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Background: Histopathological growth patterns are one of the strongest prognostic factors in patients with resected colorectal liver metastases. Development of an efficient, objective and ideally automated histopathological growth pattern scoring method can substantially help the implementation of histopathological growth pattern assessment in daily practice and research. This study aimed to develop and validate a deep-learning algorithm, namely neural image compression, to distinguish desmoplastic from non-desmoplastic histopathological growth patterns of colorectal liver metastases based on digital haematoxylin and eosin-stained slides., Methods: The algorithm was developed using digitalized whole-slide images obtained in a single-centre (Erasmus MC Cancer Institute, the Netherlands) cohort of patients who underwent first curative intent resection for colorectal liver metastases between January 2000 and February 2019. External validation was performed on whole-slide images of patients resected between October 2004 and December 2017 in another institution (Radboud University Medical Center, the Netherlands). The outcomes of interest were the automated classification of dichotomous hepatic growth patterns, distinguishing between desmoplastic hepatic growth pattern and non-desmoplatic growth pattern by a deep-learning model; secondary outcome was the correlation of these classifications with overall survival in the histopathology manual-assessed histopathological growth pattern and those assessed using neural image compression., Results: Nine hundred and thirty-two patients, corresponding to 3.641 whole-slide images, were reviewed to develop the algorithm and 870 whole-slide images were used for external validation. Median follow-up for the development and the validation cohorts was 43 and 29 months respectively. The neural image compression approach achieved significant discriminatory power to classify 100% desmoplastic histopathological growth pattern with an area under the curve of 0.93 in the development cohort and 0.95 upon external validation. Both the histopathology manual-scored histopathological growth pattern and neural image compression-classified histopathological growth pattern achieved a similar multivariable hazard ratio for desmoplastic versus non-desmoplastic growth pattern in the development cohort (histopathology manual score: 0.63 versus neural image compression: 0.64) and in the validation cohort (histopathology manual score: 0.40 versus neural image compression: 0.48)., Conclusions: The neural image compression approach is suitable for pathology-based classification tasks of colorectal liver metastases., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: As differentiating between lipomas and atypical lipomatous tumors (ALTs) based on imaging is challenging and requires biopsies, radiomics has been proposed to aid the diagnosis. This study aimed to externally and prospectively validate a radiomics model differentiating between lipomas and ALTs on MRI in three large, multi-center cohorts, and extend it with automatic and minimally interactive segmentation methods to increase clinical feasibility., Methods: Three study cohorts were formed, two for external validation containing data from medical centers in the United States (US) collected from 2008 until 2018 and the United Kingdom (UK) collected from 2011 until 2017, and one for prospective validation consisting of data collected from 2020 until 2021 in the Netherlands. Patient characteristics, MDM2 amplification status, and MRI scans were collected. An automatic segmentation method was developed to segment all tumors on T1-weighted MRI scans of the validation cohorts. Segmentations were subsequently quality scored. In case of insufficient quality, an interactive segmentation method was used. Radiomics performance was evaluated for all cohorts and compared to two radiologists., Findings: The validation cohorts included 150 (54% ALT), 208 (37% ALT), and 86 patients (28% ALT) from the US, UK and NL. Of the 444 cases, 78% were automatically segmented. For 22%, interactive segmentation was necessary due to insufficient quality, with only 3% of all patients requiring manual adjustment. External validation resulted in an AUC of 0.74 (95% CI: 0.66, 0.82) in US data and 0.86 (0.80, 0.92) in UK data. Prospective validation resulted in an AUC of 0.89 (0.83, 0.96). The radiomics model performed similar to the two radiologists (US: 0.79 and 0.76, UK: 0.86 and 0.86, NL: 0.82 and 0.85)., Interpretation: The radiomics model extended with automatic and minimally interactive segmentation methods accurately differentiated between lipomas and ALTs in two large, multi-center external cohorts, and in prospective validation, performing similar to expert radiologists, possibly limiting the need for invasive diagnostics., Funding: Hanarth fonds., Competing Interests: JV received a grant to institution from Qure.ai/HealthHolland/Enlitic; consulting fees from Tegus; payment to institution for lectures from Roche; travel grant from Qure.ai; participation on a data safety monitoring board or advisory board from Contextflow, Noaber Foundation, and NLC Ventures; leadership or fiduciary role on the steering committee of the PINPOINT Project (payment to institution from AstraZeneca) and RSNA Common Data Elements Steering Committee (unpaid); phantom shares in Contextflow and Quibim; chair scientific committee EuSoMII (unpaid); chair ESR value-based radiology subcommittee (unpaid); member editorial board European Journal of Radiology (unpaid). SD and RJ received support from the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, and by The Royal Marsden Cancer Charity. RJ recieved consulting fees from Adaptimmune/Astex/Athenex/Bayer/B.I./Blueprint/Clinigen/Eisai/Epizyme/Daiichi/Deciphera/Immune Design/Immunicum/Karma Oncology/Lilly/Merck/PharmaMar/Tracon; LN is supported by the In Vivo Translational Imaging Shared Resources with funds from NCI P30CA093373; is principal investigator of a service agreement with United Imaging Healthcare; has been the PI of more than 1 service agreements with United Imaging Healthcare; is site PI of clinical trials supported by Novartis Pharmaceuticals Corporation; is PI of a clinical trial supported by Telix Pharmaceuticals; is PI of clinical trial supported by Lantheus Medical Imaging; is PI of a clinical trials supported by GE Healthcare; is Co-I of a clinical trial supported by Lilly; has a speaker engagement agreement with Lilly; served a panel reviewer for the European Health and Digital Executive Agency. UC Davis has a revenue-sharing agreement with United Imaging Healthcare that is based on uEXPLORER sales. SK is scientific director of the ICAI lab “Trustworthy AI for MRI”, a public-private research program partially funded by General Electric Healthcare. SK and MS received an unrestricted research grant from Stichting Hanarth Fonds, The Netherlands. MS acknowledge funding from the research project EuCanImage (European Union's Horizon 2020 research and innovation programme under grant agreement Nr. 95210). The other authors do not have any conflicts of interest., (© 2024 The Author(s).)

