , histologic grade (high or low), histologic type (seven categories), depth , and site . Among the strengths of the model are the large development cohort (2163 patients) and the extensive external validation that always showed good calibration and discrimination . Si. Si34]. In addition to prognostication, the Sarculator was shown to be a very important predictor of anthracycline plus ifosfamide (AI) chemotherapy efficacy in high-risk STS of the extremities and trunk wall. Indeed, a study analyzing data from ISG-STS 1001—a randomized study that tested AI chemotherapy versus histology-tailored chemotherapy in STS—showed that neoadjuvant AI benefits patients with a Sarculator 10-yr predicted OS < 60%, while this was not true for patients with a lesser risk . The useIn 2017, van Praag et al. used an international multicentric cohort to develop a model (not a nomogram) that predicts the cumulative incidence of LR and OS for patients with high-grade eSTS . In contIn 2018, Rueten-Budde et al., expanding the cohort of PERSARC, developed the first dynamic model to predict 5-year OS during the first 5 years of FU in patients operated on for primary high-grade eSTS . VariablMore recently, INT guided an international multicentric collaboration to develop and externally validate a dynamic nomogram (available on the Sarculator app) that predicts 5-year OS during the first 3 years of follow-up in pts operated on for primary eSTS . It is wSarcomas arising in the retroperitoneum represent approximately one fifth of all STS. Although virtually any STS may arise at this site, four main histological types account for nearly 90% of tumors in the retroperitoneum, each showing a peculiar pattern of recurrence . Well-diTogether with histology, tumor size, grade, and multifocality are the tumor related factors significantly affecting the risk of recurrence ,43,46,47Nomograms for RPS are shown in The first two nomograms for RPS were developed in 2010 by Anaya et al.  and ArdoIn 2013, Gronchi et al. used the merged data of three referral centers  to develop a nomogram to predict OS after curative intent surgery for RPS and DFS after macroscopically complete surgical resection .In 2016, Tan et al. used the MSKCC cohort of patients surgically treated for RPS to develop 3 separate nomograms to predict disease-specific death, LR, and DM incidence at 10 years.While age was included only in the nomogram by Gronchi et al. (as a continuous variable), size was included in both models, as a categorical  in the model by Tan et al., and as a continuous variable in the model by Gronchi et al. As previously in the nomogram by Ardoino et al. . Of. Of49]. Of note, this nomogram is not applicable to unresectable cases, which account for almost half of the patients with recurrent RPS. The decision to offer surgery to patients with LR should always be validated by a multidisciplinary tumor board, aiming at balancing the risks related to the planned surgical procedure with the expected oncologic outcomes . In thisIn 2021, Callegaro et al. collaborated to develop and externally validate the first dynamic nomogram for RPS . The nomThese instruments might help healthcare professionals tailor the follow-up schedule to the actual, updated, and individualized risk, decreasing the intensity of FU in patients at low risk of disease recurrence/death. Of note, the OS dynamic nomogram also accounts for non-tumor-related causes of death, giving a more comprehensive and realistic picture of patients’ prognosis.Of note, dynamic nomograms find a different application compared to static postoperative nomograms and should be used by experts as complementary tools. In fact, dynamic nomograms can be used anytime during follow-up, either in the absence of events (OS and DFS nomograms) or at the occurrence of an event but before the delivery of any treatment (OS nomogram). Since prognosis computation is performed regardless if the tumor is resectable or not and regardless of the nature of the surgery eventually performed, in the event of a recurrence, the OS dynamic nomogram can guide the decision-making process to select the best treatment. In contrast, the static nomograms for recurrent patients can only be applied after the occurrence of the local relapse and after its surgical treatment, since the completeness of the resection at the time of recurrence is one of the prognostic variables. Of note, once a LR has occurred, DFS can only be estimated by a static nomogram because the dynamic DFS nomogram can only be used in patients with uneventful follow-up. In addition, only static nomograms are able to factor in some important prognostic variables, such as tumor multifocality and the number of organs resected at primary surgery.Nonetheless, all the available nomograms for RPS still share some important limitations. First, none of them can be used in the preoperative setting because some of the variables included are not available before surgery. Second, none of them is designed or applicable to patients with metastatic or unresectable disease at diagnosis. Only the dynamic nomogram developed by Callegaro et al. can be applied to patients who develop metastases after surgery for a resectable localized RPS . Third, With the hypothesis that neoadjuvant RT might interfere with the applicability of existing RPS-specific nomograms ,10,24,48Liposarcoma (LS) is the most common soft tissue sarcoma (STS), accounting for 20% of all sarcomas in adults. There are four main histological subtypes of liposarcoma, with dedifferentiated liposarcoma and well-differentiated liposarcoma arising mainly in the retroperitoneum and myxoid liposarcoma and round cell liposarcoma arising mainly in the extremities. Histology, site, and differentiation grade are the most important determinants of prognosis.In 2016, Dalal et al. from the MSKCC developed a nomogram to predict 5- and 12-year disease-specific survival in patients surgically treated for liposarcoma, assuming that the patient does not die of another cause first  Table 3Table 3. Accounting for approximately 8–10% of all soft tissue sarcomas, synovial sarcoma typically occurs in adolescents and young adults (mean age of 39 at diagnosis) and shows aggressive behavior with a strong tendency to metastatic spread. The translocation between chromosomes X and 18  is present in more than 95% of patients and is therefore considered pathognomonic. Three main histologic variants do exist: monophasic SS, biphasic, and poorly differentiated. Validated negative prognostic factors are older patient age at diagnosis, male sex, larger tumor size, positive surgical margins, advanced stage, and site (with a worse outcome for tumors arising from anatomic sites other than the extremities). Conversely, the prognostic role of histological subtype and fusion protein status is less clear .In 2008, Canter et al. from the MSKCC group developed a nomogram based on preoperative variables to calculate 3- and 5-year disease-specific survival (DSS) in surgical patients with synovial sarcoma who did not receive preoperative ChT. When applied to a group of patients who pretreated with anthracycline-ifosfamide, the observed DSS for the first 3 