Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)

Professional and personal opinions of doctors in training during the first wave of the COVID19 pandemic.

BACKGROUND: The COVID19 pandemic is one of the greatest modern global healthcare crises. The resultant morbidity and mortality of public and healthcare professionals has led to psychological impacts and economic repercussions. We set out to assess the concerns of doctors in training during this crisis. METHODS: A questionnaire was developed and delivered via Survey Monkey to doctors in training from 27 March to 6 April 2020, 2 weeks prior to the expected surge in Ireland and UK. The Perceived Stress Scale (PSS) was incorporated to gauge respondent stress as they prepared for the COVID19 impact. RESULTS: A total of 285 participants engaged with 197 (69%) completing all questions. Almost 86% of respondents had been trained in donning and doffing personal protective equipment (PPE), and nearly 85% felt confident in the process. Overall, most respondents felt somewhat prepared (60%) or well prepared (20%) to treat COVID19 patients. However, 42% worried that their hospital would struggle, or not cope at all; in particular, 91% highlighted the risk of running out of PPE. Family health (86%), personal health (72%), and social life (47%) topped the list of junior doctor concerns. According to the PSS, the majority of respondents (62%) had moderate stress. CONCLUSIONS: This survey is the first to measure the concerns of doctors in training in Ireland as regards the COVID19 pandemic. Worries included PPE exhaustion and personal and family health. A significant majority had moderate stress. Additional supports for doctors in training are essential to aid stress and manage concerns better.

Dural spread from metastatic prostate cancer.

A 59-year-old man with a known breast cancer type 1 gene mutation and a 2-year history of metastatic prostate cancer to bone and lymph nodes presented with a sudden onset of thunderclap headache, photophobia and a left sided facial droop. He was being treated at the time with the poly ADP ribose polymerase inhibitor Rucaparib. Of note, 6 weeks prior to this presentation, he had been diagnosed with malignant spinal cord compression at T3-T6, he underwent an emergency decompressive laminectomy and had received palliative postoperative radiotherapy. An urgent CT brain revealed dural metastases from his prostate cancer, with extensive oedema and midline shift. He underwent palliative whole brain radiotherapy but died 2 weeks later.

An Unusual Case of Gastrointestinal Bleeding in Metastatic Renal Cell Carcinoma.

Approximately 340 patients are diagnosed with renal cell cancer (RCC) in Ireland each year. Metastatic spread to the lung, lymph nodes and bones is common. Metastatic spread to the gastrointestinal tract, including the small bowel, is a rare phenomenon. Therapeutic advances have led to an improved overall survival in RCC and, as a result, unusual sites of metastatic spread are becoming more common. We present the case of a 68-year-old gentleman presenting with upper gastrointestinal bleeding as a result of metastases to the duodenum from renal cell carcinoma.

Paradoxical scintigraphy bone scan findings with malignancy-associated extreme hypercalcemia.

We report the first case of extreme hypercalcemia (Ca 2+ >6.0 mmol/L) as the initial presentation of de novo metastatic breast cancer. Following treatment and stabilization of the patient, imaging revealed a large breast mass and widespread osseous metastases. Whole body bone scintigraphy demonstrated significant extra osseous uptake of radiotracer in the lungs, liver, and kidneys-a rare phenomenon secondary to profound hypercalcemia. Biopsy revealed estrogen receptor (ER) positive breast carcinoma, for which the patient was treated.

Iron deficiency anaemia in a coeliac: a cause for concern?

A 70-year-old woman with a 15-year history of coeliac disease was admitted for treatment and investigation of symptomatic anaemia. Of note, she was recently commenced on aspirin therapy for retinal artery occlusion. This followed a normal gastro-duodenoscopy, colonoscopy and CT abdomen as workup for iron deficiency anaemia. On this occasion, the patient was further investigated with small bowel capsule endoscopy. This revealed an ulcerated lesion in her proximal jejunum suspicious for malignancy, namely lymphoma. A biopsy of the lesion confirmed adenomatous changes and high-grade dysplasia without malignant changes. Given the endoscopic appearances of the lesion, she was further evaluated with a small bowel MRI. This revealed a 3 cm lesion with associated lymphadenopathy but no distant metastases. She proceeded to resection of her small bowel which confirmed an invasive adenocarcinoma of her proximal jejunum. She is currently undergoing adjuvant chemotherapy on an outpatient basis.