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INTRODUCTION By 1 January 2021, the FDA has approved a total of 62 small-molecule kinase inhibitors (SMKIs). The increasing clinical use of small-molecule kinase inhibitors has led to some side effects, the most common of which is cutaneous toxicity, as reflected by approximately 90% (57 of 62) of the FDA-approved SMKIs have reported treatment-related cutaneous toxicities. Since these cutaneous toxicities may have a crucial influence on the emotional, physical and psychosocial health of the patients, it is of great importance for doctors, patients, oncologists and interrelated researchers to be aware of the cutaneous side effects of these drugs in order to make the diagnosis accurate and the treatment appropriate. AREAS COVERED This review aims to summarize the potential cutaneous toxicities and the frequency of occurrence of FDA-approved 62 SMKIs, and provide a succinct overview of the potential mechanisms of certain cutaneous toxicities. The literature review was performed based on PubMed database and FDA official website. EXPERT OPINION It is significant to determine the risk factors for SMKI-induced cutaneous toxicity. The mechanisms underlying SMKI-induced cutaneous toxicities remain unclear at present. Future research should focus on the mechanisms of SMKI-induced cutaneous toxicities to find out mechanistically driven therapies.

Immunotherapy and target therapy have revolutionized treatment of stage III/IV melanoma. Both treatments show a favorable toxicity profile even if cutaneous adverse events (AEs) are frequent (30%-40% of cases). This is a retrospective single center cohort study that included patients with stage IV or inoperable stage III metastatic melanoma (AJCC 8th) who received BRAFi + MEKi therapy or immunotherapy with Checkpoint inhibitors. All cutaneous AEs were ascertained by a dermatologist based on clinical and histological findings. The primary outcome was to provide a detailed clinical dermatological classification of cutaneous adverse events and an evaluation of the incidence of skin toxicity in the two arms of therapy (immunotherapy and target therapy). A total of 286 patients with stages III-IV metastatic melanoma were included: 146 received immunotherapy and 140 target therapy. In the immunotherapy cohort, 63 (43.1%) cutaneous reactions were observed while 33 skin reactions (23.6%) were identified in patients treated with target therapy. All the skin toxicities observed were grade I, excepted four cases: an erythema multiforme-like eruption, a grade III psoriasis and two grade III maculopapular rashes. Immunotherapy in older age resulted statistically related to skin toxicities (p = 0.011), meanly in metastatic setting (p = 0.011). Cumulative incidence of skin toxicities was 65.63% in immunotherapy cohort (p = 0.001). Also multivariate logistic regression shows a significant association between skin adverse events and immunotherapy (odds ratio [OR] = 0.50; 95% confidence interval [CI]: 0.29-0.85, p: 0.01) and between cutaneous AEs and metastatic setting (OR = 1.97; 95% CI: 1.04-3.74, p: 0.04). We have also shown that as the age of initiation of therapy increases the probability of developing skin toxicity grows. However, stratifying by type of therapies the effect of age persists only in immunotherapy (OD: 1.04; CI: 1.01-1.06; p: 0.04) while for target therapy age does not affect the onset of skin toxicity (OD 1.01; CI 0.98-1.04; p = 0.42). No differences were shown between patients on target therapy and immunotherapy regarding gender. Patients were also evaluated regarding concomitant therapies and seems that Levotyroxine may be involved in AEs during immunotherapy treatment. More studies are needed to deepen this aspect, also considering the medical history and diverse drug associations. Cutaneous adverse events are characterized by heterogeneous manifestations, are more often seen in patients on immunotherapy and dermatologists can play a crucial role in multidisciplinary care.

The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs).To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders.This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014.62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors.Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

In All-Russian Scientific Research Institute for Fundamental and Applied Parasitology of Animals and Plant – a branch of the Federal State Budget Scientific Institution "Federal Scientific Centre VIEV" a prototype of a new drug form of Ivermectin was developed for cutaneous use against endo- and ectoparasites. The dosage form is a transparent solution for application to the skin with an Ivermectin content of 0.5%. For the experiment, 18 white male rats weighing 180-200 g were selected, which were divided into 2 experimental and one control group of 6 heads each. The coat of all animals was shaved on the back with an area of about 5x5 cm. The drug was applied at doses of 5 000 and 10 000 mg / kg, the control group did not receive the drug. The LD50 of the Ivermectin dosage form is more than 10 000 mg / kg, according to GOST 12.1.007-76 the drug belongs to the 4th class of danger when applied to the skin. The drug does not have an irritating effect when applied once to intact rat skin.

