Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.Cancer immunotherapy is used in the treatment of different cancer types. Immunotherapy activates the immune system to detect and attack cancer cells, but side effects may arise from the immune system inadvertently attacking normal tissues and organs. The increased use of immunotherapy has led to an increase in the reporting of rare but potentially life-threatening treatment-related side effects. In this case series, the authors report the clinical features and outcomes of seven patients who developed inflammation of the heart, muscles, nerve and muscle junctions and liver following treatment with immunotherapy. The authors review the scientific literature and discuss the current understanding of and management approach to this rare syndrome. The authors' report highlights the importance of a high degree of clinical suspicion, prompt comprehensive testing to confirm diagnosis, early involvement of experts from different specialties and early initiation of treatment in the management of this unique syndrome.
Molecular tumor boards (MTBs) require specialized activities to leverage genomic data for therapeutic decision-making. Currently, there are no defined standards for implementing, executing, and tracking the impact of MTBs. This study describes the development and validation of ACTE-MTB, a tool to evaluate the maturity of an organization’s MTB to identify specific areas that would benefit from process improvements and standardization. The ACTE-MTB maturity assessment tool is composed of 3 elements: 1) The ACTE-MTB maturity model; 2) a 59-question survey on MTB processes and challenges; and 3) a 5-level MTB maturity scoring algorithm. This tool was developed to measure MTB maturity in the categories of Access, Consultation, Technology, and Evidence (ACTE) and was tested on 20 MTBs spanning the United States, Europe, and Asia-Pacific regions. Validity testing revealed that the average maturity score was 3.3 out of 5 (+/- 0.1; range 2.0–4.3) with MTBs in academic institutions showing significantly higher overall maturity levels than in non-academic institutions (3.7 +/- 0.2 vs. 3.1 +/- 0.2; P = .018). While maturity scores for academic institutions were higher for Consultation, Technology, and Evidence domains, the maturity score for the Access domain did not significantly differ between the two groups, highlighting a disconnect between MTB operations and the downstream impact on ability to access testing and/or therapies. To our knowledge, ACTE-MTB is the first tool of its kind to enable structured, maturity assessment of MTBs in a universally-applicable manner. In the process of establishing construct validity of this tool, opportunities for further investigation and improvements were identified that address the key functional areas of MTBs that would likely benefit from standardization and best practice recommendations. We believe a unified approach to assessment of MTB maturity will help to identify areas for improvement at both the organizational and system level.
Drug induced pancreatitis is rare and establishing the exact causal relationship is challenging. Here, we discuss the management of a 60 year-old female patient with stage 3a breast cancer who developed doxorubicin induced pancreatitis 3 days after her first treatment with cyclophosphamide and doxorubicin chemotherapy. This patient had locally advanced cancer and there remained a significant risk of metastatic disease in the absence of chemotherapy. Therefore, she opted for rechallenge despite the risk of recurrent pancreatitis. She commenced cyclophosphamide and PEGylated-liposomal doxorubicin at 30mg/m2, instead of conventional doxorubicin and tolerated this well, without recurrence of pancreatitis. Doxorubicin is becoming increasingly associated with pancreatitis, with high incidence of recurrence upon rechallenge. PEGylated liposomal doxorubicin has not been shown to cause pancreatitis and there is evidence supporting its use for treating breast cancer. A potential strategy for continued treatment following doxorubicin-induced pancreatitis, may be to substitute conventional doxorubicin with PEGylated liposomal doxorubicin.
Advanced adrenocortical cancer (ACC) is a rare, highly aggressive malignancy, which typically has a poor prognosis. In advanced ACC, the overall trend is toward a short PFS interval following first-line systemic therapy, highlighting a clear need for improved second-/third-line treatment strategies. We conducted a review of the literature and relevant scientific guidelines related to systemic therapy for advanced ACC. Public indexes including PubMed/MEDLINE were searched. Treatment selection in the second-line setting is based on small phase 2 trials, case reports, and pre-clinical evidence. The best data available for initial second-line therapy selection supports the use of gemcitabine and capecitabine (G + C) or streptozotocin (S), both with or without mitotane. G + C is becoming increasingly recommended based on phase 2 clinical trial data in patients of good PS, due to the inferred superior PFS and OS from non-comparative trials. Alternatively, streptozotocin was better tolerated than EDP + M in the FIRM-ACT study and remains an option when warranted. Beyond this, further treatment approaches should be tailored to individual patient characteristics, utilizing a mixture of systemic therapies, local therapies, and enrolment in clinical trials where available. Additionally, the role of molecular stratification, predictive biomarkers, and immune checkpoint inhibitors in specific individuals, such as Lynch syndrome, is evolving and may become increasingly utilized in clinical practice. Advanced ACC necessitates a multidisciplinary approach and is best managed in a specialist center. Although there is no one definitive second-line treatment strategy, there are some favorable approaches, which require further validation in larger clinical trials.
