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European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (ECBP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research. This meeting report presents all discussions that shed light onto how infrastructures can be effectively shaped for translational, prevention, clinical and outcomes cancer research, with a focus on implementation and sustainability and while engaging patients and the public. In addition, we summarize recommendations on how to introduce frameworks for the digitalization of European cancer research. Finally, we discuss what structures, commitment and resources are needed to establish a collaborative cancer research environment in Europe to achieve the scale required for innovation.

The Great Debate session at the 2022 Melanoma Bridge congress (December 1–3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge Great Debates, the speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect personal views. Audiences voted in favour of either side of the argument both before and after each debate.

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Purpose: The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes.Results: We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin.Sorafenib induced BRAF–CRAF dimerization in cultured keratinocytes and activated CRAF with a dose-dependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.Conclusion: Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors. Clin Cancer Res; 18(1); 263–72. ©2011 AACR.

Vemurafenib-induced BRAF-CRAF dimerization (2 µM, 24h) detected by in situ PLA in SK-MEL2 cell line is not decreased by the adjunction of MEK inhibitor PD0325901 (1µM, 24h): each red dot represents a BRAF-CRAF heterodimer. The cells were counterstained with DAPI (blue).

BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin and extracutaneous tumors in 31 patients who underwent BRAFi therapy. The majority of patients presented with classic epidermal tumors such as verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC). However, 15 patients exhibited new or rapidly progressing tumors distinct from these classic subtypes, such as lymph node metastasis, new melanomas, and genital and oral mucosal SCCs. Genotyping of the tumors revealed that oncogenic RAS mutations were found in 58% of the evaluable tumor samples (38/66) and 49% of the control tumors from patients not treated with BRAFi (30/62). Notably, proximity ligation assays demonstrated that BRAF–CRAF heterodimerization was increased in fixed tumor samples from BRAFi-treated patients compared with untreated patients. Our findings reveal that BRAF–CRAF complex formation is significantly associated with BRAFi treatment, and may therefore serve as a useful biomarker of BRAFi-induced cutaneous and extracutaneous tumor formation. Cancer Res; 76(6); 1476–84. ©2016 AACR.

Supplementary Figure 3: NF2 deleterious mutations and sensitivity to lorlatinib (corresponding to main Figure 4).

Purpose:Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental Design:Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.Results:Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial–mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.Conclusions:This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.

Supplementary figure legends

Tumoral and non tumoral biospies from patients treated with or without BRAF inhibitors: Mutational status, pERK level and BRAF-CRAF PLA score.

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Supplementary figures legends

Proximity Ligation Assay principle. Two primary antibodies recognize the two antigens BRAF and CRAF. Specific secondary antibodies (Probes) bind to the primary antibodies and are bound to a unique short DNA. When the PLA probes are in close proximity, the DNA strands can interact. After joining they are amplified via rolling circle amplification (RCA) using a polymerase. The signal is easily made visible as a distinct brown or fluorescent dot after enzymatic conversion of a substrate.

Extending the success of cellular immunotherapies against blood cancers to the realm of solid tumors will require improved in vitro models that reveal therapeutic modes of action at the molecular level. Here we describe a system, called BEHAV3D, developed to study the dynamic interactions of immune cells and patient cancer organoids by means of imaging and transcriptomics. We apply BEHAV3D to live-track >150,000 engineered T cells cultured with patient-derived, solid-tumor organoids, identifying a ‘super engager’ behavioral cluster comprising T cells with potent serial killing capacity. Among other T cell concepts we also study cancer metabolome-sensing engineered T cells (TEGs) and detect behavior-specific gene signatures that include a group of 27 genes with no previously described T cell function that are expressed by super engager killer TEGs. We further show that type I interferon can prime resistant organoids for TEG-mediated killing. BEHAV3D is a promising tool for the characterization of behavioral-phenotypic heterogeneity of cellular immunotherapies and may support the optimization of personalized solid-tumor-targeting cell therapies.

Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up.KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment.Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [lt;1%]), rash (seven [1%] vs two [lt;1%]), autoimmune hepatitis (seven [1%] vs two [lt;1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported.Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting.Merck Sharpamp; Dohme, a subsidiary of Merckamp; Co.