Although the arrival of new chemotherapy drugs and combinations has brought progress in terms of cancer patient survival, they entail many adverse effects that can compromise treatment, and hence prognosis, of the disease. Cytostatic agents can cause dermatological toxicity, among other side effects. The most familiar adverse effect of chemotherapy is alopecia. Although not serious, this changes the outward appearance of cancer patients. Other adverse effects include hypersensitivity and photosensitivity reactions, hand-foot syndrome, epidermal necrolysis, recall reactions, scleroderma-like reactions, Raynaud's phenomenon, eccrine squamous syringometaplasia, neutrophilic eccrine hidradenitis, nail abnormalities, pigmentation changes and extravasation injuries. Onset of these adverse effects often causes ose reduction and/or delayed treatment, which can affect patient survival and quality of life. It is therefore important to prevent their occurrence and treat them promptly, which requires cooperation between medical oncologists and dermatologists. This article reviews chemotherapy ssociated dermatological toxicity, along with its diagnosis and therapeuticmanagement. (C) 2019 AEDV. Published by Elsevier Espana, S.L.U. All rights reserved.

Background: Adverse drug reactions (ADRs) involving both the skin and the heart may affect a wide range of patients world-wide, leading to significant mortality, morbidity and high health-care costs.

Immune-modulatory therapy, especially with immune-checkpoint inhibitors (ICIs), has reshaped cancer therapeutics. Immunotherapy is relatively a novel approach that can effectively delay the progression of aggressive tumors and inhibit tumor recurrence and metastasis in many different tumor types. In the past years, ICIs have shown a sustained response and promising long-term survival in patients with advanced hepatocellular carcinoma (HCC). Nevertheless, ICI therapy can unbalance the immune system and result in a wide range of immune-related adverse events (irAEs), which are generally manageable but occasionally lead to a fatal outcome. HCC generally develops in the context of liver cirrhosis which is typically caused by viral hepatitis and non-alcoholic steatohepatitis. These underlying diseases may cause symptoms that overlap with irAEs and lead to consequences such as late recognition, inadequate work-up, and inappropriate treatment. Owing to the growing use of immunotherapy in HCC, it is necessary for clinicians to strengthen their understanding of the frequency, clinical features, and management of irAEs. This review focuses on the common toxicities associated with ICI therapy in patients with HCC and summarizes therapeutic strategies that can be used to monitor and manage such toxicities.

The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists.In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.

Enfortumab vedotin is an antibody-drug conjugate targeting nectin-4 and is being studied in the treatment of various epithelial carcinomas including urothelial carcinoma; early data suggests efficacy and tolerability. Rash has been described as an adverse event associated with treatment with enfortumab vedotin, but has not been characterized to date. We report a patient with metastatic urothelial carcinoma treated with enfortumab vedotin who developed erythematous, scaly papules and plaques on his torso and extremities with corresponding histologic features of vacuolar interface dermatitis and maturation disarray of keratinocytes. He was successfully treated with topical corticosteroids. Cutaneous toxicity appears to be a common adverse reaction in this growing class of antibody-drug conjugates.

Resume Les envenimations par les amphibiens anoures sont tres rares en France metropolitaine ; nous rapportons l’observation d’une patiente de 20 ans sans antecedent, ayant saisi a pleine main un crapaud commun, Bufo bufo ; elle a presente tres rapidement des lesions erythemateuses douloureuses, puis maculo-papuleuses, sans signe systemique. Un avis au centre antipoison et de toxicovigilance a ete pris et la guerison a ete obtenue en treize jours avec un traitement symptomatique. B. bufo dispose de glandes granuleuses sur toute sa face dorsale, particulierement dans la region postoculaire (les glandes parotoides) contenant un venin riche en amines biogenes et en steroides (bufogenines et bufotoxines). La litterature mentionne des cas de keratites severes en cas de projections oculaires, mais aussi des cas de cardiotoxicite mortelle de type « digitalique-like » en cas d’ingestion d’extraits de bufonides (soupe, œufs, poudres a visee aphrodisiaque). Un traitement par Fab’2 antigitalique a ete propose lors de ces envenimations. Nous n’avons pas retrouve de publication de cas cutanes similaires chez l’homme. Il existe d’autres anoures (Dendrobatides : Phyllobates ) dans le Nouveau Monde responsable de tableaux cliniques mortels.

Cabozantinib is a tyrosine kinase inhibitor which is increasingly being used for the treatment of metastatic renal cell cancer. Skin toxicity such as palmar-plantar erythrodysesthesia is not uncommon with such agents. However, bullous skin reactions are not common and we report the case of a patient with metastatic renal cell cancer who experienced such cutaneous toxicity.

Thiotepa, a highly lipophilic, alkylating agent, and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. We present a case of cutaneous toxicity observed in a 4.5-year-old girl patient with medulloblastoma treated with a high-dose thiotepa conditioning regimen before autologous stem cell transplantation. Skin lesions, as well as their pattern and locations, were evocative of thiotepa toxidermia. After the case herein described, preventive care guidelines were implemented in our unit as from 2014. A retrospective follow-up of 26 pediatric patients receiving thiotepa prior to stem cell transplantation was performed until March 2018. In this series of patients, only one patient experienced cutaneous toxicity as reported herein. Thereafter, only mild cutaneous toxicity was observed, even with double or triple transplantation protocols with high-dose thiotepa. Clear preventive care instructions should be detailed in the Summary of Product Characteristics in order to minimize the cutaneous toxicity of thiotepa.

The relationship between treatment outcome and cutaneous toxicity induced by anticancer therapy has gained attention in the past decade. In this article, we have provided an overview of the 3 main classes of anticancer agents—specifically, molecularly targeted kinase inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapeutics—and described the data evaluating the association between cutaneous toxicity induced by these agents and survival benefit. Although preliminary studies are promising with regard to the potential role of cutaneous toxicities as a surrogate biomarker of efficacy of treatment, larger prospective studies are needed to confirm this relationship. Dermatologists have a unique opportunity to collaborate with oncologists in the multidisciplinary treatment paradigm by helping to identify and manage these dermatologic events in patients with cancer. A heightened awareness of these toxicities is critical, as it can potentially allow recognition of the efficacy of anticancer therapy and may influence treatment decisions and patient outcomes.

The introduction of BRAF inhibitors (BRAFi), vemurafenib and dabrafenib, revolutionized BRAFV600-mutated metastatic melanoma treatment with improved response rate and overall survival compared to standard chemotherapy. However, the mechanism related cutaneous toxicity remains a concern. In addition, intrinsic and acquired resistance remain the key challenges in BRAFi therapy. Extensive efforts to elucidate the mechanisms have led to an improved understanding of disease biology and resulted in exploration of multiple new therapeutic options. While the future looks bright with multiple new therapeutic strategies in exploration and possible new generations of BRAFi, there are questions remaining to be answered to enable more efficient use of BRAFi in cancer therapy.

The predictable side effects in the form of cutaneous toxicity sometimes do not allow to carry out the adequate course of antineoplastic therapy. The most frequent adverse reactions of the skin to such treatment include xerosis and pruritus. We observed 18 patients given various antineoplastic preparations who developed manifest xerosis and pruritus. The combined treatment included infrared therapy (in the frequency range of 590-620 nm) and an agent for the topical application containing 2% urea. A course of adjuvant therapy resulted in all the patients in the reduction of the severity of clinical symptoms of cutaneous toxicity of the antineoplastic preparations. In addition, certain subjective sensations (such as pruritus, skin tightness and hypersensitivity) were eliminated which significantly promoted tolerability to the course of the antineoplastic treatment. It is recommended to supplement the antineoplastic therapy by a course of phototherapy using orange light in combination with the application of a moistening agent for the external use.

Epidermal growth factor inhibitors are currently an essential treatment for many advance-stage epithelial cancers as colorectal and lung cancer. Although they are safe, these agents often present cutaneous adverse events that can cause dosage reduction, interruption of treatment and psychosocial discomfort. We report two cases of cutaneous toxicity in patients with solid tumors using different epidermal growth factor inhibitors.

