Overall survival from tebentafusp versus nivolumab plus ipilimumab in first-line metastatic uveal melanoma: a propensity score-weighted analysis.

BACKGROUND: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.

Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Access to novel cancer medicines in four countries in Central and Eastern Europe in relation to clinical benefit.

BACKGROUND: Almost 100 novel cancer medicines have been approved in Europe over the last decade. Limited public health care resources in countries in Central and Eastern Europe (CEE) call for a prioritization of access to effective medicines. We investigated how both reimbursement status and waiting time to reimbursement correlate with the magnitude of clinical benefit provided by novel medicines in four selected countries (Czechia, Hungary, Poland, and Slovakia). MATERIALS AND METHODS: A total of 124 indications of 51 cancer medicines with marketing authorization by the European Medicines Agency in 2011-2020 were included and followed up until 2022. Data on reimbursement status and waiting time to reimbursement (i.e. time from marketing authorization to national reimbursement approval) were collected for each country. Data were analyzed in relation to clinical benefit status (i.e. substantial versus nonsubstantial clinical benefit) of indications according to the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). RESULTS: The degree of reimbursement differed between countries with 64% of indications with reimbursement in Czechia, 40% in Hungary, 51% in Poland, and 19% in Slovakia. In all countries, a significantly greater proportion of indications with a substantial clinical benefit was reimbursed (P < 0.05). The median waiting time to reimbursement ranged from 27 months in Poland to 37 months in Hungary. No significant differences in waiting time in relation to clinical benefit were observed in any country (P = 0.25-0.84). CONCLUSIONS: Cancer medicines with a substantial clinical benefit are more likely to be reimbursed in all four CEE countries. Waiting times to reimbursement are equally long for medicines with or without a substantial clinical benefit, indicating a lack of prioritization of fast access to medicines delivering a substantial benefit. Incorporation of the ESMO-MCBS in reimbursement assessments and decisions could aid in better utilization of limited resources to deliver more effective cancer care.

Circulating tumor DNA analysis of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor treated with avapritinib or regorafenib.

BACKGROUND: The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility. PATIENTS AND METHODS: VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes. RESULTS: A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib. CONCLUSIONS: ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.

Spinal tumours: recommendations of the Polish Society of Spine Surgery, the Polish Society of Oncology, the Polish Society of Neurosurgeons, the Polish Society of Oncologic Surgery, the Polish Society of Oncologic Radiotherapy, and the Polish Society of Orthopaedics and Traumatology.

PURPOSE: The purpose of these recommendations is to spread the available evidence for evaluating and managing spinal tumours among clinicians who encounter such entities. METHODS: The recommendations were developed by members of the Development Recommendations Group representing seven stakeholder scientific societies and organizations of specialists involved in various forms of care for patients with spinal tumours in Poland. The recommendations are based on data yielded from systematic reviews of the literature identified through electronic database searches. The strength of the recommendations was graded according to the North American Spine Society's grades of recommendation for summaries or reviews of studies. RESULTS: The recommendation group developed 89 level A-C recommendations and a supplementary list of institutions able to manage primary malignant spinal tumours, namely, spinal sarcomas, at the expert level. This list, further called an appendix, helps clinicians who encounter spinal tumours refer patients with suspected spinal sarcoma or chordoma for pathological diagnosis, surgery and radiosurgery. The list constitutes a basis of the network of expertise for the management of primary malignant spinal tumours and should be understood as a communication network of specialists involved in the care of primary spinal malignancies. CONCLUSION: The developed recommendations together with the national network of expertise should optimize the management of patients with spinal tumours, especially rare malignancies, and optimize their referral and allocation within the Polish national health service system.

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Systemic treatment of advanced clear cell sarcoma: results from a retrospective international series from the World Sarcoma Network.

