Driving innovation for rare skin cancers: utilizing common tumours and machine learning to predict immune checkpoint inhibitor response

Metastatic Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC) are rare and both show impressive responses to immune checkpoint inhibitor treatment. However, at least 40% of patients do not respond to these expensive and potentially toxic drugs. Development of predictive biomarkers of response and rational, effective combination treatment strategies in these rare, often frail patient populations is challenging. This review discusses the pathophysiology and treatment of MCC and cSCC, with a particular focus on potential biomarkers of response to immunotherapy, and discusses how transfer learning using big data collected from patients with common tumours can be used in combination with deep phenotyping of rare tumours to develop predictive biomarkers and elucidate novel treatment targets

COVID-19 vaccination: the VOICE for patients with cancer

Pathogenesis and treatment of chronic pulmonary disease

Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma

Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy

Cognitive navigation modeling in robots

This thesis addresses the problem of SLAM: simultaneous localization and mapping by robots in a dynamic environment. A multimodal approach using single-camera images and ultrasone range detectors on Pioneer-II robots is used. Kohonen self-organized maps are used to learn salient landmarks in the environment. Using odometry, it could be shown that the essential layout of the landmarks in the 2D plane can be reconstructed approximately using principal-component analysis on the odometry-distance map between pairs of visual landmarks.

The role of chemokines in lymphocyte infiltration in ovarian cancer: from MRNA microarray to tissue microarray

Introduction: High numbers of CD8+ cytotoxic T lymphocytes (CTL) are associated with a survival advantage in ovarian cancer. Chemokines may play a role in T lymphocyte recruitment to the tumor, but they are also linked to metastasis and angiogenesis. Aim: To determine to what extent chemokines are involved in lymphocyte infiltration of ovarian cancer. Methods: We used microarray technology to rank chemokines based on their differential expression levels between tumors with many and few tumor infiltrating CTL. Next, we further investigated these results using immunohistochemistry and cytokine bead arrays. Results: Six chemokines and chemokine receptors were differentially expressed between 24 CTL high and 35 CTL low tumors. Based on these data and previous literature, we selected CXCL9, CXCL10, CXCL6 and CXCR6 for further validation. Stainings for these chemokines were performed on 254 tumor samples using tissue microarrays. There were no associations between chemokine (receptor) staining intensity and CTL infiltration. However, for CXCL10, high expression was associated with high stage, serous tumors, and >2 cm residual tumor after surgery. In univariate survival analysis, CXCL10 was associated with a worse prognosis. Next, we analyzed soluble CXCL10 at the serum level. For 98 patients, both tissue and serum were available. There were no associations between CXCL10 staining and serum concentrations. However, we found a positive correlation between CXCL10 in serum and CTL infiltration in the tumor. Conclusion: After validation of microarray results, we found a very limited role for chemokines in lymphocyte migration. However, CXCL10 is implicated in more aggressive tumor behavior

Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer

Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer. Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N-0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways. Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-beta, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N-0, and two pathways (beta-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P < 0.001) were involved in beta-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-beta and beta-catenin) confirmed that the TGF-beta pathway (positivity of Smad4) was related to N-0 (OR:0.20, 95% CI: 0.06-0.66) and the beta-catenin pathway (p120 positivity) to N+ (OR: 1.79, 95% CI: 1.05-3.05). Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-beta and p120-associated noncanonical beta-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res; 17(6); 1317-30. (C)2011 AACR

A survival tree of advanced melanoma patients with brain metastases treated with immune checkpoint inhibitors

The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanomathat develop brain metastases (BM) remains unpredictable. In this study, we aimed to identifyprognostic factors in patients with melanoma BM who are treated with ICIs. Data from advancedmelanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained fromthe Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment ofBM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potentialclassifiers and overall survival (OS) as the response variable. In total, 1278 patients were included.Most patients were treated with ipilimumab–nivolumab combination therapy (45%). The survivaltree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. Thestrongest clinical parameter associated with survival in advanced melanoma patients with BM wasthe serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomaticBM had the worst prognosis. The clinicopathological classifiers identified in this study can contributeto optimizing clinical studies and can aid doctors in giving an indication of the patients’ survivalbased on their baseline and disease characteristics.</p

META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IN CELIAC DISEASE AND RHEUMATOID ARTHRITIS IDENTIFIES FOURTEEN NON-HLA SHARED LOCI

Pathophysiology and treatment of rheumatic disease