Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.</p

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275

The HIV manifestations within the gastrointestinal tract: A pictorial review

The aim of the pictorial review are to review the HIV manifestations within the gastrointestinal tract. We have detailed five conditions, with reference to the patients’ CD4 count – gastrointestinal tuberculosis, Kaposi’s sarcoma, small bowel lymphoma, cytomegalovirus colitis and anal carcinoma

Molecular features toward high photo-CIDNP hyperpolariztion explored through the oxidocyclization of tryptophan

Photo-chemically induced dynamic nuclear polarization (photo-CIDNP) is a promising solution to the inherent lack of sensitivity in NMR spectroscopy. It is particularly interesting in biological systems since it operates in water, at room temperature, and it can be repeated if the bleaching of the system can be controlled. However, the photo-CIDNP signal enhancement is well below those of other hyperpolarization techniques. While DNP, PHIP, and SABRE reach polarization enhancements of 103 to 104-fold, photo-CIDNP enhancement is typically only one order of magnitude for 1H and two orders of magnitude for 13C in the amino-acids tryptophan and tyrosine. Here we report on a photo-oxidation product of tryptophan that is strongly photo-CIDNP active under continuous wave light irradiation. In conjunction with the dye Atto Thio 12, a 1H signal enhancement of 120-fold was observed on a 600 MHz spectrometer, while at 200 MHz the enhancement was 380-fold. These enhancements in signal to noise correspond to a reduction in measurement time of 14 400-fold and 144 400-fold, respectively. The enhancement for 13C is estimated to be over 1200-fold at 600 MHz which corresponds to an impressive measurement time reduction of 1 440 000-fold. This photo-CIDNP active oxidation product of tryptophan has been identified to be 3α-hydroxypyrroloindole. The reasons for its improved signal enhancement compared to tryptophan have been further investigated.ISSN:1463-9084ISSN:1463-907

Consumer trust, risk and food safety: a review

Consumers' attitudes to trust and risk are key issues in food safety research and attention needs to be focused on clearly defining a framework for analysing consumer behaviour in these terms. In order to achieve this, a detailed review of the recent literature surrounding risk, trust and the relationship between the two must be conducted. This paper aims to collate the current social sciences literature in the fields of food safety, trust and risk. It provides an insight into the economic and other modelling procedures available to measure consumers' attitudes to risk and trust in food safety and specifically notes the need for future research to concentrate on examining risk and trust as inter-related variables rather than two distinct, mutually exclusive concepts. A framework is proposed which it is hoped will assist in devising more effective research to support risk communication to consumers

Tehnike indukcije haploidov in podvojenih haploidov

Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy