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The aim of this study is to evaluate Breast Imaging Reporting and Data Systems (BI-RADS) 4A/B subcategory risk estimates for ductal carcinoma in situ (DCIS) and invasive cancer (IC), determining whether changing the proposed cutoffs to a higher biopsy thre

This paper presents an evaluation of a prototype diffuse optical tomography (DOT) system. Seventeen women with 18 breast lesions (10 invasive carcinomas, 2 fibroadenomas, and 6 benign cysts; diameters 13-54 mm) were evaluated with DOT and magnetic resonance imaging (MRI). A substantial fraction of the original 36 recruited patients could not be examined using this prototype due to technical problems. A region of interest (ROI) was drawn at the lesion position as derived from MRI and at the mirror image site in the contralateral healthy breast. ROIs were assessed quantitatively and qualitatively by two observers independently in two separate readings. Intra- and interobserver agreements were calculated using kappa statistics (k) and intraclass correlation coefficients (ICCs). Discriminatory values for presence of malignancy were determined by receiver operating characteristic (ROC) analyses. Intraobserver agreements were excellent (k 0.88 and 0.88; ICC 0.978 and 0.987), interobserver agreements were good to excellent (k 0.77-0.95; ICC 0.96-0.98). Discriminatory values for presence of malignancy were 0.92-0.93 and 0.97-0.99 for quantitative and qualitative ROC analysis, respectively. This DOT system has the potential to discriminate malignant from benign breast tissue in a reproducible qualitative and quantitative manner. Important technical improvements are required before this technique is ready for clinical application. [ABSTRACT FROM AUTHOR]

Introduction: The association of body composition with checkpoint inhibitor outcomes in melanoma is a matter of ongoing debate. In this study, we aim to investigate body mass index (BMI) alongside CT-derived body composition metrics in the largest cohort to date., Methods: Patients treated with first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were retrospectively identified from 11 melanoma centers in The Netherlands. From baseline CT scans, five body composition metrics were extracted: subcutaneous adipose tissue index, visceral adipose tissue index and skeletal muscle index, density and gauge. These metrics were correlated in uni- and multivariable Cox proportional hazards analysis with progression-free, overall and melanoma-specific survival (PFS, OS and MSS)., Results: A total of 1471 eligible patients were included. Median PFS and OS were 9.1 and 38.1 months, respectively. Worse PFS was observed in underweight patients (multivariable HR = 1.86, 95% CI 1.14-3.06). Furthermore, prolonged OS was observed in patients with higher skeletal muscle density (multivariable HR = 0.88, 95% CI 0.81-0.97) and gauge (multivariable HR = 0.61, 95% CI 0.82-0.998), whereas higher visceral adipose tissue index was associated with worse OS (multivariable HR = 1.12, 95% CI 1.04-1.22). No association with survival outcomes was found for overweight, obesity or subcutaneous adipose tissue., Discussion: Our findings suggest that underweight BMI is associated with worse PFS, whereas higher skeletal muscle density and lower visceral adipose tissue index were associated with improved OS. These associations were independent of known prognostic factors, including sex, age, performance status and extent of disease. No significant association between higher BMI and survival outcomes was observed., (© The Author(s) 2025. Published by Oxford University Press.)

Intrapatient heterogeneity of estrogen receptor (ER) expression on 16α-[ 18 F]fluoro-17β-estradiol ([ 18 F]FES) PET is related to outcome in patients with ER-positive metastatic breast cancer (MBC), but a validated and practical method to support clinical decision-making is lacking. Therefore, the [ 18 F]FES PET heterogeneity score (i.e., percentage of [ 18 F]FES-positive metastases) was validated as a prognostic factor for endocrine therapy response and survival in a large cohort of patients with newly diagnosed MBC. Furthermore, we explored 2 less laborious methods to predict the [ 18 F]FES PET heterogeneity score. Methods: Patients with ER-positive MBC included in the IMPACT-MBC study, who received baseline [ 18 F]FES and [ 18 F]FDG PET and first-line endocrine therapy, were included in this subanalysis. ER homogeneous (100% [ 18 F]FES-positive lesions) and ER heterogeneous (both [ 18 F]FES-positive and [ 18 F]FES-negative lesions) MBC was distinguished by manual segmentation of all lesions on [ 18 F]FES PET and related to progression-free survival (PFS) and overall survival (OS). In addition, the positive predictive value of the visual assessment and the 5-largest-lesions assessment to predict homogeneous MBC in all lesions on [ 18 F]FES PET was determined. Results: From the 102 MBC patients eligible for the present retrospective subanalysis, 46 had ER homogeneous MBC and 56 had ER heterogeneous MBC. Differences were found between ER homogeneous and ER heterogeneous MBC for median PFS (19.8 vs. 15.0 mo; hazard ratio, 0.63; 95% CI, 0.41-0.96; P = 0.03) and median OS (62.5 vs. 34.7 mo; hazard ratio, 0.65; 95% CI, 0.38-1.08; P = 0.09). Twenty-one (38%) of 61 patients with ER homogeneous MBC by visual analysis and 37 (45%) of 83 patients with ER homogeneous MBC by the 5-largest-lesions method had ER heterogeneous MBC by manual segmentation of all lesions on [ 18 F]FES PET (positive predictive value, 0.66 and 0.55, respectively). Conclusion: Patients with ER-positive homogeneous MBC showed a trend toward superior PFS and OS compared with patients with ER heterogeneous MBC. This analysis confirmed and validated the prognostic value of the [ 18 F]FES PET heterogeneity score for endocrine therapy response and survival in a large cohort of MBC patients. The less laborious visual and 5-largest-lesions methods were inferior compared with assessment based on the [ 18 F]FES PET heterogeneity score in all lesions., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To evaluate dosimetry, dose-response and dose-toxicity relationships for holmium-166 ( 166 Ho) radioembolisation in patients with hepatocellular carcinoma (HCC)., Methods: Thirty-one patients with hepatocellular carcinoma were included in the HEPAR Primary study (NCT03379844, registered on December 20th, 2017) and underwent 166 Ho-microspheres radioembolisation. Linear mixed models assessed the association between tumour absorbed doses and response based on mRECIST both on tumour and patient level. Preliminary tumour absorbed dose thresholds were estimated based on predictive value. Linear regression models assessed the association between non-tumour absorbed dose and Common Terminology Criteria for Adverse Events version 4.03., Results: Median tumour absorbed dose (tumour level) was 95.5 Gy (range 44-332 Gy). Median non-tumour absorbed dose based on whole liver volume was 19 Gy (range 3 - 48 Gy) and based on target liver volume was 30 Gy (range 13 - 54 Gy). There was a significant association between non-tumour absorbed dose and toxicity. Tumours with partial response/complete response (PR/CR, responders) received a 41% higher absorbed dose than tumours with progressive disease/stable disease (PD/SD, non-responders) (95%CI: 2%-93%, p = 0.04). A predictive value of 90% for tumour response was observed at a tumour absorbed dose threshold of 155 Gy, 100% predictive value was achieved at 184.5 Gy., Conclusion: This study confirms a positive relationship between tumour absorbed dose and response and between non-tumour absorbed dose and toxicity. Dose thresholds found in this study can serve as a basis for personalized dosimetry in HCC patients treated with 166 Ho-microspheres., Competing Interests: Declarations. Ethics approval: This clinical study was approved by the Medical Ethics Committee of University Medical Centre Utrecht and Erasmus Medical Centre and by the institutional radiation protection committee. Furthermore, this study was performed in concordance with Good Clinical Practice and the declaration of Helsinki. Consent to participate: All participants provided written, informed consent before undergoing any study-specific activity. Conflicts of interest: Margot Reinders-Hut is currently employed by Genmab B.V., acted as a speaker for Boston Scientific. Marnix Lam acts as a consultant for Terumo, Quirem Medical and Boston Scientific, receives research support from Terumo, Quirem Medical and Boston Scientific. Maarten Smits and Arthur Braat are consultants for Terumo. The department of Radiology and Nuclear Medicine of the University Medical Centre Utrecht receives royalty payments from Quirem Medical., (© 2024. The Author(s).)

