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Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti-cancer and anti-metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase-type plasminogen activator and matrix metalloproteinase-2. Gossypol reversed TGF-β-induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p-FAK, p-Src and p-paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice., (© 2024 Wiley Periodicals LLC.)

Oral chemotherapy is commonly prescribed, and by using decision aids (DAs), clinicians can facilitate shared decision-making (SDM) to align treatment choices with patient goals and values. Although products exist commercially, little evidence informs the development of DAs targeting the unique challenges of oral chemotherapy. To address this gap in the literature, our objective was to review DAs developed for oral anticoagulation, DA use in oncology, and patient preference surveys to guide the development of DAs for oral chemotherapy. We focused on reviewing SDM, patient preferences, and specifically the development, efficacy, and patient experience of DAs in oral anticoagulation and oncologic conditions, ultimately including conclusions and data from 30 peer-reviewed publications in our viewpoint paper. We found that effective DAs in oral anticoagulation improved knowledge, lowered decisional conflict, increased adherence, and covered a broad range of SDM elements; however, limited information on patient experience was a common shortcoming. In oncology, DAs increased knowledge and aligned decisions with the values of the patients. Ineffective oncology DAs provided general, unclear, or overly optimistic information, while providing "too much" information was not shown to do harm. Patients preferred DAs that included pros and cons, side effects, questions to ask, and expected quality of life changes. In developing DAs for oral chemotherapy, patients should be included in the development process, and DA content should be specifically tailored to patient preferences. Providing DAs ahead of appointments proved more effective than during, and additional considerations included addressing barriers to efficacy. There is a need for evidence-based DAs to facilitate SDM for patients considering oral chemotherapy. Developers should use data from studies in oral anticoagulation, oncology, and preference surveys to optimize SDM., (©Daniel E McLoughlin, Fabiola M Moreno Echevarria, Sherif M Badawy. Originally published in JMIR Cancer (https://cancer.jmir.org), 11.09.2024.)

Hidradenitis suppurativa patients have an increased risk of developing cancer. This includes not only hematologic malignancies and solid tumors, but also cutaneous squamous cell carcinoma originating within the hidradenitis suppurativa lesions. The development of squamous cell carcinoma is most commonly associated with Caucasian men who smoke and have severe gluteal or perianal lesions of more than 25 years duration. Other factors that have occasionally been associated with hidradenitis suppurativa-related squamous cell carcinoma include treatment with a tumor necrosis factor-alpha inhibitor (such as infliximab and adalimumab), genodermatoses (such as keratitis-ichthyosis-deafness syndrome and Dowling-Degos disease), and paraneoplastic syndromes (such as hypercalcemia, hypercalcemia-leukocytosis, and paraneoplastic neuropathy). The tumor may demonstrate the presence of human papillomavirus; even after treatment, patients have a poor prognosis since cancer metastasis, or recurrence, or both commonly occurs. The potential role of human papillomavirus vaccination for cancer prevention and early treatment of squamous cell carcinoma with targeted therapy (with an epidermal growth factor inhibitor such as cetuximab) and/or checkpoint inhibitor immunotherapy (such as cemiplimab and pembrolizumab) remains to be determined. Rarely, hidradenitis suppurativa lesions have mimicked cutaneous metastases in patients with visceral malignancy by demonstrating an increased uptake of fluorine-18 fluorodeoxyglucose on positron emission tomography and/or computerized tomography scans. Also, both primary cancers (such as cutaneous squamous cell carcinoma and mucinous adenocarcinoma) and breast cancer skin metastases can masquerade as hidradenitis suppurativa lesions. Therefore, when a lesion is located at a current or prior site of hidradenitis suppurativa that is new or rapidly growing and/or does not respond to hidradenitis suppurativa-directed therapy, prompt evaluation to establish or exclude the diagnosis of cancer should be considered., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy., Patients and Methods: We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated., Results: Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant., Conclusion: Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337)., (© The Author(s) 2024. Published by Oxford University Press.)

The aim of this study is to evaluate the safety and efficacy of the use of the IMACTIS ® CT-Navigation™-electromagnetic navigation system (EMNS) in cryoablation CT-guided procedures under local anesthesia for the treatment of upper kidney pole and adrenal lesions. We conducted a retrospective analysis of patients with upper kidney pole lesions and adrenal metastases who underwent cryoablation using the IMACTIS-CT ® -EMNS between January 2019 and April 2023. The EMNS was used to guide the placement of the cryoprobes with CT guidance under local anesthesia. The primary outcome was technical success, defined as the successful placement of the cryoprobes in the target lesion. A total of 31 patients were studied, of whom, 25 patients were treated with cryoablation for upper pole kidney masses, and 6 patients underwent the cryoablation of adrenal metastases during the study period. The mean age was 60 years (range, 36-82 years), and 21 patients were male. All the upper kidney pole lesions were renal cell carcinomas, and regarding adrenal metastases, the primary cancer sites were the lungs ( n = 3), breast ( n = 2), and the colon ( n = 1). The median size of the lesions was 3,8 cm (range, 1.5-5 cm). All procedures were technically successful, with the cryoprobes accurately placed in the target lesions under CT guidance using the EMNS, avoiding the penetration of any other organs using an oblique trajectory. No major complications were reported, and local tumor control was achieved in all cases. Our initial experience using the EMNS for cryoprobe placement during CT-guided interventional procedures under local anesthesia for the cryoablation treatment of upper pole kidney lesions and adrenal metastases showed that it is safe and effective.

Understanding which patients with human epidermal growth factor receptor 2 (HER2)-negative or -low metastatic breast cancer (MBC) benefit from HER2-targeted strategies is urgently needed. We assessed the whole-body heterogeneity of HER2 expression on 89 Zr-trastuzumab PET (HER2 PET) and the diagnostic performance of HER2 PET in a large series of patients, including HER2-negative and -low MBC. Methods: In the IMPACT-MBC study, patients with newly diagnosed and nonrapidly progressive MBC of all subtypes were included. Metastasis HER2 status was determined by immunohistochemistry and in situ hybridization. 89 Zr-trastuzumab uptake was quantified as SUV max and SUV mean HER2 immunohistochemistry was related to the quantitative 89 Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, uptake heterogeneity, and qualitative scan evaluation. A prediction algorithm for HER2 immunohistochemistry positivity based on uptake was developed. Results: In 200 patients, 89 Zr-trastuzumab uptake was quantified in 5,163 metastases, including 186 biopsied metastases. With increasing HER2 immunohistochemistry status, uptake was higher (geometric mean SUV max of 7.0, 7.6, 7.3, and 17.4 for a HER2 immunohistochemistry score of 0, 1, 2, or 3+, respectively; P < 0.001). High uptake exceeding 14.6 (90th percentile) was observed in one third of patients with a HER2-negative or -low metastasis biopsy. The algorithm performed best when lesion site and size were incorporated (area under the curve, 0.86; 95% CI, 0.79-0.93). Conclusion: HER2 PET had good diagnostic performance in MBC, showing considerable whole-body HER2 heterogeneity and uptake above background in HER2-negative and -low MBC. This provides novel insights into HER2-negative and -low MBC compared with standard HER2 immunohistochemistry on a single biopsy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Circulating tumor cells (CTCs) are cells that have separated from a solid cancerous lesion and entered the bloodstream. They play a crucial role in driving the metastatic spread to distant organs, which is the leading cause of cancer-related deaths. Various concepts for blood purification devices aiming to remove CTCs from the blood and prevent metastases have been developed. Until now, it is not clear if such devices can indeed reduce new metastasis formation in a significant way. Here, we present a simple theoretical model of CTCs in the bloodstream that can be used to predict a reduction in metastatic burden using an extracorporeal or intracorporeal blood purification device. The model consists of a system of ordinary differential equations that was numerically solved and simulated. Various simulations with different parameter settings of extracorporeal and intracorporeal devices revealed that only devices implanted directly in tumor-draining vessels can reduce the metastatic burden significantly. Even if an extracorporeal device is used permanently, the reduction in metastases is only 82%, while a permanently operating implanted device in the tumor-draining vessel would achieve a reduction of 99.8%. These results are mainly due to the fact that only a small fraction of CTCs reaches peripheral circulation, resulting in a proportionally small amount of purified blood in extracorporeal devices.