Prostate-specific membrane antigen (PSMA) tracers have increased sensitivity in the detection of prostate cancer, compared with conventional imaging. We assessed the management impact of 18 F-DCFPyL PSMA PET/CT in patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) and report early biochemical response in patients who underwent radiation treatment. Methods: One hundred patients were enrolled into a prospective study, with a prior RP for prostate cancer, a PSA of 0.2-2.0 ng/mL, and no prior treatment. All patients underwent diagnostic CT and PSMA PET/CT, and management intent was completed at 3 time points (original, post-CT, and post-PSMA) and compared. Patients who underwent radiotherapy with 6-mo PSA response data are presented. Results: Ninety-eight patients are reported, with a median PSA of 0.32 ng/mL (95% CI, 0.28-0.36), pT3a/b disease in 71.4%, and an International Society of Urological Pathology grade group of at least 3 in 59.2%. PSMA PET/CT detected disease in 46.9% of patients, compared with 15.5% using diagnostic CT (PSMA PET, 29.2% local recurrence and 29.6% pelvic nodal disease). A major change in management intent was higher after PSMA than after CT (12.5% vs. 3.2%, P = 0.010), as was a moderate change in intent (31.3% vs. 13.7%, P = 0.001). The most common change was an increase in the recommendation for elective pelvic radiation (from 15.6% to 33.3%), nodal boost (from 0% to 22.9%), and use of concurrent androgen deprivation therapy (ADT) (from 22.9% to 41.7%) from original to post-PSMA intent because of detection of nodal disease. Eighty-six patients underwent 18 F-DCFPyL-guided radiotherapy. Fifty-five of 86 patients either did not receive ADT or recovered after ADT, with an 18-mo PSA response from 0.32 to 0.02 ng/mL; 94.5% of patients had a PSA of no more than 0.20 ng/mL, and 74.5% had a PSA of no more than 0.03 ng/mL. Conclusion: 18 F-DCFPyL PET/CT has a significant impact on management intent in patients being considered for salvage radiotherapy after RP with PSA recurrence. Increased detection of disease, particularly in the pelvic lymph nodes, resulted in increased pelvic irradiation and concurrent ADT use. Early results in patients who are staged with 18 F-DCFPyL PET/CT show a favorable PSA response., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: To investigate the impact on efficiency and quality of preprostatectomy multidisciplinary therapy conferences (MDT) at Karolinska University Hospital related to the use of a digital solution compared with standard of care. Further, to explore whether gains in MDT efficiency and quality impact oncological or functional patient outcomes., Methods: We conducted a prospective, observational study of preoperative prostate cancer MDT at Karolinska between February 2017 and March 2021, including 1329 patients. We compared efficiency and quality of the standard MDT and the MDT using the digital solution IntelliSpace Precision Medicine Multidisciplinary Team Orchestrator (ISPM) based on the previously used MDT-MODe approach. Clinical and patient-reported functional outcomes were derived from the medical records and the Swedish National Prostate Cancer Register., Results: While ISPM was used during the MDT meeting, the time spent per patient was reduced by 24% (p<0.001) and most of the MDT-MODe items were scored significantly higher. There was a reduction in pelvic lymph-node dissection procedures in the ISPM cohort (p=0.001) and an increased proportion of unilateral nerve-sparing procedures (p=0.005), while all other outcome-related measures were not significantly different between the two patient groups., Discussion and Conclusion: To increase the value of the MDT, all data relevant for treatment decision need to be purposefully presented and compiled, which also enables secondary use of the data.The use of a digital solution during preoperative MDTs for prostate cancer decision making at Karolinska University Hospital improved the efficiency and quality of this multidisciplinary team meeting without impacting