Purpose: In this study, we aimed to explore if the combination of tumor infiltrating lymphocytes (TILs) and change in tumor load on dynamic contrast-enhanced magnetic resonance imaging leads to better assessment of response to neoadjuvant chemotherapy (NAC) in patients with breast cancer, compared to either alone., Methods: In 190 NAC treated patients, MRI scans were performed before and at the end of treatment. The percentage of stromal TILs (%TILs) was assessed in pre-NAC biopsies according to established criteria. Prediction models were developed with linear regression by least absolute shrinkage and selection operator and cross validation (CV), with residual cancer burden as the dependent variable. Discrimination for pathological complete response (pCR) was evaluated using area under the receiver operating characteristic curves (AUC). We used Cox regression analysis for exploring the association between %TILs and recurrence-free survival (RFS)., Results: Fifty-one patients reached pCR. In all patients, the %TILs model and change in MRI tumor load model had an estimated CV AUC of 0.69 (95% confidence interval (CI) 0.53-0.78) and 0.69 (95% CI 0.61-0.79), respectively, whereas a model combining the variables resulted in an estimated CV AUC of 0.75 (95% CI 0.66-0.83). In the group with tumors that were ER positive and HER2 negative (ER+/HER2-) and in the group with tumors that were either triple negative or HER2 positive (TN&HER2+) separately, the combined model reached an estimated CV AUC of 0.72 (95% CI 0.60-0.88) and 0.70(95% CI 0.59-0.82), respectively. A significant association was observed between pre-treatment %TILS and RFS (hazard ratio (HR) 0.72 (95% CI 0.53-0.98), for every standard deviation increase in %TILS, p = 0.038)., Conclusion: The combination of TILs and MRI is informative of response to NAC in patients with both ER+/HER2- and TN&HER2+ tumors., Competing Interests: Declarations. Competing interests: All authors have declared no conflict of interest. Ethical approval: Cohort A: Requirement for informed consent and ethical review was waived by the institutional review board (Medical Research Ethics Committee Utrecht, No. 19-245). Cohort B: study was approved by the Medical Ethics Review Committee of the University Medical Center Utrecht (No. 19-396, NL67308.041.19)., (© 2024. The Author(s).)

Immune checkpoint inhibitor (ICI) treatment has proven successful for advanced melanoma, but is associated with potentially severe toxicity and high costs. Accurate biomarkers for response are lacking. The present work is the first to investigate the value of deep learning on CT imaging of metastatic lesions for predicting ICI treatment outcomes in advanced melanoma. Adult patients that were treated with ICI for advanced melanoma were retrospectively identified from ten participating centers. A deep learning model (DLM) was trained on volumes of lesions on baseline CT to predict clinical benefit. The DLM was compared to and combined with a model of known clinical predictors (presence of liver and brain metastasis, level of lactate dehydrogenase, performance status and number of affected organs). A total of 730 eligible patients with 2722 lesions were included. The DLM reached an area under the receiver operating characteristic (AUROC) of 0.607 [95%CI 0.565-0.648]. In comparison, a model of clinical predictors reached an AUROC of 0.635 [95%CI 0.59 -0.678]. The combination model reached an AUROC of 0.635 [95% CI 0.595-0.676]. Differences in AUROC were not statistically significant. The output of the DLM was significantly correlated with four of the five input variables of the clinical model. The DLM reached a statistically significant discriminative value, but was unable to improve over known clinical predictors. The present work shows that the assessment over known clinical predictors is an essential step for imaging-based prediction and brings important nuance to the almost exclusively positive findings in this field., Competing Interests: Declarations. Competing interests: AvdE has advisory relationships with Bristol-Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre and has received research study grants not related to this paper from Sanofi, Bristol-Myers Squibb, TEVA, Idera and has received travel expenses MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre and has received speaker honoraria from BMS and Novartis. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. PJ has a research collaboration with Philips Healthcare and Vifor Pharma. MBS has consultancy/advisory relationships with Pierre Fabre, MSD and Novartis, none related to current work and paid to institute. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, Bayer, EISAI and Ipsen paid to the institute, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre Fabre. PD has consultancy/advisory relationships with Paige, Pantarei and Samantree paid to the institution and research grants from Pfizer, none related to current work and paid to institute. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, AbbVie, Sairopsa and received honoraria from Novartis and MSD and research funding from Bristol Myers Squibb, TigaTx and Philips. TL has received research funding from Philips. GH consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research grants from Bristol-Myers Squibb, Seerave. All payments to the Institution. HW received honoraria from Merck, Astellas, Roche and travel expenses from Ipsen and Astellas. All remaining authors have declared no conflicts of interest., (© 2024. The Author(s).)

