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Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal events in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. The accumulation of Hypoxia Induced Factor (HIFα) resulting from VHL loss can promote ccRCC tumorigenesis by regulating microRNA (miRNA) expression. Here, we performed miRNA profiling and high-throughput analysis to identify a panel of VHL-dependent miRNAs in ccRCC. Validation of these miRNAs revealed the overexpression of miR-2355-5p in ccRCC cell models and primary tumors. Moreover, we showed a significant increase in circulating miR-2355-5p in plasma from patients with ccRCC. Mechanistically, miR-2355-5p overexpression was confirmed to be HIF-2α dependent. Targeting miR-2355-5p with the CRISPR/Cas9 system not only negatively disrupted the ability of ccRCC cells to stimulate angiogenesis but also decreased cell proliferation and drastically reduced tumor growth in mouse xenograft models. Finally, a miR-2355-5p pulldown assay identified five tumor suppressor genes, ACO1, BTG2, CMTM4, SLIT2, and WDFY2, as potential targets. All five genes were significantly downregulated in ccRCC tumors and mouse xenograft tumors. The results from this research demonstrate the oncogenic ability of miR-2355-5p and shed light on the possible mechanism by which this miRNA controls angiogenesis and tumor growth in VHL-deficient ccRCC., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent and approval were obtained from all the patients and the Ethics Committee of the Centre Hospitalier Universitaire de Sherbrooke, and the Université de Moncton (Approval #2021–4061). All animal experiments were performed following the Canadian Council on Animal Care from our institution and were approved by the Ethics Committee at the Université de Moncton (#19 − 01). Consent for publication: All authors approved the final version of the manuscript and the submission to this journal. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Trace elements (TE) function as essential micronutrients involved in the biochemical and physiological processes of the human body. We evaluated the baseline serum concentrations of TE as a predictor of clinical outcomes in critically ill trauma patients and monitored the concentrations of TE during the patients intensive care unit (ICU) stay. A total of 89 patients were enrolled. Within the first 24 h of patients' admission, concentrations of TE, zinc (Zn), selenium (Se), copper (Cu), manganese (Mn), and iron (Fe) were measured and monitored on the 5th and 10th day of patients ICU stay. The concentrations of Zn, Se, Cu and Mn were determined from serum using atomic absorption spectrophotometry, whereas the concentration of Fe using the photometric method. ANOVA and logistic regression analyses were used for statistical analysis with the level of significance set at 0.05. At the time of ICU admission, deficiency of Cu was observed in 11 out of 89 (0.13), Zn in 82 (0.92), Se in 5 (0.06) and Fe in 52 (0.58) patients, while excess of Mn was detected in 27 (0.30) and Cu in 3 (0.03) patients. A significant increase of Zn and Cu concentrations was observed from admission to 10th day (P < 0.001 for both), although Zn concentrations did not reach the lower limit of the reference interval. Logistic regression analysis found that only a low concentration of Zn at admission was associated with mechanical ventilation (OR = 0.78; 95%CI: 0.64-0.96; P = 0.018). Furthermore, the concentrations of TE at admission in critically ill trauma patients did not have an impact on the overall length of the ICU and hospital stay, nor on mortality., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Telehomecare monitoring (TM) in patients with cancer is a complex intervention. Research shows variations in the benefits and challenges TM brings to equitable access to care, the therapeutic relationship, self-management, and practice transformation. Further investigation into these variations factors will improve implementation processes and produce effective outcomes., Objective: This study aims to concurrently analyze implementation and evaluate the effectiveness of TM for patients receiving anticancer oral therapy. The objectives are to (1) contextualize how and why TM is implemented according to (a) site characteristics, (b) team characteristics, and (c) characteristics of patients receiving anticancer oral therapy; (2) assess TM effectiveness for recording electronic patient-reported outcome measures (ePROMs) and patient-reported experience measures (ePREMs) according to the site, implementation process, and patient characteristics; (3) describe the acceptability and feasibility of TM from the perspectives of the people directly or indirectly involved and provide evidence-based actionable guidance in anticipation of provincewide implementation., Methods: This type II hybrid effectiveness-implementation study uses a concurrent mixed methods design. Evaluability assessment is integrated into an emerging practice in 3 participating sites to enable the evaluation of implementation strategies on TM clinical outcomes. Quantitative data for ePROMs and ePREMs will be collected using validated oncology questionnaire. Descriptive statistics and repeated measures using multiple linear mixed models and generalized estimating equations analyses will be undertaken alongside interpretive descriptive coding of qualitative data. Qualitative data will be gathered from key informants guided by the RE-AIM (reach, efficacy, adoption, implementation, maintenance) framework and its extension, PRISM (practical robust implementation and sustainability model). The concurrent approach allows results at multiple stages of this study to be integrated iteratively. The methodological choice aims to provide real-world data that are rigorous, rapidly usable in practice, and transferable to other settings., Results: Questionnaires were pretested and the technological platform was codeveloped with members of the cancer care team and patients. Preparatory work was carried out to configure the TM platform and activate coordinating mechanisms between members of the cancer care team, patients, information technology experts, and the research team. A steering committee with 3 working groups was established to oversee the technological, clinical, and evaluation aspects of this study. Recruitment of patients for ePROMs started in February 2024, and data collection is expected to continue until March 2025. Interviews with members of the cancer care team began in November 2024. Full analysis should be completed by September 2025., Conclusions: This study will clarify how, why, for whom, and under what conditions TM can complement current care models. Our evaluability assessment will help to address implementation complexities and better understand intervention-to-practice operationalization so that implementation might be adapted to contextual factors without potentially harmful or inequitable impacts on patients., International Registered Report Identifier (irrid): DERR1-10.2196/63099., (©Dominique Tremblay, Thomas Joly-Mischlich, Annick Dufour, Marie-Claude Battista, Djamal Berbiche, José Côté, Marco Décelles, Catherine Forget, Brigitte Guérin, Manon Larivière, Frédéric Lemay, Manon Lemonde, Éric Maillet, Nathalie Moreau, Michel Pavic, Sara Soldera, Catherine Wilhelmy. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.01.2025.)

Background: Immunotherapy is the cornerstone of treatment for many cancers. The effectiveness of immunotherapy in hospitalized patients is unknown due to the exclusion of this fragile population from clinical trials. This study evaluates the efficacy of immunotherapy in fragile hospitalized patients., Method: We conducted a single-center retrospective study involving 49 patients who started an immunotherapy (IO) during a hospitalization or within 3 months after a hospitalization at the Centre Hospitalier de l'Université de Sherbrooke (CHUS). Efficacy analysis included objective response rate (ORR), overall survival (OS), and progression-free survival (PFS)., Results: Immunotherapy resulted in 30.6% of all grades combined and 18.4% of grade three to four immune-related adverse events (irAE). Efficacy outcomes were inferior in the fragile cohort of patients with ORR of 38.9%, PFS of 2.8 months (95% CI [2.17-3.35]), and OS of 3.2 months (95% CI [1.60-4.84]). Performance status of ECOG three to four compared to ECOG zero predicts poor OS (HR 5.666 [1.207-26.594]; p = 0.028) and PFS (HR 4.136 [0.867-19.733]; p = 0.075). Fitness to receive four to six cycles (HR 0.335 [0.152-0.0.738]; p < 0.007) or more predicts greater OS compared to one to three cycles of immunotherapy. Low levels of serum albumin (HR 0.917 [0.852-0.987]; p = 0.021) and elevated levels of serum LDH (HR 2.224 [1.469-3.367]; p < 0.001) are associated with a reduced OS., Conclusion: The effectiveness of immunotherapy in fragile hospitalized patients is compromised, although they exhibit significant irAE. Excellent performance status, fitness to receive many IO treatments, and normal levels of serum LDH and albumin may be useful in selecting patients who will benefit from immunotherapy.

Intrapatient intermetastatic heterogeneity (IIH) has been demonstrated in metastatic castration-resistant prostate cancer (mCRPC) patients and is of the utmost importance for radiopharmaceutical therapy (RPT) eligibility. This study was designed to determine the prevalence of IIH and RPT eligibility in mCRPC patients through a triple-tracer PET imaging strategy. Methods: This was a multisite prospective observational study in which mCRPC patients underwent both 18 F-FDG and 68 Ga-prostate-specific membrane antigen (PSMA)-617 PET/CT scans. A third scan with 68 Ga-DOTATATE, a potential biomarker of neuroendocrine differentiation, was performed if an 18 F-FDG-positive/ 68 Ga-PSMA-negative lesion was found. Per-tracer lesion positivity was defined as having an uptake at least 50% above that of the liver. IIH prevalence was defined as the percentage of participants having at least 2 lesions with discordant features on multitracer PET. Results: IIH was observed in 81 patients (82.7%), and at least 1 18 F-FDG-positive/ 68 Ga-PSMA-negative lesion was found in 45 patients (45.9%). Of the 37 participants who also underwent 68 Ga-DOTATATE PET/CT, 6 (16.2%) had at least 1 68 Ga-DOTATATE-positive lesion. In total, 12 different combinations of lesion imaging phenotypes were observed. On the basis of our prespecified criteria, 52 (53.1%) participants were determined to be eligible for PSMA RPT, but none for DOTATATE RPT. Patients with IIH had a significantly shorter median overall survival than patients without IIH (9.5 mo vs. not reached; log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1-6.8). Conclusion: Most mCRPC patients showed IIH, which was associated with shorter overall survival. On the basis of a triple-tracer PET approach, multiple phenotypic combinations were found. Correlation of these imaging phenotypes with genomics and treatment response will be relevant for precision medicine., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Non-pharmaceutical interventions (NPIs) decrease COVID-19 transmission. Reliability and validity of adherence to NPIs in accordance with normalization process theory (NPT) in coherent and convenient social subgroups using reflective measurement model assessment has not been evaluated., Methods: In February 2021, a sample of medical students and people with substance use disorders in treatment as coherent (based on continuous probability distribution) vs. convenient groups (based on convenience, not equal probability) composed of travellers and COVID-19 suspected persons from Split-Dalmatia County (SDC) (n = 656) in the Mediterranean completed self-administered surveys. Partial least squares structural equation modelling (PLS-SEM) was used to measure reflective model assessment of adherence to NPIs according to NPT., Results: PLS-SEM reflective model assessment provided two-group specific factors in inverse relationships which determined adherence to NPIs with excellent goodness-of-fit [χ2 = 1.292, df = 1; P = 0.297, CFI = 1, TLI = 0.997, RMSEA = 0.011 (90% CI 0-0.105), RMSEA P = 0.604, SRMR = 0.008, Hoelter CN (α = 0.05) = 2322.757]. Significant negative factors covariance estimate (-0.716) revealed an inverse relationship between first (adherence to NPIs and internal locus of control (LoC) (0.640)) and second factor; young adulthood age (≤25) and highest level of education (1362). As the first factor increased the second tended to decrease. LoC is expected potential mechanism by which sex (MLsex = -0.017, SE = 0.007, P < 0.016) and belonging to coherent subgroups (MLgroup = -0.008, SE = 0.003, P = 0.015) can produce indirect effect of adherence to NPIs., Conclusions: Coherent subgroups had a more pronounced tendency toward integration of NPIs in everyday life. Group factors that facilitate the normalization were higher educated younger adults with a tendency toward external LoC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

Introduction: Monoclonal gammopathy of renal significance (MGRS) is a rare entity describing patients with renal impairment related to the secretion of immunoglobulins without hematological criteria for treatment of a specific disease. We present 3 cases of MGRS identified at our center that were either rare or difficult to diagnose. Case Presentations . The first patient presented with monoclonal membranoproliferative glomerulonephritis in the context of known chronic lymphocytic leukemia (CLL), diagnosed about 10 years prior. She presented with nephritic syndrome with serum protein electrophoresis revealing an IgG/lambda peak of less than 1 g/L, stable from the last few years. A renal biopsy confirmed a diagnosis of monoclonal membranoproliferative glomerulonephritis with granular IgG and C3 deposits of various sizes. The second patient presented with renal TMA in the context of IgM MGUS. The patient was admitted for acute nephritic syndrome and thrombotic microangiopathy. Serum protein electrophoresis demonstrated IgM/kappa paraprotein at 1.8 g/L, with a kappa/lambda ratio of 5.48. Renal biopsy demonstrated endocapillary proliferative glomerulonephritis associated with the presence of numerous monotypic IgM/kappa intracapillary pseudothrombi. Characteristic changes of thrombotic microangiopathy were also described. The third patient presented with immunotactoid glomerulonephritis likely from small B-cell lymphoma that later transformed to DLBCL. The patient presented with acute renal failure with IgM/kappa paraprotein of less than 1 g/L on electrophoresis and with a kappa/lambda ratio of 7.09. A diagnosis of immunotactoid glomerulonephritis was made on renal biopsy. Bone marrow with limited specimen revealed a B-cell infiltrate. Biopsy of a breast lesion was compatible with diffuse large B-cell lymphoma (DLBCL). Lymphomatous cells expressed IgM/kappa, thus confirming paraprotein-associated renal lesion., Conclusion: We described 3 different cases of MGRS, highlighting the diversity of renal pathohistological presentations and different associated lymphoproliferative disorders. Biopsy should rapidly be considered, as early diagnosis of MGRS is essential to initiate clone-directed therapy promptly to prevent progression to ESRD or hematologic progression to malignancy., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024 Anjellica Chen et al.)

Background: Plasma cell leukemia (PCL) is a rare monoclonal gammopathy, associated with short survival. Because of its very low incidence, only a few cohorts have been reported and thus, information on this disease is scarce. The goal of this study was to better understand the clinical features, prognostic factors, and efficacy of modern treatments in both primary PCL (pPCL) and secondary PCL (sPCL)., Methods: We performed a retrospective, multicenter study of patients diagnosed with PCL, defined as circulating plasma cells ≥20% of total leukocytes and/or ≥2 × 10 9 /L., Results: We identified 99 eligible PCL patients, of whom 33 were pPCL and 66 were sPCL. The median progression-free survival (PFS) to frontline treatment and overall survival (OS) were, respectively, 4.8 (95% CI, 0.4-9.2) and 18.3 months (95% CI, 0.0-39.0) for pPCL and 0.8 (95% CI, 0.5-1.1) and 1.2 months (95% CI, 0.9-1.5) for sPCL (both p < 0.001). We observed no improvement in OS over time (2005-2012 vs. 2013-2020, p = 0.629 for pPCL and p = 0.329 for sPCL). Finally, our data suggested that sPCL originates from a high-risk multiple myeloma (MM) population with a short OS (median 30.2 months), early relapse after stem cell transplant (median 11.9 months) and a high proportion of patients with multiple cytogenetic abnormalities (36% with ≥2 abnormalities)., Conclusions: This study is one of the largest PCL cohorts reported. We are also the first to investigate characteristics of MM before its transformation into sPCL and demonstrate that high-risk biologic features already present at the time of MM diagnosis. Moreover, our data highlights the lack of improvement in PCL survival in recent years and the urgent need for better treatment options., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: It has been suggested that the acute natural killer (NK) cell response to aerobic exercise might contribute to the tumor suppressor effect of regular exercise observed in preclinical studies. Moreover, because this response is modulated by exercise intensity, high-intensity intervals exercise (HIIE) might represent an interesting therapeutic approach in cancer patients. However, this immune response remains unstudied in cancer patients currently undergoing chemotherapy., Objective: To characterize the acute NK cell response following a moderate-intensity continuous aerobic exercise session (MOD), and a HIIE session in metastatic cancer patients treated with chemotherapy., Methods: Twelve cancer patients (45-65 years old) underwent a MOD and a duration and work-matched HIIE trial, in a block-randomized order. Peripheral blood mononuclear cells (PBMC) were isolated before, after and 1h after each trial. NK cell subsets were enumerated using flow cytometry and complete blood counts. The surface expression of the cytotoxic NK cell (cNK; CD56 dim CD16 + ) subset was evaluated for its expression of the differentiation markers CD57 and CD158a, the activating receptor NKG2D, the immune checkpoints TIM-3 and PD-1, and the chemokine receptors CXCR3, CXCR4 and CCR2., Results: cNK cell blood counts increased immediately following MOD (p < 0.001) and decreased back to pre-exercise values 1 h after exercise cessation (p < 0.001). The most responsive cNK cell subsets were expressing CD57, CD158a, NKG2D, TIM-3 and CXCR3. The HIIE trial elicited a similar biphasic response, without any difference between trials (all p ≥ 0.38). However, significant changes in the MFI values of CXCR4 and NKG2D were observed in the cNK cell subset following HIIE (all p ≤ 0.038), but not MOD., Conclusion: In metastatic cancer patients undergoing chemotherapy, both MOD and HIIE can elicit an acute mobilisation and egress of NK cells exhibiting phenotypic characteristics associated with high cytotoxicity and tumor homing. Future longitudinal trials are needed to determine if combining aerobic exercise training and chemotherapy will translate towards favorable immune and clinical outcomes., Competing Interests: There are no conflict of interest among all authors., (© 2024 The Authors.)

