Plasmacytoid dendritic cells of melanoma patients present exogenous proteins to CD4+ T cells after FcγRII-mediated uptake

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons. Although human pDCs can induce T cell responses upon viral infection, it remains unclear if pDCs can present exogenous antigens. Here, we show that human pDCs exploit FcγRII (CD32) to internalize antigen–antibody complexes, resulting in the presentation of exogenous antigen to T cells. pDCs isolated from melanoma patients vaccinated with autologous monocyte-derived peptide- and keyhold limpet hemocyanin (KLH)–loaded dendritic cells, but not from nonvaccinated patients or patients that lack a humoral response against KLH, were able to stimulate KLH-specific T cell proliferation. Interestingly, we observed that internalization of KLH by pDCs depended on the presence of serum from vaccinated patients that developed an anti-KLH antibody response. Anti-CD32 antibodies inhibited antigen uptake and presentation, demonstrating that circulating anti-KLH antibodies binding to CD32 mediate KLH internalization. We conclude that CD32 is an antigen uptake receptor on pDCs and that antigen presentation by pDCs is of particular relevance when circulating antibodies are present. Antigen presentation by pDCs may thus modulate the strength and quality of the secondary phase of an immune response

Real-world cost-effectiveness of cetuximab in the third-line treatment of metastatic colorectal cancer based on patient chart review in the Netherlands

Objective: To assess the cost effectiveness of cetuximab in third-line treatment of patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) in routine clinical practice compared with best supportive care (BSC). Methods: Patients (n = 287) with KRAS wt mCRC treated with cetuximab or BSC in eight hospitals in the Netherlands between 2009 and 2012 were included in our real-world study. Outcome measures were costs per life-year (LY) and costs per quality-adjusted LY (QALY) gained. A Markov model was developed, and a time horizon of four years was applied. Outcomes were calculated from Kaplan-Meier survival curves from patient-level data and literature. Direct medical costs were estimated in all centers (2013 values), and incremental cost-effectiveness ratios (ICERs) were calculated. Results were discounted, and a probabilistic sensitivity analysis was performed. Results: Administration of cetuximab in third-line treatment of mCRC resulted in a gain of 0.29 LYs and 0.25 QALYs compared with BSC. In the four-year study period, average discounted healthcare costs were €36,637 in the cetuximab group vs. €3648 in the BSC group. The discounted ICERs of cetuximab vs. BSC in the real-world setting were €114,907and €133,527 per LY and QALY gained, respectively. Conclusions: Results of this cost-effectiveness analysis showed that third-line treatment with cetuximab for patients with KRAS (exon 2) wt mCRC offered clinical benefits at additional cost. The real-world ICERs were in line with those of previously published cetuximab and panitumumab cost-utility models

Tumour-derived extracellular vesicles in blood of metastatic cancer patients associate with overall survival

Background: Circulating tumour cells (CTCs) in blood associate with overall survival (OS) of cancer patients, but they are detected in extremely low numbers. Large tumour-derived extracellular vesicles (tdEVs) in castration-resistant prostate cancer (CRPC) patients are present at around 20 times higher frequencies than CTCs and have equivalent prognostic power. In this study, we explored the presence of tdEVs in other cancers and their association with OS. Methods: The open-source ACCEPT software was used to automatically enumerate tdEVs in digitally stored CellSearch® images obtained from previously reported CTC studies evaluating OS in 190 CRPC, 450 metastatic colorectal cancer (mCRC), 179 metastatic breast cancer (MBC) and 137 non-small cell lung cancer (NSCLC) patients before the initiation of a new treatment. Results: Presence of unfavourable CTCs and tdEVs is predictive of OS, with respective hazard ratios (HRs) of 2.4 and 2.2 in CRPC, 2.7 and 2.2 in MBC, 2.3 and 1.9 in mCRC and 2.0 and 2.4 in NSCLC, respectively. Conclusions: tdEVs have equivalent prognostic value as CTCs in the investigated metastatic cancers. CRPC, mCRC, and MBC (but not NSCLC) patients with favourable CTC counts can be further prognostically stratified using tdEVs. Our data suggest that tdEVs could be used in clinical decision-making.</p

Short-Term Outcomes of Secondary Liver Surgery for Initially Unresectable Colorectal Liver Metastases following Modern Induction Systemic Therapy in the Dutch CAIRO5 Trial