As the knowledge on cancer genetic alterations progresses, it fosters the need for more personalized therapeutic intervention in modern cancer management. Recently, mutations in KRAS, BRAF, and PIK3CA genes have emerged as important mechanisms of resistance to EGFR-targeted therapy in metastatic colorectal cancer (mCRC). Here we report the first case of a mCRC patient whose disease had progressed on standard lines of treatment and for which we devised a personalized therapeutic approach consisting of vemurafenib (ZelborafTM) and panitumumab (VectibixTM), based on the following molecular profile: BRAFV600E-mutant, amplified EGFR (double positive) and WT KRAS, WT PIK3CA, not-amplified HER2 (triple negative). This new combination therapy was well tolerated and resulted in a strong control of the disease. In particular, the vemurafenib-panitumumab combination appears to limit the typical toxicity of single agents, since no cutaneous toxic effects typically associated with vemurafenib were observed. Here we report the first clinical evidence that the combination of an anti-EGFR (panitumumab) and an inhibitor of BRAFV600E (vemurafenib) is well tolerated and results in a strong disease control in an extensively pretreated mCRC patient.

e23063 Background: Clinical symptom is often a direct method to evaluate the treatment effects. With the emergence of EGFR-targeted drugs on market, it is unclear to apply cutaneous toxicity in evaluating treatment effects and outcomes in cancer patients. This study aimed to determine whether adverse skin event as a survival indicator for patients treated with EGFR tyrosine kinase inhibitors. Methods: PubMed, EMBASE, Scopus, trial register and Cochrane Library were searched on November 11, 2018 to identify studies reporting survivals outcomes. The following search/exploded terms were used: “ EGFR-TKIs: gefitinib/erlotinib/afatinib/osimertinib ”, “ cutaneous toxicity”, “ survival”. Two investigators performed study selection independently and assessed risk of bias with ROBINS-I method. Data were pooled with random effects models and further subgroup by cancer types. Funnel plot, Egger test and Begg test were performed for detection of publication bias. Sensitivity analysis was performed by excluding potential outliers. Results: There were 24 studies identified with 4696 patients included. Skin adverse event was found to be significantly associated overall survival rate (HR, 0.48; 95% CI, 0.43-0.53; P < 0.00001; I2 = 83%) and progression free survival rate (HR, 0.59; 95% CI, 0.41-0.85; P= 0.004; I2 = 88%). Subgroup analysis suggested among non-small cell lung cancer patients, skin adverse event was significantly associated with overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .0001; I2 = 86%) but not progression free survival (HR, 0.65; 95% CI, 0.29-1.45; P= 0.29; I2 = 95%). Among other cancer types patients, skin adverse event was significantly associated with overall survival (HR, 0.59; 95% CI, 0.41-0.84; P= 0.004; I2 = 70%) and progression free survival (HR, 0.61; 95% CI, 0.41-0.91; P= 0.02; I2 = 80%). Begg test and Egger test suggested no evidence of publication bias. Sensitivity analysis also showed similar results. Conclusions: Skin eruption had 52% lower risk of death and 41% lower risk of progression in cancer patients treated with EGFR-TKIs. This association should be further incorporated with cancer survivorship care planning.