patient outcomes., Competing Interests: Competing interests: RH, MdK-S, PV, MCWG, HH and MJ are employees of Philips Research, Eindhoven, Netherlands., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Prostate-specific membrane antigen (PSMA) PET/CT is increasingly used in patients with biochemical recurrence post prostatectomy to detect local recurrence and metastatic disease at low PSA levels. The aim of this study was to assess patterns of disease detection, predictive factors and safety using [ 18 F]DCFPyL PET/CT versus diagnostic CT in patients being considered for salvage radiotherapy with biochemical recurrence post prostatectomy., Methods: We conducted a prospective trial recruiting 100 patients with detectable PSA post prostatectomy (PSA 0.2-2.0 ng/mL) and referred for salvage radiotherapy from August 2018 to July 2020. All patients underwent a PSMA PET/CT using the [ 18 F]DCFPyL tracer and a diagnostic CT. The detection rates of [ 18 F]DCFPyL PET/CT vs diagnostic CT were compared and patterns of disease are reported. Clinical patient and tumour characteristics were analysed for predictive utility. Thirty-day post-scan safety is reported., Results: Of 100 patients recruited, 98 were suitable for analysis with a median PSA of 0.32 ng/mL. [ 18 F]DCFPyL PET/CT was positive 46.4% and equivocal 5.2%, compared to 15.5% positivity for diagnostic CT. Local recurrence was detected on [ 18 F]DCFPyL PET/CT in 28.5%, nodal disease in 27.5% and bony metastases in 6.1% of patients. Both ISUP grade group (p < 0.001) and pre-scan PSA (p = 0.029) were significant predictors of [ 18 F]DCFPyL PET/CT positivity, and logistic regression generated probabilities combining the two showed improved prediction rates. No significant safety events were reported post [ 18 F]DCFPyL administration., Conclusions: [ 18 F]DCFPyL PET/CT increases detection of disease in patients with biochemical recurrence post prostatectomy compared to diagnostic CT. Patients being considered for salvage radiotherapy with a PSA >0.2 ng/mL should be considered for [ 18 F]DCFPyL PET/CT scan., Trial Registration: Australian New Zealand Clinical Trials Registry Number: ACTRN12618001530213 ( http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375932&isReview=true )., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Several questionnaires exist to assess frailty, a geriatric syndrome. None of these has been validated in older patients with rheumatoid arthritis (RA). Our objective was to assess aspects of validity of two frailty questionnaires: Groningen Frailty Indicator (GFI) and Geriatric 8 (G8) among RA patients., Methods: In a cross-sectional study among patients ≥65 years information was collected on socio-demographics, disease characteristics including comorbidities and physical function and on frailty using the GFI and G8. Content validity was assessed by linking items of the GFI and G8 to the International Classification of Functioning, Disability and Health (ICF). Classic psychometric methods were used to test hypotheses on construct validity and interpretability., Results: Eighty patients (74.6 years (SD 5.9); 66% female) participated. The GFI has more items on social and mental functions; the G8 more on functions of the digestive system (e.g. nutritional status). As hypothesised, correlations (r) with physical function (RGFI=0.54; RG8=0.56) and disease activity (RGFI=0.24; RG8=0.36) were moderate to weak. However, correlations with age (RGFI=0.20; RG8=0.11) or comorbidities (RGFI=0.30; RG8=0.16) were lower than expected. Instrument-specific thresholds classified 43 (54%) of participants as frail on the GFI and 44 (55%) on the G8; 33 (41%) were frail on both instruments., Conclusions: The GFI and G8 differ in content with more emphasis on nutritional status for the G8. Both instruments are insensitive to age and comorbidities. Before deciding on their usefulness in RA, their predictive validity for mortality and resource utilisation independent of disease activity and physical function should be further evaluated.