Background: Expedited market access for novel and efficacious drugs is warranted for patients. Since 2020, Swissmedic (The Swiss Agency for Therapeutic Products) has been participating in Project Orbis, a collaborative parallel-review programme launched by the US Food and Drug Administration (FDA) in 2019 to expedite patient access to cancer drugs. This programme allows regulatory agencies to remain independent in their decisions. We aimed to evaluate the effect of the first 2 years of Project Orbis from the Swissmedic perspective., Methods: In this comparative analysis, we compared submission gap (time between submission at the FDA and Swissmedic), review time, approval and consensus decision rate, and the approved indications between Swissmedic and the FDA for marketing authorisation applications (MAAs) in oncology submitted to Swissmedic through Project Orbis (Orbis MAAs) or outside of Project Orbis (non-Orbis MAAs) from Jan 1, 2020, to Dec 31, 2021. Swissmedic review time was evaluated with a decision until June 30, 2022. For the decision comparison analysis, non-Orbis oncology MAAs submitted and evaluated from Jan 1, 2009, to Dec 31, 2018 (referred to as the pre-Orbis era) were also considered. Inferential statistics were done using Wilcoxon rank-sum test and the 95% CI for the median was based on binomial distribution. For each hypothesis testing, the significance level was set to 5%. No correction for multiple testing was performed., Findings: We analysed the submission gap, review time, and regulatory decision for 31 Orbis MAAs and 41 non-Orbis MAAs during the Orbis era. The median submission gap was 33·0 days (95% CI 19·0-57·0) for Orbis MAAs versus 168·0 days (56·0-351·0) for non-Orbis MAAs (p<0·0001). The median review time at Swissmedic was 235·5 days (198·0-264·0) for Orbis MAAs versus 314·0 days (279·0-354·0) for non-Orbis MAAs (p=0·0002). Approval rates at Swissmedic were consistent between Orbis MAAs (20 [77%] of 26) and non-Orbis MAAs (31 [76%] of 41). The rate of consensus decisions between Swissmedic and the FDA was 21 (81%) of 26 for Orbis MAAs and 31 (76%) of 41 for non-Orbis MAAs. Swissmedic approval rates were lower for indication extensions than for new active substances for Orbis MAAs (13 [72%] of 18 vs seven [88%] of eight) and non-Orbis MAAs (17 [71%] of 24 vs 14 [82%] of 17). Divergent decisions between agencies were predominantly observed for indication extensions (11 [73%] of 15 divergent decisions). During the pre-Orbis era, Swissmedic approved 61 (88%) of 69 MAAs for new active substances., Interpretation: Submission gap and review time for oncology applications at Swissmedic were significantly reduced by participation in Project Orbis, and approval consensus decisions were increased between agencies. These findings suggests that participating in Project Orbis could lead to faster patient access to drugs., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Because health resources are limited, health programs should be compared to allow the most efficient ones to emerge. To that aim, health utility instruments have been developed to allow the calculation of quality-adjusted life-year (QALY). However, generic instruments, which can be used by any individual regardless of their health profile, typically consider the preferences of the general population when developing their value set. Consequently, they are often criticized for lacking sensitivity in certain domains, such as cancer. In response, the latest version of the Short Form 6-Dimension (SF-6Dv2) has been adapted to suit the preferences of patients with breast or colorectal cancer in the Canadian province of Quebec. By extension, our study's aim was to determine cancer population norms of utility among patients with breast or colorectal cancer in Quebec using the SF-6Dv2., Method: To determine the cancer population norms, we exploited the data that were used in the development of a new value set for the SF-6Dv2. This value set was developed considering the preferences of patients with breast or colorectal cancer. Stratification by time of data collection (i.e., T1 and T2), sociodemographic variables (i.e., age, sex, body mass index, and self-reported health problems affecting quality of life), and clinical aspects (i.e., cancer site, histopathological classification, cancer stage at diagnosis, modality, and treatment characteristics) was performed., Results: In 353 observations, patients were more likely to have negative utility scores at T1 than at T2. Males had higher mean utility scores than females considering type of cancer and comorbidities. Considering the SF-6Dv2's dimensions, more females than males reported having health issues, most which concerned physical functioning. Significant differences by sex surfaced for all dimensions except "Role Limitation" and "Mental health." Patients with multifocal cancer had the highest mean and median utility values in all cancer sites considered., Conclusion: Cancer population norms can serve as a baseline for interpreting the scores obtained by a given population in comparison to the situation of another group. In this way, our results can assist in comparing utility scores among cancer patients with different sociodemographic groups to other patients/populations groups. To our knowledge, our identified utility norms are the first for patients with breast or colorectal cancer from Quebec., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cancer-related fatigue (CRF) is a prevalent and persistent issue affecting cancer patients, with a broad impact on their quality of life even years after treatment completion. The precise mechanisms underlying CRF remain elusive, yet its multifaceted nature involves emotional, physical, and cognitive dimensions. The absence of effective medical treatments has prompted researchers to explore integrative models for potential insights. Notably, physical exercise emerges as a promising strategy for managing CRF and related symptoms, as studies showed a reduction in CRF ranging from 19% to 40%. Current recommendations highlight aerobic training at moderate intensity as beneficial, although questions about a dose-response relationship and the importance of exercise intensity persist. Despite the positive impact of exercise on CRF, the underlying mechanisms remain elusive. This review aims to provide a theoretical model explaining how aerobic exercise may alleviate CRF. Focusing on acute exercise effects, this review delves into the potential influence on peripheral and neural inflammation, immune function dysregulation, and neuroendocrine system disruptions. The objective is to enhance our understanding of the intricate relationship between exercise and CRF, ultimately paving the way for tailored interventions and potential pharmacological treatments for individuals unable to engage in physical exercise.

Locally advanced or metastatic urothelial carcinoma (aUC) presents a significant challenge with high mortality rates. Platinum-based chemotherapy remains the established frontline standard of care, and a switch-maintenance strategy with immunotherapy has now emerged as a new standard for aUC patients without disease progression, following initial platinum therapy. Examining the treatment patterns is imperative, given the evolving therapeutic landscape. In this study, we conducted a retrospective medical chart review of 17 Canadian oncologists treating patients with aUC to assess unmet needs in Canadian aUC patient care. Data from 146 patient charts were analyzed, revealing important clinical insights about the management of aUC. A substantial proportion of patients (53%) presented with de novo metastatic disease, which was possibly influenced by pandemic-related care disruptions. Variability was evident in the cisplatin eligibility criteria, with a majority (70%) of oncologists utilizing a 50 mL/min threshold. Most favored four cycles of platinum-based chemotherapy to spare the bone marrow for future therapies and prevent patient fatigue. Notably, some eligible patients were kept under surveillance rather than receiving maintenance therapy, suggesting a potential gap in awareness regarding evidence-based recommendations. Furthermore, managing treatment-related adverse events was found to be one of the biggest challenges in relation to maintenance immunotherapy. In conclusion, our findings provide the first comprehensive overview of aUC treatment patterns in Canada following the approval of maintenance immunotherapy, offering insights into the decision-making process and underscoring the importance of evidence-based guidelines in aUC patient management.

Introduction: Additional considerations are required for the benefit-risk assessment of new drugs or indications in the setting of (neo)adjuvant cancer treatment as compared to the metastatic/advanced setting, possibly leading to different decision patterns for the (neo)adjuvant versus the metastatic and advanced setting within a health authority but also among different health authorities., Methods: We analyzed regulatory decisions at the Swiss Agency for Therapeutic Products Swissmedic (SMC) for all oncology indications (mostly metastatic indications) and indications in the (neo)adjuvant setting and compared these to decisions taken by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA)., Results: Comparing the positive and negative decisions within SMC between July 2017 and December 2021, the approval rates were with 66.7% lower for (neo)adjuvant indications versus 88.4% in the metastatic and advanced indications. While the approval rates for metastatic and advanced new active substances (NAS) applications were similar at SMC as compared to the EMA and the FDA, they were lower for (neo)adjuvant applications at SMC as compared to the EMA and the FDA. The underlying reason in all cases with divergent decisions at SMC as compared to EMA and FDA was that no overall survival benefit as compared to control arm has been observed in the submitted data package., Conclusion: Approval and consensus decision rates at SMC in comparison to EMA and FDA were lower for (neo)adjuvant indications but not for advanced and metastastic NAS oncology indications., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Radiotherapy in expiration breath-hold (EBH) has the potential to reduce treatment volumes of abdominal targets compared to an internal target volume concept in free-breathing. The reproducibility of EBH and required safety margins were investigated to quantify this volumetric benefit. Pre- and post-treatment diaphragm position difference and the positioning variability were determined on computed tomography. Systematic and random errors for EBH position reproducibility and positioning variability were calculated, resulting in margins of 7 to 12 mm depending on the prescription isodose and fractionation. A reduced volume was shown for EBH for lesions with superior-inferior breathing motion above 4 to 8 mm., Competing Interests: 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., (© 2023 The Author(s).)

Purpose: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes., Methods: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS)., Results: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression., Conclusion: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA., (© 2023. The Author(s).)

