Anatomical and functional response after conversion to aflibercept using the treat-and-extend regimen protocol in bevacizumab treatment-resistant wet age-related macular degeneration

Objective: To evaluate the functional and anatomical response after the switch from bevacizumab to aflibercept in treatment-resistant wet age-related macular degeneration (wAMD) using the treat-and-extend regimen protocol. Design: A retrospective single-center study. Participants: The registry consisted of 576 patients with wAMD. Of these, a total of 41 eyes of 37 patients met the study inclusion criteria with a minimum of three prior bevacizumab injections and at least 1-year follow-up after the switch to aflibercept injections for the treatment of wAMD. Methods: Central retinal thickness (CRT) and best-corrected visual acuity (BCVA) were recorded before and after bevacizumab loading phase, before the switch to aflibercept, after aflibercept loading phase, and after the last injection or at the study end point at a minimum of 1 year from the switch. Results: At the switch to aflibercept injections, the mean CRT was 361.1 +/- 117.7 mu m (mean +/- SD) and BCVA was 0.29 +/- 0.19 decimals. The switch to aflibercept resulted in mean CRT resolution by 59.9 +/- 80.2 mu m after the loading phase and by 61.3 +/- 102.9 mu m at the study end point. Anatomical response to aflibercept switch was found in 34 of 41 eyes (83%) after the loading phase, and in 32 of 41 eyes (78%)at the study end point. BCVA improvement was 0.08 +/- 0.13 decimals in 26 of 41 eyes (63%) after the loading phase, and 0.04 +/- 0.17 decimals in 17 of 41 eyes (41%) at the study end point. The mean treatment interval of aflibercept was 8.0 +/- 2.2 weeks at the study end point. Conclusion: Regardless of impressive anatomical outcomes of aflibercept switch, functional response was modest for most of the study eyes at long term.Peer reviewe

Unohdetut yksinäiset miehet

Kirja-arvostelu: Asunnottomuus ja alkoholi Ilkka Taipal

Oncograms Visualize Factors Influencing Long-Term Survival of Cancer Patients Treated with Adenoviral Oncolytic Immunotherapy

The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as "oncograms." Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-81, HMGB1, antiviral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy.Peer reviewe

Ei tämän enempää avusta alkoholiongelmiin

Kirja-arvostelu: Apu alkoholiongelmaan Kari Poikolainen, LasseMurto, RaunoMäkelä, Ilkka Taipal

Interleukin 8 activity influences the efficacy of adenoviral oncolytic immunotherapy in cancer patients

After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy. We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses. We found high baseline serum IL-8 concentration to be independently associated with poor prognosis (p <0.001). Further, normal baseline IL-8 was associated with improved prognostic potential of calculation of the neutrophil-to-lymphocyte ratio (p <0.001). Interestingly, a decrease in IL-8 concentration after treatment with oncolytic adenovirus predicted better overall survival (p <0.001) and higher response rate, although this difference was not significant (p=0.066). We studied the combination of adenovirus and IL-8 neutralizing antibody ex vivo in single cell suspensions and in co-cultures of tumor-associated CD15+ neutrophils and CD3+ tumor-infiltrating lymphocytes derived from fresh patient tumor samples. These results indicate a role for IL-8 as a biomarker in oncolytic virotherapy, but additionally provide a rationale for targeting IL-8 to improve treatment efficacy. In conclusion, curtailing the activity of IL-8 systemically or locally in the tumor microenvironment could improve anti-tumor immune responses resulting in enhanced efficacy of adenoviral immunotherapy of cancer. © Taipale et al.Peer reviewe

Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer

Background Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. Methods Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3 increment 24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher's test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. Results Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. Conclusions Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.Peer reviewe

Resolving phytoplankton pigments from spectral images using convolutional neural networks

Motivated by the need for rapid and robust monitoring of phytoplankton in inland waters, this article introduces a protocol based on a mobile spectral imager for assessing phytoplankton pigments from water samples. The protocol includes (1) sample concentrating; (2) spectral imaging; and (3) convolutional neural networks (CNNs) to resolve concentrations of chlorophyll a (Chl a), carotenoids, and phycocyanin. The protocol was demonstrated with samples from 20 lakes across Scotland, with special emphasis on Loch Leven where blooms of cyanobacteria are frequent. In parallel, samples were prepared for reference observations of Chl a and carotenoids by high-performance liquid chromatography and of phycocyanin by spectrophotometry. Robustness of the CNNs were investigated by excluding each lake from model trainings one at a time and using the excluded data as independent test data. For Loch Leven, median absolute percentage difference (MAPD) was 15% for Chl a and 36% for carotenoids. MAPD in estimated phycocyanin concentration was high (102%); however, the system was able to indicate the possibility of a cyanobacteria bloom. In the leave-one-out tests with the other lakes, MAPD was 26% for Chl a, 27% for carotenoids, and 75% for phycocyanin. The higher error for phycocyanin was likely due to variation in the data distribution and reference observations. It was concluded that this protocol could support phytoplankton monitoring by using Chl a and carotenoids as proxies for biomass. Greater focus on the distribution and volume of the training data would improve the phycocyanin estimates

Fatty liver is associated with blood pathways of inflammatory response, immune system activation and prothrombotic state in Young Finns Study

Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver's response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR < 0.05) in subjects with FL. These pathways related to extracellular matrix (ECM) turnover, immune response regulation, prothrombotic state and neural tissues. After adjustment for known risk factors and biomarkers of FL, we found i) integrin A4B1 signaling, ii) leukocyte transendothelial migration, iii) CD40/CD40L and iv) netrin-1 signaling pathways to be upregulated in individuals with FL (nominal p < 0.05). From these all but not ii) remained significantly upregulated when analyzing only subjects without history of heavy alcohol use. In conclusion, FL was associated with blood gene sets of ECM turnover, inflammatory response, immune system activation and prothrombotic state. These may form a systemic link between FL and the development of cardiovascular diseases

WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described.We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas.To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture.We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.Peer reviewe

Transcriptome Analysis Reveals Signature of Adaptation to Landscape Fragmentation

Peer reviewe