Background: Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation., Methods: The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263., Findings: We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21·5 (SD 21·7) in the prednisolone group and -5·2 (24·3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16·5 (95% CI -26·1 to -6·9; p=0·0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee)., Interpretation: Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease., Funding: Dutch Arthritis Society., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In non-small cell lung cancer (NSCLC), mesenchyme to epithelial transition (MET) protein abundance increases with disease stage and is implicated in resistance to tyrosine kinase inhibitors. To better clarify the impact of MET overexpression on tumor behavior, we investigated a large cohort of patients who underwent curative surgical resection to determine whether MET gene amplification or protein abundance was prognostic., Methods: Tissue microarrays (TMAs) were constructed using triplicate 1 mm cores of FFPE primary NSCLC specimens. TMAs underwent immunohistochemical (IHC) staining with the SP44 clone (Ventana) and cores were considered positive if >50% of tumor exhibited 2+ staining. The highest of triplicate values was used. MET gene amplification was detected using either SISH using Ventana's MET DNP probe or FISH using the D7S486/CEP 7 Abbott Probe. DNA was subjected to mutational profiling using Sequenom's LungCarta panel., Results: Data from two institutions comprising 763 patients (516; 68%) male were generated, including 360 stage I, 226 stage II, 160 stage III and 18 resected stage IV. High MET protein expression was detected in 25% (193/763), and was significantly more common in adenocarcinomas than squamous cell carcinoma (P<0.01). MET gene copy number (GCN) correlated with high MET protein expression by IHC (P=0.01). Increased MET protein expression was associated with EGFR and KRAS mutations (P<0.01 for both). Once polysomy was excluded, true MET gene amplification was detected in only 8/763 (1%) of samples. In multivariate analysis, neither MET protein abundance nor GCN were correlated to overall patient survival., Conclusions: MET expression by IHC and GCN amplification was not prognostic in this large Caucasian surgical series. MET's primary role remains as a therapeutic target., Competing Interests: Conflicts of Interest: G Rivalland reports personal fees from Astra-Zeneca, non-financial support from Roche, outside the submitted work. P Mitchell reports personal fees and other from Merck, personal fees and non-financial support from Roche, from Boehringer Ingelheim, non-financial support from Bristol Myers-Squibb, from Celgene, non-financial support and other from Astra-Zeneca, outside the submitted work. AL Morey reports speaking fees from Pfizer. B Solomon reports advisory Boards and Honoraria from Pfizer, Novartis, Roche-Genetech, AstraZeneca, BMS, and Merck. T John reports personal fees from Pfizer, personal fees from Roche, personal fees from AstraZeneca, personal fees from BMS, personal fees from Novartis, outside the submitted work. The other authors have no conflicts of interest to declare.

To explore in elderly patients with rheumatoid arthritis (RA) and comorbidity (1) in which order and why patients prioritize their morbidities with regard to functioning and health, (2) their beliefs about common (age-related) musculoskeletal complaints, and (3) experiences about the influence of comorbidity on medication treatment of RA. Patients between 50 and 85 years with RA and ≥ 1 comorbidity or lifestyle risk factor were invited for a semi-structured interview. Two readers coded the transcripts of the interviews, by using NVivo11 software. Fifteen patients (14 women; mean age 67 years (range 51-83 years); mean disease duration 14 years (range 1-39 years)) were interviewed. Only 3 (20%) out of 15 patients prioritized RA over their comorbidity; these patients often experienced severe functional limitations. The level of current or (perceived) future disability, risk of dependency, and the perceived lethality of a condition were considered by participants when prioritizing morbidities. Most participants had misconceptions about common age-related musculoskeletal complaints. Consequently, these participants attributed all joint complaints or even all physical complaints to RA, disregarding degenerative joint disease and physiological aging as alternative diagnoses. Half of the participants ever had to change RA medication because of comorbidity. Most of these patients had prioritized the comorbidity, sometimes even over treatment of RA disease activity. Most elderly RA patients with comorbidity prioritize the importance and treatment of comorbidity over RA. Better understanding of patients' beliefs on RA and comorbidity is essential when managing chronic conditions in elderly patients.

Objective: In this qualitative study we analyzed the (1) influence of age, comorbidity, and frailty on management goals in elderly patients with RA; (2) experiences of rheumatologists regarding the use of the Disease Activity Score at 28 joints (DAS28) to monitor disease activity; and (3) differences in management strategies in elderly patients with RA compared to their younger counterparts., Methods: Rheumatologists were purposively sampled for a semistructured interview. Two readers independently read and coded the interview transcripts. Important concepts were taxonomically categorized and combined in overarching themes by using NVivo 11 software., Results: Seventeen rheumatologists (mean age 44.8 yrs, SD 7.7 yrs; 29% male) from 9 medical centers were interviewed. Preserving an acceptable level of functioning was the most important management goal in patients ≥ 80 years and in patients with high levels of comorbidity and frailty. The DAS28 score less frequently steered the management strategy, because rheumatologists commented that comorbidity and an age-related erythrocyte sedimentation rate elevation might distort the DAS28 score. Instead, management of elderly patients highly depended on comorbidity, frailty, and their subsequent effects such as cognitive and physical decline, dependency, and polypharmacy. Presence of 1 or more of these factors frequently resulted in a less future-oriented management approach with less emphasis on the maximal prevention of joint erosions., Conclusion: The treat-to-target model is not automatically adopted in the elderly patient population. Future evidence-based RA management recommendations for elderly patients with RA are needed and should account for factors such as comorbidity and frailty.

Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)