Objective: To present short-term outcomes of liver surgery in patients with initially unresectable colorectal liver metastases (CRLM) downsized by chemotherapy plus targeted agents. Background: The increase of complex hepatic resections of CRLM, technical innovations pushing boundaries of respectability, and use of intensified induction systemic regimens warrant for safety data in a homogeneous multicenter prospective cohort. Methods: Patients with initially unresectable CRLM, who underwent complete resection after induction systemic regimens with doublet or triplet chemotherapy, both plus targeted therapy, were selected from the ongoing phase III CAIRO5 study (NCT02162563). Short-term outcomes and risk factors for severe postoperative morbidity (Clavien Dindo grade ≥ 3) were analyzed using logistic regression analysis. Results: A total of 173 patients underwent resection of CRLM after induction systemic therapy. The median number of metastases was 9 and 161 (93%) patients had bilobar disease. Thirty-six (20.8%) 2-stage resections and 88 (51%) major resections (>3 liver segments) were performed. Severe postoperative morbidity and 90-day mortality was 15.6% and 2.9%, respectively. After multivariable analysis, blood transfusion (odds ratio [OR] 2.9 [95% confidence interval (CI) 1.1-6.4], P = 0.03), major resection (OR 2.9 [95% CI 1.1-7.5], P = 0.03), and triplet chemotherapy (OR 2.6 [95% CI 1.1-7.5], P = 0.03) were independently correlated with severe postoperative complications. No association was found between number of cycles of systemic therapy and severe complications (r = -0.038, P = 0.31). Conclusion: In patients with initially unresectable CRLM undergoing modern induction systemic therapy and extensive liver surgery, severe postoperative morbidity and 90-day mortality were 15.6% and 2.7%, respectively. Triplet chemotherapy, blood transfusion, and major resections were associated with severe postoperative morbidity

Long Overall Survival After Dendritic Cell Vaccination in Metastatic Uveal Melanoma Patients

Purpose: To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma. Design: Interventional case series. Methods: We analyzed 14 patients with metastatic uveal melanoma treated with dendritic cell vaccination. Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase. The main outcome measures were safety, immunologic response, and overall survival. Results: Tumor-specific immune responses were induced with dendritic cell vaccination in 4 (29%) of14 patients. Dendritic cell-vaccinated patients showed a median overall survival with metastatic disease of 19.2months, relatively long compared with that reported in the literature. No severe treatment-related toxicities (common toxicity criteria grade 3 or 4) were observed. Conclusions: Dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell-based immunotherapy is potent to enhance the host's antitumor immunity against uveal melanoma in approximately one third of patients. Compared with other prospective studies with similar inclusion criteria, dendritic cell vaccination may be associated with longer than average overall survival in patients with metastatic uveal melanoma

From registration to publication: A study on Dutch academic randomized controlled trials

Introduction: Registration of clinical trials has been initiated in order to assess adherence of the reported results to the original trial protocol. This study aimed to investigate the publication rates, timely dissemination of results, and the prevalence of consistency in hypothesis, sample size, and primary endpoint of Dutch investigator-initiated randomized controlled clinical trials (RCTs). Methods: All Dutch investigator-initiated RCTs with a completion date between December 31, 2010, and January 1, 2012, and registered in the Trial Register of The Netherlands database were included. PubMed was searched for the publication of these RCT results until September 2016, and the time to the publication date was calculated. Consistency in hypothesis, sample size, and primary endpoint compared with the registry data were assessed. Results: The search resulted in a total of 168 Dutch investigator-initiated RCTs. In September 2016, the results of 129 (77%) trials had been published, of which 50 (39%) within 2 years after completion of accrual. Consistency in hypothesis with the original protocol was observed in 108 (84%) RCTs; in 71 trials (55%), the planned sample size was reached; and 103 trials (80%) presented the original primary endpoint. Consistency in all three parameters was observe

Interconnectivity between molecular subtypes and tumor stage in colorectal cancer

BACKGROUND: There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. METHODS: We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. RESULTS: CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p < 0.001). The observed differential gene expression between cancer stages is at least partly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated (r = 0.77, p < 0.001). CMS4 cancers showed an increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the high-risk stage II tumors compared to the total stage II cohort (5-year DFS 41.7% versus 100.0%, p = 0.008). CONCLUSIONS: Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, might also reflect distinct biological disease entities. These insights can potentially be utilized to optimize identification of high-risk stage II colo

Modeling Personalized Adjuvant TreaTment in EaRly stage coloN cancer (PATTERN)

Aim To develop a decision model for the population-level evaluation of strategies to improve the selection of stage II colon cancer (CC) patients who benefit from adjuvant chemotherapy. Methods A Markov cohort model with a one-month cycle length and a lifelong time horizon was developed. Five health states were included; diagnosis, 90-day mortality, death other causes, recurrence and CC death. Data from the Netherlands Cancer Registry were used to parameterize the model. Transition probabilities were estimated using parametric survival models including relevant clinical and pathological covariates. Subsequently, biomarker status was implemented using external data. Treatment effect was incorporated using pooled trial data. Model development, data sources used, parameter estimation, and internal and external validation are described in detail. To illustrate the use of the model, three example strategies were evaluated in which allocation of treatment was based on (A) 100% adherence to the Dutch guidelines, (B) observed adherence to guideline recommendations and (C) a biomarker-driven strategy. Results Overall, the model showed good internal and external validity. Age, tumor growth, tumor sidedness, evaluated lymph nodes, and biomarker status were included as covariates. For the example strategies, the model predicted 83, 87 and 77 CC deaths after 5 years in a cohort of 1000 patients for strategies A, B and C, respectively. Conclusion This model can be used to evaluate strategies for the allocation of adjuvant chemotherapy in stage II CC patients. In future studies, the model will be used to estimate population-level long-term health gain and cost-effectiveness of biomarker-based selection strategies.Financial support for this study was provided by a grant from ZonMw (Grant number: 848015007). ZonMw had no role in designing the study, interpreting the data, writing the manuscript, and publishing the report