Background: The human body is most immunologically primed to respond to injury one hour after awakening when peak cortisol levels are achieved. Previous studies have shown that acute stressors like surgery induce a redistribution of immune cells within the body and immediate leukocyte trafficking to the skin in response to cutaneous injury. When surgery is performed during peak cortisol levels (AM), recovery is significantly shorter due to the rapid immunologic response. However, no study has assessed whether the timing of daily radiotherapy (RT) treatment (AM vs. PM) impacts cutaneous healing in breast cancer patients undergoing whole breast RT. The purpose of this study is to compare cutaneous toxicity and recovery in breast cancer patients treated in the morning vs. those treated in the afternoon with standard breast RT. Methods: Forty post-lumpectomy breast cancer patients were enrolled in a prospective, longitudinal ultrasound imaging study to objectively quantify RT-induced cutaneous toxicity and recovery. Twenty-two women received treatment before 9am and eighteen were treated after 3pm for the duration of their treatment course. All subjects received standard whole breast RT (50 Gy plus a 10 Gy boost in 30 total fractions). Patients were assessed 1 week prior to RT (baseline, T1), week 6 of RT (T2), and 6 weeks (T3), 3 months (T4), 6 months (T5) and 1 year (T6) post-RT. All four quadrants of the affected and unaffected breast were imaged with a 10-MHz ultrasound. Epidermal thickness was measured as a proxy for cutaneous toxicity. A skin thickness ratio (STRA) was generated by normalizing the epidermal thickness measurements to the corresponding contralateral breast measurements. RT-induced skin toxicity was assessed by measuring the change in STRA from baseline to T2, T3, T4, T5 and T6. The recovery time point was determined by identifying the STRA ratio measured after RT most closely approximating that of baseline. Differences in STRA for each patient was assessed at each time point and subsequently compared between patients treated daily before 9am vs. those treated after 3pm. Results: A total of 138 ultrasound scans were examined. Regardless of treatment time (AM vs. PM), the STRA returned to near normal levels at T6 as indicated by non-significant STRA differences when compared to baseline. Skin thickness change maximized at T5 for the pre-9am group (0.380, 95%CI 0.118-0.641) and at T4 for the post-3pm group (0.487, 95%CI 0.162-0.813). Comparison of STRA changes between subjects treated before 9am and after 3pm showed significantly better recovery at T4 for the morning group (p = 0.049), but were not conclusively different at all other time points. Conclusions: This study is the first of its kind to objectively document the development of skin toxicity in breast cancer patients treated with daily RT in the AM vs. PM using quantitative ultrasound. Our findings suggest that morning treatment with RT may result in less skin toxicity 3 months post-RT but timing of daily RT did not impact cutaneous toxicity during RT or recovery by 6 months and 1 year post-RT. Further investigation is warranted with a larger cohort and consistent follow up to better ascertain the effect size. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-07.

Epidermal growth factor receptor (EGFR) inhibitors are biological factors used in the treatment of non-small-cell lung cancers (NSCLC) that are positive for EGFR mutations. Afatinib is one such drug that has been approved for use in this capacity. Cutaneous toxicity is the second most commonly reported adverse event with the use of afatinib. A 39-year-old woman with inoperative right lung adenocarcinoma was initially treated with afatinib. She not only developed a severe papulopustular eruption but also had a dramatic reduction of her tumor. Her cutaneous symptoms and lesions were effectively treated with oral and topical corticosteroids, oral antibiotics, and oral antihistamines. After one month of afatinib treatment, her tumor was resected, and there was no evidence of metastases. Afatinib-induced cutaneous toxicity has a positive correlation with tumor response to anti-neoplastic therapy. Supplemental systemic and topical treatments can be initiated to palliate adverse skin events in order to enable adequate duration of treatment with afatinib.

Bleomycin toxicity predominantly affects the skin and lungs. Cutaneous toxicity classically known to present with bleomycin are flagellate erythema and drug rash. We hereby report an isolated case of (bleomyicn)-induced acquired partial (lipodytrophy) having potential cosmetic implications in a young women prescribed postoperatively following a case of germ cell carcinoma of ovary (endodermal sinus tumor).

Die neuen, oral verabreichten Zytostatika vom Typ der Tyrosinkinasehemmstoffe (TKI) z. B. gegen den Wachstumsfaktor-Rezeptor EGFR/HER2 (Epidermal growth factor receptor) sind mit typischen Nebenwirkungen wie Hautveranderungen und Diarrhoen assoziiert. Auch wenn diese klinisch meist mild und nicht vital gefahrdend sind, kann die psychische Belastung fur den Patienten erheblich sein und bis zum Therapieabbruch fuhren. Durch die einfache orale Administration kommen EGFR-TKI aus den Fachkliniken zunehmend in den Bereich der niedergelassenen Arzte. Daher soll dieser Review dem niedergelassenen Arzt konkrete Handlungsanweisungen zur Bewertung und Therapie der haufigsten Nebenwirkungen an die Hand geben. Mittlerweile sind mehrere TKI zugelassen, weitere, wie beispielsweise Afatinib, befinden sich in spaten Stadien der klinischen Prufung. Afatinib ist eine Substanz der neuesten Generation (irreversible TKI) mit breiterem TKI-Spektrum (Erb familyblocker) und den klassentypischen Nebenwirkungen. Gastrointestinale Nebenwirkungen wie Durchfall sind insbesondere zu Behandlungsbeginn haufig, konnen aber analog zu Chemotherapeutika nach dem hier vorgestellten Schema auf Basis von Loperamid und ggf. Octreotid behandelt werden. Stomatitis/Mukositis konnen durch gezielte Pflege und Kuhlung gelindert werden. Fur akneiforme Dermatitiden ist in Abhangigkeit vom Schweregrad eine gezielte topische oder systemische Antibiose in Verbindung mit weiteren lokalen Masnahmen sinnvoll. Fatigue ist bei Afatinib eine eher seltener auftretende, dennoch ernst zu nehmende Nebenwirkung.

