Apalutamide-Induced Toxic Epidermal Necrolysis in a Caucasian Patient with Metastatic Castration-Sensitive Prostate Cancer: A Case Report and Review of the Literature.

Apalutamide is a novel nonsteroidal androgen receptor inhibitor that has been shown to improve outcomes for patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer when combined with androgen deprivation therapy. Apalutamide-induced skin rash occurred commonly in clinical trials, with 23.8-27.1% of patients experiencing a rash of any grade, and 5.2-6.3% experiencing a rash of grade three or higher. There were no cases of severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) reported in clinical trials; however, there are rare cases reported in the literature with the majority occurring in Asian patients. An 83-year-old Caucasian male was commenced on apalutamide, combined with degarelix, for the management of metastatic castration-sensitive prostate cancer. During week five of apalutamide treatment, the patient developed a widespread erythematous maculopapular rash. On presentation, the rash affected 80% of his body surface area (BSA) and a diagnosis of a severe cutaneous drug eruption was made. He was commenced on methylprednisolone (MP) therapy. Despite 5 days of MP, the rash continued to deteriorate involving 95% of his BSA. Nikolsky's sign was positive. A diagnosis of overlap SJS/TEN was made, supported by skin biopsy. His SCORTEN score was three. He was then commenced on intravenous immunoglobulin and transferred to the intensive care unit. Over the coming days, the rash began to stabilise, and his steroid dose was weaned. He was discharged from hospital 38 days after rash onset. We report the first suggested case of apalutamide-induced SJS/TEN in a Caucasian patient. We discuss other cases of apalutamide-induced SCARs reported in the literature. Risk factors seem to include low body weight and Japanese race, as well as short time to onset of rash.

An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer.

PURPOSE: Breast cancer is one of the most prevalent malignant diseases in women. The development of dose dense chemotherapy regimens has improved clinical outcomes but has been associated with increased hematological toxicity. Currently there is a paucity of data on the use of lipegfilgrastim in dose dense AC treatment in early breast cancer. The purpose of this study was to assess the use of lipegfilgrastim in the treatment of early breast cancer and to examine the incidence of treatment-related neutropenia during the dose dense AC phase and subsequent paclitaxel treatment. METHODS: This was a single arm, non-interventional, prospective study. The primary endpoint was to determine the rate of neutropenia defined as ANC of < 1.0 × 109/L, during four cycles of dose dense AC with lipegfilgrastim support. The secondary endpoints were the incidence of febrile neutropenia, (temperature > 38 °C and ANC < 1.0 × 109/L), treatment delays, premature treatment cessation and toxicity. RESULTS: Forty-one participants were included in the study. Of the 160 planned dose dense AC treatments, 157 were administered, and 95% (152/160) of these were given on time. The rate of treatment delay was 5% (95% CI 2.2 to 9.9%) due to infection (4) and mucositis (1). Four (10%) patients developed febrile neutropenia. The most frequently occurring adverse event was grade 1 bone pain. CONCLUSION: Lipegfilgrastim is an effective option in the prophylaxis of chemotherapy-induced neutropenia, and its use in everyday anti-cancer treatment can be considered.

The cost of cancer care: how far would you go for a trial?

BACKGROUND: Clinical trials are often considered the gold standard in cancer care. However, patients face barriers in trial participation including distances to cancer centres and personal costs including changing employment status, cost of medications, inpatient admissions, and parking tariffs. AIM: Our aim was to compare the distances patients travelled for clinical trials compared to those receiving standard systemic anticancer therapy (SACT). We also investigated the additional costs associated with this. METHODS: This was a retrospective review of electronic patient medical records. The distance from the patients' home address to Beaumont was calculated as a one-way journey in kilometres. Patients attending for clinical trials were compared to those receiving standard of care SACT. RESULTS: A total of 271 patients receiving standard SACT over a 5-day period and 111 patients enrolled on 24 clinical trials were included. The median one-way distance travelled by patients enrolled in clinical trials was 41.4 km, compared to 14 km in those patients' receiving standard of care SACT. The median estimated cost was €13 vs €4.20 for those enrolled on clinical trials compared to those receiving standard of care treatment, respectively. CONCLUSION: Patients enrolled on clinical trials often travel more than twice as far to receive their anti-cancer treatment compared to those receiving standard of care SACT and incur an increased cost of travel expenses.

COVID-19-related mortality in cancer patients in an Irish setting.

BACKGROUND: The COVID-19 pandemic has impacted significantly on healthcare across the globe. It has been reported to have higher incidence and be associated with worse outcomes in patients with cancer. AIM: To examine the characteristics of patients with cancer who were diagnosed with COVID-19 and to identify factors which may predict a poorer outcome. METHODS: Patients attending oncology services in Beaumont Hospital who were diagnosed with COVID-19 between March and May 2020 were included. Demographics and outcomes were determined by chart review. RESULTS: Twenty-seven patients were included in the study. The median age was 62; 59% were male. Ten patients (37%) died all of whom had metastatic or incurable locally advanced disease. Patients with lung cancer had a higher rate of COVID-19 and poorer outcomes. Those with a performance status (PS) ≥ 3 were more likely to die than those with PS ≤ 2. Compared to those who recovered, patients who died had a higher number of organs affected by cancer and a higher mean Palliative Prognostic Score. CONCLUSION: Patients attending oncology services during the initial phase of the COVID-19 pandemic had an increased rate of SARS-CoV-2 infection and a higher mortality rate than the general population. Those who died had more advanced cancer as demonstrated by poorer performance status, a greater burden of metastatic disease and a higher Palliative Prognostic Score.

Delivery of systemic anti-cancer therapy during the COVID-19 pandemic.

BACKGROUND: The first confirmed case of COVID-19 in Ireland was on February 29th 2020. From March until late April, the number of cases increased exponentially. The delivery of anti-cancer therapy during the COVID-19 pandemic was extremely challenging. In order to balance the benefits of continuing anti-cancer therapy with the associated increased hospital visits, combined with the risk of COVID-19 infection, we undertook a series of system changes in the delivery of cancer care. METHODS: Patients who attended our dayward over a 4-month period were included. Data were obtained from patient and chemotherapy prescribing records. Patients were screened for symptoms of COVID-19 at two separate timepoints: prior to their visit via telephone, and using a symptom questionnaire on arrival at the hospital. If patients displayed COVID-19 symptoms, they were isolated and a viral swab arranged. RESULTS: A total of 456 patients attended from January 1st to April 30th. The numbers of visits from January to April were 601, 586, 575, and 607, respectively. During this period, there were 2369 patient visits to the dayward and 1953 (82%) intravenous regimens administered. Of the 416 visits that did not lead to treatment, 114 (27%) were scheduled non-treatment review visits, 194 (47%) treatments were held due to disease-related illness, and 108 (26%) treatments were held due to treatment-related complications. Screening measurements were implemented on March 18th due to rising COVID-19 prevalence in the general population. Overall, 53 treatments were held due to the screening process: 19 patients (36%) elicited COVID-19 symptoms via telephone screening; 34 patients (64%) were symptomatic in our pre-assessment area and referred for swabs, of which 4 were positive. Those with a negative swab were rescheduled for chemotherapy the following week. CONCLUSIONS: With careful systematic changes, safe and continued delivery of systemic anti-cancer therapy during the COVID-19 pandemic is possible.

Immunotherapy for Stage III NSCLC: Durvalumab and Beyond.

Immunocheckpoint inhibitors (ICIs) have altered the treatment landscape of a wide range of malignancies, including non-small cell lung cancer (NSCLC). This class of agents inhibits the interaction between PD1 and PDL1, and was shown to be efficacious in the landmark PACIFIC trial with 1 year of maintenance durvalumab (anti-PDL1 antibody). This trial demonstrated that its use as a consolidation treatment given after definitive chemoradiotherapy improved progression free survival and overall survival compared to standard-of-care treatment. In this review, we discuss both clinical trial and real-world data that have been published since PACIFIC that support the use of durvalumab for stage III unresectable NSCLC. In addition, we highlight specific populations that may require special considerations for the use of durvalumab in this setting, such as oncogene-addicted NSCLC, the toxicity of immunotherapy, and future directions in ICI research in stage III NSCLC.

Profile of Trastuzumab Deruxtecan in the Management of Patients with HER2-Positive Unresectable or Metastatic Breast Cancer: An Evidence-Based Review.

Trastuzumab deruxtecan is a novel antibody-drug conjugate for the treatment of advanced solid tumors, including breast cancer, which overexpress or have amplification of the human epidermal growth factor receptor 2 (HER2). The novel structure of this exciting new agent means that it can deliver a highly potent cytotoxic agent to HER2-expressing tissues resulting in selective killing of cancer cells. In phase I and II trials, trastuzumab deruxtecan has shown impressive response rates in heavily pretreated populations, including patients who had received prior treatment with trastuzumab emtansine, another highly active antibody-drug conjugate. The most common side effects are gastrointestinal and hematological. Importantly, a high rate of interstitial lung disease was seen in early trials, but this appears manageable in most patients with corticosteroids. In light of its efficacy, this promising new drug may change the treatment paradigm of HER2-positive breast cancer.

Chemotherapy in the Covid-19 era: the patient's perception.

BACKGROUND: The Covid-19 pandemic poses significant challenges for the management of patients with cancer. In our institution, we adapted our delivery of outpatient systemic anti-cancer therapy (SACT) by introducing a number of 'risk-reducing' measures including pre-assessment screening. AIMS: We sought to evaluate the experience and perceptions of patients with cancer undergoing SACT during the Covid-19 pandemic. METHODS: Patients on SACT during the Covid-19 pandemic were eligible for participation. Data were collected by anonymous survey over a 1 week period during the most intensive phase of government restrictions. Patients were asked questions under three headings: perceived risk of infection exposure, changes to treatment plan and psychological impact of Covid-19. RESULTS: One hundred patients were assessed, 60% were male, 41% were > 65 years of age and 67% had advanced cancer. Eleven percent of patients were living alone. Fifty-seven percent reported feeling at increased risk in general of contracting Covid-19. Sixty-eight percent of patients did not feel worried about contracting Covid-19 in the hospital. Ninety-two percent of patients reported wanting to continue on SACT as originally planned. Fifty-eighty percent felt isolated and 40% reported increased anxiety. CONCLUSION: Though patients on active treatment for cancer during the Covid-19 pandemic reported increased anxiety and feelings of isolation due to Covid-19, the majority of patients wanted to continue SACT as originally planned. Patients would benefit from enhanced psycho-oncological supports in the event of a prolonged Covid-19 pandemic.

Prevalence and relationship between burnout and depression in our future doctors: a cross-sectional study in a cohort of preclinical and clinical medical students in Ireland.

OBJECTIVES: This cross-sectional study was designed to measure burnout and its impact on risk of depression in a medical student population, comparing the preclinical and clinical years. DESIGN: We conducted a survey of 269 medical school students in both preclinical and clinical years at the Royal College of Surgeons in Ireland, using the Beck Depression Inventory-Fast Screen (BDI-FS), the Maslach Burnout Inventory-Student Survey and items assessing willingness to use mental health services. Burnout scores were calibrated to probability of depression caseness and classified as low risk (<25%), intermediate (25%-50%) and high risk (>50%) of depression. RESULTS: There was a 39% (95% CI 33% to 45%) prevalence of depressive caseness based on a score of ≥6 on the BDI-FS. Prevalence did not vary significantly between clinical and preclinical years. The rate of burnout varied significantly between years (p=0.032), with 35% in the high-burnout category in clinical years compared with 26% in preclinical years. Those in the low burnout category had a 13% overall prevalence of depressive symptoms, those in the intermediate category had a 38% prevalence and those in the high category had a 66% prevalence of depressive symptoms. Increasing emotional exhaustion (OR for one-tertile increase in score 2.0, p=0.011) and decreasing academic efficacy (OR 2.1, p=0.007) increased the odds of being unwilling to seek help for mental health problems (11%). CONCLUSION: While previous studies have reported significant levels of burnout and depression, our method of calibrating burnout against depression allows burnout scores to be interpreted in terms of their impact on mental health. The high prevalences, in line with previous research, point to an urgent need to rethink the psychological pressures of health professions education.

Analysis of the Impact of CD200 on Phagocytosis.

One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is observed with age, in models of Alzheimer's and Parkinson's disease as well as in the human diseases. There is evidence of increased microglial activation in CD200-deficient mice, and isolated microglia prepared from these mice are more reactive to inflammatory stimuli like Toll-like receptor 2 and 4 agonists, and interferon-γ. Here, we examined the impact of CD200 deficiency on amyloid-ß (Aß)-induced changes in microglia and report, perhaps unexpectedly, that the effect of Aß was attenuated in microglia prepared from CD200-deficient mice. The evidence indicates that this is a consequence of increased phagocytosis, associated with increased lysosomal activity in CD200-deficient microglia. The data suggest that mTOR-related signalling is decreased in these cells and that inhibiting mTOR by rapamycin increases phagocytosis. Thus, while the findings to date have emphasized the anti-inflammatory effects of CD200-CD200R interaction, the present evidence indicates a previously unreported impact on lysosomal function.

Inhibition of JAK2 attenuates the increase in inflammatory markers in microglia from APP/PS1 mice.

There is a wealth of evidence indicating that macrophages adopt distinct phenotypes when exposed to specific stimuli and, in the past few years, accumulating data suggest that microglia behave somewhat similarly. Therefore, microglia can adopt the so-called M1 or M2 phenotypes in response to interferon-γ (IFNγ) and interleukin-4, respectively. Although it has yet to be unequivocally proven in the context of microglia, acutely activated M1 cells are probably protective, although a persistent M1 state is likely to be damaging, whereas M2 cells may be reparative and restorative. In this case, particularly because the current evidence suggests the development of a predominantly M1 state with age and in neurodegenerative diseases, it is important to identify mechanisms by which polarization of microglia can be modulated. The present findings indicate that exposure of cultured microglia to IFNγ increased expressions of the archetypal markers of the M1 phenotype, tumour necrosis factor-α, and inducible nitric oxide synthase, and preexposure of cells to amyloid-ß (Aß) sensitized microglia to subsequent stimulation with IFNγ. Importantly, this synergy was also evident in microglia prepared from the brains of transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1, APP/PS1 mice) and are exposed to a combination of increasing concentrations of endogenous Aß from 4 or 5 months of age and an age-related increase in IFNγ. Significantly, the JAK2 inhibitor, TG101209, attenuated the IFNγ-induced changes in cultured microglia and in isolated microglia prepared from APP/PS1 mice. These findings suggest that targeting JAK2 may be a potential strategy for reducing neuroinflammation in Alzheimer's disease.