Cutaneous Squamous Cell Carcinoma Waldman, Abigail; Schmults, Chrysalyne
Hematology/oncology clinics of North America,
02/2019, Volume:
33, Issue:
1
Journal Article
Peer reviewed
Cutaneous squamous cell carcinoma represents 20% of all skin cancers, resulting in 1 million cases in the United States each year. The lifetime risk of developing squamous cell carcinoma continues to ...increase annually and will likely continue to increase because of the aging population. Most cutaneous squamous cell carcinoma are treated locally, with a subset leading to recurrence, metastasis, and death. This review of cutaneous squamous cell carcinoma covers incidence, recurrence rates, mortality rates, risk factors, staging systems, treatment, prevention, and monitoring.
The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic ...melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options.
In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397.
Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 49%), arthralgia (1259 39%), fatigue (1093 34%), photosensitivity reaction (994 31%), alopecia (826 26%), and nausea (628 19%). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 12%), rash (155 5%), liver function abnormalities (165 5%), arthralgia (106 3%), and fatigue (93 3%). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 59%, 95% CI 53-65 and ten 4%, 2-7, respectively) than in those younger than 75 years (n=2965; 1286 43%, 42-45 and 82 3%, 2-3, respectively).
Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug.
F Hoffmann-La Roche.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL ...remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches.
Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology-Human T-Lymphotropic Virus and Related Retroviruses-in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents.
As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement).
This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL.
Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. Z-DNA binding protein 1 (ZBP1) activates inflammatory cell death, PANoptosis, ...whereas adenosine deaminase acting on RNA 1 (ADAR1) serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining interferons (IFNs) and nuclear export inhibitors (NEIs) activates ZBP1-dependent PANoptosis. ADAR1 suppresses this PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wild-type mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1-dependent manner. Our findings suggest that ADAR1 suppresses ZBP1-mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to informing therapeutic strategies for cancer and other diseases.
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•Combining IFNs with NEIs induces ZBP1-mediated inflammatory cell death, PANoptosis•ADAR1 negatively regulates the ZBP1-mediated PANoptosis•Blocking ADAR1 activity unleashes ZBP1-mediated PANoptosis to inhibit tumorigenesis•In mice, IFN-γ + KPT-330 dramatically regresses tumors in a ZBP1-dependent manner
Karki et al. identify a critical role for ADAR1 in regulating ZBP1-mediated inflammatory cell death, PANoptosis. Treating with IFNs, which upregulate ADAR1 and ZBP1, and nuclear export inhibitors, which sequester ADAR1 in the nucleus, induces robust cell death that inhibits tumorigenesis in vivo, suggesting a therapeutic strategy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour ...activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. Methods BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov , number NCT01327053. Findings Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 32% of 79 patients vs 90 60% of 150) or treatment discontinuation (17 22% vs 54 36%) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five 6% in the 200 mg group vs 19 13% in the 800 mg group) and lipase concentration (four 5% vs eight 5%). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. Interpretation The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Funding Novartis Pharmaceuticals Corporation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of ...melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials.
To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status.
A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations.
Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status.
The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype WT). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios 95% CIs), NRAS+ melanoma was associated with presence of mitoses (1.8 1.0-3.3), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 0.3-0.8; and brisk, 0.3 0.5-0.7 vs absent TILs), and anatomic site other than scalp/neck (0.1 0.01-0.6 for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 0.5-1.0; and ages >70 years, 0.5 0.3-0.8 vs <50 years), superficial spreading subtype (nodular, 0.5 0.2-1.0; lentigo maligna, 0.4 0.2-0.7; and unclassified/other, 0.2 0.1-0.5 vs superficial spreading), and presence of mitoses (1.7 1.1-2.6) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios 95% CIs) for melanoma harboring mutations in NRAS (1.7 0.8-3.4) or BRAF (1.5 0.8-2.9) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 1.1-7.7) or BRAF (3.1 1.2-8.5) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 0.3-3.0) or BRAF (0.6 0.2-1.7) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center.
Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher–AJCC stage primary melanomas.
Update on Keratinocyte Carcinomas Nehal, Kishwer S; Bichakjian, Christopher K
The New England journal of medicine,
07/2018, Volume:
379, Issue:
4
Journal Article
Peer reviewed
Squamous-cell and basal-cell carcinomas of the skin are increasing in frequency. Basal-cell carcinomas are responsive to inhibition of the hedgehog pathway; squamous-cell cancers may be responsive to ...immune checkpoint inhibitors.
Skin cancer, the most common human malignancy, is primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy and ...histopathological examination. Automated classification of skin lesions using images is a challenging task owing to the fine-grained variability in the appearance of skin lesions. Deep convolutional neural networks (CNNs) show potential for general and highly variable tasks across many fine-grained object categories. Here we demonstrate classification of skin lesions using a single CNN, trained end-to-end from images directly, using only pixels and disease labels as inputs. We train a CNN using a dataset of 129,450 clinical images-two orders of magnitude larger than previous datasets-consisting of 2,032 different diseases. We test its performance against 21 board-certified dermatologists on biopsy-proven clinical images with two critical binary classification use cases: keratinocyte carcinomas versus benign seborrheic keratoses; and malignant melanomas versus benign nevi. The first case represents the identification of the most common cancers, the second represents the identification of the deadliest skin cancer. The CNN achieves performance on par with all tested experts across both tasks, demonstrating an artificial intelligence capable of classifying skin cancer with a level of competence comparable to dermatologists. Outfitted with deep neural networks, mobile devices can potentially extend the reach of dermatologists outside of the clinic. It is projected that 6.3 billion smartphone subscriptions will exist by the year 2021 (ref. 13) and can therefore potentially provide low-cost universal access to vital diagnostic care.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
To identify factors associated with survival in Merkel cell carcinoma (MCC).
Merkel cell carcinoma is a rare cutaneous neoplasm. Staging and treatment are based on studies, which incompletely ...characterize the disease.
Review of a prospective database was performed. Overall survival (OS) was estimated by the Kaplan-Meier method. Disease-specific death (DSD) was analyzed by the competing risks method. Factors associated with OS and DSD were determined by the log-rank test and Gray's test, respectively.
A total of 500 patients with MCC treated at our institution from 1969 to 2010 were identified. Eighty-eight patients presented older than 6 months after diagnosis and were excluded from further analysis. Of the remaining 412 patients, the median age at diagnosis was 71 years. Median follow-up was 3 years. Fifty percent of patients died during follow-up: 25% died of disease, 24% died of other causes. Five-year OS and DSD were 56% and 30%, respectively. Pathologic stage and lymphovascular invasion were independent predictors of DSD. Patients with metastatic disease (stage 4) or clinically positive lymph nodes (stage 3b) had increased DSD compared with patients with microscopically positive (stage 3a) or negative lymph nodes (stage 1 and 2). There was no difference in DSD between stage 3a or 2 compared with stage 1. Importantly, only 1 of 132 patients without lymphovascular invasion died of MCC.
OS is a poor measure of the influence of MCC on life expectancy. The presence of lymphovascular invasion and clinically, but not microscopically, positive lymph nodes were associated with increased DSD. These factors should be incorporated into MCC staging and treatment recommendations.
With a 5-year minimum follow-up in patients with metastatic melanoma, overall survival at 5 years was 52% with a combination of nivolumab plus ipilimumab, as compared with 44% with nivolumab alone ...and 26% with ipilimumab alone. Programmed cell death ligand 1 expression did not influence the response rate or progression-free survival.
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