Management Of Merkel Cell Carcinoma Research Articles

The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis.

Simple SummaryMerkel cell carcinoma is a deadly skin cancer with few treatment options. When the tumor has spread, less than 18% of patients survive past five years, and the mortality rate is 3-times higher than melanoma. Cancer immunotherapy is a promising field, harnessing the patient’s immune system to fight cancer and offering hope to many patients. However, ineligibility or resistance to immunotherapy is a critical challenge; half of all MCC patients are ineligible, and many treated patients either stop responding after an initial positive response or don’t respond at all. In this study, we tested a promising drug based on genomic information from MCC patient tumors. We found that it was highly effective in killing MCC cells and MCC tumors grown in mice; we also observed that MCC genetic characteristics partly predicted how well the drug worked. These results provide strong evidence for its potential clinical application in MCC patients.Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

The role of 18F-FDG PET/CT in the management of Merkel cell carcinoma: The experience of 51 studies in our institution

ObjectivesMerkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor with limited evidence on the role of 18F-FDG PET/CT. The aim of this study was to assess the impact of the 18F-FDG PET/CT in the management of MCC. MethodsFifty-one studies of 18F-FDG PET/CT of 35 patients (19 men [54.30%]; 72.17±14.63 years) with histologic diagnosis of MCC were retrospectively evaluated. The change in tumor staging and the impact on the treatment were analysed. ResultsThere were 23 PET/CT positive studies (45.10%) and 28 (54.90%) negative. Thirty four (66.7%) studies were performed for assessment of stage at initial presentation and 17 (33.3%) were performed during the follow up: 6 (35.29%) for suspected recurrence; 7 (41.18%) for restaging; 4 (23.53%) as a part of ongoing surveillance. On the basis of PET/CT results, there was a change in disease stage (SC) in 20 studies (39.20%) and impact in the management (MI) in 28 (54.90%): 11 (32.40%) SC and 12 (35.30%) MI in the initial staging; 5 (71.43%) SC and 7 (100%) MI in the restaging; 3 (50%) SC and 6 (100%) MI in suspected recurrence; 1 (25%) SC and 3 (75%) MI in the surveillance. 18F-FDG PET/CT incidentally detected one additional histologically confirmed cancer. The presence of nodal involvement in the beginning (0.0098; HR 3.82; 95% CI: 1.38–10.6), chemotherapy treatment (6e−04; HR 7.06; 95% CI: 2.30–21.60), size of primary tumor >2cm (6e−04; HR 7.06; 95% CI: 2.30–21.60) and positive resection margin (0.00069; HR 4.01; 95% CI: 1.46–11.00) were statistically significant prognostic factors for overall survival. There was a trend towards significance for worse overall survival with initial positive 18F-FDG PET/CT but the trend did not reach statistical significance. Conclusion18F-FDG PET/CT altered the stage in 2 out of 5 studies and changed the treatment in more than half of the studies performed. The study confirms the important impact of 18F-FDG PET/CT on the management of MCC patients.

How we treat Merkel cell carcinoma: within and beyond current guidelines.

Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.

The changing paradigm of managing Merkel cell carcinoma in Australia: An expert commentary.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin with an estimated disease‐associated mortality of 15–33%. Australia has a higher incidence of MCC compared to the rest of the world, thought to be due to a higher ultraviolet index. The Australian MCC population is distinct from the MCC population of the Northern hemisphere, characterized by a predominantly viral negative etiology with high tumor mutational burden. The optimal management of MCC and the choice of treatment modality vary significantly across the world and even between institutions within Australia. Historically, the treatment for MCC has been resection followed by radiotherapy (RT), though definitive RT is an alternative treatment used commonly in Australia. The arrival of immune checkpoint inhibitors and the mounting evidence that MCC is a highly immunogenic disease is transforming the treatment landscape for MCC. Australia is playing a key role in the further development of treatment options for MCC with two upcoming Australian/New Zealand investigator‐initiated clinical trials that will explore the interplay of RT and immunotherapy in the treatment of early and late stage MCC.

Current concepts and approaches to merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive and rare cutaneous cancer of the mechanoreceptor unit of the skin with a neuroendocrine origin. MCC incidence has been on the rise over the past two decades. Risk factors include old age, chronic UV exposure, and immunosuppression. Although MCC is a cutaneous malignancy that is often misdiagnosed as a benign nodule at the time of diagnosis, it has an aggressive disease course due to its high recurrence and metastatic potential. The PD-1/PD-L1 checkpoint blockade has recently shown promising results in the management of advanced MCC. Avelumab and pembrolizumab are considered the new standard of care for metastatic MCC. Despite advances in the field, studies are needed to elucidate the role of immunotherapy for patients who are resistant to treatment. Most ongoing clinical trials aim to assess the efficacy of checkpoint inhibitor combination therapies. This article reviews the most current literature on the surgical and medical management of MCC.

A Therapeutic and Diagnostic Multidisciplinary Pathway for Merkel Cell Carcinoma Patients.

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin. Due to its rarity, the management of MCC is not standardized across centers. In this article, we present the experience of the Veneto region in the North-East of Italy, where a committee of skin cancer experts has proposed a clinical pathway for the diagnosis and treatment of MCC. Putting together the evidence available in the international literature, we outlined the best approach to the management of patients affected with this malignancy step- by- step for each possible clinical situation. Crucial in this pathway is the role of the multidisciplinary team to deal with the lack of robust information on each aspect of the management of this disease.

Recent advances in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that has been historically associated with limited treatment options and poor prognosis. In the past 10 years, research in MCC has progressed significantly, demonstrating improved outcomes when treating with immunotherapy, particularly PD-1/PD-L1 inhibitors, when compared with conventional chemotherapy. There is also increasing evidence of the abscopal effect, a phenomenon describing the regression of untreated, distant MCC tumors following local radiation therapy. Additionally, antibodies to Merkel cell polyomavirus oncoproteins have been found to correlate with disease burden in a subset of patients, providing a useful tool for surveillance after treatment. Guidelines for the management of MCC will likely continue to change as research on surveillance and treatment of MCC continues.

Immune checkpoint inhibition in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is arare but aggressive form of skin cancer in which Merkel cell polyomavirus infection and chronic exposure to ultraviolet radiation are key risk factors. Immune checkpoint inhibition has revolutionized the treatment of locally advanced, inoperable and metastatic MCC. To outline the modern management of MCC based on advances in our understanding of MCC tumour biology and the development of immune checkpoint inhibitors, namely inhibitors of programmed cell death protein (PD)-1- and PD‑1 ligand1 (PD-L1). Areview of the scientific literature listed in PubMed. First line therapy with the PD-L1 blocking antibody avelumab is associated with aresponse rate of 62%. In the second line setting, for example after chemotherapy, the response rate only reaches 33%. However, in patients who responded in the second line setting, 69% remained relapse free after 2years. Treatment responses occurred on average after 6.1weeks of therapy. First line treatment with pembrolizumab (anti-PD‑1 antibody) is associated with a2-year survival rate of 69% and the median survival rate has not been reached. Whilst the various chemotherapy regimens are associated with similar response rates, these are typically short lived. Checkpoint inhibition offers an effective treatment option for patients with MCC. Avelumab is currently licensed as atreatment for metastatic disease. Chemotherapy remains an option to reduce tumor load, or in the context of resistance and/or contraindications to immune checkpoint therapy. Adjuvant and neoadjuvant use of checkpoint inhibition in MCC may represent afuture treatment strategy pending the results of on-going clinical trials.

Recent updates in the management of Merkel Cell Carcinoma

Merkel cell carcinoma is an aggressive non-melanomatous cutaneous tumour of neuroendocrine origin with an increasing incidence in the recent years. It is a tumour of the elderly and immunosuppressed, which most often appears on sun-exposed areas of the body. The clinical features of the cutaneous or subcutaneous lesions hardly contribute to the diagnosis, and, hence, histopathology and immunohistochemistry play a vital role in diagnosis. The latest staging system by the American Joint Committee on Cancer includes non-nodal invasion to adjacent structures i.e. bone, muscle, fascia, or cartilage into the criteria, in additionto size and depth of invasion. The management reliesheavily on a multidisciplinary approach due to rarity of incidence of this disease. According to the international guidelines, surgical management is still the preferred choice. The beneficial role of adjuvant radiotherapy has now been more clearly documented. Data is insufficient to assess whether chemotherapy improves disease-free or overall survival.

Merkel Cell Carcinoma: Updates on Pathogenesis, Diagnosis, and Management

To describe updates on the pathogenesis, diagnosis, and management of Merkel cell carcinoma (MCC). Sequencing studies revealed that MCCs have either a low mutational burden and integrated Merkel cell polyomavirus (MCPyV), or they have a high number of ultraviolet-associated somatic mutations and no MCPyV. Clinically, prognosis was better for stage III MCC of unknown primary than known primary. Similarly, lack of immunosuppression conferred better prognosis. The immunogenicity of MCC was reflected in high response rates to PD-1/PD-L1 checkpoint inhibitors. MCC is a rare but aggressive neuroendocrine skin cancer associated with advanced age and immunosuppression. Approximately 80% of MCCs are MCPyV driven, whereas MCPyV-negative tumors have mutations in genes such as p53 and RB1. MCC is highly immunogenic, and recently, the anti-PD-L1 antibody avelumab was approved to treat metastatic MCC. Here, we summarized features of the pathogenesis, diagnosis, and management of MCC.

