Antibody-Drug Conjugates: Ushering in a New Era of Cancer Therapy.

Antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy, and targeted agents are occurring.

Effects of Endocrine Therapy on Cognitive Function in Patients with Breast Cancer: A Comprehensive Review.

Endocrine therapy forms the backbone of systemic therapy for the majority of persons with early and late-stage breast cancer. However, the side effects can negatively affect quality of life, and impact treatment adherence and overall oncological outcomes. Adverse effects on cognition are common, underreported and challenging to manage. We aim to describe the nature, incidence, risk factors and underlying mechanisms of endocrine therapy-induced cognitive dysfunction. We conducted a comprehensive literature review of the studies reporting on cognitive dysfunction associated with endocrine therapies for breast cancer. We also summarise prevention and treatment strategies, and ongoing research. Given that patients are taking endocrine therapies for longer durations than ever before, it is essential that these side effects are managed pro-actively within a multi-disciplinary team in order to promote adherence to endocrine therapy and improve patients' quality of life.

Central Venous Catheter Thrombosis in Cancer: A Multi-Centre Retrospective Study Investigating Risk Factors and Contemporary Trends in Management.

OBJECTIVES: Central venous access is needed to facilitate chemotherapy for many cancer patients. Central venous catheter-related thrombosis (CVCT) is a major complication that can cause significant morbidity and mortality. We sought to explore the rate of CVCT in a general cancer population in Australia and to identify factors associated with increased risk of thrombosis. DESIGN: This is a multi-centre retrospective cohort study. SETTING AND PARTICIPANTS: We analysed key patient, treatment, and cancer-related factors for 317 patients with cancer and central venous catheters inserted for systemic therapy. MAIN OUTCOME MEASURES: Symptomatic CVCT confirmed with imaging and management of patients with CVCT. RESULTS: A total of 402 cases of central line insertion were analysed. Central venous catheter-related thrombosis occurred in 24 patients (6.0%). Having a peripherally inserted central catheter (PICC; HR = 3.78, 95% CI = 1.28-11.19, P = .02) compared with an implantable port and a body mass index of ⩾25.0 kg/m2 (HR = 3.60, 95% CI = 1.31-9.85, P = .01) were independently associated with increased risk of thrombosis. Central venous catheter-related thrombosis was managed mostly with removal of the catheter (19 of 24 cases) and anticoagulation, including direct-acting oral anticoagulants in 5 patients. CONCLUSIONS: This work explored rates of CVCT in a general cancer population, observing increased rates in those with PICCs or increased body mass index.

Factors influencing recurrence of stage I-III rectal cancer in regional Australia.

BACKGROUND: As treatments for rectal cancer improve with developments in surgical techniques, radiotherapy and chemotherapy, the nature of recurrences are evolving. We used a comprehensive database of a large Australian population with stage I-III rectal adenocarcinoma to identify timing and prognostic significance of recurrences, and factors associated with risk of developing recurrent disease. METHODS: All patients with locoregional rectal cancer treated with curative intent in our health district from 2006 to 2017 were included. Multivariate analysis using Cox regression models were used to identify factors associated with recurrence. RESULTS: A total of 483 patients were included. Recurrence occurred in 117 (24.2%) of 483 patients, being locoregional in 15 (3.1%) patients, distant in 85 patients (17.6%) and both locoregional and distant in 17 (3.5%) patients. Compared to those with locoregional recurrence, those with both locoregional and distant recurrence had worse cancer-specific survival. On univariate analysis, factors associated with recurrence included stage, grade, radiotherapy, chemotherapy, surgery type and distal tumour location. Factors which remained significant on multivariate analysis included higher grade and stage. CONCLUSION: In the era of multimodality therapy for rectal cancer, recurrences are predominantly distant. Traditional predictors including higher stage, grade and distal tumour location remain independently associated with recurrence, despite current treatment paradigms.

Disseminated intravascular coagulation and melanoma: a novel case occurring in metastatic melanoma with BRAF and NRAS mutations and systematic review.

Disseminated intravascular coagulation is a complex and potentially lethal complication of malignancy, in which the fundamental abnormality is excessive activation of the coagulation system. It is a rare complication of melanoma which can be difficult to diagnose in some circumstances, leading to delay in treatment. Herein, we describe the first case of disseminated intravascular coagulation occurring in BRAF and NRAS-mutant metastatic melanoma, and systematically review the literature regarding disseminated intravascular coagulation in melanoma. This review summarizes the reported cases of disseminated intravascular coagulation in melanoma and those secondary to the novel treatment of melanoma, and explores the pathophysiology of disseminated intravascular coagulation in melanoma, highlighting the key role of expression of markers of coagulation and fibrinolysis in disseminated intravascular coagulation, as well as more widely in melanoma. Current limitations in the literature are also identified and discussed, particularly with respect to improving the management of this lethal complication. Disseminated intravascular coagulation is a rare complication of melanoma that typically portends poor prognosis.