years of follow-up was better than expected, supporting a possible role of chemotherapy in survival in these patients . Only tuRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, represents approximately 5% of all childhood cancers, and can arise in nearly any site. According to the WHO classification, there are four main histologic subtypes with different biological behavior and prognosis: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. In addition, RMS can be classified according to the presence or absence of the PAX-FOXO1 fusion protein in fusion positive or fusion negative RMS. Fusion-negative tumors, embryonal subtype, age 3–10, and head and/or neck and genitourinary sites are all favorable prognostic factors, while age > 10 years, tumors arising in the trunk or limbs, alveolar subtype, and the presence of PAX-FOXO1 carry a worse prognosis. Other prognostic factors include TNM stage, local invasion, parameningeal site, and lack of response to induction therapies ,59,60.The first histology-specific nomogram for RMS was developed in 2011 by Chisholm et al. It estimates the probability of curing patients with nonmetastatic RMS who relapsed after achieving complete local control with initial therapy . This tyIn 2014, Yang et al. developed and internally validated a nomogram to predict 5- and 10-year overall survival and median survival time in children and adolescents with RMS using population-based data collected by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The nomogram relies on easily available tumor and patient-related variables as well as treatment variables, i.e., surgical treatment and RT delivery, and was built on a large series of 1679 patients. Nevertheless, it has some important limitations related to the SEER database. In fact, this public dataset does not include information on ChT delivery, surgical margins, or patients’ comorbidities, all of which are regarded as important prognostic factors in this disease. Furthermore, the SEER program does not provide a central pathology review. In addition, the cohort covers a wide time span (1990–2010) during which improvements in the management of these tumors possibly improved the prognosis of these patients .Two further nomograms were built using the SEER database —and are Desmoid-type fibromatosis is a rare mesenchymal neoplasm with no metastatic potential but unpredictable local behavior, potentially occurring at any site. Typically, patients with desmoid-type fibromatosis present with a mass that has become symptomatic due to local compression symptoms that vary depending on the site of occurrence: pain due to nerve compression or invasion, digestive symptoms in abdominal desmoid-type fibromatosis, functional morbidity in desmoid-type fibromatosis of the extremity. In 5–15% of cases, desmoid-type fibromatosis arises in patients with familiar adenomatous polyposis (APC gene mutation), while the rest of cases are sporadic and characterized by a mutation in the CTNNB1 gene. Both mutations result in abnormal β-catenin accumulation within the cell.Surgery was long considered the standard of care for the initial treatment of resectable disease. However, the unpredictable biological behavior of desmoid tumors, with relatively high rates of spontaneous regression or stabilization, the very high rates of recurrence post-resection, and the significant morbidity of surgery, prompted the international community to re-evaluate non-surgical strategies for their management. In fact, in light of the recent evidence, the ESMO and Desmoid Tumor Working Group (DTWG) guidelines support a wait-and-see frontline approach to observe tumor behavior over time ,63. MediIn 2013, Crago et al. from the MSKCC developed and externally validated a nomogram to predict postoperative 3-year, 5-year, and 7-year LR-free survival . InteresWith this nomogram, patients with a high risk of local recurrence might be easily selected to receive other therapeutic options in the case of disease progression or symptomatic disease. However, the shift towards a non-surgical and wait-and-see approach calls for the development of a nomogram able to predict the chance of disease progression in non-operated patients.Uterine leiomyosarcoma (ULMS) is the most frequent type of uterine sarcoma and accounts for about 5% of all uterine cancers. Though rare, the disease carries a poor prognosis with high rates of local and distant recurrence. Surgical resection  is the mainstay of treatment in all resectable cases. Radiotherapy and/or chemotherapy can be considered according to the stage at time of diagnosis. However, no adjuvant treatment strategy has demonstrated a survival benefit, and high rates of recurrence and progression are registered despite standard therapies.Traditionally, ULMS are classified using the Federation Internationale de Gynecologie et d’Obstetrique (FIGO) staging system developed in 2009 or the AJCC/UICC staging system for STS. The FIGO staging system identifies four stages according to tumor size, extension with respect to the uterus and pelvic organs, and the presence/absence of DM, while the AJCC staging system is based on tumor dimension, regional lymph node involvement, and the presence of DM.In 2012, Zivanovic et al.  from theOf note, it cannot be applied to patients not eligible for surgery  because the development cohort included only surgically treated patients. The nomogram underwent external validation on a series from the Brigham and Women’s Hospital/Dana-Farber Cancer Institute and the European Institute of Oncology, demonstrating good discrimination  and calibration .Breast phyllodes tumors (BFT) are a rare group of mammary fibroepithelial tumors with recurrent and metastatic potential and a wide spectrum of morphologies. The WHO classification stratifies BFT into three categories  on the basis of several histologic features  . Of noteIn 2012, a nomogram based on degree of stromal atypia, stromal mitoses per 10 high-power fields, stromal overgrowth, and surgical resection margins (AMOS criteria) was developed by Tan et al.  from SinWith the aim of improving the accuracy and discriminative ability of available tools for prognosis prediction, recent research focused on the identification of new prognostic markers of outcome, and particular attention was recently put on genomic, radiomic, or immunologic markers.Although FNCLCC grading is one of the best available predictors of oncological outcomes and, as such, is included in several nomograms, it is still limited by its reproducibility from one pathologist to another and by the fact that it forces each tumor into one of three categories.In contrast, the identification of genomic markers of outcome  might potentially give a more granular and accurate picture of the different behaviors of sarcomas, and their integration into outcome prediction tools might improve their prognostic power.In 2010, Chibon et al. identified a gene expression signature composed of 67 genes associated with mitosis and chromosome management—named Complexity Index in SARComas (CINSARC)—able to predict metastatic outcome in non-translocation-related sarcomas . CINSARCOf note, the French Sarcoma Group