Paul Nghiem

Bio: Paul Nghiem is an academic researcher from University of Washington Medical Center. The author has contributed to research in topics: Merkel cell carcinoma & Merkel cell polyomavirus. The author has an hindex of 37, co-authored 55 publications receiving 8999 citations. Previous affiliations of Paul Nghiem include Seattle Cancer Care Alliance & Medical University of Graz.

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

Abstract: BackgroundMerkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. MethodsIn this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti–PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. ResultsA total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patient...

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

Abstract: Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Funding Merck KGaA, Darmstadt, Germany.

Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features

Abstract: Background Merkel cell carcinoma (MCC) is an aggressive skin cancer with a mortality of 33%. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. No systematic analysis has been published to define the clinical features that are characteristic of MCC. Objective We sought to define the clinical characteristics present at diagnosis to identify features that may aid clinicians in recognizing MCC. Methods We conducted a cohort study of 195 patients given the diagnosis of MCC between 1980 and 2007. Data were collected prospectively in the majority of cases, and medical records were reviewed. Results An important finding was that 88% of MCCs were asymptomatic (nontender) despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). A majority of MCC lesions (56%) were presumed at biopsy to be benign, with a cyst/acneiform lesion being the single most common diagnosis (32%) given. The median delay from lesion appearance to biopsy was 3 months (range 1-54 months), and median tumor diameter was 1.8 cm. Similar to earlier studies, 81% of primary MCCs occurred on ultraviolet-exposed sites, and our cohort was elderly (90% >50 years), predominantly white (98%), and often profoundly immune suppressed (7.8%). An additional novel finding was that chronic lymphocytic leukemia was more than 30-fold overrepresented among patients with MCC. Limitations The study was limited to patients seen at a tertiary care center. Complete clinical data could not be obtained on all patients. This study could not assess the specificity of the clinical characteristics of MCC. Conclusions To our knowledge, this study is the first to define clinical features that may serve as clues in the diagnosis of MCC. The most significant features can be summarized in an acronym: AEIOU ( a symptomatic/lack of tenderness, e xpanding rapidly, i mmune suppression, o lder than 50 years, and u ltraviolet-exposed site on a person with fair skin). In our series, 89% of primary MCCs had 3 or more of these findings. Although MCC is uncommon, when present in combination, these features may indicate a concerning process that would warrant biopsy. In particular, a lesion that is red and expanding rapidly yet asymptomatic should be of concern.

Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5823 cases as the basis of the first consensus staging system

Abstract: Background The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems. Objective We sought to determine the prognostic significance of tumor size, clinical versus pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC. Methods A total of 5823 prospectively enrolled MCC cases from the National Cancer Data Base had follow-up data (median 64 months) and were used for prognostic analyses. Results At 5 years, overall survival was 40% and relative survival (compared with age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal, and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I, ≤2 cm, 66% relative survival at 5 years; stage II, >2 cm, 51%; P Limitations The National Cancer Data Base does not capture disease-specific survival. Overall survival for patients with MCC was therefore used to calculate relative survival based on matched population data. Conclusion Although the majority (68%) of patients with MCC in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.

The immune contexture in human tumours: impact on clinical outcome

Abstract: Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.

Cancer immunotherapy using checkpoint blockade

Abstract: The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.

Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints

Abstract: DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.

Clonal integration of a polyomavirus in human Merkel cell carcinoma.

Abstract: Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin. We studied MCC samples by digital transcriptome subtraction and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to identification and sequence analysis of the 5387-base-pair genome of a previously unknown polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

Abstract: During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.