LBA9500 Background: In previous analyses of the phase 3, double-blind KEYNOTE-716 study, adjuvant pembrolizumab (pembro) significantly improved recurrence-free survival compared with placebo in patients (pts) with resected AJCC-8 stage IIB or IIC melanoma. We present new data from the analysis of distant metastasis-free survival (DMFS), and recurrence-free survival (RFS) with longer follow up. Methods: A total of 976 pts aged ≥12 years with complete resection of cutaneous stage IIB or IIC melanoma and negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (approximately 1 year) in Part 1 of the study. Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. Pts who received placebo in Part 1, or who did not experience disease progression within 6 months of completing Part 1 were eligible for additional cycles of pembro Q3W at recurrence (Part 2). The primary endpoint was RFS per investigator. DMFS by investigator is a secondary endpoint. The data cut-off date for this interim analysis was Jan 4th, 2022. Results: At median follow-up of 26.9 mo (range, 4.6-39.2), adjuvant pembro significantly improved DMFS (HR 0.64, 95% CI, 0.47-0.88; P=0.0029; median not reached [NR] for both) vs placebo. The 24-mo DMFS rate was 88.1% vs 82.2%. There was consistent reduction in the risk of recurrence with pembro vs placebo (HR 0.64, 95% CI, 0.50-0.84) with further follow-up. The 24-mo RFS rate was 81.2% vs 72.8%. Grade ≥ 3 any-cause AEs occurred in 137 (28.4%) vs 97 (20.0%) pts in the pembro vs placebo arms. Grade ≥ 3 drug-related AEs occurred in 83 (17.2%) vs 24 (4.9%) pts. One pt in the pembro arm and 5 pts in the placebo arm died due to an any-cause AE. No deaths were drug-related. Immune-mediated AEs occurred in 182 (37.7%) vs 45 (9.3%) pts, most commonly hypothyroidism (17.2% vs 3.7%). Conclusions: Adjuvant pembrolizumab vs placebo for resected stage IIB and IIC melanoma significantly improved DMFS, with continued reduction in the risk of recurrence, and a favorable benefit-risk profile. Clinical trial information: NCT03553836.

9564 Background: AJCC v8 includes Breslow thickness and ulceration to subdivide stage I and II CM pts into risk groups. In light of the results from adjuvant therapy in stage II CM, it has been discussed that pts’ follow-up and eventually treatment should consider additional markers, namely CP-GEP, to further refine the risk classification provided by the AJCC v8. The aim of this single center study was to clinically validate a prognostic CP-GEP-based risk score for stage I/II CMs combining Breslow, age and the expression of 8 genes SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA. Methods: All obtainable formalin-fixed paraffin-embedded primaries of stage I/II CMs with negative sentinel lymph node (SLN) from the Central Malignant Melanoma Registry of Germany diagnosed between 2000-2017 and archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. Quantitative reverse transcription polymerase chain reaction of the 8 genes was performed and combined with age and tumor thickness to define CP-GEP low- vs. high-score groups. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier curves. CP-GEP score performance was tested using multivariate Cox regression adjusted for tumor thickness, ulceration and age. Results: We included 543 pts with Stage IA (n=78); IB (n=223); IIA (n= 123); IIB (n=73); IIC (n=46). 43% were females, median Breslow was 1.7mm and 25% of tumors had ulceration. The median follow-up was 78 months (IQR 47-116). 311 (57%) patients had a high-risk CP-GEP score. The 5-y RFS rate was 71% and 92% (HR 4.2; p