is running a prospective, randomized, phase 3 trial to explore the potential benefit of chemotherapy in high-risk CINSARC patients and to prospectively validate the prognostic role of CINSARC in FNCLCC grade 1 and 2 STS . HoweverIn the last decade, growing attention has been put on the potential role of radiomic analysis. Radiomics consists in the extraction of a large number of quantitative data from radiologic imaging by the application of sophisticated software with artificial intelligence. These data are intended to reveal tumoral patterns and characteristics that are not visible to the naked eye and may significantly contribute to the diagnosis, management, and prognosis of tumors. The identification of radiomic signatures able to predict prognosis is in its early phases, and while the first studies have been recently reported, none of them has been validated and incorporated into clinical practice. Of note, one of the most important limitations of radiomics is its reproducibility when it comes to the way the exam was performed, the IV contrast medium delivered, etc.Similar to radiology, a shift from traditional pathology toward the use of artificial intelligence-based systems for the analysis of tissue samples is becoming an increasingly likely prospect. With the application of machine learning techniques, digital pathology with whole-slide imaging enables the capture of information far beyond that obtained with traditional pathology. However, although it represents a promising tool for the diagnosis and clinical management of sarcoma patients, its application is just at the very beginning and needs to be further explored in the future ,75.Immunologic markers are also being studied as prognosticators in sarcoma, but we are far from having developed a similar tool, such as the inflammosome in colonic cancer , for sarFinally, the impact of multimodal therapy on outcome is not incorporated in any of the available nomograms, as it has been performed, for example, in breast cancer.This requires data from larger patient data sets than the ones used so far to build the available tools. A large series of patients with sarcoma requires large collaborations. Large collaborations, networks, working groups, and registries have all been critical for advancing knowledge in recent years and will continue to be so, even as access to real-world data makes it easier to collect information and run prognosis and outcome studies.The authors should discuss the results and how they can be interpreted from the perspective of previous studies and the working hypotheses. The findings and their implications should be discussed in the broadest possible context. Future research directions may also be highlighted.


Gopi  RSC Advances article due to concerns with the reliability of the data in the published article.The Royal Society of Chemistry, with the agreement of the named authors, hereby wholly retracts this The optical images presented in Fig. 6a and c are identical. Furthermore, the images in Fig. 6a, c and e have been duplicated in other publications. The panels in Fig. 6a and c have been duplicated as Fig. 9a in Part of the image in Fig. 10c has been duplicated in Fig. 10e.The authors informed the Editor that the characterization of the original samples was outsourced, and they do not have the original raw data for the published results.Given the significance of the concerns about the validity of the data, and the lack of raw data, the findings presented in this paper are not reliable.N. Murugan was contacted but did not respond.Signed: D. Gopi, S. Ramya, E. Shinyjoy and L. KavithaDate: 16th March 2023RSC AdvancesRetraction endorsed by Laura Fisher, Executive Editor, Retractions


Thyroid cancer is the most common endocrine cancer and is becoming increasingly prevalent. Although its prognosis is generally favorable, bone metastasis is a notable complication that significantly decreases survival rates. Currently, there is no definitive cure as most treatments are palliative to relieve patients of any pain or other symptoms. We assessed the incidence and influence of bone metastasis on thyroid cancer patients to understand the risk factors and outcomes which can improve clinical decision making and research endeavors.Bone is the second most common site of metastasis in patients with thyroid cancer (TC) and dramatically impacts overall survival and quality of life with no definitive cure, yet there is no extensive study of the demographic and clinical risk factors in the recent literature. Data regarding 120,754 TC patients with bone metastasis were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses were used to identify the risk factors of bone metastasis occurring in various histologies of TC. Cox regression was performed to analyze the influence of bone metastasis on overall survival. Hazard ratios were computed to analyze the association between bone metastasis and the primary outcomes. Of the 120,754 records collected from the SEER database from 2000 to 2019, 976 (0.8%) presented with bone metastasis, with occurrence being the greatest in patients of age ≥ 55 years , males , Blacks  and Asian or Pacific Islanders , and single marital status. TC patients presenting with bone metastasis  or concurrent bone and brain metastases  had a higher mortality risk. Older age, gender, race, and single marital status were associated with bone metastasis and poorer prognosis in TC patients at initial diagnosis. Understanding such risk factors can potentially assist clinicians in making early diagnoses and personalized treatment plans, as well as researchers in developing more therapeutic protocols. Thyroid cancer (TC) is a neoplasm that originates from the follicular cells of the thyroid gland, representing the most prevalent endocrine malignancy. In recent decades, there has been a significant global increase in the incidence of TC, making it the fastest-growing cancer type in both men and women . Despite131I therapy [Bone metastases can develop in various TC histologies. According to the literature, such metastases occur in roughly 7–28% of follicular (FTC), 1.4–7% of papillary (PTC), and 16–19% of medullary (MTC) TC patients during follow-up . The decThis prompts the need to identify risk factors predicting bone metastases in TC patients, as early detection and treatment entail prolonged survival and better patient outcomes . RecentlOur study aims to conduct a comprehensive, population-based analysis of bone metastases in TC, intending to decipher the multifaceted layers of its epidemiological characteristics, risk factors, disease outcomes, and the consequential impact of diverse treatment modalities. Such an analysis will manifest into actionable insights, shedding light on the prevalence, geospatial distribution, and characteristic patterns of bone involvement in TC, which will subsequently direct us toward more strategic prevention and management strategies. Understanding and identifying risk factors will provide a robust platform for risk stratification, aiding in the implementation of personalized treatment plans designed to meet the unique needs and characteristics of individual