Background: Quality-adjusted life-year instruments help comparison among programs by capturing their effects in terms of utility. Generic instruments are applicable to everyone, and for this reason, they are known to lack sensitivity when measuring gains in some domains. Specific instruments tend to fill this gap but, in domains like cancer, existing instruments are either nonpreferences-based or based on the general population's preferences., Patients and Methods: This study describes the development of a new value set for a well-known and highly used generic instrument, the Second Version of the Short Form 6-Dimension, to better consider the preferences of patients with cancer. In this aim, a hybrid approach combining the time trade-off and the discrete choice experiment was used. The population of interest was the Quebec population, Canada, with breast or colorectal cancer. Their preferences were elicited in 2 periods: before (T1) and 8 days after the beginning of a chemotherapy procedure (T2)., Results: A total of 2808 observations for the time trade-off and 2520 observations for the discrete choice experiment were used. The parsimonious model encompassing the 2 periods was the preferred model. The new value set allows a greater utility range than the EQ-5D-5L and the Second Version of the Short Form 6-Dimension reference value sets and helps in better considering patients experiencing severe health situations. A good correlation between these 2 instruments and other specific cancer instruments (ie, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, QLU-C10D, and Functional Assessment of Cancer Therapy-General) was observed. Significative differences in utility values were also noted within periods and types of cancer., Competing Interests: T.G.P. is a member of the FRQS-funded CR-IUSMM. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC)., Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS)., Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months ( P = .0007)., Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies., Competing Interests: PW received research grants from BMS AstraZeneca. LM received a research grant from BMS. MP received honoraria from EMD Serono, Pfizer, Astellas, Merck, Janssen, AstraZeneca and is in the advisory boards of BMS, Amgen, EMD Serono, Janssen, and Sanofi. SO received honoraria from Pfizer, Roche, Merck, BMS, AstraZeneca and Bayer and is in the advisory boards of AstraZeneca, Bayer, BMS and Roche. BR received consulting fees from BMS. MT received a research grant from Celgene, honoraria from BMS, Merck, Taiho, Celgene, AstraZeneca and is in the advisory boards of BMS, Merck, Taiho, Pfizer, and AstraZeneca. DR received a research grant from BMS, received honoraria from Siemens Healthineers, Rocher and Bayer, travel support from Accuray, is in the advisory board of Novocure and has stocks in AFC medical., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials., Competing Interests: Declaration of interests FA declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian, Elekta, Brainlabs, outside of this Policy Review. CBe declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis. CBe also declares support for attending meetings and travel from Pfizer and Eli Lilly, unrelated to this Policy Review. CBi declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from SPCC congress, unrelated to this Policy Review. BdB declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Debiopharma, Ipsen, and Astellas; support for attending meetings and travel from Debiopharma and Micropos medical; and leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, SAKK, and SASRO, unrelated to this Policy Review. BAJ-F declares grants or contracts from Italian Association for Cancer Research, FIEO-CCM and FUV, Accuray, and IBA Dosimetry; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Roche, Astellas, Ipsen, and Accuray; and participation on a data safety monitoring board or advisory board for Bayer, unrelated to this Policy Review. XG declares a grant from Varian paid to their institution; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Congress Care and Sanofi; and a leadership or fiduciary role in the board, society, committee, or advocacy group for RIZIV–INAMI and FANC–AFCN. YL declares grants or contracts from ImmunoSABR, EU Project, and HERO–VBHC; consulting fees paid to the institution by AstraZeneca; and a leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, Belgian College of Oncology, and EORTC–ESTRO Radiation Infrastructure for Europe project, unrelated to this Policy Review. PO declares grants or contracts from Varian and Bayer; consulting fees from Bayer, AAA, Curium, Janssen, Telix, MSD, and Ferring; and support for attending meetings and travel from Ferring, unrelated to this Policy Review. SP declares personal fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational event from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Sereno, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Sereno; support for attending meetings and travel from Janssen and Roche; participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, and Seattle Genetics; and leadership or fiduciary role in the board, society, committee, or advocacy group of British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP–IBCSG Partners Foundation Board, unrelated to this Policy Review. SR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD Italia, Genetec, and Istituto Gentili Amgen; and participation on a data safety monitoring board or advisory board for Roche and AstraZeneca, unrelated to this Policy Review. UR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Elekta and Accuray, unrelated to this Policy Review. MS declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Roche, and Merck; participation on a data safety monitoring board or advisory board for Janssen, Ipsen, and Merck; and a leadership or fiduciary role in the board, society, committee, or advocacy group for ESMO, unrelated to this Policy Review. TZ declares grants or contracts from Varian Medical Systems and Debiopharm; consulting fees from Janssen and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Astellas, Debiopharm, Bayer, and Ferring; support for attending meetings and travel from Debiopharm; and participation on a data safety monitoring board or advisory board for SAKK scientific board and GFRU, unrelated to this Policy Review. All other authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Prior to implementing a new computerized prescription order entry (CPOE) application, the potential risks associated with this system were assessed and compared to those of paper-based prescriptions. The goal of this study is to identify the vulnerabilities of the CPOE process in order to adapt its design and prevent these potential risks., Methods and Materials: Failure mode and effects analysis (FMEA) was used as a prospective risk-management technique to evaluate the chemotherapy medication process in a university hospital oncology clinic. A multidisciplinary team assessed the process and compared the critical steps of a newly developed CPOE application versus paper-based prescriptions. The potential severity, occurrence and detectability were assessed prior to the implementation of the CPOE application in the clinical setting., Results: The FMEA led to the identification of 24 process steps that could theoretically be vulnerable, therefore called failure modes. These failure modes were grouped into four categories of potential risk factors: prescription writing, patient scheduling, treatment dispensing and patient follow-up. Criticality scores were calculated and compared for both strategies. Three failure modes were prioritized and led to modification of the CPOE design. Overall, the CPOE pathway showed a potential risk reduction of 51% compared to paper-based prescriptions., Conclusion: FMEA was found to be a useful approach to identify potential risks in the chemotherapy medication process using either CPOE or paper-based prescriptions. The e-prescription mode was estimated to result in less risk than the traditional paper mode.

Purpose: This study evaluated pretreatment 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT-based radiomic signatures for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibition (ICI)., Material and Method: Fifty-six consecutive metastatic melanoma patients treated with ICI and available imaging were included in the study and 330 metastatic lesions were individually, fully segmented on pre-treatment CT and FDG-PET imaging. Lesion hyperprogression (HPL) was defined as lesion progression according to RECIST 1.1 and doubling of tumor growth rate. Patient hyperprogression (PD-HPD) was defined as progressive disease (PD) according to RECIST 1.1 and presence of at least one HPL. Patient survival was evaluated with Kaplan-Meier curves. Mortality risk of PD-HPD status was assessed by estimation of hazard ratio (HR). Furthermore, we assessed with Fisher test and Mann-Whitney U test if demographic or treatment parameters were different between PD-HPD and the remaining patients. Pre-treatment PET/CT-based radiomic signatures were used to build models predicting HPL at three months after start of treatment. The models were internally validated with nested cross-validation. The performance metric was the area under receiver operating characteristic curve (AUC)., Results: PD-HPD patients constituted 57.1% of all PD patients. PD-HPD was negatively related to patient overall survival with HR=8.52 (95%CI 3.47-20.94). Sixty-nine lesions (20.9%) were identified as progressing at 3 months. Twenty-nine of these lesions were classified as hyperprogressive, thereby showing a HPL rate of 8.8%. CT-based, PET-based, and PET/CT-based models predicting HPL at three months after the start of treatment achieved testing AUC of 0.703 +/- 0.054, 0.516 +/- 0.061, and 0.704 +/- 0.070, respectively. The best performing models relied mostly on CT-based histogram features., Conclusions: FDG-PET/CT-based radiomic signatures yield potential for pretreatment prediction of lesion hyperprogression, which may contribute to reducing the risk of delayed treatment adaptation in metastatic melanoma patients treated with ICI., Competing Interests: KK: Grant from the Iten-Kohaut-Foundation. MH: Speaker’s fees and grants from GE Healthcare. Grant for translational and clinical cardiac and oncological research from the Alfred and Annemarie von Sick legacy. Grant from the Artificial Intelligence in Oncological Imaging Network by the University of Zurich. RD: Intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome MSD, Bristol-Myers Squibb BMS, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touchIME. Funding: URPP and Skintegrity. ML: Intermittent, project specific research funding from Roche, Novartis, Molecular Partners, and Oncobit AG. The remaining 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 © 2022 Gabryś, Basler, Burgermeister, Hogan, Ahmadsei, Pavic, Bogowicz, Vuong, Tanadini-Lang, Förster, Kudura, Huellner, Dummer, Levesque and Guckenberger.)