Background: Despite advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), primary and secondary resistance to current therapies remains. Elevated circulating sphingolipids are associated with poor outcomes in patients with mCRPC, including therapeutic resistance and shorter overall survival. PCPro is a clinically accessible, regulatory compliant plasma lipid biomarker of poor prognosis in mCRPC, which incorporates prognostic sphingolipids. We hypothesize that reversal of the PCPro signature in men with mCRPC by sphingolipid-lowering agents will improve their clinical outcomes. However, the first step is to determine whether this poor prognostic lipid signature can be modulated. A potential sphingolipid-lowering agent is the PCSK9-inhibitor evolocumab, which is used in the management of hypercholesterolemia. Objectives: Our primary objective is to assess whether treatment with evolocumab during standard anticancer therapy can safely modify the PCPro signature in men with mCRPC. Design: This is a multicenter, open label phase II trial. Methods: Men with mCRPC commencing docetaxel, cabazitaxel, abiraterone, enzalutamide, olaparib, or lutetium-177 PSMA for disease progression will be screened for the presence of PCPro. Those who are PCPro positive will receive a 12-week course of evolocumab concurrent with their standard therapy. Dosage is as per cardiovascular guidelines (420 mg subcutaneously every 4 weeks). PCPro will be repeated after 12 weeks. The primary endpoint is reversal of PCPro. The secondary endpoint is the safety of combination therapy with exploratory endpoints characterizing changes in comprehensive lipid profiles pre- and post-treatment. Discussion: This study will evaluate whether evolocumab can safely modify the PCPro signature in men with mCRPC, providing essential data to the development of precision metabolic therapy in the management of prostate cancer. Trial registration: This study is approved by the Human Research Ethics Committee (X22-0072 and 2022/ETH00427). It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622001003763).
e14574 Background: Oncolytic virus (OV) can specifically replicate in cancer cells causing cell lysis. Together with the expression of immune stimulating payloads, OV can induce an anti-tumor immune response. The aim of this study is to assess the safety, tolerability, and PK profile of VG161, a novel HSV-1 OV armed with IL12, IL15 with its receptor α unit, and PD-L1 antagonist (Fc-fused 14 amino acid peptide), after single intra-tumoral injection (IT) in patients with advanced refractory solid tumors. Methods: This is an open label, single-arm, accelerated titration design pilot trial. Based on preclinical NOAEL, the first cohort dose level was calculated as 5×10 7 /subject, followed with 2 cohorts (1×10 8 and 2×10 8 PFU), 1-3 patients per cohort. One patient was treated in each cohort and the subsequent cohorts were initiated only after the safety observation of the current cohort was completed (21 days) with no DLT and no > 2 moderate toxicity events deemed possibly, probably, or definitely related to VG161, otherwise, it would be expanded per the 3+3 design. DNA copy number of VG161 was measured with qPCR in the tumor biopsy and blood, in urine for virus shedding, as well as swabs of injection site and mouth. Immune cytokines were measured with MSD assay (electrochemiluminescence detection) in blood. Peripheral lymphocyte subsets were analyzed with flowcytometry. Results: Three patients (1 per cohort) were treated and completed safety observation. No DLT, and 10 AEs (fever, low neutrophils and lymphocytes, etc.) were possibly, probably, or definitely related. Grade 3 fever was the only related SAE, which recovered in 3 days. Dose dependent increase of VG161 DNA copy was detected in the tumor 2-3 days after treatment (C-max: 10, 1000, and 1000000 times increase from low to high dose), in contrast, it remained undetectable in blood, oral swab, and urine. Virus DNA was detected in injection site swab for the patient at the highest dose level but not for those treated at lower dose levels. After dosing, increases of IL-12 (C-max: 2.0, 2.4, and 21 times of baseline), IL-15 (C-max: 1.6, 3.2, and 2.5 times of baseline), IFN-γ (C-max: 49, 638, and 236 times of baseline) and TNF-α (C-max: 2.3, 3.7, and 2.2 times of baseline) from low to high dose were seen. Peripheral lymphocyte subset analysis and immune profiling of injected tumor are ongoing. Interestingly, partial regression of multiple visible non-injected lesions was observed in 1 patient shortly after dosing, however no durable direct or abscopal responses were seen to date. Conclusions: Single IT injection of VG161 up to 2×10 8 PFU/subject is safe and well tolerated, with no unexpected viral spread or shedding. The post-dose increase in cytokines and the transit regression of non-injected lesions imply the activation of anti-cancer immunity induced by VG161. This holds potential for further dose optimization to assess the safety and efficacy. Clinical trial information: ACTRN12620000244909.
Taxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.
Abstract Birt–Hogg–Dubé (BHD) syndrome is a rare, autosomal dominant disorder caused by a germline mutation in the folliculin gene (17p11.2). It is characterized by benign skin lesions, renal tumours, and pulmonary cysts, with pneumothoraces seen exceptionally rarely in patients younger than 40 years. We report the case of a 15‐year‐old boy who presented with sudden onset left‐sided chest pain and acute dyspnoea secondary to a large left‐sided pneumothorax. This failed to resolve despite chest drain insertion and he required video‐assisted thoracoscopic surgical pleurodesis, which revealed macroscopic pulmonary cyst formation. Following this, he made a good recovery and a further high‐resolution computerized tomography (CT) scan of his chest identified multiple, small, subpleural parenchymal lung cysts that were not initially visible on prior imaging. Further questioning revealed a strong family history of spontaneous pneumothoraces and additional genomic sequencing confirmed a diagnosis of BHD syndrome. We highlight the diagnostic, management, and surveillance challenges for this rare syndrome.
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