Background: International consensus on classifications of appendiceal mucinous neoplasms (AMNs) and associated pseudomyxoma peritonei (PMP) have been carefully made but clinicopathological associations supporting decision making remain scarce., Objective: This study aimed to assess interdependence between AMNs and PMP and provide directions for clinical management., Methods: This two-center retrospective cohort study reviewed patients with PMP treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between 2005 and 2021. The primary objective was to reassess histopathologic grade of AMNs and PMP according to the Peritoneal Surface Oncology Group International classification and to establish its interdependence. Secondary outcomes were recurrence rate, PMP grade progression, ovarian involvement, and overall survival (OS)., Results: Of 105 patients included, 78 (74.3%) had low-grade AMNs as the primary tumor, 8 (7.6%) had high-grade AMNs, 7 (6.7%) had mucinous adenocarcinoma (MAC), 1 (0.9%) had MAC with signet ring cells (SRC), and 11 (10.5%) had unidentified tumors. Overall, 11 patients (10.5%) had no PMP, 21 (20.0%) had acellular mucin, 56 (53.3%) had low-grade PMP, 12 (11.4%) had high-grade PMP, and 5 (4.8%) had PMP-SRC. In 11 cases (13.3%), AMNs and matching PMP grade differed. Over a 16-year follow-up, recurrence occurred in 31.8%, with three cases showing histopathologically changed PMP. Ovarian involvement was observed in 43/65 females (66.2%). Median OS was 13.8 years, and 5-year OS rates were 100%, 74.4%, 44.4%, and 20% for acellular mucin, low-grade PMP, high-grade PMP and PMP-SRC, respectively (p < 0.001)., Conclusions: AMN histology does not always reflects its associated PMP grade, while PMP grade strongly influences survival. Ovarian involvement and recurrent PMP showing unchanged histopathological features are common., (© 2024. Society of Surgical Oncology.)

Background:  Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals., Methods:  In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists., Results:  1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91)., Conclusion:  Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies., Competing Interests: The authors declare that P. Siersema received grants or speaker's fees from Pentax Japan, The E-Nose Company The Netherlands, Microtech China, Lucid Diagnostics USA, Magentiq Eye Israel, Norgine UK/The Netherlands, and Motus GI USA; A. Masclee received research grants from the Dutch Cancer Society (KWF) and the Dutch Organization for Health Research and Innovation (ZonMW); L. Moons acts as a consultant for Boston Scientific. The other authors declare that no conflicts of interest exist., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

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.)

Objectives: Insight into the aggressiveness of potential breast cancers found in screening may optimize recall decisions. Specific growth rate (SGR), measured on mammograms, may provide valuable prognostic information. This study addresses the association of SGR with prognostic factors and overall survival in patients with invasive carcinoma of no special type (NST) from a screened population., Methods: In this historic cohort study, 293 women with NST were identified from all participants in the Nijmegen screening program (2003-2007). Information on clinicopathological factors was retrieved from patient files and follow-up on vital status through municipalities. On consecutive mammograms, tumor volumes were estimated. After comparing five growth functions, SGR was calculated using the best-fitting function. Regression and multivariable survival analyses described associations between SGR and prognostic factors as well as overall survival., Results: Each one standard deviation increase in SGR was associated with an increase in the Nottingham prognostic index by 0.34 [95% confidence interval (CI): 0.21-0.46]. Each one standard deviation increase in SGR increased the odds of a tumor with an unfavorable subtype (based on histologic grade and hormone receptors; odds ratio 2.14 [95% CI: 1.45-3.15]) and increased the odds of diagnosis as an interval cancer (versus screen-detected; odds ratio 1.57 [95% CI: 1.20-2.06]). After a median of 12.4 years of follow-up, 78 deaths occurred. SGR was not associated with overall survival (hazard ratio 1.12 [95% CI: 0.87-1.43])., Conclusions: SGR may indicate prognostically relevant differences in tumor aggressiveness if serial mammograms are available. A potential association with cause-specific survival could not be determined and is of interest for future research., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy., Methods: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m 2 ) with intravenous leucovorin (20 mg/m 2 ) and 5-fluorouracil (400 mg/m 2 ). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS)., Results: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached)., Conclusions: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor., Patients and Methods: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098., Results: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm., Conclusions: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD., Methods: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation., Results: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration., Conclusions: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program., Methods: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups., Results: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68)., Conclusions: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival., Competing Interests: M. Koopman has an advisory role for Eisai, Nordic Farma, Merck-Serono, Pierre Fabre, and Servier and has received institutional grants from Bayer, Bristol Myers Squibb, Merck, Personal Genome Diagnostics (PGDx), Pierre Fabre, Roche, Sirtex, and Servier. G.R. Vink has received institutional grants from BMS, Merck, Servier, Personal Genome, Diagnostics, Bayer, Sirtex, Pierre Fabre, Lilly, and Delfi Diagnostics. F.P. Vleggaar is a consultant for Boston Scientific. L.M.G. Moons is a consultant for Boston Scientific. L. van der Schee, K.J.C. Haasnoot, S.G. Elias, K.M. Gijsbers, Y.A. Alderlieste, Y. Backes, A.-M. van Berkel, F. Boersma, F. ter Borg, E.C.H. Breekveldt, K. Kessels, I. Lansdorp-Vogelaar, M.E. van Leerdam, G. Rasschaert, R.-M. Schreuder, R.W.M. Schrauwen, T.C.J. Seerden, M.B.W.M. Spanier, J.S. Terhaar Sive Droste, E. Toes-Zoutendijk, J.B. Tuynman, W.H. de Vos tot Nederveen Cappel, and M.M. Laclé declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies., Methods: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness., Results: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003)., Conclusions: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens., (© 2024. The Author(s).)

Background: In metastatic breast cancer (MBC), [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [ 18 F]FDG uptake in corresponding metastases., Patients and Methods: Patients with non-rapidly progressive MBC of all subtypes prospectively underwent a baseline histological metastasis biopsy and [ 18 F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [ 18 F]FDG uptake was expressed as maximum standardized uptake value (SUV max ) and results were expressed as geometric means., Results: Of 200 patients, 188 had evaluable metastasis biopsies, and 182 of these contained tumor. HER2 positivity and Ki-67 ≥ 20% were correlated with higher [ 18 F]FDG uptake (estimated geometric mean SUV max 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [ 18 F]FDG uptake was lowest in ER-positive/HER2-negative BC and highest in HER2-positive BC (geometric mean SUV max 6.8 and 10.0, respectively; p = 0.0058). Although [ 18 F]FDG uptake was lower in invasive lobular carcinoma ( n = 31) than invasive carcinoma NST ( n = 146) (estimated geometric mean SUV max 5.8 versus 7.8; p = 0.014), the metastasis detection rate was similar., Conclusions: [ 18 F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [ 18 F]FDG uptake, [ 18 F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332).

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer., (© 2024. The Author(s).)

Purpose: The FLAME trial (NCT01168479) showed that isotoxic focal boosting to the intraprostatic lesion(s) in patients with intermediate- and high-risk prostate cancer improves 5-year disease-free survival (DFS). Although the near-minimum dose to the gross tumor volume (D98%) was associated with improved outcomes, a closer look suggested that this might not be the same for all patients. Therefore, we investigated whether risk factors that are associated with a benefit of focal boosting can be identified., Methods and Materials: We described the distribution of clinical characteristics and the number of high-risk factors with respect to the D98% in 526 FLAME trial patients. We used penalized Cox regression to develop a prediction model. To investigate a potential benefit in patient subgroups, we compared the model-based predictions of 5-year DFS assuming standard whole-gland radiation therapy of 77 Gy to the predictions assuming an additional focal boost with D98% of 95 Gy., Results: Patients with high-risk factors were well represented in the group of 120 patients that received D98% > 85 Gy and showed fewer recurrences compared with the group that received 77 Gy. Applying the model simulating a standard dose of 77 Gy, we predicted a high DFS for grade group (GG) 1 patients, whereas patients with high-risk characteristics appeared to show a low DFS. All risk groups showed a high level of DFS when simulating D98% of 95 Gy., Conclusions: Our results suggest that GG 1 patients already show a low level of failure at a standard dose of 77 Gy, limiting the additional benefit of focal boosting. In contrast, patients with high-risk characteristics, especially GG 4 or 5, show a low 5-year DFS, while focal boosting might improve this substantially. This suggests that reaching a high focal boost dose may be particularly beneficial for these patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Prior studies on the effect of smoking on the risk of colitis-associated colorectal neoplasia (CRN) have reported conflicting results. We aimed to further elucidate the association between smoking, including possible dose-effects, and the development of colorectal neoplasia in patients with inflammatory bowel disease (IBD)., Methods: We performed a prospective multicenter cohort study including patients with colonic IBD enrolled in a surveillance program in four academic hospitals between 2011 and 2021. The effects of smoking status and pack-years at study entry on subsequent recurrent events of CRN (including indefinite, low- and high-grade dysplasia, and colorectal cancer [CRC]) were evaluated using uni- and multivariable Prentice, Williams, and Peterson total-time Cox proportional hazard models. Adjustment was performed for extensive disease, prior/index dysplasia, sex, age, first-degree relative with CRC, primary sclerosing cholangitis, and endoscopic inflammation., Results: In 501 of the enrolled 576 patients, at least one follow-up surveillance was performed after the study index (median follow-up 5 years). CRN occurred at least once in 105 patients. Ever smoking was not associated with recurrent CRN risk (adjusted hazard ratio [aHR] 1.04, 95% confidence interval [CI] 0.75-1.44), but an increasing number of pack-years was associated with an increased risk of recurrent CRN (aHR per 10 pack-years 1.17, 95% CI 1.03-1.32; p < 0.05). Separate analyses per IBD type did not reveal differences., Conclusions: This study found that an increase in pack-years is associated with a higher risk of recurrent CRN in patients with IBD, independent of established CRN risk factors (NCT01464151)., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins., (© 2023. Springer Nature Limited.)

