Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis.

OBJECTIVE: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. METHODS: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. RESULTS: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6-10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. CONCLUSION: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.

Comparison of a PACS workstation with laser hard copies for detecting scaphoid fractures in the emergency department.

Picture archiving and communication systems (PACS) for imaging studies is rapidly being adopted in hospitals throughout the UK. However, very little comparison has been made between PACS and laser hard copies for assessing the diagnostic accuracy of detecting fractures by emergency physicians. A prospective paired comparison study was undertaken looking at correct reporting of scaphoid X-rays on PACS and conventional film by emergency department medical staff. A total of 34 imaging studies were reported by 38 physicians using both PACS workstations and laser-printed films. The percentage of emergency physicians correctly reporting imaging studies was similar when comparing PACS images to laser film copies (80.7% versus 81.0%). The sensitivity and specificity of PACS for diagnosing scaphoid fractures was 79.5% and 81.6%, versus 78.1% and 83.8% for conventional films. There is no significant difference in accuracy of diagnosis between PACS and laser film copies when scaphoid X-rays are reported by emergency physicians.

A novel use of portable ultrasound in the management of shoulder dislocation.

Dislocation of the shoulder joint is a common presentation in the emergency department, the reduction of which is usually performed under sedation. At present post-reduction x rays are taken after the patient has recovered from this sedation. If reduction is unsuccessful, repeated attempts under further sedation may be required. In this small case series, bedside ultrasound was found to be accurate in determining whether reduction had been successful.

Multiple spontaneous dislocations in a patient with Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of inherited connective tissue disorders, characterised by generalised joint hypermobility, hyperextensibility of the skin, dystrophic scars, and a tendency to excessive bleeding. Sequelae include recurrent low impact trauma dislocations, chronic joint pain, and early osteoarthritis. This report describes a case of multiple simultaneous dislocations at distant sites. We highlight the importance of paying consideration to the exposure of patients to large cumulative doses of ionising radiation to diagnose and confirm reduction of frequent dislocations, and ask whether radiographic confirmation is necessary on every occasion in this subset of patients.

Benefits of CT urography in patients presenting to the emergency department with suspected ureteric colic.

BACKGROUND: Ureteric colic is a common presentation in the emergency department and accounts for approximately 1% of all hospital admissions. Diagnosis depends on a typical history, clinical examination and the presence of haematuria. Intravenous urography has traditionally been used as the means of investigation, but over recent years this has been superseded by CT urography. This latter investigation gives potentially more information and may detect alternative or additional pathology which would otherwise be missed on intravenous urography. METHODS: 100 consecutive patients attending the emergency department with a provisional diagnosis of ureteric colic undergoing CT urography were studied to detect the incidence of alternative or incidental pathology. RESULTS: Stone disease was found in 58% of patients, with obstruction present in 43%. The most common site of obstruction was the vesicoureteric junction. Significant incidental or alternative pathology was found in 16% of patients. It was estimated that, in 12%, these findings would not have been detected by intravenous urography. CONCLUSION: The use of non-contrast CT urography is recommended in the initial investigation of patients with ureteric colic.

Dissection of the carotid artery as a cause of fatal airway obstruction.

Carotid artery dissection is a rare entity, and most cases are attributable to causative factors, which include trauma and local malignancy. The vast majority of dissections present with cerebral infarct; those few that present with local mass effect and respiratory compromise may deteriorate rapidly, requiring urgent resuscitation and consideration of endotracheal intubation, which is often dangerous and/or impossible. The case of a spontaneous internal carotid artery dissection in an otherwise healthy young man, leading to gross mass effect and eventual fatal airway obstruction, is presented here. The need for a high index of suspicion for cervical vascular injury in cases of neck injury (even trivial), known head and neck malignancy/irradiation, or coagulopathy is highlighted. Patients presenting with unilateral neck swelling and symptoms related to mass effect must be assumed to have progressive airway obstruction, and difficult intubation should be anticipated.

Managing heart failure: update from Michael Reese's special program.

Heart failure is a major health problem, particularly among the elderly who experience the long term consequence of coronary artery disease. Over the past several years, the heart failure program at Michael Reese Hospital has seen a large number of elderly patients with heart failure. Two-thirds of these patients had a previous myocardial infarction, while 20% had an idiopathic (dilated) cardiomyopathy. Herein, we review that experience, focusing particularly on clinical presentation, our non-invasive approach to objectively determining their functional capacity and the severity of their failure, and, finally, a consideration of the various aspects of their medical management.

The obstetric and gynaecological complications of bladder exstrophy and epispadias.

A study has been made of 16 girls (14 with bladder exstrophy and 2 with epispadias) treated in the United Birmingham Hospitals since 1946 and surviving to puberty. Eight of these are married, of whom 5 have been delivered of 8 children. Ten have required some form of gynaecological surgery, with uterine prolapse as the most troublesome lesion.

High PEEP decreases hyaline membrane formation in surfactant deficient lungs.

Lung lavage was performed in 16 anaesthetized rabbits to produce surfactant-deficient lungs. This resulted in alveolar collapse, an arterial PO2 of less than 15 kPa on 100% oxygen and an inflection point on the inspiratory limb of the pressure-volume curve at an airway pressure of 8-10 mm Hg. One group of eight animals was then ventilated with a positive end-expiratory pressure (PEEP) equal to the pressure at the inflection point, whilst the second group of eight was ventilated with a PEEP 5 mm Hg less than the inflection point. Animals in the high PEEP group had a significantly greater arterial PO2 than those in the low PEEP group, but the mean survival time for each group was similar. However, there was a significantly greater incidence of hyaline membranes in the low PEEP group. Various mechanisms to explain these findings are discussed.