Explore the vast range of titles available.

Cruises are the primary form of tourism in the Polar Regions and cruise ship tourism in both the Arctic and Antarctic is expanding rapidly. The industry has moved beyond its infancy, and is now entering a maturing phase with increased numbers and types of vessels, more demanding routes, and more regular and predictable patterns of activity. The increase in cruise activities, and the associated risks of accidents, as well as the potential and actual impacts of the large numbers of tourists in the polar regions bring with it management challenges for sustainable use of these regions. This book discusses critically the issues around environmental and social sustainability of the cruise industry in Polar Regions. Authors from Canada, USA, Europe, Australia and New Zealand are experts in their respective fields and take an innovative, critical and at times controversial approach to the subject.

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against m IDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of d -2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with m IDH1 -R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with m IDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197. The dual IDH1/IDH2 inhibitor vorasidenib exhibited better brain permeability and target engagement than ivosidenib in a pilot perioperative randomized clinical trial in patients with IDH1-mutant glioma.

Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

Accumulation of fumarate resulting from mutations in fumarate hydratase,which are associated with renal and other cancers, is shown to induce epithelial-to-mesenchymal transition—a process associated with cancer initiation. Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer 1 . Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome 2 . Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite 3 . Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation 4 , 5 . However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis 6 . We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster 6 mir-200ba429 , leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.

In a phase 3 trial, vorasidenib, an oral brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), resulted in improved progression-free survival (primary endpoint) and time to next intervention (key secondary endpoint) at second interim analysis, resulting in study unblinding. We report 6 months of additional double-blind data, from second interim analysis (Sept 6, 2022) to unblinding (March 7, 2023), and the effect of vorasidenib on volumetric tumour growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control. INDIGO was a randomised, double-blind, placebo-controlled, phase 3 trial done in 92 hospitals in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the UK, and the USA. Patients aged 12 years or older with residual or recurrent grade 2 IDH1/2-mutant diffuse glioma, a Karnofsky performance-status score of 80 or higher, at least one previous surgery, and no other previous anticancer treatment were eligible. Patients were randomly assigned (1:1; stratified according to locally determined chromosome 1p/19q codeletion status and baseline tumour size) to oral vorasidenib (40 mg) or placebo once a day in continuous 28-day cycles until disease progression or unacceptable toxicity. Progression-free survival per masked independent review committee was the primary endpoint, and time to next intervention was the key secondary endpoint. Prespecified secondary endpoints included tumour growth rate (6-monthly change in tumour volume) and HRQOL (Functional Assessment of Cancer Therapy–Brain [FACT-Br]). Prespecified exploratory endpoints included neurocognitive function (cognitive performance instruments) and seizure activity (self-reported). The full analysis set was used for all efficacy analyses and included all randomly assigned patients, and the safety analysis set was used for all safety analyses and included all patients who received one or more doses of vorasidenib or placebo. The trial is registered with ClinicalTrials.gov, NCT04164901. Recruitment is complete and the trial is ongoing. Between Jan 9, 2020, and Feb 22, 2022, 331 patients were enrolled and randomly assigned to vorasidenib (n=168) or placebo (n=163). 187 (56%) patients were male, 144 (44%) were female, and 257 (78%) were White. Median follow-up was 20·1 months (IQR 15·9 to 23·8). With an additional 6 months of follow-up, median progression-free survival (not reached [95% CI 22·1 to not estimated] vs 11·4 months [95% CI 11·1 to 13·9]; hazard ratio [HR] 0·35 [95% CI 0·25 to 0·49]) and time to next intervention (not estimated [not estimated to not estimated] vs 20·1 months [17·5 to 27·1]; HR 0·25 [0·16 to 0·40]) remained substantially improved with vorasidenib versus placebo. Tumour growth rate was –1·3% (95% CI –3·2 to 0·7) with vorasidenib and 14·4% (95% CI 12·0 to 16·8) with placebo (difference 15·9% [95% CI 12·6 to 19·3]). Mean FACT-Br total scores were similar between the vorasidenib and placebo groups (158·2 [SD 26·4] and 158·8 [23·3]) at baseline and remained high (154·2 [29·8] and 153·2 [29·4]) by the end of treatment. There was no difference between vorasidenib or placebo in neurocognitive functions of verbal learning, executive function, attention, working memory, and psychomotor function from baseline through to end of treatment. The vorasidenib group had lower rates of seizures than the placebo group (18·2 seizures per person-year [95% CI 8·4 to 39·5] vs 51·2 seizures per person-year [22·9 to 114·8]). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) in the vorasidenib and placebo groups, respectively, were increased alanine aminotransferase (17 [10%] and two [1%]), increased aspartate aminotransferase (eight [5%] and none), seizures (seven [4%] and five [3%]), and increased γ-glutamyltransferase (five [3%] and two [1%]). Serious TEAEs occurred in 20 (12%) patients in the vorasidenib group and ten (6%) in the placebo group; the most common were seizures. There were no treatment-related deaths. Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition. Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma. These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy. Servier.

Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43–0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39–0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34–0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31–0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43–0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35–1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32–0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19–0·86, p=0·02) and an IRR of 0·37 (0·18–0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

Using pair-end transcriptome sequencing, this study provides the identification of Raf pathway gene rearrangements in a small proportion of prostate and gastric cancers and in melanomas. The fusion proteins show tumorigenic potential and represent a unique activating alteration of this oncogenic pathway, which seems to be mutually exclusive from known cancer-associated Raf mutations. This suggests that therapeutic Raf inhibition can be expanded to this fusion-harboring subset of solid tumors. Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific ( ETS ) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase ( ALK ) gene, have been identified in 1–5% of lung cancers 1 , suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement–negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3–v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1–v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion–harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.