Skin cancer risk in CHEK2 mutation carriers.

CHEK2 mutations have been linked with an increased risk of breast cancer. A unique challenge for oncodermatologists and oncologists is in the monitoring and counselling of patients regarding skin cancer risk due to CHEK2 mutation carrier status. In this review, we highlight current information in the literature on the risk of melanoma and non-melanoma skin cancers in CHEK2 mutation carriers. On the molecular level, CHEK2 is a cell cycle regulator that has been linked to cancer pathogenesis, though evidence from clinical studies regarding skin cancer risk has been inconsistent and conflicting. For melanoma, one study has demonstrated a statistically significant twofold risk of melanoma in individuals with CHEK2 mutations, particularly the CHEK2*1100delC variant. Five other studies did not show an association. For non-melanoma skin cancer, fewer data exist, with one prevalence study of CHEK2 mutations in a cohort of patients with basal cell carcinomas. Although there are currently no known studies of CHEK2 and cutaneous squamous cell carcinoma (SCC), data from other disciplines associating CHEK2 with head and neck SCCs are emerging. Overall, while there is currently not enough evidence to make conclusive statements regarding increased risk of melanoma and non-melanoma skin cancers in CHEK2 carriers, a molecular mechanism associating the mutation with cutaneous malignancy pathogenesis is evident, and further work is needed. Patient with CHEK2 mutations may benefit from screening dermatologic examinations with particular attention to skin cancers.

De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy: clinicopathological correlation.

Immune checkpoint inhibitors (ICI) may cause eruptions resembling cutaneous autoimmune diseases. There are six cases of immunotherapy-associated subacute cutaneous lupus erythematosus (SCLE) in the literature. We present details of five patients referred to the Skin Toxicity Program at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center who developed de novo immunotherapy-associated SCLE-like eruptions, along with clinicopathological correlation and highlight potential mechanistic features and important diagnostic points. Two patients were maintained on topical corticosteroids, antihistamines and photoprotection. One had complete clearance and two had improvement with addition of hydroxychloroquine. Four patients continued their immunotherapy uninterrupted, while one had immunotherapy suspended for a month before restarting at full dose. Histopathologically, this series illustrates the temporal evolution of ICI-induced immune cutaneous reactions with SCLE subtype. Looking beyond the universally present lichenoid infiltrate, features of evolving SCLE were evident. We hypothesize that programmed death-1 blockade may induce immunological recognition of previously immunologically tolerated drug antigens, leading to epitope spreading and the SCLE phenotype.

Pityriasis rubra pilaris-like erythroderma secondary to phosphoinositide 3-kinase inhibition.

BACKGROUND: Phosphoinositide 3-kinase (PI3K) inhibitors are a class of small-molecule inhibitors approved for the treatment of certain leukaemias and lymphomas. Their dermatological adverse event profile is poorly described. AIM: To characterize a rare cutaneous adverse event from PI3K inhibitors in order to help dermatologists and oncologists identify and effectively manage such eruptions. METHODS: This was a retrospective analysis of patients receiving PI3K inhibitors referred to the Skin Toxicities Program in The Center for Cutaneous Oncology. RESULTS: Three patients on PI3K inhibitors for treatment of malignancy developed diffuse erythroderma and keratoderma. Clinical and histopathological findings were consistent with pityriasis rubra pilaris (PRP)-like reactions. All patients improved with topical and oral corticosteroids, oral acitretin, and drug discontinuation. CONCLUSIONS: PRP-like cutaneous eruptions may develop secondary to PI3K inhibition. Early dermatological evaluation of cutaneous toxicities to PI3K inhibitors as well as rapid initiation of disease-specific treatments may help keep patients on life-prolonging anti-cancer therapies.

Ixazomib-induced cutaneous necrotizing vasculitis.

Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti-cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Fatal disseminated Acanthamoeba infection in a liver transplant recipient immunocompromised by combination therapies for graft-versus-host disease.

Immunosuppressed solid organ transplant recipients are at increased risk for acquisition of opportunistic pathogens, with potentially fatal consequences. With the introduction of novel immunosuppressive agents used to prevent organ rejection and to treat the sequelae of transplantation, severity and rates of infection with unusual opportunistic pathogens may increase. Various monoclonal antibodies are now being used in the treatment of severe, acute graft-versus-host disease (GVHD), including rituximab, daclizumab, and alemtuzumab. These therapies, particularly when used in combination and with other traditional forms of immunosuppression, may have profound effects on the immune system. Acanthamoeba species are ubiquitous, free-living protozoa that rarely cause disseminated disease in the immunocompromised host. We report a fatal case of disseminated Acanthamoeba infection with a dramatic cutaneous presentation in a liver transplant recipient severely immunocompromised by sequential standard and novel therapies used to successfully treat life-threatening acute GVHD. This case illustrates the current major limitation of these therapies, discusses the cutaneous findings in disseminated acanthamoebiasis, and highlights the need to maintain vigilance for the presence of unusual infection in patients receiving similar therapeutic regimens.

Short-term response to dietary counseling of hyperlipidemic outpatients of a lipid clinic.