9581 Background: Adjuvant pembro improved RFS vs placebo (HR, 0.61; 95% CI, 0.45-0.82) and had manageable safety in patients (pts) with resected high-risk stage II melanoma at second interim analysis of KEYNOTE-716 (NCT03553836). HRQoL results are presented. Methods: Pts aged ≥12 y with resected stage IIB/C melanoma were randomized 1:1 to adjuvant pembro 200 mg (2 mg/kg for pts ≥12 and < 18 y) Q3W or placebo for ≤17 cycles. Change from baseline in HRQoL was an exploratory end point. EORTC QLQ-C30 and EQ-5D-5L were administered at baseline; cycles 5, 9, 13, and 17 in y 1; every 12 wk in y 2; and every 6 mo in y 3. The HRQoL population included all pts who received ≥1 dose of study treatment and had ≥1 HRQoL assessment available. Least-squares mean (LSM) change from baseline to wk 48 in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) and physical functioning (PF) and EQ-5D-5L visual analog scale (VAS) were calculated using a constrained longitudinal data analysis model; HRQoL score was the response variable with treatment by time interaction and T stage at baseline as covariates. Empirical mean change from baseline in QLQ-C30 GHS/QoL and PF scores over time was evaluated. A ≥10-point improvement or decline in QLQ-C30 scores was considered clinically meaningful. Data cutoff was June 21, 2021. Results: Of 976 pts enrolled, 969 were included in the HRQoL population (483 pembro; 486 placebo). Median follow-up in the ITT population was 20.5 mo (range, 4.6-32.7). At wk 48, compliance (adherence) for EORTC QLQ-C30 was 83.4% for pembro and 89.3% for placebo and completion was 70.6% and 75.7%, respectively. At wk 48, compliance for EQ-5D-5L was 84.1% for pembro and 90.0% for placebo and completion was 71.2% and 76.3%, respectively. QLQ-C30 GHS/QoL and PF and EQ-5D-5L VAS scores were similar between arms at baseline. LSM change from baseline to wk 48 in QLQ-C30 GHS/QoL score was −4.49 (95% CI, −6.19 to −2.79) for pembro and −0.82 (95% CI, −2.47 to 0.83) for placebo (LSM difference: −3.67; 95% CI, −5.91 to −1.44). LSM change from baseline to wk 48 in QLQ-C30 PF score was −3.27 (95% CI, −4.61 to −1.92) for pembro and −1.77 (95% CI, −3.07 to −0.46) for placebo (LSM difference: −1.50; 95% CI, −3.33 to 0.32). LSM change from baseline to wk 48 in EQ-5D-5L VAS score was −2.19 (95% CI, −3.52 to −0.85) for pembro and −0.25 (95% CI, −1.54 to 1.04) for placebo (LSM difference: −1.94; 95% CI, −3.72 to −0.16). LSM change from baseline to wk 48 in other QLQ-C30 functioning and symptom scales was similar in both arms. Empirical mean change from baseline in QLQ-C30 GHS/QoL and PF was similar over 96 wk in both arms. Conclusions: No clinically meaningful decreases in EORTC QLQ-C30 or EQ-5D-5L VAS scores were observed for adjuvant pembro or placebo. These results, along with improved RFS and manageable safety, support the use of adjuvant pembro in resected high-risk stage II melanoma. Clinical trial information: NCT03553836.

TPS9589 Background: The treatment of melanoma has improved markedly with the emergence of new immune therapies, and both anti-PD-1 monotherapy and the combination of the anti-PD-1 antibody nivolumab and anti-CTLA-4 therapy ipilimumab are now considered standard-of-care in the unresectable or metastatic (advanced) melanoma setting. However, many patients have primary or acquired resistance to these therapies, thereby underpinning the need for more effective approaches. IO102-IO103 is a potentially first-in-class, dual-antigen, immune-modulatory therapy targeting the key cancer immune resistance pathways mediated by IDO and PD-L1. The ability of IO102 and IO103 to respectively activate the specific T cells that recognize these checkpoint molecules and directly modulate immune regulation has previously been demonstrated both preclinically and in human clinical trials. A synergistic anti-tumor response upon treatment against both IDO and PD-L1 has also previously been demonstrated in a preclinical model where IDO and PD-L1 were expressed by different cells in the tumor microenvironment. Due to the distinctive mechanisms of action of IO102-IO103 and anti-PD-1 antibodies, there may be a further synergistic effect when treatment is combined. A previous Phase 1/2 trial investigating the use of IO102-IO103 plus nivolumab in patients with anti-PD-1-naïve metastatic melanoma has demonstrated promising anti-tumor activity with an overall response rate (ORR) of 80%, median progression-free survival (PFS) of 26 months and a manageable safety profile (NCT03047928; Kjeldsen et al, Nat Med 2021). Methods: This is a Phase 3, multicenter, open-label, randomized, 2-arm trial investigating the efficacy and safety of IO102-IO103 plus pembrolizumab versus pembrolizumab alone (EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254). Inclusion criteria include: adult patients with untreated, unresectable (Stage III), or metastatic (Stage IV) melanoma; > 6 months since last dose of (neo)adjuvant treatment with targeted or immune therapy (in those previously treated); and ≥1 measurable lesion by RECIST v1.1. Primary endpoint is PFS by blinded independent central review. Secondary endpoints include ORR, durable response rate, complete response rate, duration of response, time to response, disease control rate, overall survival, and safety/tolerability. Target enrollment is 300 patients at > 100 sites in 20 countries. Patients are randomized 1:1 to receive either pembrolizumab 200 mg intravenously (IV) every 3 weeks up to 2 years or pembrolizumab 200 mg IV every 3 weeks up to 2 years with dual-antigen IO103-IO102 85-85 µg and Montanide adjuvant subcutaneously on Day 1 and 8 of cycle 1 and 2 and on Day 1 of each cycle thereafter. Enrolment for the study is ongoing. Clinical trial information: EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254.

Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti–CTLA-4 and anti–PD-1/anti–PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas. For the treatment of advanced disease, approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014), the combination ipilimumab plus nivolumab (2015), and the oncolytic virus vaccine laherparepvec (2015). The combination dabrafenib plus trametinib for BRAF-mutant melanoma was approved in 2014, with similar success for other BRAF plus MEK inhibitor combinations. Because of its unique therapeutic index (high efficacy and low toxicity) anti–PD-1 agents (nivolumab and pembrolizumab) have now been placed at the center of practically all combination therapy development strategies in melanoma. Anti–PD-1 agents are the central molecule for combinations with a great variety of other immunotherapeutics such as immune checkpoint inhibitors, agonists, IDO inhibitors, macrophage polarizing agents, monoclonal antibodies, vaccines, targeted agents, chemotherapeutics, radiation therapy, and even microbiome modulators.

Purpose The impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate. Methods We reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not. Results Multivariable analysis (both weighted multiple linear regression and random effects meta-regression) demonstrated that the personalized approach, compared with a nonpersonalized approach, consistently and independently correlated with higher median RR (31% v 10.5%, respectively; P < .001) and prolonged median PFS (5.9 v 2.7 months, respectively; P < .001) and OS (13.7 v 8.9 months, respectively; P < .001). Nonpersonalized targeted arms had poorer outcomes compared with either personalized targeted therapy or cytotoxics, with median RR of 4%, 30%, and 11.9%, respectively; median PFS of 2.6, 6.9, and 3.3 months, respectively (all P < .001); and median OS of 8.7, 15.9, and 9.4 months, respectively (all P < .05). Personalized arms using a genomic biomarker had higher median RR and prolonged median PFS and OS (all P ≤ .05) compared with personalized arms using a protein biomarker. A personalized strategy was associated with a lower treatment-related death rate than a nonpersonalized strategy (median, 1.5% v 2.3%, respectively; P < .001). Conclusion Comprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. In addition, nonpersonalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy.

Melanoma has been the most important cancer to drive immunotherapy development in the field of solid tumors. Where immune-stimulating approaches with cytokines in the 1980s and 1990s lead to approvals of interferon-alpha and interleukin-2, the clinical impact was rather small. Since 2010 immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, i.e., anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD1/anti-PDL1 (programmed death-1 receptor and its ligand PD-L1), is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease in over 50% of metastatic patients. We are only at the beginning of discovering its transversal impact throughout oncology. FDA-approved treatments for melanoma are at present: interferon-alpha as adjuvant therapy (1996), interleukin-2 (1998) for advanced disease, and more recently pegylated interferon-alpha as adjuvant therapy (2011). For the treatment of advanced disease approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014) and the combination ipilimumab + nivolumab (2015), and the oncolytic virus vaccine laherparepvec (T-VEC) in 2015. Ipilimumab is the first checkpoint inhibitor that has also been approved as adjuvant therapy for high-risk stage III melanoma (2015). Results regarding adjuvant therapy with either nivolumab or pembrolizumab are expected in 2018. Further developments in the field of melanoma are focused on combination therapies between various immunotherapeutic agents, such as vaccines and antibodies, and combination therapies between immunotherapeutic agents with chemotherapeutic or targeted agents or even radiation therapy. Thanks to in particular anti-PD1/anti-PDL1-based immunotherapies, the activity of the combination of anti-PD1/anti-CTLA4 immunotherapy is now developed in a transversal manner across multiple tumor types (a.o. lung, head and neck, esophageal/gastric, liver, MSI-colorectal, MSI-any tumor type, renal, bladder cancers, and Hodgkin lymphoma) with unprecedented success.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a,0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.

