Metastatic non-small cell lung cancer presenting with an orbital metastasis: a case report

Metastatic disease to the orbit occurs in up to 7% of cancers. In approximately 20% of cases, there is no diagnosis of cancer at the time of presentation with orbital metastatic disease. This is a case of a 53-year-old female smoker whose initial presentation of metastatic non-small cell lung cancer was with an orbital metastasis

Dexamethasone-induced flares of Trichophyton rubrum masquerading as docetaxel cutaneous toxicity: a case report

Docetaxel chemotherapy is increasingly used in the treatment of castration-resistant prostate cancer. Cutaneous toxicity is common with docetaxel, occurring in up to 75% of cases. We present an unusual case of castration-resistant prostate cancer in which our patient developed recurrent but transient episodes of skin rash following each cycle of docetaxel. Initially, the rash was attributed to docetaxel cutaneous toxicity however a microbiological diagnosis of Trichophyton rubrum was subsequently made. We postulated that dexamethasone pre-medication transiently suppressed anti-fungal immunity, and indeed further flares were prevented by significantly reducing the dose of dexamethasone while continuing treatment with docetaxel

Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design

PARP inhibitor; Androgen receptor; EnzalutamideInhibidor de PARP; Receptor d'andrògens; EnzalutamidaInhibidor de PARP; Receptor de andrógenos; EnzalutamidaPARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197)

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer

Atezolizumab; Cabozantinib; Immune checkpoint inhibitorAtezolizumab; Cabozantinib; Inhibidor del punto de control inmunitarioAtezolizumab; Cabozantinib; Inhibidor del punt de control immunitariCabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy – a population with a significant unmet need for treatment options.This study is funded by Exelixis but includes support (including the provision of atezolizumab) from Roche

Plain language summary of the design of the TALAPRO-2 study comparing talazoparib and enzalutamide versus enzalutamide and placebo in men with metastatic castration-resistant prostate cancer

Clinical trial; Enzalutamide; TalazoparibEnsayo clínico; Enzalutamida; TalazoparibAssaig clínic; Enzalutamida; TalazoparibWhat is this summary about? This summary describes the design of an ongoing research study (also known as a clinical trial) called TALAPRO-2. The TALAPRO-2 trial is testing the combination of two medicines called talazoparib and enzalutamide as a first treatment in adult men with metastatic castration-resistant prostate cancer. The study began in December 2017 and has enrolled 1037 adult men with metastatic castration-resistant prostate cancer from 26 countries. What is metastatic castration-resistant prostate cancer? Metastatic castration-resistant prostate cancer is a type of cancer that has advanced beyond the prostate and continues to grow even when testosterone levels in the blood are suppressed. Which medicines are being tested? The combination of talazoparib plus enzalutamide will be compared with enzalutamide plus placebo. Enzalutamide is approved to treat men with prostate cancer. Talazoparib is not approved to treat men with prostate cancer. A placebo does not contain any active ingredients and is also known as a sugar pill. What are the aims of the TALAPRO-2 trial? The TALAPRO-2 trial will find out if combining talazoparib with enzalutamide increases the length of time the men in the study live without their cancer getting worse compared with enzalutamide plus placebo. The study will also measure how long men in the study live and any side effects the men have while they are taking the study medicines. Researchers are also testing the DNA from the tumor cells of all men in the study to find out if they have faulty DNA repair genes. Clinical Trial Registration: NCT0339519 (ClinicalTrials.gov

Severe cutaneous toxicity following treatment with radiotherapy and cetuximab: a case report

While the addition of cetuximab to radiotherapy improves clinical outcomes in locoregionally advanced head and neck squamous cell cancers, there are a small number of reports of severe radiation dermatitis occurring with this therapeutic combination. We present the case of a 69 year old male who developed severe radiation dermatitis following treatment with cetuximab and radiotherapy for a locoregionally advanced head and neck squamous cell cancer

An MBSE Approach for Development of Resilient Automated Automotive Systems

Advanced driver assistance and automated driving systems must operate in complex environments and make safety-critical decisions. Resilient behavior of these systems in their targeted operation design domain is essential. In this paper, we describe developments in our Model-Based Systems Engineering (MBSE) approach to develop resilient safety-critical automated systems. An MBSE approach provides the ability to provide guarantees about system behavior and potentially reduces dependence on in-vehicle testing through the use of rigorous models and extensive simulation. We are applying MBSE methods to two key aspects of developing resilient systems: (1) ensuring resilient behavior through the use of Resilience Contracts for system decision making; and (2) applying simulation-based testing methods to verify the system handles all known scenarios and to validate the system against potential unknown scenarios. Resilience Contracts make use of contract-based design methods and Partially Observable Markov Decision Processes (POMDP), which allow the system to model potential uncertainty in the sensed environment and thus make more resilient decisions. The simulation-based testing methodology provides a structured approach to evaluate the operation of the target system in a wide variety of operating conditions and thus confirm that the expected resilient behavior has indeed been achieved. This paper provides details on the development of a utility function to support Resilience Contracts and outlines the specific test methods used to evaluate known and unknown operating scenarios. Document type: Articl

Modern paradigms for prostate cancer detection and management

Early detection and management of prostate cancer has evolved over the past decade, with a focus now on harm minimisation and reducing overdiagnosis and overtreatment, given the proven improvements in survival from randomised controlled trials. Multiparametric magnetic resonance imaging (mpMRI) is now an important aspect of the diagnostic pathway in prostate cancer, improving the detection of clinically significant prostate cancer, enabling accurate localisation of appropriate sites to biopsy, and reducing unnecessary biopsies in most patients with normal magnetic resonance imaging scans. Biopsies are now performed transperineally, substantially reducing the risk of post-procedure sepsis. Australian-led research has shown that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior accuracy in the staging of prostate cancer than conventional imaging (CT and whole-body bone scan). Localised prostate cancer that is low risk (International Society for Urological Pathology [ISUP] grade 1, Gleason score 3 + 3 = 6; and ISUP grade group 2, Gleason score 3 + 4 = 7 with less than 10% pattern 4) can be offered active surveillance, reducing harms from overtreatment. Prostatectomy and definitive radiation remain the gold standard for localised intermediate and high risk disease. However, focal therapy is an emerging experimental treatment modality in Australia in carefully selected patients. The management of advanced prostate cancer treatment has evolved to now include several novel agents both in the metastatic hormone-sensitive and castration-resistant disease settings. Multimodal therapy with androgen deprivation therapy, additional systemic therapy and radiotherapy are often recommended. PSMA-based radioligand therapy has emerged as a treatment option for metastatic castration-resistant prostate cancer and is currently being evaluated in earlier disease states

A Randomized Ph2 Study of MEDI0680 in Combination With Durvalumab vs. Nivolumab Monotherapy in Patients With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

BACKGROUND: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase 2 study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy naïve patients with advanced clear cell renal cell carcinoma who received at least one prior line of anti-angiogenic therapy. METHODS: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all IV Q2W. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden (TMB), and tumor-infiltrated immune cell profiles. RESULTS: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% (7/42; 95% CI, 7.0-31.4) with combination treatment and 23.8% (5/21; 95% CI, 8.2- 47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Due to AEs, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. CONCLUSIONS: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy