Pembrolizumab-induced follicular eruption and response to isotretinoin

Background: Pembrolizumab is a monoclonal antibody targeting PD-1. Folliculitis secondary to pembrolizumab has rarely been reported in the treatment of malignant melanoma. Case: A 49-year-old with a history of mild lower limb folliculitis developed metastatic malignant melanoma, and immunotherapy with pembrolizumab was initiated. Following 19 doses of pembrolizumab, a folliculocentric pustular eruption developed on the lower legs. Biopsy was consistent with folliculitis. Treatment with topical corticosteroids, high-dose prednisolone, lymecycline, clarithromycin, trimethoprim and clindamycin was unsuccessful. Pembrolizumab was stopped after 22 cycles, but the folliculitis persisted. Oral isotretinoin was required for disease control. Discussion: Drug-induced follicular eruptions have rarely been described with anti PD-1 therapy. Isotretinoin may be required to achieve remission. Lay abstract: Pembrolizumab (trade name Keytruda©) is a type of immune therapy that stimulates the body's immune system to fight cancer cells. This immune therapy can cause a variety of rashes. In this article, the authors describe a patient who developed a rash around hair follicles that is not commonly described with pembrolizumab. A man with a history of mildly infected hair follicles on his legs was diagnosed with advanced melanoma and was treated with pembrolizumab. After 19 treatments, he developed a rash on his legs, centered around hair follicles. Treatment with steroid ointments, steroid tablets and antibiotic tablets was not helpful. Pembrolizumab was stopped, but the rash persisted. A medicine called isotretinoin was required to control the rash. This type of rash has rarely been described with this kind of immune therapy, and isotretinoin might be required to treat it

Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition?

Background: Nutrition screening on admission to hospital is mandated in many countries, but to date, there is no consensus on which tool is optimal in the oncology setting. Wasting conditions such as cancer cachexia (CC) and sarcopenia are common in cancer patients and negatively impact on outcomes; however, they are often masked by excessive adiposity. This study aimed to inform the application of screening in cancer populations by investigating whether commonly used nutritional screening tools are adequately capturing nutritionally vulnerable patients, including those with abnormal body composition phenotypes (CC, sarcopenia, and myosteatosis). Methods: A prospective study of ambulatory oncology outpatients presenting for chemotherapy was performed. A detailed survey incorporating clinical, nutritional, biochemical, and quality of life data was administered. Participants were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST), and the Nutritional Risk Index (NRI). Computed tomography (CT) assessment of body composition was performed to diagnose CC, sarcopenia, and myosteatosis according to consensus criteria. Results: A total of 725 patients (60% male, median age 64 years) with solid tumours participated (45% metastatic disease). The majority were overweight/obese (57%). However, 67% were losing weight, and CT analysis revealed CC in 42%, sarcopenia in 41%, and myosteatosis in 46%. Among patients with CT-identified CC, the MUST, MST, and NRI tools categorized 27%, 35%, and 7% of them as ‘low nutritional risk’, respectively. The percentage of patients with CT-identified sarcopenia and myosteatosis that were categorised as ‘low nutritional risk’ by MUST, MST and NRI were 55%, 61%, and 14% and 52%, 50%, and 11%, respectively. Among these tools, the NRI was most sensitive, with scores <97.5 detecting 85.8%, 88.6%, and 92.9% of sarcopenia, myosteatosis, and CC cases, respectively. Using multivariate Cox proportional hazards models, NRI score < 97.5 predicted greater mortality risk (hazard ratio 1.8, confidence interval: 1.2–2.8, P = 0.007). Conclusions: High numbers of nutritionally vulnerable patients, with demonstrated abnormal body composition phenotypes on CT analysis, were misclassified by MUST and MST. Caution should be exercised when categorizing the nutritional risk of oncology patients using these tools. NRI detected the majority of abnormal body composition phenotypes and independently predicted survival. Of the tools examined, the NRI yielded the most valuable information from screening and demonstrated usefulness as an initial nutritional risk grading system in ambulatory oncology patients

Impact of weight loss and sarcopenia on response to chemotherapy, quality of life and survival.

The prevalence of malnutrition in patients with cancer has frequently been shown to be one of the highest of all hospital patient groups. Weight loss is a frequent manifestation of malnutrition in patients with cancer. Several large-scale studies over the last 35 years have reported that involuntary weight loss affects 50-80% of these patients with the degree of weight loss dependent on tumour site, type and stage of disease. This review will focus on the consequences of malnutrition, weight loss and muscle wasting in relation to chemotherapy tolerance, post-operative complications, quality of life and survival in oncology patients. The prognostic impact of weight loss on overall survival has long been recognised with recent data suggesting losses as little as 2.4% predicts survival independent of disease, site, stage or performance score. Recently the use of gold-standard methods of body composition assessment, including computed tomography, have led to an increased understanding of the importance of muscle abnormalities, such as low muscle mass (sarcopenia), and more recently low muscle attenuation, as important prognostic indicators of unfavourable outcomes in patients with cancer. Muscle abnormalities are highly prevalent (ranging from 10-90%, depending on cancer site and the diagnostic criteria used). Both low muscle mass and low muscle attenuation have been associated with poorer tolerance to chemotherapy; increased risk of postoperative complications; significant deterioration in a patients' performance status, and poorer psychological well-being, overall quality of life, and survival

General public awareness and views of community pharmacy in Scotland: the 'first port of call' study.

The recently published ‘Achieving Excellence in Pharmaceutical Care: a Strategy for Scotland’ urges community pharmacy (CP) to make itself the ‘first port of call’ for healthcare advice. The aim of this research is to explore the Scottish general public's awareness of CP services and their openness to consider CP their ‘first port of call’ for healthcare advice

Cancer-related fatigue and self-care agency: A multicentre survey of patients receiving chemotherapy

Aims and objectives: To measure cancer-related fatigue (CRF), self-care agency (SCA) and fatigue self-care strategies, and to explore the relationship between CRF and SCA. Background: Cancer-related fatigue has been consistently rated as the most elusive, common and severe of symptoms that patients with cancer undergoing chemotherapy experience. Despite its frequency and severity, CRF is poorly managed. A renewed focus on supporting self-care among patients with cancer has been found to reduce symptom burden, empower patients and improve patient satisfaction. Understanding the link between self-care agency (i.e. capability and willingness to self-care) and CRF levels will help practitioners to better support individuals on the cancer journey. Design: A descriptive, correlational survey design was employed. Methods: Patients (n = 362) undergoing chemotherapy with a primary diagnosis of breast, colorectal, Hodgkin's and non-Hodgkin's lymphoma cancers were recruited from four oncology centres in one city in the South of Ireland. Participants completed the Piper Fatigue Scale-Revised, Appraisal of Self-care Agency Scale and a researcher-developed Fatigue Self-Care Survey. Multivariate logistic regression was used to examine the relationship between CRF and self-care agency using a dichotomous dependent variable score of four as the cut-off between those deemed to be fatigued (≥4) and those not fatigued (<4). As recommended by the EQUATOR Network, the STROBE checklist of items for cross-sectional studies is used to report the study. Results: The incidence of CRF was high with 75% of participants scoring clinically relevant CRF. Higher SCA (OR = 0.96, 95% CI = 0.93–0.99, p = .011) was associated with decreased odds of developing CRF. Having non-Hodgkin's lymphoma (OR = 3.02, 95% CI = 1.29–7.07, p = .011) was associated with increased odds of developing CRF. Conclusions: Patient's undergoing chemotherapy experience significant fatigue. Higher capability for self-care is associated with lower fatigue. The promotion of SCA and self-care strategies can impact on CRF. Relevance to clinical practice: Understanding the link between self-care abilities and fatigue can lead to more individualised and tailored approaches to CRF

High concordance of BRAF mutational status in matched primary and metastatic melanoma