The promise of precision medicine for cancer is already being realized with the recent introduction of many targeted therapies, some with companion diagnostic tests that identify patients most likely to benefit from treatment. The utility of molecular profiling of cancer to identify actionable aberrations has been suggested by several small clinical trials conducted in patients with advanced cancer and by many anecdotes but is yet to be proven in well-designed, prospective, randomized trials. Several trials that will definitively test this strategy are now underway or soon to be launched. Melanoma, a disease once largely untreatable when metastatic, may be a paradigm for understanding how the molecular drivers of a disease can lead to highly effective targeted therapies, as well as for realizing the enormous therapeutic potential of unleashing the immune system against cancer to produce long-term disease control. Looking to the future, advanced omics technologies and computational techniques will enable assessment of not only genomic variants, as performed today, but also of pathway and network aberrations that will greatly facilitate selection of drug combinations likely to benefit specific patients. As our deepening understanding of tumor biology converges with rapid advances in measurement science and technology and computational analysis, we have an enormous opportunity to create a future for precision medicine in oncology that provides for highly specific, minimally toxic, and dramatically effective treatment for each patient.

Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology.We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation inGermline mutations in

Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically and staging is based upon the AJCC system. CMs are excised with one to two centimetre safety margins. Sentinel lymph node dissection (SLND) is routinely offered as a staging procedure in patients with tumours more than 1 mm in thickness, although there is as yet no clear survival benefit for this approach. Interferon-α treatment may be offered to patients with stage II and III melanoma as an adjuvant therapy, as this treatment increases at least the disease-free survival (DFS) and less clear the overall survival (OS) time. The treatment is however associated with significant toxicity. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic treatment is indicated. BRAF inhibitors like vemurafenib for BRAF mutated patients as well as the CTLA-4 antibody ipilimumab offer new therapeutic opportunities apart from conventional chemotherapy. Therapeutic decisions in stage IV patients should be primarily made by an interdisciplinary oncology team ('tumour board'). © 2012 Elsevier Ltd. All rights reserved.

Female melanoma patients generally exhibit significantly longer survival than male patients. This population-based cohort study aimed to investigate gender differences in survival and disease progression across all stages of cutaneous melanoma. A total of 11,774 melanoma cases extracted from the Munich Cancer Registry (Germany), diagnosed between 1978 and September 2007, were eligible to enter the study. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for tumor and patient characteristics, were estimated for the end points of survival, regional and systemic progression, and survival after progression. A significant female advantage was observed for melanoma-specific survival (adjusted HR 0.62; 95% CI 0.56-0.70). Women were at a lower risk of progression (HR 0.68; 95% CI 0.62-0.75), including a lower risk of lymph node metastasis (HR 0.58; 95% CI 0.51-0.65) and visceral metastases (HR 0.56; 95% CI 0.49-0.65). They retained a significant survival advantage after first progression (HR 0.81; 95% CI 0.71-0.92) and lymph node metastasis (HR 0.80; 95% CI 0.66-0.96), but this became borderline significant (HR 0.88; 95% CI 0.76-1.03) after visceral metastasis. Localized melanomas in women had a lower propensity to metastasize, resulting in a better survival when compared with men, even after first disease progression. These results suggest differences in tumor-host interaction across gender.

Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.

In this paper, we report on a study to quantifystudents’ attitudes towards the common first yearprogram offered at the Schulich School of Engineering. Asurvey of students from all four years of each of theSchool’s seven BSc programs is performed to determine ifthe common first year program is achieving its objectivesfrom a student perspective. More specifically, the surveyfocuses on both student opinion and student behaviourwith respect to the common first year and programselection. Students are asked to provide their input onbenefits of a common first year (i.e., as a foundation forengineering studies and exposure to the range ofengineering disciplines) and its role in the programselection process (i.e., if a different process is preferred,and how their program selection choice was impacted bya common first year).

International audience; The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/ Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-gamma-producing gamma delta Tau cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable ''oncomicrobiotics'' ameliorating the efficacy of the most common alkylating immunomodulatory compound.