Context: Data on giant pheochromocytomas (PHEO), defined based on size ≥ 10 cm, are scarce., Objective: to compare presentation, management, and outcomes of patients with giant vs non-giant PHEOs., Design: retrospective cohort study, 2000-2023., Setting: referral center., Patients: consecutive patients with giant PHEO and randomly chosen patients with non-giant PHEO (referents) at a 1:6 ratio., Outcomes: perioperative complications, metastases, mortality., Results: Of 828 patients with PHEO, 31 (3.7%) had giant PHEO (median size 12 cm, IQR 10.0-13.5). In comparison to referents (n=186, median size 4 cm, IQR, 2.9-5.0), patients with giant PHEO had more symptoms of catecholamine excess (median of 2 vs 1, P=.04) and presented with a higher prevalence of severe catecholamine excess (76% vs 30%, P<.0001).Adrenalectomy was performed in 94% of patients with giant PHEOs and 100% referents. In addition to preoperative alpha-adrenergic blockade (89%), metyrosine was used in 14 (7%) patients, mostly in patients with giant PHEO (26% vs 3%, P<.0001). Patients with giant PHEO had a higher perioperative complication rate (31% vs 10%, P=.004).During a median follow-up of 3 years, metastases developed at a higher rate in patients with giant PHEOs (45% vs 4% in referents, P<.0001). Disease-specific mortality was 7% in patients with giant PHEOs and 0% in referents (P=.02)., Conclusion: Patients with giant PHEO as compared to referents were more symptomatic, had a higher degree of catecholamine excess, and had a higher rate of perioperative complications. Almost half of patients with giant PHEO developed metastases, warranting a close follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Mediastinal monophasic synovial sarcoma is a rare subtype that often lacks specific imaging characteristics, posing diagnostic challenges. This case report describes a mediastinal monophasic synovial sarcoma with vertebral metastasis, emphasizing imaging findings, differential diagnosis, and pathological features, thereby providing crucial support for accurate diagnosis and treatment planning., Competing Interests: All authors have completed the ICMJE uniform disclosure form. The authors have no conflicts of interest to declare., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Liver cancer, a leading cause of cancer mortality, is often diagnosed by analyzing the grayscale variations in liver tissue across different computed tomography (CT) images. However, the intensity similarity can be strong, making it difficult for radiologists to visually identify hepatocellular carcinoma (HCC) and metastases. It is crucial for the management and prevention strategies to accurately differentiate between these two liver cancers. This study proposes an automated system using a convolutional neural network (CNN) to enhance diagnostic accuracy to detect HCC, metastasis, and healthy liver tissue. This system incorporates automatic segmentation and classification. The liver lesions segmentation model is implemented using residual attention U-Net. A 9-layer CNN classifier implements the lesions classification model. Its input is the combination of the results of the segmentation model with original images. The dataset included 300 patients, with 223 used to develop the segmentation model and 77 to test it. These 77 patients also served as inputs for the classification model, consisting of 20 HCC cases, 27 with metastasis, and 30 healthy. The system achieved a mean Dice score of 87.65 % in segmentation and a mean accuracy of 93.97 % in classification, both in the test phase. The proposed method is a preliminary study with great potential in helping radiologists diagnose liver cancers., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

High-activity radioactive iodine (RAI) therapy for metastatic thyroid cancer (TC) requires isolation to minimize radiation exposure to third parties, thus posing challenges for patients needing hands-on care. There are limited data on the approach to high-activity RAI treatment in paraplegic patients. We report a state-of-the-art multidisciplinary approach to the management of bedbound patients, covering necessary radiation safety measures that lead to radiation exposure levels as low as reasonably achievable. Given the limited literature resources on standardized approaches, we provide a practical example of the safe and successful treatment of a woman with BRAFV600E -mutant tall-cell-variant papillary TC and pulmonary metastases, who underwent dabrafenib redifferentiation before RAI therapy. The patient was 69 y old and had become paraplegic because of a motor-vehicle accident. Since caring for a paraplegic patient with neurogenic bowel and bladder dysfunction poses radiation safety challenges, a multidisciplinary team comprising endocrinologists, nuclear medicine physicians, radiation safety specialists, and the nursing department developed a radiation mitigation strategy to ensure patient and staff safety during RAI therapy. The proposed standardized approach includes thorough monitoring of radiation levels in the workplace, providing additional protective equipment for workers who handle radioactive materials or are in direct patient contact, and implementing strict guidelines for safely disposing of radioactive waste such as urine collected in lead-lined containers. This approach requires enhanced training, role preparation, and practice; use of physical therapy equipment to increase the exposure distance; and estimation of the safe exposure time for caregivers based on dosimetry. The effective and safe treatment of metastatic TC in paraplegic patients can be successfully implemented with a comprehensive radiation mitigation strategy and thorough surveying of personnel for contamination., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The current World Health Organization (WHO) classification of central nervous system (CNS) tumours includes several neoplasms that, while occurring in this location, are more frequently seen extracranially. These include mesenchymal, melanocytic and haematolymphoid neoplasms, as well as metastases. A few of these entities are exclusive of the CNS and have no extracranial counterpart. Despite their diverse histogenesis, these neoplasms share a peculiar predilection for involving meningeal structures. In fact, in the context of an intraoperative pathologic consultation of a meningeal tumour, virtually all these entities should be considered as potential diagnoses. Metastases in the CNS are very common. Most are carcinomas that cytologically resemble their site of origin. Loss of differentiation with cell dissociation and anaplasia and presence of accompanying fibrillary brain parenchyma can be a source of diagnostic problems. In this review, we intend to show the most relevant cytologic features of these tumours, and it is especially aimed at their analysis during intraoperative studies., (© 2023 John Wiley & Sons Ltd.)

Purpose: In metastatic breast cancer, differences in expression patterns of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) between the primary tumor (PT) and metastatic site (MET) have been reported. However, there is limited understanding of the relationship of tumor subtype discordance and overall survival (OS). We evaluated patterns of ER/PR/HER2 in PTs and corresponding METs and assessed the relationship between these patterns and OS., Methods: Patients diagnosed at our center with metastatic breast cancer (2011-2020) were included. ER/PR were stratified as < 1%/1-10%/ > 10% by immunohistochemistry and HER2 as positive/negative by immunohistochemistry/FISH. Tumor subtypes were classified as ER or PR + /HER2-, HER2+ , or triple-negative. Biomarker discordance data from PTs to METs were analyzed for expression patterns. OS was assessed., Results: Of 254 patients, 41 (16.1%) had synchronous and 213 (83.9%) had metachronous METs. Category change of ER/PR/HER2 expression was observed in 56 (22.0%), 117 (40.5%), and 30 (11.8%) patients, respectively. Tumor subtype changed in 56 (22.0%) patients. We identified a difference between PT and MET from ER > 10% to ER < 1% (n = 28,16.2% p < 0.01); PR > 10% to PR < 1% (n = 54,48.2%, p < 0.001); PR > 10% to PR 1-10% (n = 18,16.1%, p < 0.001), and ER or PR+/HER2- to triple-negative (n = 19,13.0%, p = 0.03). In log-rank analysis, change from an ER or PR+/HER2- (5-year OS 88.6%) PT to a HER2+(67.5%) or triple-negative (54.6%) MET was associated with decreased survival (p < 0.01); however, in multivariate analysis, discordant biomarker expression was not associated with decreased survival (p > 0.05)., Conclusion: Tumor expression of ER/PR/HER2 can differ between the PT and MET. Loss of ER/PR expression is common and may be related to worse survival. Routine assessment of MET tumor markers could inform prognosis and therapeutic decision-making., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To evaluate diagnostic yield and accuracy of image-guided core needle biopsy (ICNB) of suspected malignant osseous lesions in a large cohort of adults, evaluate what factors influence these measures, and offer technical recommendations to optimize yield., Methods: A retrospective analysis of 2321 ICNBs performed from 2010 to 2021 was completed. The diagnostic yield and accuracy of the biopsies as well as a series of patient, lesion-related, and technical factors were retrospectively analyzed. Multivariate statistical analysis was performed to evaluate what factors were associated with yield and accuracy. Different cutoff values of total core length and core number were then tested to determine threshold values in relation to increased diagnostic yield., Results: Diagnostic yield was 98.2% (2279/2321) and accuracy was 97.6% (120/123). Increased total core length (odds ratio [OR] = 2.34, 95% confidence interval [CI] (1.41-3.90), p = 0.001), core number (OR = 1.51, 95% CI (1.06-2.16), p = 0.02) and presence of primary malignancy (OR = 2.81, 95% CI (1.40-5.62), p = 0.004) were associated with improved yield. Lesion location in an extremity (OR = 0.27, 95% CI (0.11-0.68), p = 0.006) and using fluoroscopic imaging guidance (OR = 0.33, 95% CI (0.12-0.90), p = 0.03) were associated with lower yield. Cutoff thresholds in relation to increased diagnostic yield were found to be 20 mm total core length (marginal OR = 4.16, 95% CI = (2.09-9.03), p < 0.001), and three total cores obtained (marginal OR = 2.78, 95% CI (1.34-6.54), p = 0.005). None of the analyzed factors influenced diagnostic accuracy., Conclusions: ICNB has a high rate of diagnostic yield and accuracy. Several factors influence diagnostic yield; 20 mm core length and three total cores optimize yield., Clinical Relevance Statement: Image-guided core needle biopsy of suspected malignant osseous lesions is a safe procedure with a very high rate of diagnostic yield and accuracy. Obtaining 20 mm total core length and three total cores optimizes diagnostic yield., Key Points: • In a retrospective cohort study, image-guided core needle biopsy of suspected osseous malignant lesions in adults was found to have very high rates of diagnostic yield and accuracy. • Increased total core length and core number of biopsies were each associated with increased diagnostic yield, and these relationships reached thresholds at 20 mm total core length and three total cores obtained. • The presence of a known primary malignancy was also associated with increased yield while using fluoroscopic imaging guidance and lesion location in an extremity were associated with decreased yield., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: Treatment of retroperitoneal lymph node metastases (RPN) from colon cancer (CC) is a therapeutic challenge. Available evidence supporting a curative approach is weak and uncertainties remain concerning the extent of the dissection, the optimal timing for surgery, and the role of adjuvant radiotherapy. We report the outcomes of a curative intent strategy in a recent monocentric series of patients., Methods: We did a retrospective review of all curative intent surgical treatment of RPN from CC performed consecutively in a French university hospital from June 2015 to April 2021. Demographics, clinicopathological, and molecular characteristics were evaluated. We describe recurrence-free and overall survival and factors related to recurrence., Results: Records from 18 patients were reviewed. The median age was 69 years. Most of the patients were male (55%), ASA 1-2 (94%), had a left-sided primary colon cancer (73%), and had metachronous RPN (62%). Thirteen patients (72%) experienced recurrence. Recurrence was often limited to RPN (27%) or liver (22%). Four patients underwent a second surgery for RPN recurrence. Median disease-free and overall survival were 22 months and 50 months after RPN surgery. We did not find any factor associated with recurrence. Short-term recurrence (< 6 months) was associated with shorter overall survival (0.031)., Conclusion: The current results suggest that RPN resection is feasible and associated with long survival in selected patients. Further studies evaluating the benefit of curative strategies including radical surgery for patients with potentially resectable RPN are warranted., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Limited research has compared cognition of people with non-central nervous system metastatic cancer (NCM) vs. metastatic brain cancer (BM). This prospective cross-sectional study was comprised 37 healthy controls (HC), 40 NCM, and 61 BM completing 10 neuropsychological tests. The NCM performed below HCs on processing speed and executive functioning tasks, while the BM group demonstrated lower performance across tests. Tasks of processing speed, verbal fluency, and verbal memory differentiated the clinical groups (BM < NCM). Nearly 20% of the NCM group was impaired on at least three neuropsychological tests whereas approximately 40% of the BM group demonstrated the same level of impairment.

Introduction: Hepatic visceral crisis (VC), characterized by a rapid total bilirubin increase with disease progression, poses a life-threatening risk in advanced breast cancer (ABC). International consensus guidelines define VC and touch on impending VC (IVC). Limited data exist on systemic treatments for hepatic VC/IVC. This study explores the safety and efficacy of cisplatin monotherapy in patients with Human Epidermal Growth Factor Receptor 2- negative breast cancer (BC) and hepatic IVC/VC., Methods: In this retrospective single-center cohort study data of patients treated with cisplatin monotherapy (60-80 mg/m 2 , every 3-4 weeks) between 2016 and 2023 at a reference Cancer Centre in Southern Poland were analyzed., Results: 33 female patients (24/33 hormonal-positive) with the mean age 53.84 years were included. Participants progressed on median 2 prior palliative systemic treatment lines. In 10/23 patients hepatic VC and in 23/33 IVC (rapid, symptomatic liver progression; extensive liver involvement; alanine or aspartate aminotransferase > 2 × normal limit; significant increases in lactate dehydrogenase, alkaline phosphatase, or gamma-glutamyl transferase) were identified. Median progression-free survival was 1.87 months and median overall survival 2.67 months. 33% of the patients presented stable disease or partial response. Eight patients experienced adverse events grade ≥ 3: in five the dose of cisplatin was reduced; two stopped the treatment., Conclusion: Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are scarce. Our study explored cisplatin's potential use, finding it to be a viable option in patients with performance status 0 or 1 experiencing hepatic IVC/VC, irrespective of liver function parameters and other factors., (© 2024. The Author(s).)

Background: Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI., Methods: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression., Results: 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated "possibly" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE., Conclusion: This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Connor Lynch: none to declare. Mark C. Korpics: none to declare. Rohan R. Katipally: none to declare. Christine M. Bestvina: Institutional funding from AstraZeneca and Bristol Myers Squibb; consulting fees from AstraZeneca, Bristol Myers Squibb, CVS, Daiichi Sankyo, Genentech, Jazz, Johnson and Johnson, Novartis, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Tempus; participates in the Data Safety Monitoring and/or Advisory Board of AstraZeneca, Bristol Myers Squibb, CVS, Daiichi Sankyo, Genentech, Jazz, Johnson and Johnson, Novartis, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Tempus. Sean P. Pitroda: Speaker’s Bureau for AACR and Immunorad conferences; co-founder of PersonaDx; co-inventor of patent related to metastatic disease and prognostication via University of Chicago IP office. Jyoti D. Patel: Consulting and Advisory Board for Abbvie, AstraZeneca, Takeda Science Foundation, Genentech, Anheart Therapeutics; travel, accommodations, or expenses from Tempus. Jason J. Luke: DSMB: Abbvie, Agenus, Evaxion, Immutep, Shionogi; Scientific Advisory Board: (no stock) 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Elipscience, Kanaph, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Consultancy with compensation: Abbvie, Agenus, Alnylam, AstraZeneca, Askgene, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, Ko Bio Labs, Krystal, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, LegoChem, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Storm, Sumoitomo, Synlogic, Synthekine, Teva; Research Support: (all to institution) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Hot Spot, Ikena, Immatics, Imugene, Incyte, Janux, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Novartis, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Tscan, Werewolf, Xencor; Patents: US-11638728 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). Steven J. Chmura: Institutional funding from Bristol Myers Squibb; Family member employed by Astellas Pharmaceuticals. Aditya Juloori: Institutional funding from AstraZeneca; Consulting fees from Isoray, General Electric, and Aqualung., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied., Materials and Methods: Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS)., Results: Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017)., Conclusion: A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs., (© 2024. The Author(s).)

Statins, widely used cardiovascular drugs that lower cholesterol by inhibiting HMG-CoA reductase, have been increasingly recognized for their potential anticancer properties. This study elucidates the underlying mechanism, revealing that statins exploit Synthetic Lethality, a principle where the co-occurrence of two non-lethal events leads to cell death. Our computational analysis of approximately 37,000 SL pairs identified statins as potential drugs targeting genes involved in SL pairs with metastatic genes. In vitro validation on various cancer cell lines confirmed the anticancer efficacy of statins. This data-driven drug repurposing strategy provides a molecular basis for the anticancer effects of statins, offering translational opportunities in oncology., (© 2024. The Author(s).)

Purpose: To evaluate the efficacy and safety of combined microwave ablation (MWA) and vertebral augmentation (VA) in the treatment of spinal metastases with posterior wall defects., Patients and Methods: A retrospective review was conducted for 67 patients (42 men, 25 women) with painful spine metastases and posterior wall defects who underwent MWA combined with VA. Among these patients, 52 vertebrae had no epidural invasion and 33 had mild invasion but did not compress the spinal cord. Procedural effectiveness was determined by comparing visual analog scale (VAS) scores and Oswestry disability index (ODI) scores before the procedure and during the follow-up period., Results: The procedure was technically successful in all patients. The mean VAS score declined significantly from 6.85 ± 1.81 before the procedure to 3.27 ± 1.97 at 24 h, 1.96 ± 1.56 at 1 week, 1.84 ± 1.50 at 4 weeks, 1.73 ± 1.45 at 12 weeks, and 1.71 ± 1.52 at 24 weeks post-procedure (p < 0.01). The mean ODI score was lower post-procedure than before the procedure (p < 0.001). Transient nerve injury occurred in two patients (SIR classification D), and the incidence of asymptomatic bone cement (SIR classification A) was 43.5% (37/85)., Conclusion: MWA combined with VA is an effective and safe treatment for painful spine metastases with posterior wall defects., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhang et al.)

Uveal melanomas represent approximately 5% of all human melanomas. Omental metastases are often diagnosed as secondary metastatic sites and only a few cases have been described as the first single manifestation of distant metastasis. In this case image, we illustrate the interesting appearance of the metastatic localization of metastatic uveal melanoma., Competing Interests: The authors state that they have no conflict of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

There are very few reports of bloodborne metastasis of lung adenocarcinoma to the gastrointestinal tract, primarily due to poor prognosis and short survival rate of metastasized carcinoma. We present a case of a 79-year-old man with a medical history of lung adenocarcinoma, who presented with complaints of weakness and melena for 1 week. He had symptomatic anemia, for which he was transfused with blood. Esophagogastroduodenoscopy showed a 10 mm sessile polyp in the gastric body that was removed. One month later, the patient presented with a similar complaint, and another esophagogastroduodenoscopy revealed 2 ulcerated lesions in the second portion of the duodenum. These lesions were treated by hemostatic clip placement and heater probe coagulation. Biopsy of lesions demonstrated thyroid transcription factor 1 and Napsin-positive tumor cells, consistent with lung adenocarcinoma. Owing to the poor prognosis of lung adenocarcinoma metastasizing to the lymph nodes, stomach, and duodenum, the patient was transferred to hospice care., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Cancer is a significant public health issue worldwide. Treatments such as surgery, chemotherapy, and radiation therapy often cause psychological and physiological side effects, affecting patients' ability to function and their quality of life (QoL). Physical activity is crucial to cancer rehabilitation, improving physical function and QoL and reducing cancer-related fatigue. However, many patients face barriers to accessing cancer rehabilitation due to socioeconomic factors, transportation issues, and time constraints. Telerehabilitation can potentially overcome these barriers by delivering rehabilitation remotely., Objective: The aim of the study is to identify how telemedicine is used for the rehabilitation of patients with cancer., Methods: This scoping review followed recognized frameworks. We conducted an electronic literature search on PubMed for studies published between January 2015 and May 2023. Inclusion criteria were studies reporting physical therapy telerehabilitation interventions for patients with cancer, including randomized and nonrandomized controlled trials, feasibility studies, and usability studies. In total, 21 studies met the criteria and were included in the final review., Results: Our search yielded 37 papers, with 21 included in the final review. Randomized controlled trials comprised 47% (n=10) of the studies, with feasibility studies at 33% (n=7) and usability studies at 19% (n=4). Sample sizes were typically 50 or fewer participants in 57% (n=12) of the reports. Participants were generally aged 65 years or younger (n=17, 81%), with a balanced gender distribution. Organ-specific cancers were the focus of 66% (n=14) of the papers, while 28% (n=6) included patients who were in the posttreatment period. Web-based systems were the most used technology (n=13, 61%), followed by phone call or SMS text messaging-based systems (n=9, 42%) and mobile apps (n=5, 23%). Exercise programs were mainly home based (n=19, 90%) and included aerobic (n=19, 90%), resistance (n=13, 61%), and flexibility training (n=7, 33%). Outcomes included improvements in functional capacity, cognitive functioning, and QoL (n=10, 47%); reductions in pain and hospital length of stay; and enhancements in fatigue, physical and emotional well-being, and anxiety. Positive effects on feasibility (n=3, 14%), acceptability (n=8, 38%), and cost-effectiveness (n=2, 9%) were also noted. Functional outcomes were frequently assessed (n=19, 71%) with tools like the 6-minute walk test and grip strength tests., Conclusions: Telerehabilitation for patients with cancer is beneficial and feasible, with diverse approaches in study design, technologies, exercises, and outcomes. Future research should focus on developing standardized methodologies, incorporating objective measures, and exploring emerging technologies like virtual reality, wearable or noncontact sensors, and artificial intelligence to optimize telerehabilitation interventions. Addressing these areas can enhance clinical practice and improve outcomes for remote rehabilitation with patients., (©Patricia Goncalves Leite Rocco, C Mahony Reategui-Rivera, Joseph Finkelstein. Originally published in JMIR Cancer (https://cancer.jmir.org), 21.08.2024.)

Background and Objective: Patients diagnosed with grade group (GG) 1 prostate cancer (PCa) following treatment for benign disease ("incidental" PCa) are typically managed with active surveillance (AS). It is not known how their outcomes compare with those observed in patients diagnosed with GG1 on biopsy. We aimed at determining whether long-term oncologic outcomes of AS for patients with GG1 PCa differ according to the type of diagnosis: incidental versus biopsy detected., Methods: A retrospective, multi-institutional analysis of PCa patients with GG1 on AS at eight institutions was conducted. Competing risk analyses estimated the incidence of metastases, PCa mortality, and conversion to treatment. As a secondary analysis, we estimated the risk of GG ≥2 on the first follow-up biopsy according to the type of initial diagnosis., Key Findings and Limitations: A total of 213 versus 1900 patients with incidental versus biopsy-diagnosed GG1 were identified. Patients with incidental cancers were followed with repeated biopsies and multiparametric magnetic resonance imaging less frequently than those diagnosed on biopsy. The 10-yr incidence of treatment was 22% for incidental cancers versus 53% for biopsy (subdistribution hazard ratio [sHR] 0.34, 95% confidence interval [CI] 0.26-0.46, p  < 0.001). Distant metastases developed in one patient with incidental cancer versus 17 diagnosed on biopsy and were diagnosed with molecular imaging in 13 (72%) patients. The 10-yr incidence of metastases was 0.8% for patients with incidental PCa and 2% for those diagnosed on biopsy (sHR 0.35, 95% CI 0.05-2.54, p  = 0.3). The risk of GG ≥2 on the first follow-up biopsy was low if the initial diagnosis was incidental (7% vs 22%, p  < 0.001)., Conclusions and Clinical Implications: Patients with GG1 incidental PCa should be evaluated further to exclude aggressive disease, preferably with a biopsy. If no cancer is found on biopsy, then they should receive the same follow-up of a patient with a negative biopsy. Further research should confirm whether imaging and biopsies can be avoided if postoperative prostate-specific antigen is low (<1-2 ng/ml)., Patient Summary: We compared the outcomes of patients with low-grade prostate cancer on active surveillance according to the type of their initial diagnosis. Patients who have low-grade cancer diagnosed on a procedure to relieve urinary symptoms (incidental prostate cancer) are followed less intensively and undergo curative-intended treatment less frequently. We also found that patients with incidental prostate cancer are more likely to have no cancer on their first follow-up biopsy than patients who have low-grade cancer initially diagnosed on a biopsy. These patients have a more favorable prognosis than their biopsy-detected counterparts and should be managed the same way as patients with negative biopsies if they undergo a subsequent biopsy that shows no cancer., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.)

The standard therapy for hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer includes the use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy. The optimal post-CDK4/6i treatment sequence is unclear. This cohort study evaluated the initiation, characteristics, and outcomes of chemotherapy following CDK4/6i-based treatment. Among the 227 patients who began CDK4/6i therapy, 114 completed it. Seventy-nine female patients received further treatment, including 55 receiving chemotherapy. The average age was 60.1 years. Post-CDK4/6i chemotherapy was typically (69.1%) first-line due to an impending visceral crisis. The median progression-free survival (mPFS) was 3.0 months (range 0.5-18.9), and the median overall survival (mOS) was 8.3 months (0.5-26.1). The median OS from the end of CDK4/6i treatment was 12.4 months (1.5-26.8). In univariate analysis, neither mPFS nor mOS was associated with age, tumor grade, receptor status, Ki67 status, time from diagnosis to CDK4/6i cessation, therapy line, or CDK4/6i type. Dose reduction occurred in 12 patients (21.8%), and chemotherapy was ceased due to adverse events in 8 patients (14.6%). Chemotherapy showed limited benefit regardless of the regimen. The role of chemotherapy may evolve with broader CDK4/6i use in adjuvant treatment.

Purpose: Implanted devices used in metastatic spine tumor surgery (MSTS) include pedicle screws, fixation plates, fixation rods, and interbody devices. A material to be used to fabricate any of these devices should possess an array of properties, which include biocompatibility, no toxicity, bioactivity, low wear rate, low to moderate incidence of artifacts during imaging, tensile strength and modulus that are comparable to those of cortical bone, high fatigue strength/long fatigue life, minimal or no negative impact on radiotherapy (RT) planning and delivery, and high capability for fusion to the contiguous bone. The shortcomings of Ti6Al4V alloy for these applications with respect to these desirable properties are well recognized, opening the field for an investigation about novel biomaterials that could replace the current gold standard. Previously published reviews on this topic have exhibited significant shortcomings in the studies they included, such as a small, heterogenous sample size and the lack of a cost-benefit analysis, extremely useful to understand the practical possibility of applying a novel material on a large scale. Therefore, this review aims to collect information about the clinical performance of these biomaterials from the most recent literature, with the objective of deliberating which could potentially be better than titanium in the future, with particular attention to safety, artifact production and radiotherapy planning interference. The significant promise showed by analyzing the clinical performance of these devices warrants further research through prospective studies with a larger sample size also taking into account each aspect of the production and use of such materials., Methods: The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used to improve the reporting of the review. The search was performed from March 2022 to September 2023., Results: At the end of the screening process, 20 articles were considered eligible for this study. Polyetheretherketone (PEEK), Carbon-fibre reinforced polyetheretherketone (CFR-PEEK), long carbon fiber reinforced polymer (LCFRP), Polymethylmethacrylate (PMMA), and carbon screw and rods were used in the included studies., Conclusion: CFR-PEEK displays a noninferior safety and efficacy profile to titanium implanted devices. However, it also has other advantages. By decreasing artifact production, it is able to increase detection of local tumor recurrence and decrease radiotherapy dose perturbation, ultimately bettering prognosis for patients necessitating adjuvant treatment. Nonetheless, its drawbacks have not been explored fully and still require further investigation in future studies. This does not exclude the fact that CFR-PEEK could be a valid alternative to titanium in the near future., (© 2024. The Author(s).)

Background/Objectives : The most important prognostic factors in curatively treated prostate cancer are T and N stage, histology, grade group and initial PSA. A recent study found that men with blood calcium levels at the high end of the normal range are over two-and-a-half times more likely to develop fatal prostate cancer than those with lower calcium levels. However, there is limited evidence regarding the prognostic value of calcium levels at the time of prostate cancer diagnosis. We aimed to determine whether a calcium level in the upper range of normal values has any prognostic value in curatively treated prostate cancer. Methods : We conducted a retrospective analysis of 84 consecutive patients with prostate cancer who underwent curative-intent radiotherapy-either as primary treatment or adjuvant therapy-using external beam radiotherapy with or without brachytherapy. We analyzed all pertinent prognostic factors that could potentially impact disease-free survival. Results : The study revealed that calcium levels at diagnosis significantly predict disease-free survival, whereas the initial PSA level did not hold prognostic significance-likely due to interference from benign prostatic hyperplasia. Conclusions : If our findings are validated, calcium levels at the time of prostate cancer diagnosis could be incorporated into future predictive and prognostic models.

Pseudocirrhosis is a diffuse nodularity of the liver that radiologically mimics cirrhosis but is a distinct pathological process. It is seen almost exclusively in patients with liver metastases and may represent a response to systemic treatment. Data on the risk factors for pseudocirrhosis and outcomes are limited. In total, 170 patients with a diagnosis of breast cancer and pseudocirrhosis in a 10-year period were identified and retrospectively analysed. Data were collected on baseline patient characteristics, treatments received, and outcomes. Median time between diagnosis of liver metastases and diagnosis of pseudocirrhosis was 17.1 months (range, 0-149 months). In total, 89.4% of patients received chemotherapy between their diagnosis of breast cancer liver metastases and their diagnosis of pseudocirrhosis, most commonly a taxane (74.7%) or capecitabine (67.1%), and the median treatment lines received was 3. Median OS from first diagnosis of pseudocirrhosis was 7.6 months (95% CI: 6.1-9.6 months) and was longer in patients with HER2+ disease at 16.7 months (95% CI: 6.4-32.9 months), which was statistically significant. In our study, pseudocirrhosis occurred in the presence of liver metastases and was associated with a poor prognosis. HER2+ patients with pseudocirrhosis had a better prognosis than other subtypes, but we did not identify other significant predictors of survival. Chemotherapy was not a prerequisite for pseudocirrhosis development, although the majority of patients had received at least one line of chemotherapy before pseudocirrhosis was diagnosed.