Background: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally., Patients and Methods: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site., Results: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific., Conclusions: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area., Competing Interests: Disclosure ER reports consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, and Pfizer; research funding from Novartis, Demo Pharmaceutical, Celldex, Radius Health, Tesaro, Parexel, and AnaBIOsis Pharmaceuticals; travel funding from Sanofi, Ipsen, Genesis Pharmaceuticals, LEO Pharma, Merck, Roche, and GENEKOR. CP reports grant funding from Pfizer and Daiichi Sankyo; honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, Seagen, and Eli Lilly. VM reports honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Seagen, Novartis, Roche, Teva, Janssen-Cilag, and Gilead; playing an advisory role for Hexal, Roche, Pfizer, Amgen, Daiichi-Sankyo, Nektar, Seagen, Gilead, and Eisai; research funding from Roche, Novartis, Seagen, Pfizer, and Genentech. RB reports advisory role for Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, and Seagen; lecture honoraria from Astra-Zeneca, Daiichi, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, and Seagen; research support from Daiichi, MSD, Novartis, and Roche. GR reports research funding (institution) from AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, Servier, Biovica, GlaxoSmithKline, and Sanofi/Aventis; and patents, royalties, other intellectual property from Agendia for MammaPrint due to the collaboration on the conduct of the MINDACT trial (Institution). SPG reports honoraria from Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; advisory/consultancy roles with Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; research grant from Roche; travel/accommodation/expenses from Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, and Daiichi Sankyo. HCK reports honoraria and travel support from AstraZeneca, Pfizer, Roche, Daiichi Sankyo, Tesaro, MSD, Onkowissen, Eli Lilly, SurgVision, Exact Sciences, and Genomic Health; and Stock ownership from Theraclion and Phaon scientific. NZ is on the advisory board for Lilly, Eisai, and AstraZeneca; reports receiving honorarium from Roche, Pfizer, Eisai, and Amgen; research funding (institutional) from Pfizer, Roche, and GSK; education funding from Roche, Novartis, and Amgen (none considered relevant to the current work). MP is on the advisory boards, and has participated in educational programs and conferences for Pfizer, BMS, Novartis, Astellas, Janssen, MD Serono, Merck, Amgen, and Sanofi; reports research funding (institutional) from Astellas, Novartis, Roche, Merck, BMS, Sanofi, and AstraZeneca. RMC has received (to institution) an unrestricted educational grant from Pfizer; and research funds from MSD Ireland and Pfizer. HT reports employment or management position with Partner and Medical Director Oncology Practice at Bethanien Hospital, Frankfurt; honoraria from Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science; consulting activities for Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science. AM reports advisory/consultant role, honoraria, and research grant from Lilly and Roche; advisory/consultant role for Novartis, Merck, Seagen, and Daiichi-Sankyo. LDM reports grants from Eli Lilly during the conduct of the study; personal fees from Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Seagen, Ipsen, and Gilead; personal fees and nonfinancial support from Roche, Pfizer, and Eisai, outside the submitted work. CC reports honoraria from Amgen, AstraZeneca, BMS, Genesis, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche. SO reports lecture fees, honoraria, or other fees paid by a single company or for-profit organization for the time or labor of a researcher engaged for conference attendance from Chugai, Lilly, AstraZeneca, and Pfizer. IM reports performing consultancy roles for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer, and Roche; travel/conference registration activities for Eli Lilly, Daiichi Sankyo, Gilead, and Novartis. ME serves on the advisory boards of Pfizer and Novartis; lecturing for Astra Zeneca (institution), but has no conflicts of interest related to this publication. KZ serves on the advisory board or performs talk for AstraZeneca, Daiichi, Exact Sciences, Lilly, Pierre Fabre, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Viatris/Mylan; unrestricted funding for organization of academic symposium from Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead, Novartis, Pfizer, Roche, Seagen, Viatris/Mylan, and Vifor; support for participation in international congress from AstraZeneca, Daiichi, Pierre Fabre, and Roche; is a member of steering committee of Eleanor study (Pierre Fabre); and research funding from Roche. MV reports honoraria from Roche, Novartis, Pfizer, and Daiichi; consulting or advisory role for Novartis and Roche; travel funds from Roche and Pfizer. DF’s institution receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi, and Pfizer for the conduct of clinical trials outside the submitted work. MG-G reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, and Pierre Fabre; travel/attending meetings for Pfizer, Roche, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo and AstraZeneca. BL reports consulting or advisory role for AstraZeneca, Pfizer, Merck, Eli Lilly, Pierre Fabre, and Daiichi Sankyo. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We explored imaging and blood bio-markers for survival prediction in a cohort of patients with metastatic melanoma treated with immune checkpoint inhibition., Materials and Methods: 94 consecutive metastatic melanoma patients treated with immune checkpoint inhibition were included into this study. PET/CT imaging was available at baseline (Tp0), 3 months (Tp1) and 6 months (Tp2) after start of immunotherapy. Radiological response at Tp2 was evaluated using iRECIST. Total tumor burden (TB) at each time-point was measured and relative change of TB compared to baseline was calculated. LDH, CRP and S-100B were also analyzed. Cox proportional hazards model and logistic regression were used for survival analysis., Results: iRECIST at Tp2 was significantly associated with overall survival (OS) with C-index=0.68. TB at baseline was not associated with OS, whereas TB at Tp1 and Tp2 provided similar predictive power with C-index of 0.67 and 0.71, respectively. Appearance of new metastatic lesions during follow-up was an independent prognostic factor (C-index=0.73). Elevated LDH and S-100B ratios at Tp2 were significantly associated with worse OS: C-index=0.73 for LDH and 0.73 for S-100B. Correlation of LDH with TB was weak (r=0.34). A multivariate model including TB change, S-100B, and appearance of new lesions showed the best predictive performance with C-index=0.83., Conclusion: Our analysis shows only a weak correlation between LDH and TB. Additionally, baseline TB was not a prognostic factor in our cohort. A multivariate model combining early blood and imaging biomarkers achieved the best predictive power with regard to survival, outperforming iRECIST., Competing Interests: MH received a grant from the CRPP AI Oncological Imaging Network of the University of Zurich, grants from GE Healthcare and a fund by the Alfred and Annemarie von Sick legacy for translational and clinical cardiac and oncological research. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touchIME outside the submitted work. The remaining 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 © 2022 Burgermeister, Gabryś, Basler, Hogan, Pavic, Bogowicz, Martínez Gómez, Vuong, Tanadini-Lang, Foerster, Huellner, Dummer, Levesque and Guckenberger.)

Background: Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial., Methods: This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale., Discussion: An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life., Trial Registration: German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213., (© 2022. The Author(s).)

Background: The inability to seamlessly exchange information across radiation therapy ecosystems is a limiting factor in the pursuit of data-driven clinical practice. The implementation of semantic interoperability is a prerequisite for achieving the full capacity of the latest developments in personalized and precision medicine, such as mathematical modeling, advanced algorithmic information processing, and artificial intelligence approaches., Objective: This study aims to evaluate the state of terminology resources (TRs) dedicated to radiation oncology as a prerequisite for an oncology semantic ecosystem. The goal of this cross-sectional analysis is to quantify the state of the art in radiation therapy specific terminology., Methods: The Unified Medical Language System (UMLS) was searched for the following terms: radio oncology, radiation oncology, radiation therapy, and radiotherapy. We extracted 6509 unique concepts for further analysis. We conducted a quantitative analysis of available source vocabularies (SVs) and analyzed all UMLS SVs according to the route source, number, author, location of authors, license type, the lexical density of TR, and semantic types. Descriptive data are presented as numbers and percentages., Results: The concepts were distributed across 35 SVs. The median number of unique concepts per SV was 5 (range 1-5479), with 14% (5/35) of SVs containing 94.59% (6157/6509) of the concepts. The SVs were created by 29 authors, predominantly legal entities registered in the United States (25/35, 71%), followed by international organizations (6/35, 17%), legal entities registered in Australia (2/35, 6%), and the Netherlands and the United Kingdom with 3% (1/35) of authors each. Of the total 35 SVs, 16 (46%) did not have any restrictions on use, whereas for 19 (54%) of SVs, some level of restriction was required. Overall, 57% (20/35) of SVs were updated within the last 5 years. All concepts found within radiation therapy SVs were labeled with one of the 29 semantic types represented within UMLS. After removing the stop words, the total number of words for all SVs together was 56,219, with a median of 25 unique words per SV (range 3-50,682). The total number of unique words in all SVs was 1048, with a median of 19 unique words per vocabulary (range 3-406). The lexical density for all concepts within all SVs was 0 (0.02 rounded to 2 decimals). Median lexical density per unique SV was 0.7 (range 0.0-1.0). There were no dedicated radiation therapy SVs., Conclusions: We did not identify any dedicated TRs for radiation oncology. Current terminologies are not sufficient to cover the need of modern radiation oncology practice and research. To achieve a sufficient level of interoperability, of the creation of a new, standardized, universally accepted TR dedicated to modern radiation therapy is required., (©Nikola Cihoric, Eugenia Vlaskou Badra, Anna Stenger-Weisser, Daniel M Aebersold, Matea Pavic. Originally published in JMIR Formative Research (https://formative.jmir.org), 19.01.2022.)

Objective: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse., Methods: OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS)., Results: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports., Conclusions: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Main purpose was to describe procedures and identify challenges in the implementation process of adaptive and non-adaptive MR-guided radiotherapy (MRgRT), especially new risks in workflow due to the new technique. We herein report the single center experience for the implementation of (MRgRT) and present an overview on our treatment practice., Methods: Descriptive statistics were used to summarize clinical and technical characteristics of treatment and patient characteristics including sites treated between April 2019 and end of March 2020 after ethical approval. A risk analysis was performed to identify risks of the online adaptive workflow., Results: A summary of the processes on the MR-Linac including workflows, quality assurance and possible pitfalls is presented. 111 patients with 124 courses were treated during the first year of MR-guided radiotherapy. The most commonly treated site was the abdomen (42% of all treatment courses). 73% of the courses were daily online adapted and a high number of treatment courses (75%) were treated with stereotactic body irradiation. Only 4/382 fractions could not be treated due to a failing online adaptive quality assurance. In the risk analysis for errors, the two risks with the highest risk priority number were both in the contouring category, making it the most critical step in the workflow., Conclusion: Although challenging, establishment of MRgRT as a routinely used technique at our department was successful for all sites and daily o-ART was feasible from the first day on. However, ongoing research and reports will have to inform us on the optimal indications for MRgRT because careful patient selection is necessary as it continues to be a time-consuming treatment technique with restricted availability. After risk analysis, the most critical workflow category was the contouring process, which resembles the need of experienced staff and safety check paths., (© 2021. The Author(s).)

