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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 organconfined 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 bladderpreservation in patients with (locally advanced) urothelial bladder cancer. [ABSTRACT FROM AUTHOR]

The post-pericardiotomy syndrome (PPS) is a common complication of cardiac surgery. In order to better understand the pathogenesis of this complication we undertook a prospective, triple blind study of consecutive long term survivors of cardiac surgery. We followed 82 patients and determined anti-heart antibodies (AHA), circulating immune complexes (CIC) and anti-viral antibodies (AVA) on sera pre-operatively and serially post-operatively. According to the clinical features of pericarditis, fever and leucocytosis, patients were divided into three groups: (I) complete PPS with all three symptoms, (2) incomplete PPS with two symptoms and (3) no PPS with one or no symptoms. Clinical PPS was found in 16 patients (19.6%). All of these patients had positive AHA, 12 patients (75%) had increased CIC and five patients (31 %) had a four-fold or greater rise in titre to viruses studied. Twenty-four patients (29.2%) had an incomplete PPS. It was accompanied by positive AHA in 17 patients (70.8%), increased CIC in 14 patients (58.3%) and a four-fold rise or greater in virus titre in seven patients (29.2%). No PPS was found in forty-two patients (51.2%). It was accompanied by positive AHA in eight patients (19%), increased CIC in 10 patients (24%) and a four-fold or greater rise in virus titre in 12 patients (28.6%). There was a good correlation between the presence of PPS, AHA, CIC and the type of operation. Heart valve replacement surgery was more frequently complicated by PPS. Development of post-operative AHA and increased CIC were also more frequently found. We found a good correlation between PPS, positive AHA and increased CIC. No correlation was found between PPS and virus serology. [ABSTRACT FROM AUTHOR]

Purpose: Simlukafusp alfa [fibroblast activation protein α-targeted IL2 variant (FAP-IL2v)], a tumor-targeted immunocytokine, comprising an IL2 variant moiety with abolished CD25 binding fused to human IgG1, is directed against fibroblast activation protein α. This phase I, open-label, multicenter, dose-escalation, and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors., Patients and Methods: Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intraparticipant uptitration regimens (15/20, 20/25, 20/20/35, and 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities, maximum tolerated dose, recommended expansion dose, and pharmacokinetics., Results: Sixty-one participants were enrolled. Dose-limiting toxicities included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (uptitration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). The uptitration regimen 15/20 mg was determined as the maximum tolerated dose and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses [NK cells, 13-fold; CD4+ T cells (including regulatory T cells), 2-fold; CD8+ T cells, 3.5-fold] but without any percentage change in regulatory T cells. Clinical activity was observed from 5 mg [objective response rate, 5.1% (n = 3); disease control rate, 27.1% (n = 16)]. Responses were durable [n = 3, 2.8 (censored), 6.3, and 43.4 months]., Conclusions: FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Advanced bladder cancer patients have historically failed to achieve prolonged duration of response to conventional chemotherapy and needed better first-line treatment regimens. The approval of nivolumab in combination with gemcitabine and cisplatin and pembrolizumab with antibody-drug conjugate enfortumab vedotin has revolutionized the first-line treatment of advanced bladder cancer in many countries. In this review, we summarize the intricate differences between the two landmark clinical trials that led to their incorporation into the current standard of care for advanced bladder cancer. We further discuss newer novel treatment options in the second and subsequent lines of treatment on progression, like immunotherapy in combination with other agents, including fibroblast growth factors receptor inhibitors, human epidermal growth factor inhibitors, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Finally, we discuss the integration of these novel therapies into current clinical practice amidst the rapidly evolving landscape of advanced bladder cancer treatment, aiming to enhance patient outcomes.

SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from 'immune-excluded' to 'immune-infiltrated' phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer., Competing Interests: Declaration of interests L.V. declares consulting fees from Adaptherapy; stock or stock options for Resolved. M.D.M. declares payment or honoraria for lectures, presentations, speakers bureaus, and manuscript writing or educational events from Janssen and MSD. A.P. declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Incyte and Roche; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Incyte, Novartis, Gilead, and BeiGen. D.B. declares consulting fees from Merck AG, Pfizer, Bayer, Cantargia AB, Faron Pharmaceuticals, and Servier. T.S. declares payment or honoraria for lectures, presentations, speakers bureaus, and manuscript writing or educational events from BMS; participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals, Merck, and Novartis; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Finnish Oncology Society. S.I. declares grants or contracts from any entity from Roche and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Roche, Astra Zeneca, Takeda, Novartis, MSD, Pierre Fabre, and Boehringer-Ingelheim. S.S. declares consulting fees from Faron Pharmaceuticals, participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals. Y.T.M. declares consulting fees from Eisai, Roche, AstraZeneca, and Ipsen; payment or honoraria for lectures, presentations, speakers bureaus, and manuscript writing or educational events for Bayer and Boston Scientific; and participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals. D.G. declares consulting fees from Clinigen and McCann Health; payment or honoraria for lectures, presentations, speakers bureaus, and manuscript writing or educational events from Cancer Drug Development Fund and Pfizer. S.P.A. declares payment or honoraria for lectures, presentations, speakers bureaus, and manuscript writing or educational events from Bayer, BMS, ASCO, and Exelixis; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Seagen, and QED Therapeutics/Helsinn; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Board-Support New India. P.J. declares participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals. C.Y. declares consulting fees from Faron Pharmaceuticals; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer. J.M. declares all support for the present manuscript from Faron Pharmaceuticals (employment); patents planned, issued or pending for Faron Pharmaceuticals; participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals; and stock or stock options for Faron Pharmaceuticals. M.K.K. declares all support for the present manuscript from Faron Pharmaceuticals (employment); patents planned, issued or pending for Faron Pharmaceuticals; and stock or stock options for Faron Pharmaceuticals. J.J. declares all support for the present manuscript from Faron Pharmaceuticals (employment); grants or contracts from any entity from European Innovation Council; and stock or stock options for Faron Pharmaceuticals. J.P.K. declares all support for the present manuscript from Faron Pharmaceuticals; consulting fees from MSD, BMS, Roche, Pfizer, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, and manuscript writing or educational events from MSD, BMS, Roche, AstraZeneca, and Sanofi; payment for expert testimony from Sanofi; support for attending meetings and/or travel from BMS; participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals; and stock or stock options from Faron Pharmaceuticals. A.M. declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Chugai, Novartis, and Bayer; support for attending meetings and/or travel from Amgen; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen, Takeda, Genmab, Merck, and Faron Pharmaceuticals. M.H. declares all support for the present manuscript from Faron Pharmaceuticals; patents issued or pending for Faron Pharmaceuticals; and stock or stock options from Faron Pharmaceuticals. P.B. declares consulting fees from Faron Pharmaceuticals, Herantis Pharma, MSD Oncology, Ipsen, Oncorena, and TILT biotherapeutics; participation on a Data Safety Monitoring Board or Advisory Board for Faron Pharmaceuticals, TILT biotherapeutics, and Oncorena; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Terveystalo (employment); stock or stock options for Terveystalo, TILT biotherapeutics; and other financial or non-financial interests for Faron pharmaceuticals, stock ownership (spouse)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Since there is no clear consensus on optimal treatment duration of PD-(L)1 targeting checkpoint inhibitors in the setting of urothelial cancer (UC) patients, even patients with durable responses are often treated up to 2 years. It is questionable whether this is necessary and whether quality of life improves when treatment is discontinued earlier and restarted when necessary., Methods: We collected available data from locally advanced or metastatic UC patients within the Netherlands between September 2017 and December 2019 treated with first or second-line pembrolizumab, to evaluate treatment duration, reasons for discontinuation, subsequent treatments and survival outcomes., Results: Data were available from 74 patients: 85% (63/74) of patients had a treatment duration of 12 months or shorter, and in seven out of them, treatment was discontinued for another reason than progressive disease. Two patients (3%) had a treatment duration between 12 and 24 months, and eight patients (11%) completed 24 months of treatment. Survival at data cut-off (1 July 2020) with a median follow-up of 35 months was 100% in patients with partial or complete response (6/7 patients) and treatment duration ≤ 12 months, and 100% in patients treated for 24 months. In total, three patients were re-treated with pembrolizumab upon progressive disease during follow-up., Conclusions: In patients who reach partial or complete response during treatment with a PD-(L)1 targeting checkpoint inhibitor, early discontinuation of treatment with pembrolizumab and restart if necessary seems to be reasonable with preserved favorable outcomes. This article should drive further efforts to optimize the treatment duration for patients who respond to treatment with pembrolizumab.