Cranial operations are associated with a high risk of postoperative intracranial hemorrhage (pICH) and venous thromboembolic events, along with increased mortality and morbidity. With the use of acetylsalicylic acid (ASA) for prophylaxis becoming more prevalent, the risk of bleeding when ASA is administered preoperatively is unknown, as are the effects of discontinuation upon the occurrence of thromboembolic events, especially in societies with aging demographics. To address these questions, a retrospective analysis was performed using medical records and radiological images of 1862 patients subjected to brain tumor surgery over a decade in our department. The risk of pICH was compared in patients with metastases receiving ASA treatment versus patients not receiving ASA treatment. The occurrence of venous thromboembolic events after surgery was also evaluated. The study group consisted of 365 patients with different types of brain metastases. In total, 20 patients suffered pICH and 7 of these were associated with clinical neurological deterioration postoperatively. Of the 58 patients who took ASA preoperatively, 2 patients experienced pICH, compared with 5 patients in the non-ASA impact group ( p = 0.120). Patients who took ASA were not at significantly higher risk of pICH and therefore a worse outcome compared to the group without ASA. Therefore, these data suggest that in patients at high cardiovascular risk, ASA can be safely continued during elective brain tumor surgery.

This study aimed to compare the diagnostic accuracy of computed tomography (CT) and magnetic resonance imaging (MRI) in detecting metastases of colorectal cancer (CRC) in a hospital in Najran, Saudi Arabia. A total of 51 patients with CRC were included in the study. The radiological findings of metastatic lesions and the diagnostic accuracy measures of CT compared to MRI were analyzed. The results showed that CT had a false negative rate of 7.8%, a false positive rate of 7.8%, a true negative rate of 27.5%, and a true positive rate of 56.9% in detecting metastases. Diagnostic accuracy measures varied based on the number of metastatic lesions, with higher sensitivity observed for cases with fewer lesions. Gender, timing of imaging in relation to surgical intervention, and administration of nonsurgical therapy showed significant associations with diagnosis mismatch between CT and MRI. The site of metastases and the site of the primary tumor in the colon also demonstrated significant associations with diagnosis mismatch. The size of the largest metastasis detected by MRI was significantly associated with diagnosis mismatch. The overall diagnostic accuracy of CT in detecting any metastases, compared to MRI as the reference standard, was estimated to have a sensitivity of 87.8%, a specificity of 77.8%, a positive predictive value of 87.8%, and a negative predictive value of 77.8%. This study provides valuable insights into the comparative diagnostic performance of CT and MRI in detecting metastases of CRC, highlighting the importance of considering patient characteristics, disease outcome, and tumor characteristics in the interpretation of imaging results., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Research Ethics Committee Najran University, Najran, Saudi Arabia issued approval 202312-076-016106-037171. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alhammami et al.)

Thymomas are benign epithelial neoplasms originating from the thymus gland and are among the most common primary mediastinal tumors. Malignancy is typically determined by evidence of pathological invasion beyond the capsule, with local invasion being the primary mode of spread to adjacent organs. Distant metastases are exceedingly rare. We present the case of a 63-year-old man who exhibited symptoms suggestive of increased intracranial pressure and motor deficit. Brain imaging revealed multiple intracranial lesions. Surgical intervention was performed to excise the largest lesion. Subsequent body CT scan and pathological examination confirmed that the brain metastases originated from a primary thymoma, classified as B3. The patient was recommended for adjuvant chemotherapy and radiotherapy, but unfortunately passed away at the initiation of therapy. The prognosis for patients with brain metastases from thymomas remains poor. Optimal management strategies typically involve prompt surgical intervention whenever feasible, followed by adjuvant therapy aimed at improving mean survival rates., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Penile cancer with bulky inguinal metastasis has a high probability of harboring pathologically involved lymph nodes best managed in a multidisciplinary care setting. Appropriate staging with cross-sectional imaging and fine-needle aspirate cytology of suspicious nodes guide decision-making for the use of platinum-based neoadjuvant chemotherapy followed by inguinal lymph node dissection. Surgical resection plays an important diagnostic, therapeutic, and guiding role in disease management. Patients with adverse pathologic features, especially those with extranodal disease extension, may derive additional benefit from adjuvant radiotherapy., Competing Interests: Disclosure The authors have no pertinent conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Extramammary metastases are uncommon and usually related to a poor prognosis, but the radiologist can suspect the diagnosis based on the patient's clinical history and specific imaging findings. Several imaging procedures may be used to evaluate breast metastases from different extramammary malignancies, including mammography, ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography-CT (PET-CT). The clinical and imaging presentation of these metastases is contingent upon how the illness spreads, however, they have the potential to resemble either benign or malignant breast tumors. Metastases that disseminate hematologically tend to appear as a single round or oval mass with circumscribed margins. Sonographically, they are usually hypoechoic, and with CT or MRI, they usually enhance. Lymphatic dissemination, for example, frequently reveals significant asymmetry with skin thickening and diffuse breast edema, which is compatible with an inflammatory breast carcinoma. Knowing the many types of cancers that have the potential to spread to the breast as well as being able to accurately diagnose them is crucial to prevent a needless mastectomy and provide guidance for subsequent treatment. The purpose of this article is to provide a better understanding of the imaging features and immunohistochemistry (IHC) of secondary tumors of the breast by presenting eight distinctive cases, which will enable radiologists to recognize this entity.

Purpose: Receptor and subtype discordance between primary breast tumours and metastases is a frequently reported phenomenon. The aim of this article is to review the current evidence on receptor discordance in metastatic breast cancer and to explore the benefit of performing a repeat biopsy in this context., Methods: Searches were undertaken on PubMed and Clinicaltrials.gov for relevant publications and trials., Conclusion: The current guidelines recommend offering to perform a biopsy of a metastatic lesion to evaluate receptor status. The choice of systemic therapy in metastatic disease is often based on the receptor status of the primary lesion. As therapeutic decision making is guided by subtype, biopsy of the metastatic lesion to determine receptor status may alter treatment. This article discusses discordance rates, the mechanisms of receptor discordance, the effect of discordance on treatment and survival outcomes, as well as highlighting some ongoing clinical trials in patients with metastatic breast cancer., (© 2024. The Author(s).)

Purpose: To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver., Materials and Methods: A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival., Results: Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes were leiomyosarcoma (23/55), followed by gastrointestinal stromal tumor (22/55). The median treated liver lesions was 2 (range, 1-8), whereas the median size of metastases were 1.8 cm (0.3-8.7 cm). Complete response at 2 months was achieved in 90.5% of the treated lesions. LPFS was 83% at 1 year and 80% at 2 years. Liver-specific progression-free survival was 66% at 1 year and 40% at 2 years. The overall survival at 1 and 2 years was 98% and 94%. The chemotherapy-free holiday from the start of ablation was 71.2% at 12 months. The complication rate was 3.6% (2/55); one of the complications was Common Terminology Criteria for Adverse Events grade 3 or higher. LPFS subgroup analysis for leiomyosarcoma versus gastrointestinal stromal tumor suggests histology-agnostic outcomes (2 years, 89% vs 82%, p = .35)., Conclusion: Percutaneous image-guided liver ablation of soft tissue sarcoma metastases is safe and efficacious., (© 2024 American Cancer Society.)

