Suzanne McGettigan

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

BACKGROUND Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy. OBJECTIVE We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib. METHODS We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients. RESULTS Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort. LIMITATIONS This study was limited by the small number of cases, all from a single institution. CONCLUSION Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.

IL8 and Cathepsin B as Melanoma Serum Biomarkers

Melanoma accounts for only a small portion of skin cancer but it is associated with high mortality. Melanoma serum biomarkers that may aid early diagnosis or guide therapy are needed clinically. However, studies of serum biomarkers have often been hampered by the serum interference that causes false readouts in immunological tests. Here we show that, after using a special buffer to eliminate the serum interference, IL-8 and cathepsin B levels were significantly elevated in melanoma patients (p < 0.05). More importantly, the combination of IL-8 and cathepsin B were also studied as a prognosis marker for melanoma mortality. Our study provides a novel approach to examine serum biomarkers.

Ipilimumab-associated Sweet syndrome in a melanoma patient

the buttocks, axillae, and groins and evolved in crops. Besides these nodules, physical examination revealed bridged scars, but no interconnecting tracts. Histologic examination of a skin biopsy and cultures ruled out Crohn disease and an opportunistic infection, respectively. The diagnosis was HS grade II according to the Hurley classification. A 6-month course of oxacillin (2 g/day), followed by a combination of rifampicin (600 mg/day) with clindamycin (600 mg/day) for 9 months were ineffective (Fig 1). In February 2012, Cs was replaced with tacrolimus (2 mg/day) based on the hypothesis of a deleterious effect of Cs on pilosebaceous apparatus and of a potential efficacy of tacrolimus as suggested in another report. In November 2012, all inflammatory lesions had disappeared (Fig 2). To our knowledge, this patient is the first case of HS appearing in the setting of organ transplantation. Although a fortuitous association cannot be excluded, considering the patient’s age, the clinical scenario speaks in favor of an iatrogenic origin of HS. Indeed, rare cases of iatrogenic HS have been reported. Even if several Cs-responsive cases of HS exist, Cs is known to induce hyperplasia of the pilosebaceous apparatus. Isotretinoin may also have played an aggravating role. This patient is similar to one suffering from HS for more than 20 years, in whom treatment with Cs had been ineffective. He was cured at the age of 40 years, a few months after kidney transplantation, while receiving tacrolimus and mycophenolate mofetil as immunosuppressive treatment. We recently observed another case of HS that appeared within 2 years after transplantation, for which we suggested a switch from Cs to tacrolimus. Although tacrolimus and Cs exert very similar immunosuppressive effects, the former proved more effective than the latter against HS in these cases. This may be due to the fact that tacrolimus exerts fewer effects on the pilosebaceous apparatus. This observation suggests that patients in whom HS develops while on Cs should be switched to tacrolimus.

Acute visual loss after ipilimumab treatment for metastatic melanoma

BackgroundIpilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs).Case presentationHere we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs.ConclusionsThis case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.

What you are missing could matter: a rare, complex BRAF mutation affecting codons 599, 600, and 601 uncovered by next generation sequencing

Testing for somatic mutations in tumor samples is becoming standard practice in a number of tumor types where targeted therapies are available. Since clinical care is dependent on the identification of the presence or absence of specific mutations, it is important that these mutations be identified consistently and accurately. Here we identify in a patient with metastatic melanoma a novel, complex mutation involving BRAF c.1798A>T (p.T599T), c.1799T>A (p.V600E), and c.1803A>T (p.K601N) that was identified by next generation sequencing but not by standard testing methods. The patient was started on a combination therapy inhibiting both BRAF and MEK, and demonstrated a dramatic clinical response. This case highlights the need for improved methods of mutation testing in tumor samples and exposes a pitfall in allele-specific testing methods that can be overcome using next generation sequencing.

Improving the Safety of Oral Chemotherapy at an Academic Medical Center

PURPOSE Over the last decade, the use of oral chemotherapy (OC) for the treatment of cancer has dramatically increased. Despite their route of administration, OCs pose many of the same risks as intravenous agents. In this quality improvement project, we sought to examine our current process for the prescription of OC at the Abramson Cancer Center of the University of Pennsylvania and to improve on its safety. METHODS A multidisciplinary team that included oncologists, advanced-practice providers, and pharmacists was formed to analyze the current state of our OC practice. Using Lean Six Sigma quality improvement tools, we identified a lack of pharmacist review of the OC prescription as an area for improvement. To address these deficiencies, we used our electronic medical system to route OC orders placed by treating providers to an oncology-specific outpatient pharmacist at the Abramson Cancer Center for review. RESULTS Over 7 months, 63 orders for OC were placed for 45 individual patients. Of the 63 orders, all were reviewed by pharmacists, and, as a result, 22 interventions were made (35%). Types of interventions included dosage adjustment (one of 22), identification of an interacting drug (nine of 22), and recommendations for additional drug monitoring (12 of 22). CONCLUSION OC poses many of the same risks as intravenous chemotherapy and should be prescribed and reviewed with the same oversight. At our institution, involvement of an oncology-trained pharmacist in the review of OC led to meaningful interventions in one third of the orders.