Background: Techniques for the accurate identification of activating mutations of BRAF in metastatic melanoma are of great clinical importance, due to the availability of targeted therapies for these tumours. There is uncertainty regarding the frequency with which BRAF status differs between primary and metastatic sites. Methods: Between 2011 and 2016, 219 melanoma cases underwent BRAF testing in our institution. In 53 of these, paired primary and metastatic specimens were available for PCR and immunohistochemical evaluation. Results: 52 out of 53 cases (98%) showed concordant BRAF status between primary and metastatic site by IHC. In one case, a metastasis and its matched primary were positive by IHC but the metastasis was negative on PCR. On further investigation, PCR was positive in the primary and repeat PCR in the metastasis was positive, following macrodissection. Conclusions: Our results suggest that discordance of BRAF mutational status between primaries and metastases is a rare occurrence. In one case, immunohistochemistry provided strong evidence that initial PCR testing had provided a false negative result due to low tumour volume. Thus, in cases where tissue is difficult to obtain from a metastasis or unavailable, the primary tumour can be used with confidence

Cancer-associated malnutrition, cachexia and sarcopenia: The skeleton in the hospital closet 40 years later

An awareness of the importance of nutritional status in hospital settings began more than 40 years ago. Much has been learned since and has altered care. For the past 40 years several large studies have shown that cancer patients are amongst the most malnourished of all patient groups. Recently, the use of gold-standard methods of body composition assessment, including computed tomography, has facilitated the understanding of the true prevalence of cancer cachexia (CC). CC remains a devastating syndrome affecting 50â 80 % of cancer patients and it is responsible for the death of at least 20 %. The aetiology is multifactorial and complex; driven by pro-inflammatory cytokines and specific tumour-derived factors, which initiate an energy-intensive acute phase protein response and drive the loss of skeletal muscle even in the presence of adequate food intake and insulin. The most clinically relevant phenotypic feature of CC is muscle loss (sarcopenia), as this relates to asthenia, fatigue, impaired physical function, reduced tolerance to treatments, impaired quality of life and reduced survival. Sarcopenia is present in 20â 70 % depending on the tumour type. There is mounting evidence that sarcopenia increases the risk of toxicity to many chemotherapy drugs. However, identification of patients with muscle loss has become increasingly difficult as 40â 60 % of cancer patients are overweight or obese, even in the setting of metastatic disease. Further challenges exist in trying to reverse CC and sarcopenia. Future clinical trials investigating dose reductions in sarcopenic patients and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.)

Sarcopenia and post-operative morbidity and mortality in patients with gastric cancer

Purpose: Surgical resection for gastric adenocarcinoma is associated with significant post-operative morbidity and mortality. The aim of this study was to assess the prognostic significance of sarcopenia in patients undergoing resection for gastric adenocarcinoma with respect to post-operative morbidity and survival. Materials and Methods: A retrospective analysis was conducted on a cohort of consecutive patients who underwent surgical resection for gastric adenocarcinoma between 2008 and 2014. Patient demographics, radiological parameters, and pathological data were collected. OsiriX software (Pixmeo) was used to measure skeletal muscle area, which was normalized for height to calculate skeletal muscle index. Results: A total of 56 patients (41 male, 15 female; mean age, 68.4 ± 11.9 years) met the inclusion criteria. Of these, 36% (20 of 56) of the patients were sarcopenic pre-operatively. Both sarcopenic and non-sarcopenic patient groups were equally matched with the exception of weight and body mass index (P=0.036 and 0.001, respectively). Sarcopenia was associated with a decreased overall survival (log-rank P=0.003) and was an adverse prognostic predictor of overall survival in multivariate analysis (hazard ratio, 10.915; P=0.001). Sarcopenia was a predictor of serious in-hospital complications in multivariate analysis (odds ratio, 3.508; P=0.042). Conclusions: In patients undergoing curative resection for gastric cancer, there was a statistically significant association between sarcopenia and both decreased overall survival and serious post-operative complications. The measurement and reporting of skeletal muscle index on pre-operative computed tomography should be considered

Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information