Severe skin ulcer caused by taking lenvatinib after proton beam therapy.

A 69-year-old man was treated with lenvatinib after three sessions of proton beam therapy (PBT) for hepatocellular carcinoma. Five months after administration of lenvatinib, a dermatitis with huge skin ulcer formed in the site of PBT irradiation. Lenvatinib was immediately withdrawn, but the skin ulcer continued growing until about 2 weeks later. With topical and antibiotic treatment, the skin ulcer resolved after about 4 months. After administration of lenvatinib, potential skin damage due to PBT at the irradiated site may have become apparent. This is the first report describing skin ulcer by the combination of lenvatinib administration and PBT.

Methotrexate Cutaneous Ulceration: A Systematic Review of Cases.

BACKGROUND: Methotrexate cutaneous ulceration is a rare methotrexate complication, and has only been described in case reports and case series. OBJECTIVE: To document patient characteristics, morphologic features, and mortality risk factors for methotrexate cutaneous ulceration. METHODS: A systematic literature review of PubMed and Embase (last date 1 November 2021) was performed with data collected from case reports and case series. This study was limited to cases of cutaneous ulceration; presence of oral ulceration was collected from within these cases. RESULTS: 114 cases (men = 57.9%, mean age = 61 years) of methotrexate cutaneous ulceration met inclusion criteria. Psoriasis (69.3%), rheumatoid arthritis (18.4%), and mycosis fungoides (6.1%) were the most common indications for methotrexate use. Morphologies included erosions localized to psoriatic plaques (33.3%), epidermal necrosis/necrolysis (35.1%), localized ulceration (16.7%), and skin-fold erosions (5.3%). Methotrexate dose preceding toxicity varied greatly; median 20 mg/week, interquartile range 15-40 mg/week, range 5-150 mg/week. Most patients had risk factors for serum toxicity (baseline renal dysfunction = 37.8%, concurrent NSAID use = 28.1%, inadequate folic acid use = 89.1%). Thirty percent of cases involved mistakenly high methotrexate doses. Fourteen patients (12%) died. Absence of folic acid use (69% vs. 100%, p value < 0.001), pancytopenia (33% vs. 86%, p value < 0.001), and renal dysfunction at presentation (47% vs. 92%, p value < 0.001) were associated with increased mortality. LIMITATIONS: Selection bias present due to abstraction from case reports and case series. CONCLUSION: Methotrexate cutaneous ulceration is commonly preceded by dosage mistakes, absence of folic acid supplementation, and concurrent use of nephrotoxic medications. Renal impairment, pancytopenia, and absence of folic acid supplementation are key risk factors for mortality from this adverse medication reaction. Providers should regularly monitor methotrexate dosing adherence, drug-drug interactions, and perform routine laboratory evaluation. Index of suspicion for this toxicity should remain high given the varied clinical presentation and high mortality.

Association between subcutaneous steroid injection for extravasation of vesicant anticancer drugs and skin ulcers requiring surgery.

PURPOSE: Although subcutaneous steroid injections are conventionally used to treat extravasation of vesicant anticancer drugs, their effects on the extravasation site remain unclear. We investigated the association between subcutaneous steroid injection in patients with extravasation of vesicant anticancer drugs and incidence of skin ulcers requiring surgery. METHODS: We performed a retrospective cohort study using the Japanese Diagnosis Procedure Combination inpatient database. We identified patients with extravasation of vesicant anticancer drugs who were prescribed steroid ointment or cream on the same day as vesicant drug use between July 2010 and March 2019. The exposure group consisted of patients who had received subcutaneous steroid injections and local anesthetic in addition to topical steroids, whereas the control group had received topical steroids alone. The outcome was the incidence of skin surgical procedures during hospitalization. We performed a mixed-effect logistic regression analysis with random intercept for each hospital to compare outcomes between the groups. RESULTS: We identified 7284 patients from 704 hospitals, including 3713 patients who had received topical steroids alone and 3571 who had received subcutaneous steroid injection in addition to topical steroids. According to mixed-effect logistic regression analysis, subcutaneous steroid injection was significantly associated with a higher incidence of skin surgery (odds ratio, 1.61; 95% confidence interval, 1.14-2.26; P = 0.007). Barthel Index, type of cancer, and type of vesicant drugs were also associated with surgery. CONCLUSIONS: Subcutaneous steroid injections after extravasation of vesicant anticancer drugs are associated with more frequent skin surgery. Randomized controlled trials are required to evaluate the safety and effectiveness of steroid injection.

