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01 januari 2023, Item does not contain fulltext, BACKGROUND: Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1-2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP. METHODS: Participants for a four round modified Delphi study were selected via a CUP literature search in PubMed and an international network of cancer researchers. A total of 90 CUP experts were invited, and 34 experts from 15 countries over four continents completed all Delphi survey rounds. FINDINGS: The Delphi procedure resulted in a multi-layer CUP classification for the diagnostic workup. Initial diagnostic workup should at least consist of history and physical examination, full blood count, analysis of serum markers, a biopsy of the most accessible lesion, a CT scan of chest/abdomen/pelvis, and immunohistochemical testing. Additionally, the expert panel agreed on the need of an ideal diagnostic lead time for CUP patients. There was no full consensus on the place in diagnostic workup of symptom-guided MRI or ultrasound, a PET/CT scan, targeted gene panels, immunohistochemical markers, and whole genome sequencing. INTERPRETATION: Consensus was reached on the contents of the first diagnostic layer of a multi-layer CUP classification. This is a first step towards full consensus on CUP diagnostics, that should also include supplementary and advanced diagnostics.

01 januari 2023, Item does not contain fulltext, BACKGROUND: Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1-2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP. METHODS: Participants for a four round modified Delphi study were selected via a CUP literature search in PubMed and an international network of cancer researchers. A total of 90 CUP experts were invited, and 34 experts from 15 countries over four continents completed all Delphi survey rounds. FINDINGS: The Delphi procedure resulted in a multi-layer CUP classification for the diagnostic workup. Initial diagnostic workup should at least consist of history and physical examination, full blood count, analysis of serum markers, a biopsy of the most accessible lesion, a CT scan of chest/abdomen/pelvis, and immunohistochemical testing. Additionally, the expert panel agreed on the need of an ideal diagnostic lead time for CUP patients. There was no full consensus on the place in diagnostic workup of symptom-guided MRI or ultrasound, a PET/CT scan, targeted gene panels, immunohistochemical markers, and whole genome sequencing. INTERPRETATION: Consensus was reached on the contents of the first diagnostic layer of a multi-layer CUP classification. This is a first step towards full consensus on CUP diagnostics, that should also include supplementary and advanced diagnostics.

Introduction: Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. Methods: The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. Discussion: This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. Clinical Trial Registration: The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

Purpose: Little is known about the prevalence of occult lymph node metastases (LNM) in muscle-invasive bladder cancer (MIBC) patients with pathological downstaging of the primary tumor. We aimed to estimate the prevalence of occult LNM in patients without residual MIBC at radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or neoadjuvant radiotherapy (NAR), and to assess overall survival (OS). Methods: Patients with cT2-T4aN0M0 urothelial MIBC who underwent RC plus pelvic lymph node dissection (PLND) with curative intent between January 1995–December 2013 (retrospective Netherlands Cancer Registry (NCR) cohort) and November 2017–October 2019 (prospective NCR-BlaZIB cohort (acronym in Dutch: BlaaskankerZorg In Beeld; in English: Insight into bladder cancer care)) were identified from the nationwide NCR. The prevalence of occult LNM was calculated and OS of patients with <(y)pT2N0 vs. <(y)pT2N+ disease was estimated by the Kaplan–Meier method. Results: In total, 4657 patients from the NCR cohort and 760 patients from the NCR-BlaZIB cohort were included. Of 1374 patients downstaged to <(y)pT2, 4.3% (N = 59) had occult LNM 4.1% (N = 49) of patients with cT2-disease and 5.6% (N = 10) with cT3-4a-disease. This was 4.0% (N = 44) in patients without NAC or NAR, 4.5% (N = 10) in patients with NAC, and 13.5% (N = 5) in patients with NAR but number of patients treated with NAR and downstaged disease was small. The prevalence of <(y)pT2N+ disease was 4.2% (N = 48) in the NCR cohort and 4.6% (N = 11) in the NCR-BlaZIB cohort. For patients with <(y)pT2N+ and <(y)pT2N0, median OS was 3.5 years (95% CI 2.5–8.9) versus 12.9 years (95% CI 11.7–14.0), respectively. Conclusion: Occult LNM were found in 4.3% of patients with cT2-4aN0M0 MIBC with (near-) complete downstaging of the primary tumor following RC plus PLND. This was regardless of NAC or clinical T-stage. Patients with occult LNM showed considerable worse survival. These results can help

Purpose:: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell–targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8⁺ T-cell–mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1–targeting antibodies for cancer treatment. Patients and Methods:: In this study, we analyzed the mode of action of a humanized IgG4 anti–Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305–induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase–mediated endosomal acidification and improved the ability of macrophages to activate CD8⁺ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.

Objectives: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. Method(s): A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Result(s): Of 17 693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Conclusion(s): Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to

Objectives: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. Method(s): A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Result(s): Of 17 693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Conclusion(s): Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to