Julia K. Tietze

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. CONCLUSION Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. CONCLUSION Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Rosacea – S1 Guideline

Rosacea is a common infl ammatory skin disorder, which usually occurs in adults and primarily affects the face. The disease is characterized by a chronic, episodic course. The severity of disease varies clinically and morphologically. Initially, there may be only transient erythema on the face which becomes persistent. Telangiectases – mainly on the cheeks – are also very common. Papules and papulopustules are typical fi ndings in stage II of disease. Not only the face, but also adjacent areas, such as the neck, chest, back, and scalp, may also be affected. Other types of rosacea are characterized by lymphedema and diffuse hyperplasia affecting the connective tissue and the sebaceous glands, known as phyma (skin thickening). Skin thickening may be associated with other skin changes, or it may occur independently. Involvement of the eyes is common. The clinical appearance of papulopustular rosacea may resemble acne, although there are no comedones, and the patients are signifi cantly older than the typical acne patient. It is still under discussion whether rosacea is primarily a follicular disease. Synonyms: acne rosacea, couperosis, facial erysipelas (obsolete terms include acne erythematosa, and in German, “copper fi ns” or “red fi ns”).

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions

BACKGROUND Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.

Topical therapy with nadifloxacin cream and prednicarbate cream improves acneiform eruptions caused by the EGFR-inhibitor cetuximab – A report of 29 patients

The epidermal growth factor receptor (EGFR) inhibitor cetuximab is used to treat advanced stages of solid tumors. Acneiform skin eruptions, the most common side effects of cetuximab, stigmatize the patient in daily life and may lower compliance. As oral treatment of acneiform eruptions with tetracyclines or isotretinoin might interfere with cetuximab efficacy or cause drug interactions, an effective topical treatment regimen is needed. An uncontrolled, open label follow-up study involving 29 oncology patients with cetuximab-induced acneiform eruptions was performed with a combination of nadifloxacin cream once daily and prednicarbate cream once daily for 6 weeks. Clinical efficacy was graded before and after 1, 2 and 6 weeks of treatment by a dermatologist using a severity score for acneiform eruptions. The majority of patients improved significantly with a reduction of papules, pustules and erythema between all time points analyzed. Topical treatment with a combination of nadifloxacin cream and prednicarbate cream is a highly efficient and well tolerated therapy for acneiform eruptions associated with cetuximab based chemotherapy and merits further investigation.

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis.

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4‐blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T‐cell type MS. Quantitative next generation sequencing of T‐cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T‐cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294–300

The Systemic Management of Advanced Melanoma in 2016

Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma. We summarize the most pertinent studies on BRAF/MEK inhibitors and blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Although most agents show robust antitumor efficacy as single agents, further improvements have been achieved by the combination of both approved and developing drugs. We discuss ongoing trials and evaluate future approaches that may provide additional efficacy with less toxicity.

Comparison of Two Kinds of Lasers in the Treatment of Acne Scars.

Acne scars are common and stigmatizing for the affected patients. Besides surgery, chemical peels, microdermabrasion, and microneedling, the treatment with fractional laser is a standard therapy. The results of reducing acne scars treated either with a fractional Er:YAG (erbium-doped yttrium-aluminum-garnet [Er:Y3Al5O1]) or a carbon dioxide (CO 2 ) laser at different wavelengths were compared and evaluated in the pilot study presented here. Fourteen patients with severe scars on both cheeks were treated four times in a random split-face approach: on one side with Er:YAG laser and on the contralateral side with CO2 laser following a standardized protocol. Therapeutic success was evaluated through the use of a high-resolution, 3D small-field capture system (PRIMOS), digital photography, and the Patient and Observer Scar Assessment Scale (POSAS) questionnaire. The evaluation was performed by a blinded investigator. Treatment results displayed a higher efficacy of the fractional CO2 laser compared with the Er:YAG laser as displayed by digital photographs. Additionally, objective (high-resolution, 3D small-field capture; PRIMOS) and subjective (POSAS) measuring results correlated positively in certain qualities (color, stiffness, thickness, surface, overall opinion). Using a novel scientific approach, we evaluated the therapeutic efficacy of different fractional lasers on acne scars using a rater-blinded approach. Compared with an Er:YAG laser, better skin smoothening was achieved by fractional CO2 laser treatment.

Oral isotretinoin as the most effective treatment in folliculitis decalvans: a retrospective comparison of different treatment regimens in 28 patients.

Folliculitis decalvans leads to scarring alopecia through inflammatory destruction of the hair follicle. Currently, antibiotics are most commonly used to treat this disease. However, treatment regimens with antibiotics feature a high relapse rate and encourage the development of resistant bacteria.

Linear and volumetric evaluation of the adrenal gland--MDCT-based measurements of the adrenals.

RATIONALE AND OBJECTIVES The purpose of this study was to provide normal values of volumetry and linear dimensions of adrenal glands. MATERIALS AND METHODS Contrast-enhanced multidetector computed tomography scans of 105 patients were evaluated in this retrospective study. Imaging software was used both to measure the adrenal gland volume and to determine linear dimensions and density. For interobserver reliability, determination was repeated by a second reader in 10 patients selected at random. RESULTS The mean adrenal volume was 4.84 (±1.67) cm³ on the left side and 3.62 (±1.23) cm³ on the right side. The total adrenal volume was mainly influenced by body weight (P < .001) and gender with women having smaller glands on average. The total width of the adrenal gland was 15.80 (±3.05) mm on the right side and 18.96 (±3.37) mm on the left side. There was a significant correlation between volume and linear measurements (P < .001). The mean density of both adrenal glands was 32.66 (±19.64) HU. Overall, interobserver reliability was high for volumetry (left adrenal, r = 0.98; right adrenal, r = 0.90) and low for linear dimensions. CONCLUSIONS Normal data for volumetry and linear dimensions are provided. There is a concordance between volumetric and linear assessment. However, volumetry is more reproducible.