Skin ulcers caused by ruxolitinib in a patient with chronic cutaneous graft-versus-host disease.

INTRODUCTION: Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT). In the treatment of chronic GVHD, skin directed therapy, systemic corticosteroids, calcineurin inhibitors (such as cyclosporine (CsA) and tacrolimus), rituximab, mycophenolate mofetil (MMF), extracorporeal photopheresis (ECP) and ruxolitinib are used. CASE REPORT: We present an 18 year old male with Philadelphia chromosome positive acute B lymphoblastic leukemia, treated with allogeneic HCT from a full matched sibling donor. The patient had grade 2 chronic cutaneous GVHD resistant to corticosteroids, CsA, MMF, and ECP treatment. Three months after initiation of ruxolitinib therapy, the patient developed skin ulcers on his lower extremities. MANAGEMENT & OUTCOME: The biopsy revealed that the changes were caused by the drug reactions. We suspected ruxolitinib as the likely cause of these ulcerative lesions after evaluating the adverse drug reaction probability scale. The adverse drug score was 4, therefore, ruxolitinib treatment was discontinued. Ulcerative lesions fully recovered after 4 weeks of follow-up. DISCUSSION: Ruxolitinib is used in the treatment of chronic GVHD that has been resistant to steroids and other salvage therapies. In our case, ruxolitinib was used as a salvage therapy in a patient who had refractory chronic skin GVHD. Ruxolitinib-related skin lesions with ulcers of lower extremities and whole body erythematous skin lesions were reported previously in patients with myelofibrosis. The pathophysiology of ruxolitinib related skin ulcers is unknown. Skin changes of patients using ruxolitinib should be closely monitored, and newly developing lesions should be suspected of being drug-related and biopsied.

Enhanced cellular engraftment of adipose-derived mesenchymal stem cell spheroids by using nanosheets as scaffolds.

The short survival time of transplanted adipose-derived mesenchymal stem cells (ASCs) is a problem for skin wound healing. Transplantation after the formation of cellular spheroids has been investigated as a promising method for prolonging cellular survival. However, there have been technical restrictions for transplantation of spheroids in clinical practice. Here, we show an effective method for transplantation of ASC spheroids onto skin wounds in order to efficiently cure refractory ulcers. To assist anchoring of spheroids onto skin wounds, we used a 120-nm-thick free-standing film (nanosheet) that has a highly adhesive property. Bioluminescence imaging showed that ASC spheroids carried by the nanosheet survived for 14 days, which is about two-times longer than that previously reported. Wounds treated with a nanosheet carrying ASC spheroids were 4-times smaller than untreated wounds on day 14. This method for transplantation of spheroids could be applied to cell therapy for various refractory skin wounds.

Impaired Wound Healing with Imatinib Mesylate Therapy.

ABSTRACT: Medication-induced ulcers are generally rare. Although the tyrosine kinase inhibitor imatinib mesylate is frequently prescribed, the occurrence of ulcers related to the medication has not been previously described. Herein, the authors report a case of a patient with impaired wound healing that was attributed to imatinib mesylate treatment. Providers should maintain suspicion for medication-induced ulcers, particularly if treatment for the presumed underlying cause of an ulcer fails.

Giant Penis paraffinoma.

A fifty-year-old healthy, Portuguese male, with prior history of paraffin injections into the penis 30 years ago, was referred for urological consultation because of a large, hardened ulcerated mass on the base of the penis causing deformity and pain. The patient underwent a biopsy that showed a benign granulomatous lesion, and then excision of the mass and penile plasty with a scrotum flap in the same surgical time. Histology confirmed the diagnosis of paraffinoma. Three months after surgery, the patient is satisfied with the functional (urinary function and erectile function) and aesthetic results. Penile paraffinoma is a rare disease (most common in Asia and Eastern Europe) and results from an inflammatory response to the subcutaneous injection of paraffin, Vaseline or other mineral oils. Treatment is usually surgery.