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., Competing Interests: Conflict of interest statements The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Biomarker-guided therapy in an experimental setting has been suggested to improve patient outcomes. However, trial-specific pre-screening tests are time and tissue consuming and complicate the personalised treatment of patients eligible for early-phase clinical trials. In this study the feasibility of whole-genome sequencing (WGS) as a one-test-for-all for guided inclusion in early-phase trials was investigated., Methods: Phase I Molecular Tumor Board (MTB) at the Erasmus MC Cancer Institute reviewed patients with advanced cancer without standard-of-care treatment (SOC) options for a 'fresh-frozen' (FF) tumour biopsy for WGS based on clinical-pathological features. Clinical grade WGS was performed by Hartwig Medical Foundation. MTB matched the patient with a trial, if available., Results: From September 2019-March 2021, 31 patients with highly diverse tumour types underwent a tumour biopsy for WGS. The median turnaround time (TAT) was 15 days [10-42 days]. At least one actionable event was found in 84% of the patients (26/31). One-third of the patients (11/31) received matched experimental treatment., Conclusions: WGS on fresh FF biopsies is a feasible tool for the selection of personalised experimental therapy in patients with advanced cancer without SOC options. WGS is now possible in an acceptable TAT and thus could fulfil the role of a universal genomic pre-screening test., (© 2022. The Author(s).)

Background: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy., Methods: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04., Results: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses., Conclusions: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition., Clinical Trial Registration: NCT03267316., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m 2 (CABA20) was non-inferior to cabazitaxel 25 mg/m 2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes., Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed., Results: All randomized patients ( n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p., Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.

Background: Bone resorption inhibitors such as denosumab may induce symptomatic hypocalcaemia if a vitamin D deficiency is present. Amongst other causes, this type of deficiency may arise following bariatric surgery., Case Description: We describe a 51-year-old woman who, a few years after undergoing bariatric surgery, developed symptomatic hypocalcaemia after she started taking denosumab., Conclusion: An adequate calcium and vitamin D status is a general condition before prescribing medication to treat osteoporosis. Therefore we recommend that before starting treatment with a bone resorption inhibitor that not only the calcium but also the vitamin D status should be determined, and if necessary, optimised.

A 71-year-old woman was treated for a relapsing pulmonary tuberculosis with reinstitution of rifampicin after a medication-free interval of 2 years. After ingestion of the second dose, she developed severe hemolytic anemia and acute renal failure (ARF) necessitating dialysis. We demonstrated the presence in the patient's serum of rifampicin-dependent immunoglobulin G (IgG) and IgM antibodies, which caused red blood cell lysis through interaction with the I antigen on the erythrocyte surface. A review of the literature yielded 48 cases of rifampicin-associated renal failure. A subgroup of 37 patients could be distinguished, which, analogous to our case, suddenly developed ARF and frequently also developed hemolytic anemia and/or thrombocytopenia during intermittent or interrupted treatment. Regarding the pathogenesis of the ARF, renal biopsy consistently revealed tubular lesions. Although intravascular hemolysis with hemoglobinuria may play a role, it is not uniformly present. Our demonstration of an antibody with anti-I specificity provides a possible explanation. The I antigen is also expressed on tubular epithelium and may, therefore, be the target structure through which rifampicin-antibody complexes lead to tubular cell destruction. The other cases of rifampicin-associated ARF were unrelated to this subgroup: two cases of rapidly progressive glomerulonephritis, five cases of acute interstitial nephritis, and four cases of light chain proteinuria were recorded.