Periarticular thenar erythema with onycholysis (PATEO) syndrome, a subtype of hand-foot syndrome first defined by Childress and Lokich [1], is a rare cutaneous toxicity that may manifest in patient...

Hand–foot syndrome, a chemotherapy-induced cutaneous toxicity, can cause an alteration in fingerprints causing a setback for cancer patients due to the occurrence of false rejections. A colon cancer patient was fingerprinted after not having been able to use fingerprint recognition devices after 6 months of adjuvant chemotherapy. The fingerprint images were digitally processed to improve fingerprint definition without altering the papillary design. No evidence of skin toxicity was present. Two months later, the situation returned to normal. The fingerprint evaluation conducted on 15 identification points highlighted the quantitative and qualitative fingerprint alteration details detected after the end of chemotherapy and 2 months later. Fingerprint alteration during chemotherapy has been reported, but to our knowledge, this particular case is the first ever reported without evident clinical signs. Alternative fingerprint identification methods as well as improved biometric identification systems are needed in case of unexpected situations.

EGFR receptor inhibitors are used for the treatment of a number of solid tumors. Their cutaneous toxicity is a specific and frequent side effect that has shown to be correlated to the antitumoral effect. Here, we present an overview of the cutaneous manifestations and management of EGF receptor inhibitors toxicity.

Resume Une mycose experimentale a dermatophyte a ete provoquee chez 104 cobayes. Le traitement de ces dermatophyties avec le P. H. B. a entraine la guerison des lesions dans un delai de 3 a 20 jours plus court que celui necessaire a la guerison spontanee des temoins. L'analyse statistique a montre que cette difference est significative. Le P. H. B. s'est avere depourvu de toxicite cutanee dans les conditions de l'experience. Summary Experimental dermatophytosis was induced in 104 guinea pigs. Under treatment with P. H. B., the healing time for the lesions was from 3 to 20 days shorter than the spontaneous healing time. Statistical analysis shows this difference to be significant. P. H. B. was devoid cutaneous toxicity under these experimental conditions. Zusammenfassung An 104 Meerschweinchen wurde experimentell eine Dermatophyten-Mykose ausgelost. Mit Phenylhydrargyri boras heilten diese Dermatophytien gegenuber den Kontrollen um 3—20 Tage schneller ab. Dieser Unterschied ist statistisch significant. Phenylhydrargyri boras hat sich unter den Versuchsbedingungen als frei von jeglicher kutanen ToxizitaUt erwiesen.

The value and predictive power of nonclinical studies for potential effects of investigational medicinal products in humans is often debated. The subject of general predictivity of animal toxicity studies has been addressed on several occasions, with one of the most recent efforts being conducted by an ILSI Task Group [Olson H, et al. Concordance of the toxicity of pharmaceuticals in humans and animals. Regul Toxicol Pharmacol 2000; 32: 56-67]. This review provides a summary of the evaluation of cutaneous toxicity, its histopathological assessment, and experience of the biopharmaceutical industry with respect to injection site reactions with parenteral drug products with a pragmatic perspective on the predictivity of standard animal studies with respect to these responses in humans.

