Melanoma and Immune Checkpoint Inhibitors

Furue, Masutaka; Ito, Takamichi; Wada, Naoko; Wada, Maiko; Kadono, Takafumi; Uchi, Hiroshi

doi:10.1007/s11912-018-0676-z

Cited by 57 publications

(51 citation statements)

References 65 publications

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“…Although the recent development of molecular targeted therapy and immunotherapy has opened a new era of melanoma treatment [24,25], it is still unclear if these therapies can be applied to acral melanoma, because the pathobiology and genetic heterogeneity of acral melanoma have not fully been elucidated due to the rarity of acral melanoma. To address these issues, we conducted a retrospective study on acral melanoma, finding several important issues.…”

Section: Discussionmentioning

confidence: 99%

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis

Ito

Kaku-Ito

Murata

et al. 2019

IJMS

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The current development of BRAF inhibitors has revolutionized the treatment of unresectable melanoma. As the potential heterogeneity of BRAF mutations in melanoma has been reported, accurate detection of BRAF mutations are important. However, the genetic heterogeneity of acral melanoma—a distinct type of melanoma with a unique genetic background—has not fully been investigated. We conducted a retrospective review of our acral melanoma patients. Of the 196 patients with acral melanoma, we retrieved 31 pairs of primary and matched metastatic melanomas. We immunostained the 31 pairs with VE1, a BRAFV600E-mutation-specific monoclonal antibody. Immunohistochemistry with VE1 showed a high degree of sensitivity and specificity for detecting BRAFV600E mutations compared with the real-time polymerase chain reaction method. A total of nine primary (29.0%) and eight metastatic (25.8%) acral melanomas were positive for VE1. In three patients (9.7%), we observed a discordance of VE1 staining between the primary and metastatic lesions. Of note, VE1 immunohistochemical staining revealed a remarkable degree of intra-tumor genetic heterogeneity in acral melanoma. Our study reveals that VE1 immunostaining is a useful ancillary method for detecting BRAFV600E mutations in acral melanoma and allows for a clear visualization of intra- and inter-tumor BRAF heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis

Ito

Kaku-Ito

Murata

et al. 2019

IJMS

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“…These aberrations all activate the mitogen-activated protein kinase (MAPK) pathway, leading to uncontrolled tumor proliferation [2]. Among these driver genes, BRAF is the most important in a clinical setting because BRAF/MEK inhibitors can be used for the treatment of BRAF-mutated melanoma [3,4]. The latest version of the National Comprehensive Cancer Network (NCCN) guidelines recommends BRAF inhibitors in combination with MEK inhibitors as a first-line treatment for unresectable melanoma with BRAF mutations [5].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Ito

Kaku-Ito

Murata

et al. 2020

JCM

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Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.

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“…Immune checkpoint blockade stimulates the immune system, reduces tumor burden, and has become an important therapy in immuno‐oncology . Nivolumab is a fully human immunoglobulin G4 monoclonal antibody directed against the programmed death 1 (PD‐1) receptor.…”

mentioning

confidence: 99%

“…Immune checkpoint blockade stimulates the immune system, reduces tumor burden, and has become an important therapy in immuno-oncology. 1,2 Nivolumab is a fully human immunoglobulin G4 monoclonal antibody directed against the programmed death 1 (PD-1) receptor. PD-1 is an inhibitory immune checkpoint receptor expressed primarily on T cells and is associated with reduced T-cell activity and exhaustion.…”

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confidence: 99%

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time‐Varying Clearance

Hamuro

Statkevich

Bello

et al. 2019

Clin Pharma and Therapeutics

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Nivolumab clearance (CL) in patients with advanced melanoma (MEL) decreases over the treatment duration, with change in CL associated with improved disease status, measured by reduced tumor burden. Here, we characterize the pharmacokinetics of nivolumab administered as adjuvant therapy for patients with MEL (AdjMEL) whose tumors were removed by surgical resection. A population pharmacokinetic model was developed using data from 1,773 patients with AdjMEL, MEL, non‐small cell lung cancer, and other solid tumors who received nivolumab over a dose range of 0.1–20 mg/kg every 2 weeks. In patients with AdjMEL, the geometric mean nivolumab CL of 6.0 mL/hour was 40% lower at baseline and did not vary with time and 20% lower at steady state compared with patients with MEL. Lower nivolumab CL in patients with AdjMEL and absence of time dependence support the hypothesis that changes in nivolumab CL in the metastatic setting are associated with disease status after treatment.

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Melanoma and Immune Checkpoint Inhibitors

Cited by 57 publications

References 65 publications

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time‐Varying Clearance

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