Introduction and Background: Through recent advances in cancer care, the number of long-term survivors has continuously increased. As a result, repetitive use of local radiotherapy for curative or palliative indications might have increased as well. This analysis aims to describe patterns of care and outcome of patients treated with multiple courses of repeat radiotherapy., Materials and Methods: All patients treated with radiotherapy between 2011 and 2019 at our department of Radiation Oncology were included into this analysis. A course of radiotherapy was defined as all treatment sessions to one anatomical site under one medical indication. Demographics, cancer and treatment characteristics and overall survival of patients having undergone multiple radiotherapy courses (minimum n = 5) were evaluated., Results: The proportion of cancer patients treated with a minimum five courses of radiotherapy increased continuously from 0.9% in 2011 to 6.5% in 2019. In the 112 patients treated with a minimum of five radiotherapy courses, the primary tumor was lung in 41.9% (n = 47), malignant melanoma in 8.9% (n = 10) and breast in 8.0% (n = 9) of cases. A median interval of 3 years (maximum 8 years) elapsed between the first and the last radiotherapy course. The maximum number of courses in a single patient were n = 10. Treatment intent was curative or palliative in 46.4% and 53.6% for the first radiotherapy, respectively. The proportion of curative intent decreased to 11.6% at the 5th, and the last radiotherapy course was following a palliative intent in all patients. Five-year overall survival measured from the 1st radiotherapy course was 32.7%. Median overall survival was 3.3, 2.4, 1.3, and 0.6 years when measured from the 1st, the 1st palliative, the 5th and last course of radiotherapy, respectively., Discussion and Conclusion: A continuously increasing number of patients is treated with multiple courses of radiotherapy throughout their long-term cancer survivorship., (© 2021. The Author(s).)

Background: Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy. Pregnancies with GDM have worse outcomes compared to pregnancies with normal glucose tolerance. The objectives of the study were to determine the prevalence of GDM and perinatal outcomes according to the old WHO criteria and IADPSG criteria., Subjects and Methods: A retrospective study included 2,405 pregnant women who delivered between January 2009 and December 2010. According to the OGTT results, pregnant women were divided into 4 groups. We analyzed the prevalence of GDM, characteristics of pregnant women and their newborns and perinatal outcomes., Results: We found significantly higher prevalence of GDM according to the IADPSG criteria compared to the WHO criteria. Pregnant women with GDM were significantly older, had higher pre-pregnancy BMI, fasting and 2-h plasma glucose. Pregnant women with GDM had worse pregnancy outcomes compared to control group. The overall proportion of overweight and obese pregnant women was the highest in the group of untreated pregnant women with GDM according to the IADPSG criteria. In this group we found significantly higher rate of fetal macrosomia and LGA. The rate of caesarean section was significantly higher in comparison to control group. Pre-eclampsia was significantly more common in groups of pregnant women with GDM compared to control group., Conclusion: IADPSG diagnostic criteria reveals more women with hyperglycemic disorders in pregnancy. A group of pregnant women who were normoglycemic according to the WHO criteria, but according to the IADPSG were diagnosed GDM, had adverse pregnancy outcomes. Lower values of glycemia, than those defined for diabetes in pregnancy, are associated with adverse pregnancy outcomes.

Background: Integration of specialist palliative care (PC) into standard oncology care is recommended. This study investigated how integration at the Cantonal Hospital St. Gallen (KSSG) was manifested 10 years after initial accreditation as a European Society for Medical Oncology (ESMO) Designated Center (ESMO-DC) of Integrated Oncology and Palliative Care., Methods: A chart review covering the years 2006-2009 and 2016 was carried out in patients with an incurable malignancy receiving PC. Visual graphic analysis was utilized to identify patterns of integration of PC into oncology based on the number and nature of medical consultations recorded for both specialties. A follow-up cohort collected 10 years later was analyzed and changes in patterns of integrating specialist PC into oncology were compared., Results: Three hundred and forty-five patients from 2006 to 2009 and 64 patients from 2016 were included into analyses. Four distinct patterns were identified using visual graphic analysis. The 'specialist PC-led pattern' (44.9%) and the 'oncology-led pattern' (20.3%) represent disciplines that took primary responsibility for managing patients, with occasional and limited involvement from other disciplines. Patients in the 'concurrent integrated care pattern' (18.3%) had medical consultations that frequently bounced between specialist PC and oncology. In the 'segmented integrated care pattern' (16.5%), patients had sequences of continuous consultations provided by one discipline before alternating to a stretch of consultations provided by the other specialty. In the 2016 follow-up, while the 'oncology-led pattern' occurred significantly less frequently relative to the 'specialist PC-led pattern' and the 'segmented integrated care pattern', the 'concurrent integrated care pattern' emerged more frequently when compared with the 2006-2009 follow-up., Conclusion: The 'specialist PC-led pattern' was the most prominent pattern in this data. The 2016 follow-up showed that a growing number of patients received a collaborative pattern of care, indicating that integration of specialist PC into standard oncology can manifest as either segmented or concurrent care pathways. Our data suggest a closer, more dynamic and flexible collaboration between oncology and specialist PC early in the disease course of patients with advanced cancer and concurrent with active treatment., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.

Purpose: Radiomics has already been proposed as a prognostic biomarker in head and neck cancer (HNSCC). However, its predictive power in radiotherapy has not yet been studied. Here, we investigated a local radiomics approach to distinguish between tumor sub-volumes with different levels of radiosensitivity as a possible target for radiation dose intensification., Materials and Methods: Of 40 patients (n=28 training and n=12 validation) with biopsy confirmed locally recurrent HNSCC, pretreatment contrast-enhanced CT images were registered with follow-up PET/CT imaging allowing identification of controlled (GTVcontrol) vs non-controlled (GTVrec) tumor sub-volumes on pretreatment imaging. A bi-regional model was built using radiomic features extracted from pretreatment CT in the GTVrec and GTVcontrol to differentiate between those regions. Additionally, concept of local radiomics was implemented to perform detection task. The original tumor volume was divided into sub-volumes with no prior information on the location of recurrence. Radiomic features from those sub-volumes were then used to detect recurrent sub-volumes using multivariable logistic regression., Results: Radiomic features extracted from non-controlled regions differed significantly from those in controlled regions (training AUC = 0.79 CI 95% 0.66 - 0.91 and validation AUC = 0.88 CI 95% 0.72 - 1.00). Local radiomics analysis allowed efficient detection of non-controlled sub-volumes both in the training AUC = 0.66 (CI 95% 0.56 - 0.75) and validation cohort 0.70 (CI 95% 0.53 - 0.86), however performance of this model was inferior to bi-regional model. Both models indicated that sub-volumes characterized by higher heterogeneity were linked to tumor recurrence., Conclusion: Local radiomics is able to detect sub-volumes with decreased radiosensitivity, associated with location of tumor recurrence in HNSCC in the pre-treatment CT imaging. This proof of concept study, indicates that local CT radiomics can be used as predictive biomarker in radiotherapy and potential target for dose intensification., Competing Interests: ST-L reports grants from Swiss National Science Foundation, during the conduct of the study, and grants from Siemens Healthcare, outside the submitted work. MG reports grants from Swiss National Science Foundation, during the conduct of the study, grants from Siemens Healthcare, and grants from Artificial Intelligence in oncological Imaging Network, University of Zurich, outside the submitted work. MH reports grants and personal fees from GE Healthcare, grants from Alfred and Annemarie von Sick legacy, and grants from Artificial Intelligence in oncological Imaging Network, University of Zurich, outside the submitted work. The remaining author declares 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 © 2021 Bogowicz, Pavic, Riesterer, Finazzi, Garcia Schüler, Holz-Sapra, Rudofsky, Basler, Spaniol, Ambrusch, Hüllner, Guckenberger and Tanadini-Lang.)

Background-smoldering multiple myeloma (SMM) risk of progression to multiple myeloma (MM) is highly heterogeneous and several models have been suggested to predict this risk. Lakshman et al. recently proposed a model based on three biomarkers: bone marrow plasma cell (BMPC) percentage > 20%, free light chain ratio (FLCr) > 20 and serum M protein > 20 g/L. The goal of our study was to test this "20/20/20" model in our population and to determine if similar results could be obtained in another cohort of SMM patients. Method-we conducted a retrospective, single center study with 89 patients diagnosed with SMM between January 2008 and December 2019. Results-all three tested biomarkers were associated with an increased risk of progression: BMPC percentage ≥ 20% (hazard ratio [HR]: 4.28 [95%C.I., 1.90-9.61]; p < 0.001), serum M protein ≥ 20 g/L (HR: 4.20 [95%C.I., 1.90-15.53]; p = 0.032) and FLCr ≥ 20 (HR: 3.25 [95%C.I., 1.09-9.71]; p = 0.035). The estimated median time to progression (TTP) was not reached for the low and intermediate risk groups and was 29.1 months (95%C.I., 3.9-54.4) in the high-risk group ( p = 0.006). Conclusions-the 20/20/20 risk stratification model adequately predicted progression in our population and is easy to use in various clinical settings.