Outcomes of older adults aged 90 and over with cutaneous malignancies after electrochemotherapy with bleomycin: A matched cohort analysis from the InspECT registry.

BACKGROUND: With extending life expectancy, more people are diagnosed with cutaneous malignancies at advanced ages and are offered nonsurgical treatment. We assessed outcomes of the oldest-old adults after electrochemotherapy (ECT). METHODS: The International Network for Sharing Practices of ECT (InspECT) registry was queried for adults aged ≥90 years (ys) with skin cancers/cutaneous metastases of any histotype who underwent bleomycin-ECT (2006-2019). These were subanalysed with patients aged <90 ys after matching 1:2 for tumor location, number, size, histotype, and previous treatments. We assessed ECT modalities, toxicity (CTCAE), response (RECIST), and patient perception (EQ-5D). RESULTS: Sixty-one patients represented the study cohort (median 92 ys, range 92-104), 122 the control group (median 77 ys, range 23-89). Among the oldest-old, 44 patients (72%) had primary/recurrent skin cancers, 17 (28%) cutaneous metastases. Median tumour size was 15 mm (range, 5-450). The oldest-old adults underwent ECT mainly under local/regional anaesthesia (59% vs 39% p = .012). We observed no differences regarding dose and route of chemotherapy (intravenous vs intratumoral, p = .308), electrode geometry (linear vs hexagonal, p = .172) and procedural duration (18 vs 21 min, p = .378). Complete response (57.4 [95%-CI 44.1%-70.0%] vs 64.7% [95%-CI 55.6%-73.2%], p = .222) and 1-year local control (76.7% vs 81.7, p = .092) rates were comparable. Pain and skin hyperpigmentation were mild in both groups. Skin ulceration persisted longer in the oldest-old patients (4.4 vs 2.4 months, p = .008). CONCLUSIONS: The oldest-old adults with cutaneous malignancies undergo ECT most commonly under local/regional anaesthesia with safety profiles and clinical effectiveness similar to their younger counterparts, except in case of ulcerated tumors.

Efficacy and tolerability of intralesional bleomycin in dermatology: A systematic review.

Bleomycin is widely used as an off-label treatment for various dermatologic indications. However, a much-needed critical appraisal of the currently available evidence is lacking. We therefore evaluated the quality of clinical evidence for the efficacy and safety of intralesional bleomycin treatment for dermatologic indications with the aim to provide evidence-based recommendations for clinical practice. The PubMed, Embase, Medline Ovid, Web of Science, Cochrane Central, and Google Scholar databases were systematically searched. Two authors independently selected relevant studies according to predefined inclusion and exclusion criteria. We assessed the methodologic quality with the Cochrane Collaboration risk-of-bias assessment tool and selected 10 randomized clinical trials and 15 clinical controlled trials. Treatment indications included common warts, nonmelanoma skin cancer, cutaneous metastases, keloid and hypertrophic scars, and hemangioma. Intralesional bleomycin treatment showed significantly higher cure rates for warts compared with other treatments. Local adverse events included erythema, blackening, eschar formation, and superficial ulceration. None of the studies reported systemic adverse events. Methodologic quality of the studies was generally low. Consequently, no firm recommendations can be made for intralesional bleomycin treatment in clinical practice. However, this review suggests that intralesional bleomycin is a successful and well-tolerated treatment for recalcitrant warts.

[Digital ischaemia with fingertip ulcers during ipilimumab therapy]. / Ischémie digitale avec ulcération pulpaire sous ipilimumab.

BACKGROUND: Anti-cancer drugs have many adverse effects including vascular side effects. Herein we present the case of a patient presenting digital ischaemia with high imputability of ipilimumab. OBSERVATION: A 47-year-old male patient was treated for popliteal melanoma, initially stage IIIA but which subsequently became metastatic (stage IV), and for which ipilimumab was given after the failure of two lines of chemotherapy. During the 4th course of ipilimumab, the patient developed autoimmune hepatitis. Ipilimumab was suspended. Three months later, he developed a drug-like neuropathy followed one month later by ulceration of the right index finger. Causes of embolic, autoimmune and occupational origin (thrombotic microangiopathy, thrombosed aneurysm) were rapidly ruled out. Although a paraneoplastic origin could not be formally excluded, drug-induced immune disorder remained the most plausible origin. DISCUSSION: This is the first reported case of digital ulceration under ipilimumab.

Severe necrotising inflammatory skin reaction to topical 5-fluorouracil.

I report two patients who developed a severe necrotising inflammatory skin reaction with ulceration and hemorrhagic crusting during the first cycle of chemotherapy with 1% 5-Fluorouracil eye drops for Ocular surface squamous neoplasia. The skin reaction subsided on stoppage of the drops and the use of a steroid ointment. 5 fluorouracil therapy was terminated and the patients were shifted to interferon therapy subsequently.

Digital ulcerative lichenoid dermatitis in a patient receiving anti-PD-1 therapy.

Programmed cell death receptor 1 inhibitors (anti-PD-1) constitute a form of immunotherapy for the treatment of several cancers. They are associated with cutaneous immune-related adverse events (irAE), occurring in up to 50% of patients. Lichenoid dermatitis is frequent and several presentations have been described. Although attempts have been made to study these reactions, they are yet to be fully characterized and the relationship with tumor response is unclear. We describe a case of digital ulcerative lichenoid dermatitis resembling ulcerative cutaneous lichen planus that occurred during pembrolizumab therapy for oral squamous cell carcinoma. The patient developed a painful ulcer on his index finger 18 months into therapy. Biopsy revealed epidermal ulceration with intense lichenoid dermatitis. Immunohistochemical study revealed intense CD8 positivity at the ulcer's edges and marked CD163 positivity at its base. Although idiopathic forms of this type of lichenoid dermatitis are particularly recalcitrant, our case was successfully managed with topical therapy and oncologic treatment did not require modification. One year after ending treatment the patient remains free of disease progression. It is unclear if this reaction is associated with his favorable oncologic response. This report adds an undescribed reaction to the increasing diversity of cutaneous irAE associated with anti-PD-1 therapy.

Electrochemotherapy for advanced cutaneous angiosarcoma: A European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT).

BACKGROUND: Cutaneous angiosarcoma (cAS) is a highly aggressive malignancy that challenges the radicality of surgical treatment. Electrochemotherapy (ECT), a skin-directed treatment based on cytotoxic chemotherapy combined with local electric pulses, may be an intraoperative adjunct and a new opportunity in the therapeutic strategy. This cohort study reports the experience with ECT as an option. METHODS: Data on patients with locally-advanced/metastatic cAS who underwent ECT between October 2013 and October 2018 at eight European centres were prospectively submitted to the InspECT (International network for sharing practices of ECT) register. Patients received therapy according to the European Standard Operating Procedures of ECT (ESOPE). Treatment feasibility was assessed based on tumour coverage with electrodes and recorded tissue current; treatment toxicity and tumour response were graded according to CTCAE v5.0 and RECIST v1.1 criteria, respectively; patient-reported outcomes (PRO) were evaluated using a visual analogue score (VAS) for pain, acceptance of retreatment and the EQ-5D questionnaire. RESULTS: We enrolled 20 patients with advanced cAS in the scalp/face (n = 7), breast/trunk (n = 10) or limbs (n = 3). Target tumours (n = 51) had a median size of 2.3 cm (range, 1-20). We administered 24 ECT courses using 1-4 cm treatment safety margin around tumours. In five patients, ECT was combined/sequenced with surgery. Median tissue current was 3 A (range, 1.5-10), tumour margins coverage rate was 75% (15/20 patients). The objective response rate (ORR) was 80% (complete, 40%). Grade-3 toxicity included skin ulceration (15%) and pain (10%), with no significant change of PRO scores. Bleeding control was achieved in 13/14 patients with ulcerated tumours. With a median overall survival of 12.5 months, the local progression-free survival (LPFS) was 10.9 months. CONCLUSION: ECT produces sustained response rate with minimal side effects and should be considered an option for advanced cAS. Palliative benefits include patient tolerability, local haemostasis and durable local control. Definition of optimal timing, treatment safety margins and combination with surgery need further investigation.