Introduction: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT., Methods and Analysis: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction., Ethics and Dissemination: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals., Trial Registration Number: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int)., Competing Interests: Competing interests: The departments of radiotherapy of both the UMC Utrecht and the Netherlands Cancer Institute have received funding from Elekta, Sweden and Philips Healthcare. PS reports consulting fees from MSD and Bayer and fees for MEDtalks educational presentations. RF reports grants from Personal Genome Diagnostics, Delfi Diagnostics, Cergentis and Merck. HMV is a member of the European Commission and the Netherlands Organization of Health Research and Development and reports grants from the Dutch Cancer Foundation. MI has received personal fees from Elekta, Sweden., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Poor prognosis in colon cancer is associated with a high content of cancer-associated fibroblasts (CAFs) and an immunosuppressive tumor microenvironment. The relationship between these two features is incompletely understood. Here, we aimed to generate a model system for studying the interaction between cancer cells and CAFs and their effect on immune-related cytokines and T cell proliferation., Methods: CAFs were isolated from colon cancer liver metastases and were immortalized to prolong lifespan and improve robustness and reproducibility. Established medium and matrix compositions that support the growth of patient-derived organoids were adapted to also support CAF growth. Changes in growth pattern and cellular re-organization were assessed by confocal microscopy, live cell imaging, and immunofluorescence. Single cell RNA sequencing was used to study CAF/organoid co-culture-induced phenotypic changes in both cell types. Conditioned media were used to quantify the production of immunosuppressive factors and to assess their effect on T cell proliferation., Results: We developed a co-culture system in which colon cancer organoids and CAFs spontaneously organize into superstructures with a high capacity to contract and stiffen the extracellular matrix (ECM). CAF-produced collagen IV provided a basement membrane supporting cancer cell organization into glandular structures, reminiscent of human cancer histology. Single cell RNA sequencing analysis showed that CAFs induced a partial epithelial-to-mesenchymal-transition in a subpopulation of cancer cells, similar to what is observed in the mesenchymal-like consensus molecular subtype 4 (CMS4) colon cancer. CAFs in co-culture were characterized by high expression of ECM components, ECM-remodeling enzymes, glycolysis, hypoxia, and genes involved in immunosuppression. An expression signature derived from CAFs in co-culture identified a subpopulation of glycolytic myofibroblasts specifically residing in CMS1 and CMS4 colon cancer. Medium conditioned by co-cultures contained high levels of the immunosuppressive factors TGFβ1, VEGFA and lactate, and potently inhibited T cell proliferation., Conclusion: Co-cultures of organoids and immortalized CAFs recapitulate the histological, biophysical, and immunosuppressive features of aggressive mesenchymal-like human CRC. The model can be used to study the mechanisms of immunosuppression and to test therapeutic strategies targeting the cross-talk between CAFs and cancer cells. It can be further modified to represent distinct colon cancer subtypes and (organ-specific) microenvironments., 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 © 2023 Strating, Verhagen, Wensink, Dünnebach, Wijler, Aranguren, De la Cruz, Peters, Hageman, van der Net, van Schelven, Laoukili, Fodde, Roodhart, Nierkens, Snippert, Gloerich, Rinkes, Elias and Kranenburg.)