Drug-induced liver injury secondary to tamoxifen.

Tamoxifen is a non-steroidal selective oestrogen receptor modulator commonly used in the treatment of breast cancer. It is associated with the development of fatty liver and steatohepatitis however drug-induced liver injury is rare. We report a woman in her 50s who developed malaise with an acute moderate aminotransferase elevation without jaundice 6 months after starting tamoxifen. She was not commenced on any other recent drugs and extensive investigation including infective and autoimmune liver screen, cross-sectional imaging and FibroScan were unremarkable. Liver biopsy revealed moderate lobular hepatitis with hepatocyte drop-out. Tamoxifen was ceased and the liver enzymes showed resolution over the following 3 months and improvement of her symptoms.

The hidden Australian skin cancer epidemic, high-risk cutaneous squamous cell carcinoma: a narrative review.

Deaths from non-melanoma skin cancers (NMSCs) have almost doubled in Australia in recent years. Cutaneous squamous cell carcinoma (cSCC) constitutes approximately 20% of NMSCs, but is responsible for most of the deaths. Most skin cancers are easy to diagnose and treat and therefore cSCC are often trivialised; however, there is a high-risk subgroup of cSCC (HRcSCC) that is associated with a high risk of metastasis and death. The definition of early HRcSCC and our ability to identify them is evolving. Many significant prognostic factors have been identified, but a universally accepted prognostic index does not exist. Guidelines for workup, treatment, and follow-up leave many important decisions open to broad interpretation by the treating physician or multidisciplinary team. Some of the treatments used for metastatic cSCC are not supported by robust evidence and the prognosis of metastatic cSCC is guarded. In this review, we highlight the rapid rise in NMSC deaths and discuss some of the deficiencies in our knowledge of how to define, diagnose, stage, and manage HRcSCC.

Management of basal cell carcinoma with pulmonary metastasis.

A man in his 50s presented with an ulcerative lesion within the left axillary fold that had progressively worsened over 18 months. Biopsy revealed an ulcerative basal cell carcinoma (BCC), which was surgically managed. CT chest scans done 7 months later assessed post-treatment of radiotherapy. This revealed pulmonary lesions, which were biopsy-proven metastatic BCC. Sonidegib, a hedgehog signalling inhibitor, was used for first-line treatment. Due to progressive disease, sonidegib was ceased. Cemiplimab, a checkpoint inhibitor, was used as second-line treatment based on a phase II trial demonstrating efficacy in the setting of metastatic BCC. CT reports were initially consistent with response but after 6 months of cemiplimab treatment, repeat CT chest scans revealed a decrease in size of the previously cited pulmonary lesions.This is a rare case of BCC metastases which has limited treatment options. This case provides insight of the patient experience on such treatment.

Toxicity and response to ipilimumab and nivolumab in older patients with metastatic melanoma: A multicentre retrospective analysis.

Combination immunotherapy with nivolumab and ipilimumab is an effective therapy in the treatment of metastatic melanoma, however, its benefit in older patients is unclear. A multicentre retrospective study was performed to compare the efficacy and toxicity of combination immunotherapy in metastatic melanoma in patients ≥65 years versus <65 years, and complications of steroids used to manage toxicity. One hundred and thirty-nine patients were included with 52 patients ≥65 years (median age: 70; range: 65-83) and 87 patients <65 years (median age: 52; range: 22-64). Median overall survival was similar in patients ≥65 years versus <65 years (14.9 vs. 17.3 months p = .58). Median progression-free survival was also similar in both groups (7.1 vs. 6.9 months p = .79), as was overall response rate (48.1% vs. 44.8% p = .73). Age was not associated with a difference in overall survival on multivariate analysis. There was similar rates of Grade 3 or higher adverse events in patients ≥65 years versus <65 years (50% vs. 49% p = 1.0) and discontinuation rates secondary to toxicity (55.8% vs. 56% p = 1.0). Median duration of steroids used to treat adverse events was similar (11 vs. 12 weeks p = .46). Complications of steroids requiring inpatient admission was numerically higher in the older patients (41.3% vs. 20.4% p = .07). Patients ≥65 years received similar benefit from combination immunotherapy in comparison to their younger counterparts with similar toxicity.

The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition.

BACKGROUND: The v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor (BRAFi) drugs dabrafenib and vemurafenib have high response rates in BRAF-mutant, metastatic melanoma; however, 50% of patients progress by 7 months. In this study, the authors examined the nature and management of disease progression (PD) on BRAFi treatment, including characteristics and outcomes of patients who received continued BRAFi treatment beyond disease progression (TBP). METHODS: Clinicopathologic data at baseline and at the time of PD were collected for all patients with BRAF-mutant metastatic melanoma who received BRAFi monotherapy within clinical trials between July 2009 and September 2012. Management and survival after PD were examined, including continued BRAFi TBP (> 28 days beyond Response Evaluation Criteria in Solid Tumor [RECIST]-defined PD). RESULTS: Ninety-five of 114 BRAFi-treated patients had PD. Fifty-three of those 95 patients (56%) progressed in extracranial sites alone, 18% (17 of 95 patients) progressed in intracranial and extracranial sites simultaneously, and 16% (15 of 95 patients) progressed in intracranial sites alone. Twenty-nine of the 95 patients (31%) who had PD progressed in a single site or organ, 48% (46 of 95 patients) progressed in existing metastases only, and 18% (17 of 95 patients) had new metastases alone. At the time of PD, 35 of 95 patients (37%) received no subsequent systemic treatment, 20% (19 of 95 patients) changed systemic treatments, and 39% (37 of 95 patients) continued BRAFi TBP for a median of 97 days. BRAFi TBP and known prognostic factors (Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, RECIST sum of the greatest dimensions of target lesions) were associated with overall survival (OS) from the time of PD; however, in multivariable analysis, BRAFi TBP improved OS (hazard ratio, 0.50; 95% confidence interval, 0.27-0.93; P = .029). CONCLUSIONS: Most BRAFi-treated patients progressed in existing extracranial sites, and 31% progressed in isolated sites. Compared with cessation, continued BRAFi TBP is associated with prolonged OS even after adjusting for potential prognostic factors at PD.

Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma.

The combination of dabrafenib and trametinib (CombiDT) is an effective treatment for BRAF-mutant metastatic melanoma; however, over 70% of patients develop drug-related pyrexia, and little is known about this toxicity. We sought to examine the features and management of CombiDT pyrexia. The association between pyrexia and patient demographics, disease characteristics and outcome variables was assessed in patients treated with CombiDT at a single institution. The clinicopathological features of pyrexic events were analysed. Fourteen of 32 (44%) patients developed pyrexia (temperature≥38.5°C). Pyrexia was recurrent in 11/14 (79%). The median time to pyrexia was 38 days. Pyrexia was not associated with age, sex nor disease burden, and did not correlate with RECIST response, progression-free nor overall survival. Paracetamol, NSAIDs and/or dose reduction (DR) were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients (n=8), including two with multiple previous pyrexic events despite several DRs. In patients with previous DRs who commenced steroids (n=3), CombiDT doses were re-escalated without pyrexia. Pyrexia is a frequent and recurrent toxicity with CombiDT, with no predictive clinical characteristics. Pyrexia does not correlate with clinical outcome. Neither DR nor antipyretics are effective secondary prophylaxis, whereas corticosteroids are effective, prevent DR and enable re-escalation of CombiDT dosing.

Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib.

BACKGROUND: Dabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib. METHODS: Clinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression-free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed. RESULTS: A total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P = .416). IC and EC response was concordant in 71% of patients. Median site-specific PFS was identical in both IC and EC sites (23.6 weeks, P = .465), and exceeded whole-body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days. CONCLUSIONS: IC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progression, with ongoing dabrafenib treatment possible in a subset of patients.

Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma.

BACKGROUND: MAPK inhibitors (MAPKi) are active in BRAF-mutant metastatic melanoma patients, but the extent of response and progression-free survival (PFS) is variable, and complete responses are rare. We sought to examine the patterns of response and progression in patients treated with targeted therapy. METHODS: MAPKi-naïve patients treated with combined dabrafenib and trametinib had all metastases ≥5 mm (lymph nodes ≥15 mm in short axis) visible on computed tomography measured at baseline and throughout treatment. RESULTS: 24 patients had 135 measured metastases (median 4.5/patient, median diameter 16 mm). Time to best response (median 5.5 mo, range 1.7-20.1 mo), and the degree of best response (median -70%, range +9 to -100%) varied amongst patients. 17% of patients achieved complete response (CR), whereas 53% of metastases underwent CR, including 42% ≥10 mm. Metastases that underwent CR were smaller than non-CR metastases (median 11 vs 20 mm, P<0.001). PFS was variable among patients (median 8.2 mo, range 2.6-18.3 mo), and 50% of patients had disease progression in new metastases only. Only 1% (1/71) of CR-metastases subsequently progressed. Twelve-month overall survival was poorer in those with a more heterogeneous initial response to therapy than less heterogeneous (67% vs 93%, P = 0.009). CONCLUSION: Melanoma response and progression with MAPKi displays marked inter- and intra-patient heterogeneity. Most metastases undergo complete response, yet only a small proportion of patients achieve an overall complete response. Similarly, disease progression often occurs only in a subset of the tumor burden, and often in new metastases alone. Clinical heterogeneity, likely reflecting molecular heterogeneity, remains a barrier to the effective treatment of melanoma patients.

The degree of safety of family replacement donors versus voluntary non-remunerated donors in an Egyptian population: a comparative study.

BACKGROUND: Screening donated blood for transfusion-transmissible infections is considered an important strategy for maximising the safety of blood transfusions. MATERIALS AND METHODS: A total of 17,118 donors, classified into two groups--family replacement donors and voluntary non-remunerated donors--were investigated for hepatitis B virus (HBV) surface antigen and antibodies against hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Treponema pallidum. In addition cytomegalovirus (CMV) antibodies were searched for in 160 donors (80 from each group). All the laboratory tests were done using enzyme-linked immunosorbent assays. RESULTS: Of the total cohort of donors, 87.7% were family donors and 12.3% were voluntary non-remunerated donors. There was a highly significant difference in age and gender between the two types of donors with voluntary donors being much younger and including a much higher proportion of male donors than female donors. The prevalences of HBV, HCV and CMV IgG were much higher in family donors than in voluntary donors, with the differences being highly statistically significant. There was also a significantly higher prevalence of syphilis among family replacement donors. As regards HIV and CMV IgM, significant differences were not detected between the two groups. DISCUSSION: The results of our study clearly showed that the prevalence of transfusion-transmissible infections is much higher among family replacement donors than among voluntary donors, and that voluntary donors are the best way of achieving safer blood.

Predicting emergency room visits and hospitalizations among hospice patients with cardiac disease.

BACKGROUND: One goal of quality palliative care in hospice is to limit emergency room visits and/or hospitalizations (ERVH). PURPOSE: The purpose of this study was to determine predisposing factors that contribute to ERVH and devise a model to predict the probability of hospice cardiac disease patients having ERVH after hospice admission. METHODS: The study was a retrospective chart review of hospice cardiac patients comparing those with ERVH (n = 65) and those who died in their homes (n = 80). Data reduction strategy included bivariate tests and model-building analyses using logistic regression analysis. RESULTS: Some factors were associated with decreased odds of having ERVH: older patients (odds ratio [OR] = 0.94; p = 0.001), increased nursing visits (OR = 0.79; p = 0.001) and chaplain visits (OR = 0.48; p = 0.040), patients' medication compliance (OR = 0.27; p = 0.029), patients treated with morphine sulfate (OR = 0.15; p = 0.001), patients with caregiver(s) (OR = 0.09; p = 0.012), patients with hospice emergency kits (OR = 0.33; p = 0.004), interaction of the latter two variables (OR = 0.26; p = 0.001), patients with do-not-resuscitate orders (OR = 0.29; p = 0.001), Caucasian patients (OR = 0.22; p = 0.001), and the interaction of the latter two variables (OR = 0.22; p = 0.001). Other factors were associated with increased odds of having ERVH: patients with diabetes (OR = 2.64; p = 0.009), peripheral vascular disease (OR = 5.30; p = 0.003), hyperlipidemia (OR = 4.52; p = 0.013), chronic pulmonary disease/asthma (OR = 2.83; p = 0.003) as comorbidities; palpitations (OR = 6.61; p = 0.010), and chest pain (OR = 3.78; p = 0.006). The best fitting forecasting model had six independent variables decreasing and two increasing the odds of having ERVH. The final model chosen was: Z = 7.817 + 2.929 (peripheral vascular disease) + 1.513 (diabetes mellitus) - 3.306 (Caucasian) - 1.824 (caregiver presence x hospice emergency kit at home) - 0.212 (frequency of nursing visits) - 3.275 (on morphine) - 4.422 (medication compliance). CONCLUSION: The forecasting model predicted the probability of ERVH correctly in 87.7% of the patients. The model is simple to use to predict hospice cardiac patients having ERVH. Future studies should validate this model. Interventions should utilize these factors and be evaluated to determine their ability to decrease ERVH in hospice cardiac patients.

An examination of cross-cultural systems implementing evidence-based assessment and intervention approaches.

Implementation of evidence-based assessment and intervention approaches for youth with behavioral and/or emotional problems is rising to recognition worldwide. Feasibility research is critical to examine what characteristics of systems allow for success or barriers to the implementation of evidence-based practices into real-world settings, especially when working cross-culturally. This paper briefly reviews the experience of 4 international sites to understand how the overall structure and specific site variables directed the implementation of the World Health Organization and the World Psychiatry Association project. Discussion includes a thematic summary of the successes and challenges experienced by the sites, and future directions of feasibility studies.

An examination of cross-cultural systems implementing evidence-based assessment and intervention approaches / Exame dos sistemas transculturais que implementam estratégias de intervenção e avaliação baseadas em evidências

Implementation of evidence-based assessment and intervention approaches for youth with behavioral and/or emotional problems is rising to recognition worldwide. Feasibility research is critical to examine what characteristics of systems allow for success or barriers to the implementation of evidence-based practices into real-world settings, especially when working cross-culturally. This paper briefly reviews the experience of 4 international sites to understand how the overall structure and specific site variables directed the implementation of the World Health Organization and the World Psychiatry Association project. Discussion includes a thematic summary of the successes and challenges experienced by the sites, and future directions of feasibility studies.

A implementação de estratégias de intervenção e avaliação baseadas em evidências para jovens com problemas comportamentais e/ou emocionais está assumindo reconhecimento internacional. Estudos de praticabilidade são críticos para examinar quais características dos sistemas permitem êxito ou se constituem em barreiras para a implementação de práticas baseadas em evidências em instituições do mundo real, especialmente quando trabalhando de forma transcultural. Este estudo revisa brevemente a experiência de quatro localidades internacionais para compreender como a estrutura geral e as variáveis específicas da localidade orientaram a implementação do projeto da Organização Mundial de Saúde e da Associação Mundial de Psiquiatria. A discussão inclui um resumo temático dos êxitos e desafios vivenciados pelas localidades e os caminhos futuros de estudos de praticabilidade.