Purpose: To assess the effects of daily adaptive MR-guided replanning in stereotactic body radiation therapy (SBRT) of liver metastases based on a patient individual longitudinal dosimetric analysis., Methods: Fifteen patients assigned to SBRT for oligometastatic liver metastases underwent daily MR-guided target localization and on-table treatment plan re-optimization. Gross tumor volume (GTV) and organs at risk (OARs) were adapted to the anatomy-of-the-day. A reoptimized plan (RP) and a rigidly shifted baseline plan (sBP) without re-optimization were generated for each fraction. After extraction of DVH parameters for GTV, planning target volume (PTV), and OARs (stomach, duodenum, bowel, liver, heart) plans were compared on a per-patient basis., Results: Median pre-treatment GTV and PTV were 14.9 cc (interquartile range (IQR): 7.7-32.9) and 62.7 cc (IQR: 42.4-105.5) respectively. SBRT with RP improved PTV coverage (V100%) for 47/75 of the fractions and reduced doses to the most proximal OARs (D1cc, Dmean) in 33/75 fractions compared to sBP. RP significantly improved PTV coverage (V100%) for metastases within close proximity to an OAR by 4.0% (≤ 0.2 cm distance from the edge of the PTV to the edge of the OAR; n = 7; p = 0.01), but only by 0.2% for metastases farther away from OAR (> 2 cm distance; n = 7; p = 0.37). No acute grade 3 treatment-related toxicities were observed., Conclusions: MR-guided online replanning SBRT improved target coverage and OAR sparing for liver metastases with a distance from the edge of the PTV to the nearest luminal OAR < 2 cm. Only marginal improvements in target coverage were observed for target distant to critical OARs, indicating that these patients do not benefit from daily adaptive replanning.

Patients with relapsed/refractory multiple myeloma (RRMM) experience several relapses, and become refractory to successive therapies. In the ICARIA-MM trial (NCT02990338), isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with RRMM. This subgroup analysis of ICARIA-MM assessed the treatment benefit of isatuximab by prior lines of therapy and refractory status. A total of 307 patients were randomized to isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, then every other week. Standard pomalidomide-dexamethasone doses were given. PFS was assessed by prior lines and refractory status. Overall, 102 (66 %) patients receiving isatuximab-pomalidomide-dexamethasone and 101 (66 %) patients receiving pomalidomide-dexamethasone had received 2-3 prior lines; 52 (34 %) and 52 (34 %) had received >3 prior lines, respectively. Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who received 2-3 prior lines of therapy (12.3 vs. 7.8 months) and >3 prior lines of therapy (9.4 vs. 4.3 months). Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who were lenalidomide-refractory (11.4 vs. 5.6 months), lenalidomide-refractory at last line (11.6 vs. 5.7 months), refractory to a proteasome inhibitor (PI) (11.4 vs. 5.6 months), and double-refractory (11.2 vs. 4.8 months). Overall response rate (ORR) in patients receiving isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone was 59.0 % versus 31.4 % in lenalidomide-refractory; 60.2 % versus 32.2 % in PI-refractory; and 58.6 % versus 29.9 % in double-refractory patients. Isatuximab-pomalidomide-dexamethasone improved PFS and ORR regardless of prior lines of therapy or refractory status, consistent with the benefit in the overall population., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: In this study, we aimed to assess the impact of different CT reconstruction kernels on the stability of radiomic features and the transferability between different diseases and tissue types. Three lung diseases were evaluated, i.e . non-small cell lung cancer (NSCLC), malignant pleural mesothelioma (MPM) and interstitial lung disease related to systemic sclerosis (SSc-ILD) as well as four different tissue types, i.e . primary tumor, largest involved lymph node ipsilateral and contralateral lung., Methods: Pre-treatment non-contrast enhanced CT scans from 23 NSCLC, 10 MPM and 12 SSc-ILD patients were collected retrospectively. For each patient, CT scans were reconstructed using smooth and sharp kernel in filtered back projection. The regions of interest (ROIs) were contoured on the smooth kernel-based CT and transferred to the sharp kernel-based CT. The voxels were resized to the largest voxel dimension of each cohort. In total, 1386 features were analyzed. Feature stability was assessed using the intraclass correlation coefficient. Features above the stability threshold >0.9 were considered stable., Results: We observed a strong impact of the reconstruction method on stability of the features (at maximum 26% of the 1386 features were stable). Intensity features were the most stable followed by texture and wavelet features. The wavelet features showed a positive correlation between percentage of stable features and size of the ROI (R2 = 0.79, p = 0.005). Lymph node radiomics showed poorest stability (<10%) and lung radiomics the largest stability (26%). Robustness analysis done on the contralateral lung could to a large extent be transferred to the ipsilateral lung, and the overlap of stable lung features between different lung diseases was more than 50%. However, results of robustness studies cannot be transferred between tissue types, which was investigated in NSCLC and MPM patients; the overlap of stable features for lymph node and lung, as well as for primary tumor and lymph node was very small in both disease types., Conclusion: The robustness of radiomic features is strongly affected by different reconstruction kernels. The effect is largely influenced by the tissue type and less by the disease type., Advances in Knowledge: The study presents to our knowledge the most complete analysis on the impact of convolution kernel on the robustness of CT-based radiomics for four relevant tissue types in three different lung diseases. .

Introduction: Pancreatic adenocarcinoma (PAC) is a highly malignant tumor with relevant morbidity and mortality. The role of adjuvant chemoradiotherapy (CRT) for primarily resected tumors remains controversial. We aimed to assess the outcome of patients treated at our institution with postoperative CRT for PAC., Methods: We present a retrospective case series of patients with pancreatic adenocarcinoma at a single center in Switzerland. These patients were treated by primary surgery followed by adjuvant CRT between 1995 and 2015. The results were compared with published data., Results: Median follow-up for the 60 patients was 33 months (range 19.9-193.9); median overall survival (OS) for patients undergoing a resection followed by combined CRT was 25.5 months. Overall, disease-free survival (DFS) was 15.2 months. A local recurrence occurred in 14 patients (23.3%) after a median time of 8.8 months, and in 43 patients (71.7%) distant metastasis was demonstrated with a median time to metastasis of 10.6 months., Conclusion: This retrospective study represents one of the sole reviews of outcome data after adjuvant CRT in resected PAC in Europe within the past years. OS was comparable to that of other institutional outcome data published previously but inferior when compared to most recent published results with an intense chemotherapy. However, not all patients are suitable to undergo such an intense chemotherapy with modified FOLFIRINOX after the extensive surgery for the PAC - these patients could benefit from adding adjuvant CRT to a less intensive chemotherapy with gemcitabine to enhance the benefit regarding locoregional recurrence-free survival., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Colorectal cancer is the third most common cancer worldwide. Half of CRC patients develop liver metastases during the course of the disease, with a 5-year survival rate close to zero in the absence of therapy. Surgical resection remains the only possible curative option, and current guidelines recommend adjuvant chemotherapy, resulting in a 5-year survival rate exceeding 50%. Neoadjuvant systemic therapy is not indicated in cases with simple resection but should be offered to all patients with extensive bilobar disease. Personalised systemic treatment is essential to convert upfront non-resectable lesions to resectable ones. Anatomical resections, non-anatomical resections and two-stage hepatectomies can be performed though open or minimally invasive (laparoscopic or robotic) surgery. The extent of a hepatic resection is limited by the risk of postoperative liver failure due to a too small liver remnant, inflow or outflow obstruction or insufficient biliary drainage. About 75% of patients are diagnosed with non-resectable liver metastases not amenable to a standard upfront resection. In recent years, effective therapeutic approaches have revolutionised liver surgery and new strategies have enabled the conversion of primarily non-resectable metastatic disease for resection. These strategies include oncological and surgical therapies, as well as combinations of the two. From an oncological perspective, colorectal liver metastases&nbsp; may be treated by systemic chemotherapy or immunotherapy, or selective intra-hepatic arterial infusion chemotherapy, depending on the extent of the disease and the mutational status. In surgery, we often apply two-stage strategies using portal vein occlusion, such as portal vein embolisation or ligation, or complex two-stage hepatectomy such as associating liver partition and portal vein ligation for staged hepatectomy. Other additive tools to reach curative resection are tumour ablations (electroporation, microwave or radiofrequency). The role of stereotactic radiation of liver metastases is not yet well defined. Modern radiation techniques, including image guidance, breath hold and gating, were only introduced for a larger patient population in recent years. Therefore, prospective studies with larger patient cohorts are still pending. Over the last decade, liver transplantation has gained increasing attention in selective cases of non-resectable colorectal liver metastases, with promising cohort studies, but definitive recommendations must await the results of ongoing randomised controlled trials. The optimal treatment of patients with colorectal liver metastases requires the timely association of various strategies, and all cases must be discussed at multidisciplinary team conferences. While colorectal liver metastases was a uniformly lethal condition a few decades ago, it has become amenable to curative therapies, with excellent quality of life in many scenarios. This review reports on up-to-date treatment modalities and their combinations in the treatment algorithm of colorectal liver metastases. &nbsp; &nbsp.

The optimal approach for magnetic resonance imaging-guided online adaptive radiotherapy is currently unknown and needs to consider patient on-couch time constraints. The aim of this study was to compare two different plan optimization approaches. The comparison was performed in 238 clinically applied online-adapted treatment plans from 55 patients, in which the approach of re-optimization was selected based on the physician's choice. For 33 patients where both optimization approaches were used at least once, the median treatment planning dose metrics of both target and organ at risk differed less than 1%. Therefore, we concluded that beam segment weight optimization was chosen adequately for most patients without compromising plan quality., Competing Interests: 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., (© 2021 The Author(s).)