Background: This study sought to identify associations between the Yost Index, a geocoded area neighborhood socioeconomic status (nSES) score, and race/ethnicity with patient refusal of recommended surgery for metastatic bone disease., Methods: Patients with metastatic bone disease were extracted from the Surveillance, Epidemiology, and End Results database. The Yost Index was geocoded using factor analysis and categorized into quintiles using census tract-level American Community Service (ACS) 5-year estimates and seven nSES measures. Multivariable logistic regression models calculated odds ratios (ORs) of refusal of recommended surgery and 95% confidence intervals (CIs), adjusting for clinical covariates., Results: A total of 138,257 patients were included, of which 14,943 (10.8%) were recommended for surgical resection. Patients in the lowest nSES quintile had 57% higher odds of refusing surgical treatment than those in the highest quintile (aOR = 1.57, 95% CI 1.30-1.91, p < 0.001). Patients in the lowest nSES quintile also had a 31.2% higher age-adjusted incidence rate of not being recommended for surgery compared with those in the highest quintile (186.4 vs. 142.1 per 1 million, p < 0.001). Black patients had 34% higher odds of refusing treatment compared with White patients (aOR = 1.34, 95% CI 1.14-1.58, p = 0.003). Advanced age, unmarried status, and patients with aggressive cancer subtypes were associated with higher odds of refusing surgery (p < 0.001)., Conclusions: nSES and race/ethnicity are independent predictors of a patient refusing surgery for metastatic cancer to bone, even after adjusting for various clinical covariates. Effective strategies for addressing these inequalities and improving the access and quality of care of patients with a lower nSES and minority backgrounds are needed., (© 2024. The Author(s).)

Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs., Competing Interests: Declaration of Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Breast cancer recurrence and lymph node metastasis significantly impact patient outcomes. Understanding the molecular mechanisms behind these processes is crucial for developing effective treatments. CCN5 and E-cadherin are proteins involved in cell adhesion and epithelial-mesenchymal transition (EMT), playing roles in breast cancer progression., Objective: This study aimed to analyze the expression levels and clinical significance of CCN5 and E-cadherin in primary and recurrent breast cancer lesions., Methods: Immunohistochemical staining using the SP method was performed to detect CCN5 and E-cadherin expression levels in 28 normal breast tissue samples, 52 primary breast cancer lesions, and paired recurrent chest wall lesions. The expression levels of these proteins were compared across different tissue types and correlated with lymph node metastasis., Results: CCN5 and E-cadherin expression levels significantly differed among normal breast tissues, primary breast cancer lesions, and recurrent lesions (Χ 2 = 18.934 and Χ 2 = 14.516, p < 0.05). Primary breast cancer lesions exhibited higher CCN5 and E-cadherin expression levels compared with recurrent lesions and normal tissues, although these differences were not statistically significant. Patients without lymph node metastases exhibited significantly higher expression levels of CCN5 and E-cadherin compared with those with lymph node metastases (Χ 2 = 9.775, Χ 2 = 9.1479, p < 0.05). A positive correlation between CCN5 and E-cadherin expression levels was found in breast cancer tissues (r = 0.398, p < 0.001)., Conclusion: CCN5 and E-cadherin were expressed at lower levels in recurrent breast cancer tissues and those with lymph node metastases, indicating their potential roles in breast cancer recurrence and metastasis. These findings suggest that CCN5 and E-cadherin might work synergistically to influence breast cancer progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Gui, Qu and Zhang.)

Background: Treatment options are limited in patients with recurrent or metastatic disease after initial treatment of soft tissue sarcoma (STS) by surgical resection, radiation, or systemic therapy. Percutaneous cryoablation may provide a complementary minimally invasive option in this setting. Objective: To assess the safety and efficacy of percutaneous cryoablation performed for local control of treatment-refractory recurrent or metastatic STS. Methods: This single-institution retrospective study included adult patients who underwent percutaneous cryoablation from March 2016 to April 2023 to achieve local control of recurrent or metastatic STS after earlier treatment (surgery, radiation, or chemotherapy). For each treated lesion, a single interventional radiologist re-reviewed intraprocedural images to assess for adequate coverage by the ice ball of the entire lesion and a ≥5-mm margin in all dimensions. Complications and outcomes were extracted from medical records. The primary endpoint for procedure efficacy was 1-year local progression-free survival. Results: The study included 141 patients (median age, 66 years; 90 female, 51 male) who underwent 217 cryoablation procedures to treat 250 recurrent or metastatic STS lesions. The most common STS histologic types were leiomyosarcoma (56/141) and liposarcoma (39/141). Lesions had a mean long-axis diameter of 2.0 cm (range, 0.4-11.0 cm). Adequate ice-ball coverage was achieved for 82% (204/250) of lesions. The complication rate was 2% (4/217), entailing three major complications and one minor complication. Patients' median post-ablation follow-up was 25 months (range, 3-80 months). Local progression-free survival was 86% at 1 year and 79% at 2 years. Chemotherapy-free survival was 45% at 1 year and 31% at 2 years. Overall survival (OS) was 89% at 1 year and 80% at 2 years. In Kaplan-Meier analysis, leiomyosarcoma, in comparison with liposarcoma, had significantly higher local progression-free survival, but no significant difference in OS. In multivariable analysis, factors independently associated with an increased risk for local progression included inadequate ice-ball coverage (HR=7.73) and a lesion location of peritoneum (HR=3.63) or retroperitoneum (HR=3.71) relative to lung. Conclusion: Percutaneous cryoablation has a favorable safety and efficacy profile in patients with recurrent or metastatic STS after earlier treatments. Clinical Impact: Percutaneous cryoablation should be considered for local control of treatment-refractory STS.

Introduction: Skin metastases arise in 10% of cancer patients, but standardized dermoscopy diagnostic criteria for skin metastases remain poor. This study's objective was to analyze the dermoscopy features of skin metastases from advanced systemic and cutaneous cancers., Methods: A retrospective study on 715 dermoscopy images of skin metastases from 33 patients with various primary cancers (breast, ovary, melanoma, non-melanoma skin cancer, and chronic leukemia) attending two academic centers between 2013 and 2023 was performed. Four independent observers blindly analyzed patterns, colors, vessels, and elementary lesions for each metastasis (30 parameters in total)., Results: The structureless white pattern was the most prominent indicator of cutaneous metastasis (81.26%, p < 0.001). Regardless of the primary tumor, colors pink, red, white, and tan were identified. Elementary lesions were infrequent, except for melanoma metastases that displayed dots (13.23%) and globules (11.11%). Breast cancer metastases presented: blue (41.48%) and red (34.32%) colors, irregular vessels (13.58%), and a blue-naevus pattern (22.22%). Melanoma metastases displayed: a blue-naevus pattern (61.38%), a blue color (85.71%), and a structureless-blue combination pattern (79.37%). Non-melanoma skin cancer metastases were characterized by vascular (42.11%) and angioma-like (31.58%) patterns, pink (57.89%) and red (57.89%) colors, irregular (57.89%), thin hairpin (47.37%), comma (47, 37%), and thick hairpin (26, 32%) vessels and a red, white and irregular vessels combination pattern (52, 63%). A pink structureless combination pattern was frequent (61.05%) in chronic leukemia metastases. Ovarian cancer metastases displayed a white and tan structureless combination pattern (100%) and frequently had dotted vessels (42.85%)., Conclusion: Papules and nodules with a white structureless pattern suggest skin metastases, regardless of the primary tumor. A blue structureless lesion is indicative of melanoma metastasis and a vascular pattern with irregular vessels indicates a non-melanoma skin cancer metastasis. Dermoscopy stands as a reliable non-invasive diagnostic method for suspected cutaneous metastases in patients with a known cancer history., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Simionescu, Petrică, Avram, Costache, Scurtu, Tudorache, Iorga and Grigore.)

Introduction: The femur is a common site for Multiple Myeloma (MM) involvement. This study explores the impact of preventive surgery for anticipated femoral pathological fractures (IFF), based on Mirels classification, versus treatment of pathological femur fracture (PFF) on MM patient mortality and morbidity., Methods: Retrospective cohort of 33 patients undergoing surgery due to femoral MM involvement (2004-2015), 18 patients with PFF, 15 patients with IFF, followed up until deceased or to July 2016. Demographic data, oncological, pathological, radiation, surgical reports, outpatient clinical records, and imaging studies were studied. Exclusion criteria included patients who had surgery at other medical centers., Results: The mean age was 70.4 ± 13.6 and 62.6 ± 12.2 years (p = 0.1) in the PFF and the IFF cohorts, respectively, primarily women (55.6% and 46.7%, respectively). The average Mirels' score was 10.4 ± 1.2. Post-operative complications were observed in 25% of patients, with no difference between IFF & PFF. We did not find a difference in mortality between IFF and PFF cohorts (p = 0.59)., Conclusion: The femur is commonly involved in MM. This study found that actual fractures, compared to imminent fractures, do not affect MM morbidity or mortality. Our study shows that proximal femoral MM behaves differently from proximal femoral metastatic disease regarding the impact of surgery on life span. Due to the fracture healing potential of MM, an IFF can probably be treated initially conservatively unless it progresses to an actual fracture needing surgery. Future, more extensive studies are required before revolutionizing the proximal femoral Multiple Myeloma-related involvement treatment paradigm., (© 2024. The Author(s).)

Study Design: Narrative review., Objective: Metastatic spine disease is an increasingly common clinical challenge that requires individualised multidisciplinary care from spine surgeons and oncologists. In this article, the authors describe the recent surgical advances in patients presenting with spinal metastases., Methods: We present an overview of the presentation, assessment, and management of spinal metastases from the perspective of the spine surgeon, highlighting advances in surgical technology and techniques, to facilitate multidisciplinary care for this complex patient group. Neither institutional review board approval nor patient consent was needed for this review., Results: Advances in radiotherapy delivery and systemic therapy (including immunotherapy and targeted therapy) have refined operative indications for decompression of neural structures and spinal stabilisation, while advances in surgical technology and technique enable these goals to be achieved with reduced morbidity. Formulating individualised management strategies that optimise outcome, while meeting patient goals and expectations, requires a comprehensive understanding of the factors important to patient management., Conclusion: Spinal metastases require prompt diagnosis and expert management by a multidisciplinary team. Improvements in systemic, radiation, and surgical therapies have broadened operative indications and increased operative candidacy, and future advances are likely to continue this trend., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Spinal metastasis of Glioblastoma is a rare occurrence, especially in pediatric patients, and extremely rare to become symptomatic. The pathology is poorly understood and remains with unclear dissemination mechanisms. The treatment approaches are varied and multimodal therapy (surgery, chemotherapy, and radiotherapy) can be employed to manage this type of metastasis. We report a case of a 17-year-old female who underwent a gross-total resection of a right frontal glioblastoma and had adjuvant therapy with chemo- and radiotherapy. In the sixth month of follow-up, the patient presented a paraparesis, and a distant recurrence at T7-T8 was detected. The patient was treated with gross-total resection of the tumor through a laminectomy. The histopathological results were consistent with an isocitrate dehydrogenase (IDH) wildtype GBM metastasis. The patient was treated with multimodal therapy, including surgery, radiotherapy, and chemotherapy. A complementary comprehensive review of current available literature on this topic is also presented., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare disorder of unknown etiology with heterogeneous clinical manifestations. We describe two cases of patients diagnosed with SAPHO syndrome mimicking spinal bone metastases. A literature review was conducted to identify similar previously reported cases. The first patient was a 56-year-old woman with progressive back pain for six months who was referred to the neurosurgery department for suspected spinal metastases. A spinal CT scan revealed hyperdense lesions at T10 and hyperdense changes in the lumbar vertebrae. Spinal MRI demonstrated bone marrow edema that was hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging in multiple thoracic vertebrae, and the PET/CT showed multiple skeletal lesions affecting the spine with low-to-moderate 18 F-FDG uptake. Scintigraphy showed the characteristic "bull's head" sign with increased uptake in the manubrium and bilateral sternoclavicular joints. The second patient was a 66-year-old woman with a four-month history of back pain, who was admitted with multiple spinal lesions. The diagnosis was made after bone scintigraphy demonstrated the characteristic findings of the syndrome. Both patients lacked cutaneous lesions on presentation but reported previous skin lesions. SAPHO syndrome is a rare condition, and bone lesions associated with the disease may be misdiagnosed as bone metastases. Knowledge of the syndrome and its imaging findings is essential for accurate diagnosis and treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Faculdade Ciências Médicas de Minas Gerais issued approval 5134. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rolemberg Dantas et al.)

Skin malignant melanoma (MM) is one of the most frequent and aggressive neoplasia worldwide. Its associated high mortality rates are mostly due to its metastases, while diagnosis and treatment of MM in its early stages is of favorable prognostic. Even skin superficial MMs at incipient local stages can already present with lymph node invasion and distant metastases. Therefore, knowledge of the controllable risk factors and pathogenic mechanisms of MM development, spreading, and metastatic pattern, as well as early diagnosis, are essential to decrease the high mortality rates associated with cutaneous malignant melanoma. Genetic factors are incriminated, although lifetime-acquired genetic mutations appear to be even more frequently involved in the development of MM. Skin melanocytes divide only twice per year and have time to accumulate genetic mutations as a consequence of environmental aggressive factors, such as UV exposure. In the search for more promising therapies, matrix metalloproteinases have become of significant interest, such as MMP-1, MMP-2, MMP-9, and MMP-13, which have been linked to more aggressive forms of cancer and earlier metastases. Therefore, the development of specific synthetic inhibitors of MMP secretion or activity could represent a more promising and effective approach to the personalized treatment of MM patients.

Painful skeletal osteolytic metastases, impending pathological fractures, and nondisplaced fractures present as a devastating clinical problem in advanced stage cancer patients. Open surgical approaches provide excellent mechanical stabilization but are often associated with high complication rates and slow recovery times. Percutaneous minimally invasive interventions have arisen as a pragmatic and logical treatment option for patients with late-stage cancer in whom open surgery may be contraindicated. These percutaneous interventions minimize soft tissue dissection, allow for the immediate initiation or resumption of chemotherapies, and present with fewer complications. This review provides the most up-to-date technical and conceptual framework for the minimally invasive management of osseous metastases with particular focus on periacetabular lesions. Fundamental topics discussed are as follows: (1) pathogenesis of cancer-induced bone loss and the importance of local cytoreduction to restore bone quality, (2) anatomy and biomechanics of the acetabulum as a weight-bearing zone, (3) overview of ablation options and cement/screw techniques, and (4) combinatorial approaches. Future studies should include additional studies with more long-term follow-up to better assess mechanical durability of minimally invasive interventions. An acetabulum-specific functional and pain scoring framework should be adopted to allow for better cross-study comparison., (Thieme. All rights reserved.)

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10 -null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10 -null cells. Mouse Hras thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, G12V /Rbm1O KO thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers., Competing Interests: J.A.F. is a co-inventor of intellectual property focused on HRAS as a biomarker for treating cancer using tipifarnib which has been licensed by MSK to Kura Oncology. J.A.F. received prior research funding from Eisai and was a former consultant for LOXO Oncology, both unrelated to the current manuscript. B.R.U. and J.A.K are co-inventors of intellectual property (HRAS as a biomarker of tipifarnib efficacy) that has been licensed by MSK to Kura Oncology. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder. O.A.-W. has received prior research funding from H3B Biomedicine, Nurix Therapeutics, Minovia Therapeutics, and LOXO Oncology unrelated to the current manuscript. R.K.B. is an inventor on patent applications filed by Fred Hutchinson Cancer Center related to modulating splicing for cancer therapy. R.K.B. and O.A.-W. are founders and scientific advisors of Codify Therapeutics, hold equity in this company and receive research support from this company unrelated to the current manuscript. R.K.B. is a founder and scientific advisor of Synthesize Bio and holds equity in this company. A.R.G is currently an Associate Professor of Surgery at the University of Sydney, Australia. M.S. is currently employed by Loxo Oncology.The remaining authors declare no competing interests.