Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands.

In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grades 3-4 adverse events. Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma. Patients with advanced melanoma who received first-line ipilimumab plus nivolumab between January 1, 2015 and June 30, 2021 were selected from the Dutch Melanoma Treatment Registry.

Long-term survival of patients with advanced melanoma treated with BRAF-MEK inhibitors.

Recent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS) of more than 2 years. This study aimed to investigate these patients' real-world survival and identify the characteristics of long-term survivors. The study population consisted of patients with advanced cutaneous melanoma with a BRAF-V600 mutated tumor who were treated with first-line BRAF-MEK inhibitors between 2013 and 2017.

Discontinuation of anti-PD-1 monotherapy in advanced melanoma-Outcomes of daily clinical practice.

There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324).

Outcomes for systemic therapy in older patients with metastatic melanoma: Results from the Dutch Melanoma Treatment Registry.

Background: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients aged ≥75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment.

Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study.

Background: Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials.

Objective: To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID.

Design: Nationwide cohort study.

Survival outcomes of patients with advanced melanoma from 2013 to 2017: Results of a nationwide population-based registry.

Background: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice.

Methods: From a Dutch nationwide population-based registry, patients with advanced melanoma diagnosed from 2013 to 2017 were analysed (n = 3616).

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease.

Background: Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now.

Real-world Outcomes of First-line Anti-PD-1 Therapy for Advanced Melanoma: A Nationwide Population-based Study.

The efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational study with nationwide population-based data from the Dutch Melanoma Treatment Registry, we analyzed real-world outcomes of first-line anti-PD-1 monotherapy in advanced melanoma patients diagnosed in 2015 to 2016. Overall survival (OS) was estimated with the Kaplan-Meier method.

Survival outcomes of patients with advanced mucosal melanoma diagnosed from 2013 to 2017 in the Netherlands - A nationwide population-based study.

Background: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM).

Real-world outcomes of advanced melanoma patients not represented in phase III trials.

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune- or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials.

Association of Anti-TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1-Treated Patients in the Dutch Melanoma Treatment Registry.

Purpose: Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.

Experimental Design: Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017.

Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI).

Metastatic Uveal Melanoma: Treatment Strategies and Survival-Results from the Dutch Melanoma Treatment Registry.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018.

[Recent treatment results for metastatic melanoma: data from the Dutch Melanoma Treatment Registry].

Objective: To evaluate treatment strategies and survival of patients with unresectable stage IIIc or IV melanoma since the 2012 introduction of new drugs in the Netherlands.

Design: Prospective cohort study.

Method: We analysed data from the Dutch Melanoma Treatment Registry (DMTR) regarding patients diagnosed with unresectable stage IIIc or IV melanoma in the period of 1 July 2012 to 31 December 2015.

Vemurafenib in BRAF-mutant metastatic melanoma patients in real-world clinical practice: prognostic factors associated with clinical outcomes.

The aim of this population-based study was to identify the factors associated with clinical outcomes in vemurafenib-treated patients and to evaluate outcomes across subgroups of patients with different risk profiles. Data were retrieved from the Dutch Melanoma Treatment Registry. Time to next treatment (TTNT) and overall survival (OS) of all metastatic melanoma patients who received vemurafenib between 2012 and 2015 were assessed using Kaplan-Meier estimates.

Real-world healthcare costs of ipilimumab in patients with advanced cutaneous melanoma in The Netherlands.

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry.

(Neo)adjuvant systemic therapy for melanoma.

Surgery still is the cornerstone of treatment for patients with stage II and III melanoma, but despite great efforts to gain or preserve locoregional control with excision of the primary tumour, satellites, intransits, sentinel node biopsy and lymphadenectomy, surgery alone does not seem to improve survival any further. Prognosis for patients with high risk melanoma remains poor with 5-year survival rates of 40 to 80%. Only interferon-2b has been approved as adjuvant therapy since 1995, but clinical integration is low considering the high risk-benefit ratio.

Intestinal vaginoplasty revisited: a review of surgical techniques, complications, and sexual function.

Introduction: Vaginal (re)construction is essential for the psychological well-being of biological women with a dysfunctional vagina and male-to-female transgender women. However, the preferred method for vagina (re)construction with respect to functional as well as aesthetic outcomes is debated. Regarding intestinal vaginoplasty, despite the asserted advantages, the need for intestinal surgery and subsequent risk of diversion colitis are often-mentioned concerns.

Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase.

A novel nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp), [(1R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyano[3,4-b]indol-1-yl] acetic acid (HCV-371), was discovered through high-throughput screening followed by chemical optimization. HCV-371 displayed broad inhibitory activities against the NS5B RdRp enzyme, with 50% inhibitory concentrations ranging from 0.3 to 1.

Identification of [(naphthalene-1-carbonyl)-amino]-acetic acid derivatives as nonnucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase.

A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carboxamide scaffold were identified by high throughput screening. Optimization of substituents by parallel synthesis and the iterative design towards understanding structure-activity relationship to improve potency are described. Tetra substituted naphthalene 31 displayed potent activity with IC(50) of 120 nM against HCV NS5B enzyme and was selective over a panel of polymerases.

DNA encapsidation as a target for anti-herpesvirus drug therapy.

The current repertoire of approved anti-herpesviral drugs consists primarily of nucleoside analogues that inhibit viral replication by targeting the virus-encoded DNA polymerase. This class of agents has been critical in controlling infections by herpes simplex, varicella zoster, and cytomegalovirus. However, because nucleoside analogues share a similar mechanism of action, treatment options are limited once resistance develops.

Identification of small molecule compounds that selectively inhibit varicella-zoster virus replication.

A series of nonnucleoside, N-alpha-methylbenzyl-N'-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target.

Post-translational modification of barley 14-3-3A is isoform-specific and involves removal of the hypervariable C-terminus.

The 14-3-3 protein family is a family of regulatory proteins involved in diverse cellular processes. In a previous study of regulation of individual 14-3-3 isoforms in the germinating barley embryo, we found that a post-translationally modified, 28 kDa form of 14-3-3A was present in specific cell fractions of the germinated embryo. In the present study, we identify the nature of the modification of 14-3-3A, and show that the 28 kDa doublet is the result of cleavage of the C-terminus.

Synthesis, processing and export of cytoplasmic endo-beta-1,4-xylanase from barley aleurone during germination.

We have identified the major endo-beta-1,4-xylanase (XYN-1) in the aleurone of germinating barley grain, and show that it is expressed as a precursor of Mr 61 500 with both N- and C-terminal propeptides. XYN-1 is synthesized as an inactive enzyme in the cytoplasm, and only becomes active at a late stage of germination when the aleurone ceases to secrete hydrolases. A series of processing steps, mediated in part by aleurone cysteine endoproteases, yields a mature active enzyme of Mr 34 000.

Novel class of thiourea compounds that inhibit herpes simplex virus type 1 DNA cleavage and encapsidation: resistance maps to the UL6 gene.

In our search for novel inhibitors of herpes simplex virus type 1 (HSV-1), a new class of thiourea inhibitors was discovered. N-(4-[3-(5-Chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl)-acetamide and its 2-fluoro-benzamide derivative inhibited HSV-1 replication. HSV-2, human cytomegalovirus, and varicella-zoster virus were inhibited to a lesser extent.