This study was designed to evaluate the predictive value of early specific toxicities on efficacy of weekly irinotecan/cetuximab administered as salvage therapy in patients with metastatic colorectal cancer (CRC) refractory to oxaliplatin and irinotecan.Seventy patients received a regimen composed of weekly irinotecan 125 mg/m2 as a 1-hour intravenous infusion and cetuximab 400 mg/m2 infused over 2 hours as the initial dose and 250 mg/m2 infused over 1 hour for subsequent administrations. A single treatment cycle was composed of 4 weekly irinotecan infusions followed by 2 weeks of rest. The predictive value of adverse events (AEs) attributable to cetuximab (rash) and major toxicities attributable to irinotecan (gastrointestinal [GI] and hematologic) were observed after the first cycle of treatment and, therefore, correlated to activity and efficacy of cetuximab and weekly irinotecan.Sixty-six of 70 patients receivedor= 1 cycle of chemotherapy and were therefore evaluable for response. Overall, toxicity observed was generally mild and manageable. According to an intent-to-treat analysis, a partial response was exhibited in 15.7% of patients, with a median progression-free survival (PFS) and median overall survival time of 4 months and 9 months, respectively. As expected, PFS (P = .01) and median survival (P = .04) correlated strongly with the presence and severity of the rash. Surprisingly, the presence of at least moderate hematologic and GI toxicity was associated with improved PFS (P = .03).Our data suggest that irinotecan-induced AEs might predict a better outcome in advanced CRC. This finding would identify a different subset of patients-those likely to benefit from a renewed sensitivity to irinotecan induced by cetuximab.

皮膚は体の中の最大の器官であり，常に化学物質や環境物質など外界からの刺激に暴露されている．皮膚毒性はその発現機序により，皮膚に触れておこる傷害である接触性皮膚炎（刺激性皮膚炎，アレルギー性接触性皮膚炎，化学熱傷），紫外線との複合作用により引き起こされる光過敏症（光毒性皮膚炎，光アレルギー性接触性皮膚炎），接触性蕁麻疹，化学挫瘡，色素沈着異常，薬疹，毛の異常，爪の異常，腫瘍に大別され，本総説では皮膚の機能・構造およびこれら皮膚毒性の特徴について概説した．近年，特定の分子・遺伝子を標的とする医薬品やナノテクノロジーを利用した医薬品開発が進歩し，新規医薬品の新たなメカニズムによる毒性発現が懸念され，ここで述べた基本的な毒性変化を理解しておくことが重要であろう． 我々は日常生活の中で化学物質や環境物質など外界からの刺激に常に暴露されており，様々な皮膚の症状を経験する．「化合物を医薬品にするために必要な安全性試験」シリーズの本稿では，1）皮膚の機能・構造，2）医薬品・化学物質による皮膚毒性の特徴について，自験例を含めて解説する．

We report a case of necrosis caused by the use of prallethrin (mosquito repellent) on the skin in a 67-year-old diabetic female patient suffering from delusions of parasitosis. Cutaneous toxicity due to pyrethroids is less known or reported, despite well-documented pyrethroid poisoning involving the gastrointestinal, respiratory, cardiac, and nervous systems. Skin irritation has been described after acute accidental exposure but, as far as we know, no data have been published on the effects of pyrethroids when applied directly to the skin.

Background In clinical practice, discontinuation or dose reduction of everolimus may be induced not only by grade 3 or 4 toxicities but also by prolonged grade 2 toxicities, such as stomatitis and/or cutaneous toxicity, which share some pathogenetic mechanisms. We assessed the correlation between either everolimus discontinuation or dose reduction induced by stomatitis–cutaneous toxicity events (SCTE) and clinical outcome of patients with metastatic renal-cell cancer (mRCC). Patients and Methods We retrospectively reviewed the clinical data of patients with mRCC treated with everolimus in 2 Italian centers. Clinical evidence of SCTE was evaluated, and corresponding clinical data were reviewed for response and clinical outcome. Results Seventy-nine mRCC patients treated with everolimus (57 male, 22 female; median age 66 years; range, 44-88 years) were evaluated. SCTE were observed in 20 (25%) of 79 patients at a median of 30.5 days of everolimus treatment (range, 10-270 days). Partial response or stable disease was achieved in 15 (79%) of 19 evaluable patients with SCTE compared to 28 (48%) of 58 with no SCTE ( P = .03). At a median follow-up of 19 months, a significant difference was found in the median PFS equal to 7.8 months (95% confidence interval [CI], 2.8-24.4) in SCTE patients versus 4.3 months (95% CI, 2.7-7.5) in non-SCTE patients ( P = .029), and in the median OS equal to 30.6 months (95% CI, 19.6–not reached) in SCTE patients versus 13.5 months (95% CI, 9.9-17.7) in non-SCTE patients ( P = .0007). Conclusion These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC patients treated with everolimus.