OBJECTIVE: To evaluate the efficacy of a limited dietary intervention delivered by dietitians in a single counseling session on plasma lipid levels in free-living subjects with hyperlipidemia. DESIGN: A 2-month, nonrandomized comparative study of dietary counseling efficacy in subjects with hyperlipidemia. Dietary instruction was conducted in a lipid clinic by dietitians. Subjects were instructed to follow a diet low in saturated fat and cholesterol (National Education Cholesterol Program step 1 or 2 diets) for 2 months with concomitant energy restriction for weight reduction when necessary. Another group of patients who did not receive dietary counseling during the same period served as a control. SUBJECTS: Ambulatory patients were recruited from the Lipid Clinic of the Montreal Clinical Research Institute. INTERVENTION: Dietary counseling was provided to 104 subjects with hypercholesterolemia and 113 subjects with hypertriglyceridemia. They were compared with 72 subjects with hypercholesterolemia and 80 subjects with hypertriglyceridemia who did not receive dietary counseling. RESULTS: In the hypercholesterolemic group, significant reductions in plasma cholesterol (mean +/- standard deviation = -5.7 +/- 11.7%) and low-density lipoprotein cholesterol (LDL-C) (-7.3 +/- 14.2%) and no changes in plasma very-low-density lipoprotein cholesterol (VLDL-C) or high-density lipoprotein cholesterol (HDL-C) were observed after dietary counseling. The LDL-C response to diet was normally distributed, and 20% of the individuals with hypercholesterolemia reached LDL-C levels below 4.1 mmol/L. In patients with hypercholesterolemia and no clinical evidence of familial hypercholesterolemia, (n = 76) the reductions in plasma cholesterol (-6.6 +/- 10.8%) and LDL-C (-8.2 +/- 14%) were more pronounced. Among the latter patients, 27.6% reached LDL-C levels below 4.1 mmol/L. In subjects with hypertriglyceridemia, the reductions in plasma cholesterol (-4.8 +/- 12.8%), triglycerides (-20.7 +/- 33%), and VLDL-C (-19.5 +/- 29%) were associated with an increase in LDL-C (+8.5 +/- 25.7%) and HDL-C (+5.5 +/- 18%). Of the subjects with hypertriglyceridemia, 20% had triglyceride levels below 2.3 mmol/L after treatment. No significant changes were observed in the control groups during the same period. CONCLUSIONS: Dietary counseling of subjects with hypercholesterolemia or hypertriglyceridemia was associated with beneficial changes in plasma lipid levels after 2 months of dietary intervention. However, longer and more controlled dietary interventions are necessary for most patients to achieve lipid goals.

Influence of probucol on enhanced LDL oxidation after fish oil treatment of hypertriglyceridemic patients.

The susceptibility of low-density lipoprotein (LDL) to oxidation was studied in hypertriglyceridemic men (5 with type III and 5 with type IV) at baseline on a low-saturated-fat, low-cholesterol diet, after 6 weeks of dietary supplementation with fish oil (Promega, 12 g/d), and after 6 weeks of fish oil combined with probucol (500 mg BID). The relative content of n-3 polyunsaturated fatty acids in plasma and LDL was increased during the two treatment periods, and a low alpha-tocopherol to n-3 polyunsaturated fatty acids ratio was observed. Plasma thiobarbituric acid-reactive substances (TBARS) levels were unchanged after 6 weeks of fish oil, but the ratio of lipid peroxides to the reduced triglyceride (TG) levels (MDA:TG) was significantly higher (P < .01). Addition of probucol lowered both absolute levels of TBARS (P < .01) and the MDA to TG ratio (P < .001). The susceptibility of LDL to Cu(2+)-catalyzed oxidation was evaluated over a 5-hour time course by determining TBARS formation, free amino group levels, and changes in LDL electrophoretic mobility. TBARS levels that were higher in native LDL (1.019 < d < 1.050 g/mL) after 6 weeks of fish oil than at baseline (P < .01) were reduced 52.3 +/- 11.3% by the addition of probucol (P < .001). With fish oil alone, TBARS production after exposure of LDL to Cu2+ for 5 hours was increased 17.0 +/- 5.8% compared with corresponding baseline values (P < .001), whereas a 64.1 +/- 14.3% reduction from the previous period was observed with fish oil + probucol (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein E polymorphism association with lipoprotein profile in endogenous hypertriglyceridemia and familial hypercholesterolemia.

Apolipoprotein (apo) E polymorphism was among the first-reported genetic polymorphisms that explained part of the normal variation in plasma cholesterol concentrations in humans. The aim of this study was to assess the influence of allelic variation at the apo E gene locus on the plasma lipoprotein profile in hyperlipidemia. The lipoprotein levels of hyperlipidemic subjects of the major apo E phenotypes (E3/2, E3/3, and E4/3) were compared. One hundred eighty-two subjects with endogenous hypertriglyceridemia and 98 subjects with familial hypercholesterolemia due to a 10-kb deletion in their low density lipoprotein (LDL) receptor genes were compared with 424 normolipidemic controls from the same environmental background. LDL concentrations were lower in the E3/2 subset than in the E3/3 or E4/3 subset in the control, hypertriglyceridemic, and familial hypercholesterolemic groups. In absolute values, the magnitude of the effect was greatest in the familial hypercholesterolemic group. However, the direction and percentage change were identical in the presence or absence of the LDL receptor defect, indicating that the apo E phenotype effect is independent of LDL receptor status. Triglyceride and very low density lipoprotein (VLDL) cholesterol concentrations were higher in E3/2 than in E3/3 or E4/3 hypertriglyceridemic subjects, but this difference was not found in the familial hypercholesterolemic or control group. Thus, there seems to be a specific interaction between apo E isoforms and VLDL metabolism in hypertriglyceridemia; allelic variation at the apo E gene locus seems to be associated with specific alterations in the plasma lipoprotein profile of subjects with well-defined types of hyperlipidemia.