Ipilimumab-associated halo-like inflammatory reactions around nevi during therapy for metastatic melanoma.

Ipilimumab is an immune-modulating drug that is being used today for various cancers including metastatic malignant melanoma. Owing to its mechanism of action, several adverse events have been reported, including some affecting skin. In this work, we report a novel display of multiple ipilimumab-associated halo lichenoid reactions surrounding benign nevi during treatment of metastatic melanoma. A patient underwent treatment with ipilimumab for treatment of stage IIIC melanoma at our center and was monitored for progress and adverse events throughout treatment. During treatment with ipilimumab, the patient clinically developed multiple halo lichenoid reactions surrounding previously present nevi, which histopathologically showed a lichenoid interface dermatitis associated with the mildly atypical nevi and ill-formed granulomata within the infiltrate. Therefore, ipilimumab may be associated with halo lichenoid reactions surrounding benign nevi and this adverse effect should be added to the various dermatologic reactions that patients can develop while being treated with this agent.

Histopathologic Features of Cutaneous Acute Graft-Versus-Host Disease in T-Cell-Depleted Peripheral Blood Stem Cell Transplant Recipients.

T-cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation demonstrates similar efficacy and reduced incidence and severity of graft-versus-host disease (GVHD) in appropriately selected patients versus T-cell-replete transplantation. The histopathology of cutaneous acute GVHD (aGVHD) after TCD peripheral blood stem cell transplants (PBSCTs) is not described. We identified 13 cases of patients after TCD PBSCT, with definitive aGVHD, and 20 cases of non-aGVHD skin rash in patients after TCD PBSCT, during multidisciplinary review by a dermatopathologist, dermatologist, and transplant physician, incorporating clinical presentation, therapeutic response, and histopathology data. Histopathologic features of aGVHD and non-aGVHD skin rash in TCD PBSCT patients were compared to each other, and also to features recently reported for non-TCD transplant recipients. aGVHD and non-aGVHD skin rash in TCD PBSCT patients' biopsies had similar rates of epidermal acanthosis, dermal melanophages, neutrophils, plasma cells, eosinophils, and extravasated erythrocytes. While satellitosis, exocytosis and adnexal involvement slightly favored aGVHD, more notable differential findings favoring aGVHD were diffuse (vs. focal/absent) basal vacuolization (77% aGVHD vs. 25% non-aGVHD rash), involvement of the entire epidermis (vs. partial thickness) by necrotic keratinocytes (42% aGVHD vs. 0% non-aGVHD rash), and nondense (rather than exuberant) inflammatory infiltrates (77% vs. 20%). After filtering features seen in all TCD samples (epidermal acanthosis, dermal melanophages, neutrophils, plasma cells, eosinophils, and extravasated erythrocytes), the most distinct features belonging to aGVHD-positive TCD samples were diffuse basal vacuolization, slight rather than dense inflammatory infiltrates, and necrotic keratinocytes involving the entire epidermis. Awareness of these features may help when evaluating a skin rash occurring after a TCD transplant.

Pruritus to anticancer agents targeting the EGFR, BRAF, and CTLA-4.

In the past decade, the expanded use of targeted anticancer drugs has significantly prolonged survival in patients treated for a variety of cancers. Despite their increased specificity, agents such as epidermal growth factor receptor inhibitors (EGFRIs), BRAF inhibitors, and targeted immunotherapies have commonly been associated with a number of dermatologic adverse events, often necessitating treatment modifications and negatively impacting patients' quality of life. Although toxicities such as rash and xerosis are frequently discussed, symptomatic pruritus, or itch, has emerged as an important, and frequently neglected, event. The present study reviews the incidence and clinical presentation of pruritus with the EFGRIs, and with two novel anti-melanoma drugs, vemurafenib and ipilimumab, with a focus on the putative underlying pathophysiology, and current management strategies.

Dermatological adverse events from BRAF inhibitors: a growing problem.

The development of targeted therapies has ushered in a new era in the management of melanoma. Inhibitors of the RAS-RAF-MEK-ERK pathway have taken the center stage with development at a rapid pace. Vemurafenib was recently approved by regulatory agencies, and other agents (e.g. dabrafenib) are in various stages of clinical testing. These agents are producing remarkable results for patients, but are also presenting new challenges. Clinical toxicities and drug resistance are topmost issues. Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations. Published trials and initial observations reflect a toxicity profile (e.g. squamous cell carcinomas/keratoacanthomas, maculopapular rashes, hyperkeratosis) that is distinct from cutaneous toxicities from EGFR and mTOR inhibitors (acneiform rash, paronychia, xerosis). Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities, skill sets unique to dermatologists. All these pose significant challenges to clinicians, and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life. In this manuscript, we provide an overview of the emerging scientific literature on dermatological adverse events arising out of BRAF inhibition.

The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis.

Axitinib is a potent, selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We have performed a systematic analysis to investigate the risk of hand-foot skin reaction (HFSR) to axitinib and compare the differences in incidences between sorafenib, sunitinib, pazopanib and axitinib. Relevant studies were identified from PubMed (1998-2012). Eligible studies were limited to prospective Phase II-III clinical trials in which cancer patients were treated with axitinib monotherapy at a starting dose of 5 mg orally twice daily. Incidence, relative risk (RR), and 95 % confidence intervals were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. A total of 984 patients from 6 prospective clinical trials were included in the analysis. The overall incidence of all-grade and high-grade HFSR was 29.2 % (95 % CI: 14.0-51.1 %) and 9.6 % (95 % CI: 4.2-20.7 %), respectively. The relative risks of all-grade and high-grade HFSR to axitinib compared to sorafenib were decreased for all-grade (RR=0.54, 95 % CI: 0.44-0.65, p<0.001) and high-grade HFSR (RR=0.31, 95 % CI: 0.19-0.52, p<0.001). The risk of all-grade and high-grade HFSR to axitinib, sunitinib and sorafenib was significantly higher as compared to pazopanib (RR=6.49, 95 % CI: 4.65-9.05, p<0.001; RR=6.40, 95 % CI: 3.60-11.37, p<0.001, and RR=4.20, 95 % CI: 3.07-5.75, p<0.001; RR=3.67, 95 % CI: 2.15-6.24, p<0.001, and RR=7.51, 95 % CI: 5.5-10.3, p<0.001; RR=5.93, 95 % CI: 3.5-10.0, p<0.001, respectively). Similar to sorafenib and sunitinib, axitinib is associated with a significant risk of HFSR, despite having an increased specificity for VEGF receptors. These findings underscore the importance of supportive dermatologic care in patients treated with axitinib, in order to maintain quality of life, adherence, and persistence to therapy.

A rapid, safe, and low-cost technique for the induction of mild therapeutic hypothermia in post-cardiac arrest patients.

AIM OF STUDY: The benefits of inducing mild therapeutic hypothermia (MTH) in cardiac arrest patients are well established. Timing and speed of induction have been related to improved outcomes in several animal trials and one human study. We report the results of an easily implemented, rapid, safe, and low-cost protocol for the induction of MTH. METHODS: All in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) patients admitted to an intensive care unit meeting inclusion criteria were cooled using a combination modality of rapid, cold saline infusion (CSI), evaporative surface cooling, and ice water gastric lavage. Cooling tasks were performed with a primary emphasis on speed. The main endpoints were the time intervals between return of spontaneous circulation (ROSC), initiation of hypothermia (IH), and achievement of target temperature (TT). RESULTS: 65 patients underwent MTH during a 3-year period. All patients reached target temperature. Median ROSC-TT was 134min. Median ROSC-IH was 68min. Median IH-TT was 60min. IH-TT cooling rate was 2.6°C/h. Complications were similar to that of other large trials. 31% of this mixed population of IHCA and OHCA patients recovered to a Pittsburgh cerebral performance score (CPC) of 1 or 2. CONCLUSION: A protocol using a combination of core and surface cooling modalities was rapid, safe, and low cost in achieving MTH. The cooling rate of 2.6°C/h was superior to most published protocols. This method uses readily available equipment and reduces the need for costly commercial devices.