patients. Furthermore, by meticulously assessing disease outcomes, we seek to offer invaluable prognostic information that will be instrumental in refining treatment decision-making processes. Moreover, evaluating the effects of different treatment modalities is expected to significantly influence clinical practices, elevating the standards of patient care by integrating the most efficient and effective treatment methods. Ultimately, our study enhances the current understanding of the burden of bone metastases in TC. By offering precise and data-driven treatment strategies, we aim to usher in a new era of improved patient outcomes, mitigating the debilitating impact of this disease.We analyzed a retrospective cohort study using “The Surveillance, Epidemiology, and End Results (SEER)” database (2000–2019), with data combined from registries 17 and 22. SEER is a comprehensive source of population-based cancer data in the United States. SEER collects and publishes cancer incidence, prevalence, survival, and mortality data from population-based cancer registries that cover approximately 34.6% of the US population. The database is maintained by the National Cancer Institute (NCI) and is widely used by researchers, clinicians, and policymakers to study cancer trends, outcomes, and disparities over time. This approach offers the advantage of capturing a diverse range of patient demographics and clinical characteristics, which can provide valuable insights into the real-world implications of osseous metastases in TC.Participants were eligible for the study if they were individuals of any age, sex, and race; diagnosed with TC as their first primary tumor; and had bone metastases at the time of diagnosis. Patients were excluded from the study if they had metastasis exclusively in other sites rather than bone or had a history of prior primary cancer before the diagnosis of TC.The study variables for our retrospective cohort analysis include a range of demographic, clinical, and treatment-related factors. Demographic variables include age, gender, race, ethnicity, marital status, metropolitan residence status, and annual household income. Clinical factors encompass histological type, T staging (primary tumor size and extent), N staging (lymph node involvement), extension to nearby structures, and management strategies such as cancer-directed surgery, radiotherapy, radioactive iodine, and systemic therapy. The primary outcomes assessed in this study are overall survival (OS), TC-specific survival (TCSS), recurrence, and subsequent second primary cancer in patients with osseous metastases at diagnosis. These outcomes help to determine the prognostic factors and real-world implications of bone metastases in TC, which can inform clinical decision making and treatment strategies. p-value of less than 0.05 was considered statistically significant for all tests.Descriptive statistics were used to summarize the demographic and clinical characteristics of the study population, including frequencies and percentages for categorical variables and means, medians, and standard deviations for continuous variables. The R packages were used for analysis. Univariate and multivariate analyses were performed to identify potential risk factors associated with osseous metastases. For categorical variables, chi-square or Fisher’s exact tests were used, whereas continuous variables were assessed using the independent t-test or Mann–Whitney U test, depending on the normality of the data distribution. Cox proportional hazards regression models were utilized to assess the impact of osseous metastases on survival outcomes, adjusting for potentially confounding variables such as age, sex, tumor size, histologic subtype, and other relevant factors. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to quantify the association between osseous metastases and the primary outcomes. Kaplan–Meier survival curves were generated, and the log-rank test was used to compare group differences. A The study analyzed 120,754 records with TC, according to the eligibility criteria. These included 119,778 patients in the M0 stage and 976 (0.8%) patients presenting with bone metastases. Across the studied years, there was generally a higher rate of patients with bone metastases detected at TC presentation .The geographical distribution of TC cases across the US states was predominantly in California (41.2%), followed by New Jersey (14.3%), Georgia (9.9%), and Seattle (58%). However, the highest proportion of bone metastases detected at diagnosis was found in Hawaii (1.2% out of 1999 patients) and Louisiana (1% of 6574 patients) . p < 0.001), males , Black , and widowed .A comparison between TC patients with and without bone metastases is presented in p < 0.001) and lymph node metastasis  (Papillary TC (PTC) was the most common  histology, accounting for 88.8% of the study population, whereas follicular (FTC), anaplastic (ATC), and medullary (MTC) TC represented 4.7% (N = 5718), 0.5% (N = 649), and 1.7% (N = 1993), respectively. The bone metastases group was more likely to have advanced T stage  .Of the 976 (0.8%) who presented with bone metastases, 489 (51.3%) had concomitant metastases in other organs. These included 63 cases with brain metastases, 123 with liver metastases, and 437 with lung metastases .p < 0.001), older than 55 years , Black  or Asian or Pacific Islander , and less likely to be married   .p = 0.89). However, 22,073 patients (18.3%) developed second primary malignancies, and those with bone metastases had a significantly higher incidence of developing these secondary cancers   .p < 0.001; bone metastases: OR = 3.64, p = 0.001). Male patients without bone metastases had a higher risk , while there was no significant association for male patients with bone metastases . Regarding race, Asian or Pacific Islander (API) patients with bone metastases had a lower risk than White patients . Patients who underwent surgery for their TC without bone metastases were less likely to develop second primary cancers , while the opposite was true for those with bone metastases .p < 0.001) (p < 0.001) . Patients with bone metastases had a significantly lower survival rate of 41.7%, compared to 94.3% in the non-metastatic group (< 0.001) . The hig< 0.001) .p < 0.001) or concomitant bone and brain metastases  had a higher risk of mortality. Advanced tumor size and nodal metastasis were also associated with an increased risk of mortality (p < 0.001), while an annual household income of ≥USD 75K  and residing in an urban area  were linked to a lower risk of mortality. p < 0.001). Those who received radiation therapy had a 34% decreased risk , while patients who received systematic therapy had a 9% decreased risk , as demonstrated in Furthermore, the study found that different treatment modalities were associated with varying degrees of survival benefit. Patients who underwent surgical resection of primary tumors had an 80% decreased mortality risk  such as pathologic fractures and spinal cord compression, dramatically impacting quality of life and morbidity. Farooki et al. found that in a study of 245 DTC patients with bone metastasis, 78% developed