Abstract 2518: Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel cell carcinoma

Abstract Folate hydrolase-1 (FOLH1) is a type II transmembrane protein. Oncologically, FOLH1 is upregulated throughout prostate cancer cells; it is also luminally expressed by the neovasculature of most solid tumors but not by normal vessels. J591, a monoclonal antibody (AB), is specific to, and is effectively endocytosed after extracellular binding to, FOLH1. J591 is presently being developed in clinical trials as a vehicle for AB-based brachytherapy in FOLH1+ cancers. Merkel cell carcinoma (MCC) is a rare, neuroendocrine tumor; metastatic (m) MCC is associated with poor survival. We characterized FOLH1 expression in MCC to determine its target potential for J591-brachytherapy. Paraffin sections from primary (p) and mMCC were deparaffinized and rehydrated. Samples were stained with 3E6 (DAKO), a mouse IgG1 monoclonal anti-human FOLH1. Mouse IgG1 (10 ug/mL in 1% bovine serum albumin) was used as an isotype-matched negative control. Anti-CD31 (IgG1) was used as a positive control. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. 81 MCC tumors were evaluated. 67% (54/81) of all cases with 77% (24/31) of pMCC and 60% (30/50) of mMCC tumors demonstrated FOLH1+ neovessels. No cellular staining of tumor cells was identified. 34 patients with FOLH1 +/- MCC were demographically homogeneous in terms of sex, age, immunosuppression status, prior therapies, stage at diagnosis, and local or distant recurrences. No significant differences were detected based on FOLH1 status, in regards to MCC specific survival (P=0.905), or overall survival (P=0.687), as measured from time of diagnosis. FOLH1 is expressed in the majority of pMCC and mMCC cases and is nonprognostic. Our findings support further investigation of targeted therapy with J591-brachytherapy for the management of MCC. Citation Format: Barbara Meier, Marigdalia K. Ramirez-Fort, Kristina Lachance, Candice D. Church, Sean S. Mahase, Joseph M. Jenrette, Christopher S. Lange, Lars E. French, Paul Nghiem, Neil H. Bander. Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2518.

Radiotherapy in the Multidisciplinary Management of Merkel Cell Carcinoma.

The management of Merkel cell carcinoma (MCC) requires multidisciplinary care for optimal patient outcomes. Radiotherapy (RT) is most commonly used as adjuvant therapy to improve locoregional control in patients with MCC who undergo surgery. Additionally, it can sometimes be used as definitive monotherapy for patients who decline or are not candidates for surgery and as palliative treatment in those with metastatic MCC. This article discusses the indications, treatment considerations, and recommended dose prescriptions for RT in the management of early- and advanced-stage disease. Considerable hope exists that immunotherapy advances will synergize with RT to further enhance clinical outcomes.

Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

Management of an Unknown Primary Merkel Cell Carcinoma: A Case Report

Merkel cell carcinoma (MCC) represents a rare skin cancer associated with sun exposure. It is an uncommon skin neoplasm of the elderly population. The majority of patients with MCC present with localized disease at diagnosis and few patients have regional lymph node (LN) involvement and distant metastases. Although it has been previously reported in various anatomical sites, LN metastatic MCC in the absence of a primary site is extremely rare and for this reason there is no standard approach to its management. Currently, there is no standard approach to the management of MCC in the absence of a primary site. Since the disease is highly aggressive and the failure rate following surgery alone is high, radiotherapy (RT) is usually administered as temporary support for numerous patients with MCC. J Med Cases. 2018;9(3):103-105 doi: https://doi.org/10.14740/jmc3004w

Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: A Trans Tasman Radiation Oncology Group Study, TROG 09:03.

TROG 09.03 prospectively studied the utility of Fluorine-18 Fluorodeoxyglucose (18-FDG) PET in the management of Merkel cell carcinoma of skin. Following consent and registration, a pre-treatment FDG-PET/CT was performed. Sites of avid disease were confirmed by cytology where practicable. Following surgery, patients with AJCCv7 Stages IIA-IIIB disease were treated with chemo-radiotherapy and reassessed with a post-treatment PET. Fifty-eight subjects (45 males and 13 females, median age 68years) were enrolled between 2011 and 2015, 43 patients of whom went on to receive chemo-radiotherapy. An occult primary was present in 22 (37.9%), T1 in 22 (37.9%) and T2 disease in 14 (24.1%). Nodal disease was present in 69% of cases. Fifty per cent of subjects had gross residual disease at the primary site and/or nodal site at the time of registration. 18-FDG PET/CT had a sensitivity of 94.74% (95% CI 82-99.3%) and a specificity of 88.24% (95% CI 63.56-98.54). The positive predictive value was 94.74% (83.01-98.51) and the negative predictive value was 88.24% (95% CI 65.81-96.69). The pre-treatment PET influenced a treatment decision in 27.6% of cases. Upstaging occurred in 15 (25.9%), with no down staging. Other diseases were identified in 4 (6.9%) patients. Univariate analysis failed to demonstrate that pre-treatment SUV levels or a negative post-treatment PET had any impact on overall survival. PET staged patients had 89% 3-year in-field loco-regional control and 76% 3-year overall survival. Staging 18-FDG-PET significantly influenced treatment decisions in approximately one-third of cases of MCC and should be considered in the routine pre-treatment work-up. Post-treatment PET was not found to be prognostic. Funding through the Medicare Benefits Schedule needs to be considered for high risk MCC.