Sarcoidosis is a systemic disease of unknown etiology, characterized by the presence of non-caseating granulomas in various organs, mainly the lungs, and the lymphatic system. Since the individualization of sarcoidosis-lymphoma association by Brincker et al., the relationship between sarcoidosis or granulomatous syndromes and malignancies has been clarified through observational studies worldwide. Two recent meta-analyses showed an increased risk of neoplasia in sarcoidosis. The granulomatosis can also reveal malignancy, either solid or hematological, defining paraneoplastic sarcoidosis. Recent cancer immunotherapies, including immune checkpoint inhibitors (targeting PD-1, PD-L1, or CTLA-4) and BRAF or MEK inhibitors were also reported as possible inducers of sarcoidosis-like reactions. Sarcoidosis and neoplasia, especially lymphoma, can show overlapping presentations, thus making the diagnosis and treatment harder to deal with. There are currently no formal recommendations to guide the differential diagnosis workup between the evolution of lymphoma or a solid cancer and a granulomatous reaction associated with neoplasia. Thus, in atypical presentations (e.g., deeply impaired condition, compressive lymphadenopathy, atypical localization, unexplained worsening lymphadenopathy, or splenomegaly), and treatment-resistant disease, targeted biopsies on suspect localizations with histological examination could help the clinician to differentiate neoplasia from sarcoidosis. Pathological diagnosis could sometimes be challenging since very few tumor cells may be surrounded by massive granulomatous reaction. The sensitization of currently available diagnostic tools should improve the diagnostic accuracy, such as the use of more "cancer-specific" radioactive tracers coupled with Positron Emission Tomography scan., (Copyright © 2020 El Jammal, Pavic, Gerfaud-Valentin, Jamilloux and Sève.)

Tumor heterogeneity is a well-known prognostic factor in head and neck squamous cell carcinoma (HNSCC). A major limitation of tissue- and blood-derived tumor markers is the lack of spatial resolution to image tumor heterogeneity. Tissue markers derived from tumor biopsies usually represent only a small tumor subregion at a single timepoint and are therefore often not representative of the tumors' biology or the biological alterations during and after treatment. Similarly, liquid biopsies give an overall picture of the tumors' secreted factors but completely lack any spatial resolution. Radiomics has the potential to give complete three-dimensional information about the tumor. We conducted a comprehensive literature search to assess the correlation of radiomics to tumor biology and treatment outcome in HNSCC and to assess current limitations of the radiomic biomarkers. In total, 25 studies that explored the ability of radiomics to predict tumor biology and phenotype in HNSCC and 28 studies that explored radiomics to predict post-treatment events were identified. Out of these 53 studies, only three failed to show a significant correlation. The major technical challenges are currently artifacts due to metal implants, non-standardized contrast injection, and delineation uncertainties. All studies to date were retrospective and none of the above-mentioned radiomics signatures have been validated in an independent cohort using an independent software implementation, which shows that transferability due to the numerous technical challenges is currently a major limitation. However, radiomics is a very young field and these studies hopefully pave the way for clinical implementation of radiomics for HNSCC in the future.

Background: Online adaptive radiotherapy is intended to prevent plan degradation caused by inter-fractional tumor volume and shape changes, but time limitations make online re-planning challenging. The aim of this study was to compare the quality of online-adapted plans to their respective reference treatment plans., Methods: Fifty-two patients treated on a ViewRay MRIdian Linac were included in this retrospective study. In total 238 online-adapted plans were analyzed, which were optimized with either changing of the segment weights (n = 85) or full re-optimization (n = 153). Five different treatment sites were evaluated: prostate, abdomen, liver, lung and pelvis. Dosimetric parameters of gross tumor volume (GTV), planning target volume (PTV), 2 cm ring around the PTV and organs at risk (OARs) were considered. The Wilcoxon signed-rank test was used to assess differences between online-adapted and reference treatment plans, p < 0.05 was considered significant., Results: The average duration of the online adaptation, consisting of contour editing, plan optimization and quality assurance (QA), was 24 ± 6 min. The GTV was slightly larger (average ± SD: 1.9% ± 9.0%) in the adapted plans than in the reference plans (p < 0.001). GTV-D 95% exhibited no significant changes when considering all plans, but GTV-D 2% increased by 0.40% ± 1.5% on average (p < 0.001). There was a very small yet significant decrease in GTV-coverage for the abdomen plans. The ring D mean increased on average by 1.0% ± 3.6% considering all plans (p < 0.001). There was a significant reduction of the dose to the rectum of 4.7% ± 16% on average (p < 0.001) for prostate plans., Conclusions: Dosimetric quality of online-adapted plans was comparable to reference treatment plans and OAR dose was either comparable or decreased, depending on treatment site. However, dose spillage was slightly increased.

Purpose: We assessed the predictive potential of positron emission tomography (PET)/CT-based radiomics, lesion volume, and routine blood markers for early differentiation of pseudoprogression from true progression at 3 months., Experimental Design: 112 patients with metastatic melanoma treated with immune checkpoint inhibition were included in our study. Median follow-up duration was 22 months. 716 metastases were segmented individually on CT and 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET imaging at three timepoints: baseline (TP0), 3 months (TP1), and 6 months (TP2). Response was defined on a lesion-individual level (RECIST 1.1) and retrospectively correlated with FDG-PET/CT radiomic features and the blood markers LDH/S100. Seven multivariate prediction model classes were generated., Results: Two-year (median) overall survival, progression-free survival, and immune progression-free survival were 69% (not reached), 24% (6 months), and 42% (16 months), respectively. At 3 months, 106 (16%) lesions had progressed, of which 30 (5%) were identified as pseudoprogression at 6 months. Patients with pseudoprogressive lesions and without true progressive lesions had a similar outcome to responding patients and a significantly better 2-year overall survival of 100% (30 months), compared with 15% (10 months) in patients with true progressions/without pseudoprogression ( P = 0.002). Patients with mixed progressive/pseudoprogressive lesions were in between at 53% (25 months). The blood prediction model (LDH+S100) achieved an AUC = 0.71. Higher LDH/S100 values indicated a low chance of pseudoprogression. Volume-based models: AUC = 0.72 (TP1) and AUC = 0.80 (delta-volume between TP0/TP1). Radiomics models (including/excluding volume-related features): AUC = 0.79/0.78. Combined blood/volume model: AUC = 0.79. Combined blood/radiomics model (including volume-related features): AUC = 0.78. The combined blood/radiomics model (excluding volume-related features) performed best: AUC = 0.82., Conclusions: Noninvasive PET/CT-based radiomics, especially in combination with blood parameters, are promising biomarkers for early differentiation of pseudoprogression, potentially avoiding added toxicity or delayed treatment switch., (©2020 American Association for Cancer Research.)

Purpose: Little is known about efficacy and toxicity of radiation therapy in the elderly, as the vast majority of prospective trials excluded patients aged over 70 years. The aim of this study was to investigate the outcome of radiation therapy in a group of so-called oldest old cancer patients (≥85 years)., Materials and Methods: We retrospectively reviewed data from patients aged ≥85 years, treated between 2010 and 2015 for any tumor histology at the University Hospital Zurich, Switzerland. Overall survival (OS), relapse-free survival (RFS), performance status (ECOG), Charlson comorbidity index (CCI) and treatment tolerance were assessed., Results: We identified and included 100 patients with a mean age of 88 years (range: 85-102 years). Most patients received a curative-intent treatment (n = 64, 64%). About one third received palliative radiation therapy for symptomatic metastatic disease (n = 36, 36%). Curative treatment was well tolerated, with no high-grade acute toxicities (≥grade 4). Median OS was 52.6 and 13.1 months for the curative and palliative treated patient groups, respectively. 5‑year OS for all patients was 39.5% (95% CI: 23.6-54.5%). The Charlson comorbidity index (CCI) had a predictive value for overall survival (CCI > 10, p = 0.0001) in the curative group., Conclusion: The number of older cancer patients will increase considerably in the next decades because of demographic changes. Our analysis supports the notion that radiation therapy for this patient group of oldest old cancer patients is feasible in general. Treatment decisions should not be based on chronological age but rather on comorbidities and functional status.

Background: Careful selection of malignant pleural mesothelioma (MPM) patients for curative treatment is of highest importance, as the multimodal treatment regimen is challenging for patients and harbors a high risk of substantial toxicity. Radiomics-a quantitative method for image analysis-has shown its prognostic ability in different tumor entities and could therefore play an important role in optimizing patient selection for radical cancer treatment. So far, radiomics as a prognostic tool in MPM was not investigated., Materials and Methods: This study is based on 72 MPM patients treated with surgery in a curative intent at our institution between 2009 and 2017. Pre-treatment Fluorine-18 fluorodeoxyglucose (FDG) PET and CT scans were used for radiomics outcome modeling. After extraction of 1404 CT and 1410 FDG PET features from each image, a preselection by principal component analysis was performed to include only robust, non-redundant features for the cox regression to predict the progression-free survival (PFS) and the overall survival (OS). Results were validated on a separate cohort. Additionally, SUVmax and SUVmean, and volume were tested for their prognostic ability for PFS and OS., Results: For the PFS a concordance index (c-index) of 0.67 (95% CI 0.52-0.82) and 0.66 (95% CI 0.57-0.78) for the training cohort (n = 36) and internal validation cohort (n = 36), respectively, were obtained for the PET radiomics model. The PFS advantage of the low-risk group translated also into an OS advantage. On CT images, no radiomics model could be trained. SUV max and SUV mean were also not prognostic in terms of PFS and OS., Conclusion: We were able to build a successful FDG PET radiomics model for the prediction of PFS in MPM. Radiomics could serve as a tool to aid clinical decision support systems for treatment of MPM in future.