Vestibular symptoms as the presenting feature of progressive supranuclear palsy.

First described in 1964, progressive supranuclear palsy (PSP) is a chronic, sporadic, progressive neurodegenerative tauopathy. Substantial phenotypic variability inherent in PSP confers difficulty to diagnosis. Although the classic presentation, termed PSP-Richardson's syndrome, has been well described, additional variants of PSP are increasingly emerging. Phenotypes described to date include PSP-parkinsonism, PSP-pure akinesia with gait freezing, PSP-corticobasal syndrome or PSP-progressive non-fluent aphasia. However, there has been scant description of vestibular features in PSP. Herein, we report three similar cases with 'probable PSP' who presented with a poorly defined vestibular syndrome and early falls, highlighting an uncommon and as yet under-recognised, vestibular presentation of PSP. Further description of the natural history of this unusual vestibular presentation of PSP may assist in earlier diagnosis and prevent mismanagement of such patients.

Functional neuroimaging offers insights into delirium pathophysiology: A systematic review.

OBJECTIVE: This systematic review describes the current functional neuroimaging literature in delirium, discusses pathophysiological implications of these results and highlights areas for further study. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, an extensive search of medical databases was undertaken, identifying eighteen studies of variable quality and design suitable for inclusion. RESULTS: Functional neuroimaging has highlighted significant abnormalities during delirium, with disturbances in cerebral haemodynamics and functional connectivity potentially playing a key role in delirium pathophysiology. CONCLUSIONS: Although employing functional neuroimaging in delirium remains difficult, these findings demonstrate the potential of functional imaging to increase our understanding of the underlying mechanisms of delirium, to lead to more efficient interventions and targeted therapies and to reduce the burden of this underdiagnosed syndrome.

2-18F-fluoro-2-deoxyglucose positron emission tomography in delirium.

Delirium is a common, serious, yet poorly understood syndrome. Growing evidence suggests cerebral metabolism is fundamentally disturbed; however, it has not been investigated using 2-18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in delirium. This prospective study thus explored FDG PET patterns of cerebral glucose metabolism in older inpatients with delirium. A particular emphasis was on the posterior cingulate cortex (PCC), a key region for attention, which is a central feature of delirium. Delirium scans were compared with post-delirium scans using visual analysis and semi-quantitative analysis with NeuroQ; 13 participants (8 female, median 84 y) were scanned during delirium, and 6 scanned again after resolution. On visual analysis, cortical hypometabolism was evident in all participants during delirium (13/13), and improved with delirium resolution (6/6). Using NeuroQ, glucose metabolism was higher post-delirium in the whole brain and bilateral PCC compared to during delirium ( p < 0.05). Greater metabolism in both PCCs correlated with better performance on a neuropsychological test of attention, the WAIS-IV Digit Span Test forwards, and with shorter delirium duration. This research found widespread, reversible cortical hypometabolism during delirium and PCC hypometabolism was associated with inattention during delirium.

Mild parkinsonian features in dystonia: Literature review, mechanisms and clinical perspectives.

Dystonia is a hyperkinetic movement disorder that can be highly stigmatizing and disabling. Substantial evidence from animal models, neuropathological, neurophysiological, neuroimaging and clinical studies emphasizes the role of dopaminergic dysfunction in the pathophysiology of dystonia, illustrating possible pathophysiological overlap with parkinsonism. Furthermore, basal ganglia dysfunction has been implicated in the pathogenesis of dystonia, and is well established to underlie the manifestations of Parkinson's disease. Clinically, parkinsonian features are a key characteristic of some combined dystonias, including dopa-responsive dystonia, and Parkinson's disease often presents with dystonia. Moreover, many treatments effective in Parkinson's disease, both medical and surgical, also offer some benefit in dystonia. Therefore, mild parkinsonian features might logically accompany idiopathic and inherited isolated dystonias. However, as the current literature is particularly scant, the present review aimed to investigate mild parkinsonism in idiopathic and inherited dystonia. We found limited evidence alluding to the presence of mildly reduced arm-swing, increased tone, and non-decremental bradykinesia in adult-onset focal dystonia. Tremor, with postures, action and rest, also occurs commonly in idiopathic isolated dystonia, and can simulate Parkinson's disease tremor and be a cause of 'scans without evidence of dopaminergic deficit'. Parkinsonian features in monogenic isolated dystonias have been less well investigated, despite the potential benefit of correlating pathophysiological and clinical findings. The recognition and improved clinical characterization of parkinsonian features in idiopathic and inherited isolated dystonia extends the clinical spectrum of motor features in dystonia, which may help avoid incorrect diagnosis and inform therapeutic research.