a first SRE after a median of 5 months, and 65% of them developed a subsequent SRE after a median of 10.7 months following the first event, with 39% of all TC patients with bone metastasis developing three or more SREs . Matta-CIn this study, a sizable cohort of 120,754 TC patients was examined, and it was discovered that 0.8% of cases presented with bone metastasis at the time of diagnosis, comparable to 0.36% as recently reported by Qi et al. , 0.5% asPatients who had bone metastasis were more likely to be over the age of 55, male, Black or Asian or Pacific Islander, or single . Recent studies corroborate the association of older age ,11,17,18The present study also found that patients recorded in Hawaii and Louisiana had the most significant proportion of bone metastasis detected at diagnosis. Multiple reasons can account for this, including but not limited to a higher density of endocrinologists and orthopedic physicians, explaining increased detection and diagnosis; lower socioeconomic status, implying delayed diagnosis and treatment of TC allowing for metastasis; or environmental factors contributing to this observation. However, this finding warrants further study.p = 0.47), the composition of patients can likely justify the finding of higher bone metastases in PTC as well as the statistically insignificant finding of ATC patients being more at risk. Patient population and referral were also used to potentially justify discrepancies between Wu et al. and Marcocci et al. regarding varying bone metastases rates in PTC [It is well known that bone metastases are present more commonly in aggressive thyroid cancers, such as ATC. Interestingly, the findings revealed that PTC was the most prevalent of all histologies that involved bone metastases, comprising 37.8% of all cases, in contrast to ATC, which comprised 23.7% of all cases. One straightforward explanation for this includes the much larger PTC patients, composed of 88.8% of the present study’s population. Several studies acknowledge this notion and justify that bone metastasis will indeed be higher in PTC cases compared to other TC histologies since there is a larger population in that cohort ,21. Sincs in PTC ,23. NevePatients with bone metastasis had a markedly lower survival rate of 41.7%, compared to 94.3% in the non-metastatic group. Multivariate analysis revealed that patients with bone metastasis or concomitant bone and brain metastases had a higher risk of mortality, while advanced tumor size and nodal metastasis were also associated with an increased risk of mortality. The study also found that different treatment modalities were associated with varying degrees of survival benefit, with surgical resection of primary tumors associated with an 80% decreased mortality risk.The present study’s findings on risk factors predicting bone metastasis at diagnosis are essential for clinicians in identifying patients at higher risk and tailoring treatment plans accordingly. Such prediction as early as the diagnosis has high clinical value as it can prevent metachronous bone metastasis, as Mazziotti et al.  recentlyAdditionally, positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) can provide valuable insights into the presence and extent of bone metastasis. These imaging modalities offer non-invasive approaches to assess bone involvement in TC patients and play a crucial role in the early detection and monitoring of metastatic lesions. In conjunction with imaging modalities, regular follow-up appointments and thorough clinical evaluations are essential to effective screening for bone metastasis in TC. Healthcare providers should maintain a high level of vigilance and carefully monitor patients for any signs or symptoms that may indicate the presence of bone metastases, such as bone pain, fractures, or elevated levels of serum markers like alkaline phosphatase. Combining clinical evaluation with appropriate imaging techniques enhances the likelihood of early detection and enables prompt intervention. Our study uniquely emphasizes the importance of screening for bone metastases. Additionally, it highlights the high incidence of second primary malignancies in patients with bone metastasis and the significant benefits of various treatment options for these patients.Although this population-based study examined the largest TC patient cohort with bone metastasis to date, certain limitations should be acknowledged. Firstly, it is essential to note that the data utilized in this study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, which primarily represents TC patients in the United States. Therefore, caution must be exercised when generalizing the findings to other populations or regions, as variations in demographics, healthcare systems, and genetic profiles may exist. The applicability of the results to different populations outside the United States should be further investigated in future studies with broader international representation. Moreover, while the SEER database is a comprehensive source of population-based cancer data in the United States, it has inherent limitations. It lacks certain subjective information, such as patient-reported outcomes, including bone pain or fatigue, which are essential factors in evaluating quality-of-life and patient-centered outcomes. The absence of these subjective measures may limit the comprehensive understanding of the impact of bone metastasis on patients’ well-being. Additionally, this study primarily focused on demographic and clinical risk factors associated with bone metastasis in TC patients without explicitly exploring the influence of genetic factors, such as mutations, that may coexist with the examined risk factors. Future research should consider integrating genetic analyses to elucidate the interplay between genetic predispositions and the identified risk factors to better understand the development and progression of bone metastasis in TC patients.Overall, this study provides valuable insights into the characteristics of TC patients with bone metastasis, including their risk factors, the impact of treatment modalities, and disease outcomes. These findings have the potential to enhance patient care and management while identifying avenues for further research and the development of novel treatment options.Understanding the epidemiology and impact of osseous metastases in TC is crucial for informing clinical decision making, prognostication, and the development of targeted therapeutic strategies. By advancing our knowledge of this complication, we aspire to improve the care and outcomes for patients at risk for or already affected by bone metastases in TC.This study significantly contributes to the existing literature on TC by presenting the most extensive population-based analysis of bone metastasis to date, elucidating the associated demographic and clinical risk factors, and examining their impact on patient survival. The findings presented herein will serve as a foundational platform for future research endeavors and have the potential to shape the development of more effective diagnostic and therapeutic strategies for TC patients with bone metastases.


There is an emerging body of knowledge on the lived experiences of parenting a child with autism from a maternal perspective. Mothers’ reactions to their children’s autism diagnoses have been identified as a key factor influencing their children’s long-term outcomes.This qualitative study aimed to explore how South African mothers experience their children’s autism diagnoses.ubuntu, social support, culture, tradition, interpersonal relationships, interconnectedness and continuity and compared to the existing scholarship, employing an Afrocentric theoretical lens.Telephonic interviews were conducted with 12 mothers from KwaZulu-Natal to understand their experiences prior, during and following their children’s autism diagnoses. The data were analysed thematically according to the values of The participants held strong cultural and religious beliefs which influenced the entire diagnosis process. Some, who waited a long time, turned to traditional healers or religious leaders. While some reported feeling relieved after the diagnosis, in the sense of at least having a name for their child’s condition, they also reported feeling overwhelmed by the realisation that there is no cure for autism. Over time, mothers’ feelings of guilt and anxiety declined, and they became increasingly resilient and empowered as their understanding of the meaning of their children’s autism diagnosis deepened, but many continued to pray for a miracle.Future research should focus on how to enhance support for mothers and their children during each of the three phases of autism diagnosis: prior, during and following their children’s autism diagnoses.ubuntu, social support, culture, tradition, interpersonal relationships, interconnectedness and continuity.The study highlighted the crucial role of community-based religious and cultural organisations in providing appropriate support to mothers and their children diagnosed with autism, aligned to the values of  Autism spectrum disorder (ADS), or autism, is a complex, lifelong neurodevelopmental disorder characterised by difficulties related to social understanding and communication, repetitive or restricted behaviours and interests, as well as challenges related to adaptive functioning  there was a shorter time lag between initially seeking help and receiving a diagnosis, (2) diagnosis was received at a young age, (3) quality information on autism accompanied the diagnosis, (4) the professional who communicated the diagnosis framed autism in a positive manner and (5) they perceived intervention and support as accessible  entrenched in culture Baloyi . In addiIn this era of decolonial and post-colonial discourse, how can we Africans allow the American Psychiatric Association to be the final arbiter of our (dis)ability? Is it not time for us to delve into the question of what it means to have a disability in African society? (p. 249)iSangoma  or iNyanga  to understand autism  pandemic, this allowed the authors to adhere to the social distancing regulations in force at the time. The first author called the participants at arranged times, without requiring them to incur any costs.The population of the study was mothers of children diagnosed with autism who were enrolled at a special school near Durban, KwaZulu-Natal. Purposive sampling was employed to obtain rich data related to mothers’ experiences of their children’s autism diagnoses in greater depth (ed. Given With a single exception (Mother 5), all the participants were raising their children without the daily presence or involvement of their fathers. Seven mothers were identified as single, two as divorced, one as married and two as separated. The divorced and separated mothers noted that their marital relationships had ‘drifted apart’ following their children’s autism diagnoses. All the children spent an extended period on the special school’s waiting list before they were admitted.During data collection, which was conducted in 2021, the authors complied with strict COVID-19 restrictions and protocols. Individual semistructured, in-depth interviews were conducted with the participants in their preferred language, either English or isiZulu, through telephone interviews that were audio-recorded and later transcribed verbatim and translated into English where necessary. The semistructured interviews allowed for an open, in-depth discussion on the 12 mothers’ experiences of the three phases of diagnosis. The first author put the mothers at ease and obtained their consent and trust before proceeding with the interviews, as recommended by Cohen et al. . To ensuThe authors relied on thematic analysis to analyse the data, focusing on recognising, evaluating and identifying patterns within the data according to the six steps proposed by Braun and Clarke . To famiThe study was conducted at a special school for learners with a range of barriers to learning. At the time of data collection, there were 23 learners diagnosed with autism at the school. The mothers of 12 of the learners with autism participated in the study. It is worth noting that all 12 mothers were dependent on the public health system.Ethics clearance was sought and obtained from the College of Education’s Ethics Review Committee at the University of South Africa (ref. no. 2020/11/11/43638430/33/AM). The authors undertook to protect the participants from harm and ensure their privacy and confidentiality. The authors obtained permission from all 12 mothers to access documents such as their children’s learner profiles and medical records. These documents provided confirmation and detailed information on their diagnoses of autism as well as recommendations for school placement.When inviting the 12 mothers to participate in the study, M.N.M. explained that there was a possibility that their participation in the study could cause distress related to sharing their past experiences of the process of their children’s diagnosis of autism  restrictions in place at the time.Three research themes were generated from the data analysis performed by the authors: (1) mothers’ experiences prior to diagnosis, (2) mothers’ experiences during the diagnosis process and (3) mothers’ experiences following their children’s diagnoses. In the sections below, each theme and related subthemes will be discussed.Analysis revealed that all mothers had experiences prior to the diagnosis that influenced them to be intrinsically and/or extrinsically motivated to seek a diagnosis. At this stage (i.e. prior to the diagnosis), they were uncertain what the diagnosis would be. The following subthemes related to mothers’ experiences prior to their children’s autism diagnoses were: (1) intrinsic factors and (2) extrinsic factors. The intrinsic factors included psychological and emotional factors. The extrinsic factors included the mothers’ experiences of family and community members’ reactions to their children’s behaviour prior to diagnosis.Many of the mothers described feeling ‘confused’ and ‘frightened’ by their children’s early behavioural difficulties and developmental delays, as they struggled to reconcile it with their children’s typical appearance. For example, one mother described how her child ‘stared at objects endlessly’ and ‘spun around until he was dizzy’. Several mothers said that although they instinctively knew that something was different, their concerns were frequently dismissed by health professionals. Mothers’ instincts were a significant intrinsic factor that motivated them to pursue a diagnosis.Mother 1 described her experiences as ‘completely chaotic and difficult’, as seen below:‘It was completely chaotic because I was still dealing with being a first-time mother to a boy who was not developing at the normal pace. It was difficult, especially when you live far from hospitals and clinics in the location. While we were trying to get a diagnosis, we weren’t doing any therapies.’ Mother 7 described her instinctual awareness of her child’s problems.‘There was just no language, but he cried a lot. He was short-tempered and he didn’t do what other kids do at his age. He was staring abnormally at one thing in the house. It looked like he was going to collapse, or he had lost his mind. I just knew … that something was not right with him.’ The extracts above reveal that the mothers experienced confusion, uncertainty and worry prior to their children’s autism diagnoses. Following the semistructured interview schedule, the mothers were guided to reflect on their emotions prior to their children’s autism diagnoses. They used the words, ‘disturbed’, ‘anxious’, ‘stressed’, ‘numb’, ‘frustrated’ and ‘hopeless’ to describe their emotions. Mother 3 articulated her confusion and uncertainty about her child’s developmental delays:‘On the report was written “global development delay.” I took him to another hospital to attend speech therapy, physiotherapy, and all that. I received an appointment for three months later. I was not sure what was happening, just that he was delayed.’ Mother 10 blamed herself for ‘overlooking the signs’, as revealed below:‘I personally wish I never just sat hoping that he would get better and overlooking the signs before I had him assessed. I thought maybe it was in his father’s family … as his uncle is a stutterer.’ These excerpts provide insight into the mothers’ emotions prior to their children’s diagnoses of autism. Mother 10 admitted that she initially ignored the warning signs and tried to find someone in the family with whom to associate her child’s behaviour. In the next section, mothers’ experiences of family and community members’ understanding of their children prior to diagnosis will be presented.As previously mentioned, all 12 mothers recognised that their children’s development was atypical or ‘delayed’. Mothers’ experiences included the reactions of family and community members to their children’s behaviour, which motivated them to seek a diagnosis. They sought advice from the elders in their families and communities. The feedback they received from the elders constituted a significant extrinsic factor that motivated them to seek a diagnosis. These reactions provide some insight into family and community members’ understanding of disability and difference.Mother 2 shared that she felt ‘disturbed’ by her child’s father’s comments as well as her child’s atypical behaviour:‘I was disturbed in my mind because his father likened him to a puppy because he was jumping on his toes, making funny noises, getting into people’s houses to steal food, and having no speech … He started making this high pitched “iiiiiiiii” sound.’ Mother 7 also described how she was influenced by the father’s remarks to delay seeking a diagnosis:‘His father insisted that he was deaf, but I was not convinced until the audio screening. I took him to the hospital, nine months later. They said that they needed to do further tests because he failed the screening.’ Mothers 1, 3 and 6 discussed the lack of understanding in their respective religious communities:‘We travelled by bus and would go to the hospital three times a week, but we weren’t seeing the correct people. My neighbour would take me to church where they did not understand my son.’ Ingane ayilashwe!” [They demanded that the child must be given proper herbs as he carries luck and truths for the family.] They said that I must have caused him to be so.’ ‘Some family members like his aunt and his uncle never understood what was going on. “fanele kuyohlolwa” [consult a Sangoma] because sometimes he groans like an animal. Maybe, “ubiziwe,” he has a calling to be a Sangoma and that has to be respected.’ ‘My older brother told me that he is noticing something about him and that I should “These excerpts reveal the crucial role of family and community support. Mother 3 noted that when she turned to her family for support, they blamed her for her child’s difficulties since they believed that ‘I must have caused him to be so’, while also recognising that the child ‘carries luck and truths for the family’. Mother 6 was advised by her brother to ‘consult a Sangoma’, noting ‘that has to be respected’.When analysing mothers’ experiences during their children’s diagnoses of autism, two sub-themes emerged, namely: (1) diagnosis is a lengthy, stressful process, (2) relief to receive a diagnosis but worried about the future, because of the lack of guidance on intervention and support.Several mothers indicated that they experienced most of the health care practitioners with whom they interacted during the diagnostic process as ‘unsupportive’ and ‘lacking in compassion’, which exacerbated their feelings of hopelessness and confusion. Some of the participants characterised their emotional distress as ‘extreme anxiety’ and ‘intense worry’, noting that the terminology carelessly used by the professionals intensified their confusion instead of providing clarity about autism and proving support. Some of the health care professionals speculated about the possible causes of the child’s behaviour without providing clear direction. This theme was especially noticeable in the following comments by Mothers 2, 6 and 7:‘I was disturbed in my mind. For the whole first year, I was just numb. I did not even have the energy to go up and down for consultations with him. The word “autism” was all over his reports from the hospital. I would just stare at it and cry.’ attention deficit hyperactivity disorder].’ ‘I waited four months for an appointment. I took him to a so-called therapist, an occupational therapist. She checked him, and said he is fine. She said he can’t sit still and can’t concentrate, which I had also observed. She then said he might have ADHD .’ ‘I had to attend the specialist though she did not tell us what she was doing with the boy, and I had to help her to calm him down so that he could sit on the table. I don’t know English; neither does the child so we were not following ‘The doctor told me that he is hyperactive and so because he cannot concentrate, they will have to put him on medication, which I honestly wonder if it works because boy is the same. They gave me appointment dates far from each other. Even when the pills were messing him up, I could not just walk into the hospital, as I only had to go on my appointment dates.’ Indeed, mothers had to turn to unorthodox practices to get help:sisi.’ ‘You see at the hospital, now you will come with the child, maybe the medication has overturned his stomach, you must wake up at 4 am to be on the queue. Sometimes they tell you that the Risperdal is running out, come back three days later. You just have to know someone that knows someone inside in order to access help at times. You know how public hospitals are, giggles]. One nurse friend of mine organised for me to get his medication straight after bloods. Well, it’s the way it goes.’ ‘There is a big public hospital in our zone behind the complex where we live. Well, I don’t have a problem saying it here, we live in South Africa ruled by the ruling party, so I would not go on the lines because of connections inside , it clarified some of the signs and then I decided to have my son assessed.’ ‘Someone mentioned Autism South Africa. I googled them even though I still didn’t comprehend what it was, so I didn’t worry much about it. Then after a while, as I read up on autism, I realised “For the other participants, the information-seeking phase started after diagnosis:‘Your heart is aching, and you wish to gather as much information as you can … I read all these books on parenting, and I watched a show on TV. The presenter said that when your child is tired, he won’t make eye contact. Besides it is only respectful to teach them to show respect by not making eye contact with the elders.’ ‘I was committed to getting every single piece of information I possibly could on autism. Gosh, I just sat on the internet every moment after my son went to sleep. I was on my phone using the last money from his government grant. Until four or five in the morning, I was doing research on autism. But it was difficult to understand, and the data was expensive.’ ‘My boy freaked me out. He would be like a robot, not talking, not smiling … At the time of the diagnosis, as this was my first child, I was lucky to come across Autism South Africa on the internet. I emailed them and described the challenges I was facing. As a young mother, I took advantage of technology and started reading on the search engines.’ These extracts reveal that following their children’s diagnoses, the mothers searched for the meaning of ‘autism’. Since quality information did not accompany the diagnosis, they had to find information on their own and were intrinsically motivated to do so. However, there were also extrinsic sources of information, remarks and behaviours of community members, which were largely informed by IKS.Yazi [you know what], it was at the crèche where they did not accept my son because he kept messing in his trousers. I felt there was an implication that I didn’t do enough.’ ‘‘In these past weeks my father, a traditional doctor himself, told me that I need to work on my parenting. See, if you ignore a lot of family issues, it manifests through the child. My father said that the elders in the family that have now passed, are living through this child and I should not force the child to speak our language as he is not of this world.’ township] was already helping me to ensure the safety of my son because in a twinkling of an eye he would run into the road or even into another person’s house eating without permission. People accepted him though others took time to understand him.’ ‘I was devastated, but the small section of my location .’ ‘I take him to Miracle Sundays. They told us to bring him consistently in the afternoons to claim his miracle. During Sunday School, he gains a lot because he socialises with other kids on the jungle gym. That is the only outing he ever takes with me [at church] he gets prayed for and I receive a lot of counselling for the entire week. It strengthens me.’ ‘Church is the one place, I tell you, where we are greatly accepted. Social events like weddings, nah forget it. There [kuzohlatshwa” [goat slaughtering] and the older men would speak and report that he is here and alive, that they should let go of him to be a normal child. We still do this to help him from time to time. He does say syllables now. Could I be winning?’ ‘I decided yes, “ukumhlabela” [meaning animal slaughter] and put the wristband around his hand because you know four years ago, he did not say a sound but four years later as I try to sacrifice every year, he is starting to speak a language that nobody understands. He can point at water and say “yuomeme.” I think it’s the language known to the elders as they watch us.’ ‘I won’t stop “combined the medical process with IKS and religion by seeking counsel from iSangoma or iNyanga , applies to the crucial role of health care professionals. While this is aligned to Afrocentrism, it is also firmly recommended in the international scholarship , abakhuzis (commanders), izinyangas and ababonayos (seers), since very few sangomas are women and mothers. It would therefore be crucial for these traditional leaders to understand mothers’ support needs, as this understanding would unlock (facilitate) ubuntu. Clearly, patriarchal power relations are a prominent barrier to acceptance. As stated above, the authors intend to explore this more deeply in an upcoming article.When seeking advice from individuals in key positions within their communities, the mothers needed to approach predominantly male When the mothers in this study sought religious support, the focus was placed on ‘healing’ rather than understanding their children’s challenges and support needs. At the African-initiated Christian churches to which most of the participants belonged, disability was viewed as a condition that required healing (cf. Amanze All 12 mothers became increasingly resilient as they educated themselves on the meaning of their children’s autism diagnoses (cf. Marsh et al. ubuntu, social support, culture, tradition, interpersonal relationships, interconnectedness and continuity (Majoko Although this study was conducted in KwaZulu-Natal and the participants were 12 Zulu mothers of children diagnosed with autism, it has raised awareness about the urgent need for culturally appropriate support for all persons diagnosed with ASD. Autism should be destigmatised through autism awareness programmes, targeting all stakeholders, including health, education, traditional, cultural and religious organisations, with useful information on the nature of autism, as well as how to access educational and therapeutic intervention and support within local communities (Hoogsteen & Woodgate y Majoko .South Africa needs a systemic approach to autism diagnosis (Clasquin-Johnson & Clasquin-Johnson