Cytological, histopathological and immunohistochemical features of merkel cell carcinoma- A case report

Merkel cell carcinoma (MCC) is a rare, potentially aggressive primary cutaneous neuroendocrine carcinoma. MCC commonly occurs on sun-exposed skin in fair-skinned elderly individuals. It usually presents as a banal-appearing lesion, and the diagnosis is rarely suspected at the time of biopsy. We describe the cytomorphologic, histopathological, and immunohistochemical characteristics of MCC in a 76-year-old male patient presenting with rapidly evolving large red raised lesion over cheek for 1 month. Cytohistopathological evaluation suggested MCC. Immunohistochemistry revealed that the tumor cells were negative for leukocyte common antigen, S-100 protein, HMB45, and cytokeratin 20 and positive for neuron specific enolase. Because of the documented aggressiveness and rising incidence, early diagnosis of this rare tumor is necessary for the management of MCC.

Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare and highly aggressive carcinoma of the skin with a high recurrence rate and propensity for metastasis. It was first described in 1972 and subsequently reclassified as a neuroendocrine tumor. Merkel cells are now thought to arise from the epidermal stem cells, not neural crest progenitor cells, as originally thought, and are the only cutaneous cells that form electron-dense neurosecretory granules. Although rare, the incidence of MCC is rapidly increasing. MCC is more often than not associated with Merkel cell polyomavirus, which may be involved in the malignant transformation and pathogenesis of MCC. Mortality exceeds that of the more commonly occurring skin cancer melanoma, with an overall 5-year survival rate ranging from 30 to 64%. Large reviews have documented recurrence rates ranging from 25 to 50% for local recurrence, 52 to 59% for regional recurrence, and 34 to 36% for distant metastases. Early-stage disease can sometimes be cured with surgery and radiation. Due to the rarity of MCC, statistically significant prospective data are lacking to validate prognostic features and treatment. Therefore, recommendations are largely based on small studies, meta-analyses, and expert consensus. Moreover, no consistent molecular activator in MCC has been identified, resulting in large variability in targeted therapies used in its treatment. New therapies to treat advanced MCC, including immunotherapy, hold promise for improved outcomes in the future. This review summarizes current knowledge regarding the etiology, prognosis, and management of MCC. This review contains 6 figures, 4 tables and 52 references Key words: Merkel cell carcinoma, Merkel cell polyomavirus, Merkel cell tactile receptor

Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare and highly aggressive carcinoma of the skin with a high recurrence rate and propensity for metastasis. It was first described in 1972 and subsequently reclassified as a neuroendocrine tumor. Merkel cells are now thought to arise from the epidermal stem cells, not neural crest progenitor cells, as originally thought, and are the only cutaneous cells that form electron-dense neurosecretory granules. Although rare, the incidence of MCC is rapidly increasing. MCC is more often than not associated with Merkel cell polyomavirus, which may be involved in the malignant transformation and pathogenesis of MCC. Mortality exceeds that of the more commonly occurring skin cancer melanoma, with an overall 5-year survival rate ranging from 30 to 64%. Large reviews have documented recurrence rates ranging from 25 to 50% for local recurrence, 52 to 59% for regional recurrence, and 34 to 36% for distant metastases. Early-stage disease can sometimes be cured with surgery and radiation. Due to the rarity of MCC, statistically significant prospective data are lacking to validate prognostic features and treatment. Therefore, recommendations are largely based on small studies, meta-analyses, and expert consensus. Moreover, no consistent molecular activator in MCC has been identified, resulting in large variability in targeted therapies used in its treatment. New therapies to treat advanced MCC, including immunotherapy, hold promise for improved outcomes in the future. This review summarizes current knowledge regarding the etiology, prognosis, and management of MCC. This review contains 6 figures, 4 tables and 52 references Key words: Merkel cell carcinoma, Merkel cell polyomavirus, Merkel cell tactile receptor

Burden of Healthcare Costs for Merkel Cell Carcinoma Management in Spain

Burden of Healthcare Costs for Merkel Cell Carcinoma Management in Spain