Side effects in melanoma patients receiving adjuvant interferon alfa-2b therapy: a nurse's perspective

PurposeThe aim of this review was to examine the toxicity profile of adjuvant interferon (IFN) alfa-2b in melanoma patients from a nursing perspective and to summarize practical information to guide the effective management of common IFN toxicities to improve patient comfort.MethodsThis is a narrative summary of both research and review articles identified by searching PubMed, National Cancer Institute, and American Cancer Society websites. It also assesses recognized guidelines on the management of adjuvant IFN toxicity relevant to nurses who are caring for patients receiving adjuvant IFN therapy.ResultsAdjuvant high-dose IFN alfa-2b (HDI) as compared with observation significantly prolongs relapse-free survival in patients with melanoma at high risk for recurrence after surgical resection; however, treatment compliance and patient quality of life can be compromised by its toxicity profile. HDI toxicities affect a number of organ systems and the majority of patients will experience some side effects. Common toxicities such as flu-like symptoms, fatigue, anorexia, neuropsychiatric symptoms, and laboratory abnormalities are discussed, along with both pharmacological and nonpharmacological management strategies.ConclusionsThe considerable side effects of HDI can be managed using established strategies. Oncology nurses play a significant role in the management of patients with melanoma receiving adjuvant HDI, and their prompt recognition of side effects, together with an understanding of effective pharmacological and nonpharmacological interventions, will improve patient comfort; this has the potential to positively influence treatment adherence and completion of the recommended treatment course.

Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse event associated with anti-PD-1 therapy

PD‐1 (programmed cell death‐1) inhibitors, used to treat metastatic melanoma and other malignancies, are associated with development of immune‐related adverse events in the skin. Such reactions include morbilliform eruptions, vitiligo, alopecia areata and bullous pemphigoid. In this report, we describe a patient who developed a lupus‐like cutaneous reaction in the setting of pembrolizumab therapy for metastatic melanoma, adding to the spectrum of reactions which may be observed in association with PD‐1 inhibitor therapy.

Timing of Onset of Adverse Cutaneous Reactions Associated With Programmed Cell Death Protein 1 Inhibitor Therapy

Importance An increasing number of cutaneous adverse reactions resulting from use of programmed cell death protein 1 (PD-1) inhibitors have been described, but with relatively little focus to date on the timing of these reactions. Objective To determine the timing of cutaneous drug reactions after initiation of PD-1 inhibitor therapy. Design, Setting, and Participants This retrospective observational study included patients referred to an academic dermatology clinic by an oncologist from January 1, 2014, through February 28, 2018, with at least 1 skin biopsy specimen of a skin reaction associated with PD-1 inhibitor use. Participants were included if they had a biopsy-proven cutaneous reaction in response to a PD-1 inhibitor used alone or in combination with ipilimumab. Exposures All patients included in this study received pembrolizumab, nivolumab, or nivolumab with ipilimumab as immunotherapy for cancer. Main Outcomes and Measures The main outcome measure was time to onset of biopsy-proven cutaneous reactions that occurred during or after use of pembrolizumab or nivolumab. Results A total of 17 patients (12 men, 5 women; mean [SD] age, 68.6 [11.1] years) were identified who presented with cutaneous adverse reactions associated with PD-1 inhibitor therapy; these reactions included lichenoid dermatitis, bullous pemphigoid, erythema multiforme, eczema, lupus, and sarcoidosis. Twelve patients presented with reactions at least 3 months after beginning pembrolizumab or nivolumab therapy. The skin reactions presented a median (range) of 4.2 months (0.5-38.0 months) after drug initiation. In 5 cases, the cutaneous adverse reactions attributed to the PD-1 inhibitor therapy developed after the drug therapy was terminated. Conclusions and Relevance Diverse cutaneous adverse reactions secondary to PD-1 inhibitor use may present with delayed onsets and even after discontinuation of therapy. Dermatologists should be aware of the potential for delayed presentations of cutaneous adverse reactions.