BACKGROUND: Clear cell sarcoma (CCS) is a translocated aggressive malignancy with a high incidence of metastases and poor prognosis. There are few studies describing the activity of systemic therapy in CCS. We report a multi-institutional retrospective study of the outcomes of patients with advanced CCS treated with systemic therapy within the World Sarcoma Network (WSN). MATERIALS AND METHODS: Patients with molecularly confirmed locally advanced or metastatic CCS treated with systemic therapy from June 1985 to May 2021 were included. Baseline demographic and treatment information, including response by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, was retrospectively collected by local investigators. Descriptive statistics were carried out. RESULTS: Fifty-five patients from 10 institutions were included. At diagnosis, the median age was 30 (15-73) years and 24% (n = 13/55) had metastatic disease. The median age at diagnosis was 30 (15-73) years. Most primary tumours were at aponeurosis (n = 9/55, 16%) or non-aponeurosis limb sites (n = 17/55, 31%). The most common fusion was EWSR1-ATF1 (n = 24/55, 44%). The median number of systemic therapies was 1 (range 1-7). The best response rate was seen for patients treated with sunitinib (30%, n = 3/10), with a median progression-free survival of 4 [95% confidence interval (CI) 1-7] months. The median overall survival for patients with advanced/metastatic disease was 15 months (95% CI 3-27 months). CONCLUSIONS: Soft tissue sarcoma-type systemic therapies have limited benefit in advanced CCS and response rate was poor. International, multicentre prospective translational studies are required to identify new treatments for this ultra-rare subtype, and access to early clinical trial enrolment remains key for patients with CCS.

Acral lentiginous melanoma histotype predicts outcome in clinical stage I-II melanoma patients: an International multicenter study.

BACKGROUND: In the American Joint Committee on Cancer (AJCC) classification, acral lentiginous melanoma (ALM) histotype ALM is not included as an independent prognostic factor; in small series its negative prognostic impact on disease-free survival (DFS) and overall survival (OS) has been linked to the greater Breslow thickness (BT). PATIENTS AND METHODS: The study was carried out at four referral melanoma centers (three Italian and one Polish). Clinical consecutive patients with stage I-II melanoma, who were diagnosed, treated, and followed up between January 1998 and March 2018 in annotated specific databases were included. RESULTS: Overall, 6734 were evaluable, 4349 with superficial spreading melanoma (SSM), 2132 with nodular melanoma (NM), and 253 with ALM. At univariable analysis, a statistically significant worse DFS [hazard ratio (HR) 2.72, 95% confidence interval (CI) 2.24-3.30; P < 0.001] and OS (HR 2.67, 95% CI 2.15-3.32; P < 0.001) were found in patients with ALM compared with SSM. Similarly, the NM histotype was associated with a worse prognosis compared with the SSM histotype (DFS: HR 2.29, 95% CI 2.08-2.52; P < 0.001 and OS: HR 2.21, 95% CI 1.99-2.46; P < 0.001). At multivariable analysis, after adjusting for age, sex, BT, ulceration, and the sentinel lymph node status, a statistically significant worse DFS [adjusted HR (aHR; ALM versus SSM) 1.25, 95% CI 1.02-1.52; P = 0.028] was confirmed for patients with ALM. For patients with NM, instead, no impact of histology was found in terms of DFS [aHR (NM versus SSM) 1.04, 95% CI 0.93-1.15; P = 0.513] and OS [aHR (NM versus SSM) 0.96, 95% CI 0.86-1.08; P = 0.548]. CONCLUSIONS: ALM is associated with a worse long-term DFS. Our results could have important clinical implications for patients' stratification in future clinical trials and the incorporation of ALM histotype in the new AJCC classification as an independent prognostic factor.

Analysis of efficacy and safety of vismodegib therapy in patients with advanced basal cell carcinoma - real world multicenter cohort study.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequent non-melanoma skin cancer. The basis of treatment is surgical resection. The treatment of locally advanced and metastatic disease is currently based on sonidegb or vismodegib, small molecule inhibitors of the hedgehog signalling pathway. OBJECTIVES: The study aimed to retrospectively analyse the efficacy and safety of treatment with vismodegib in 108 patients with locally advanced or metastatic disease treated from August 1st, 2017 to December 31st, 2020. The primary objective was to evaluate the objective response rate (ORR), overall survival (OS) and progression-free survival rates. The secondary aims of the study were the disease control rate, the incidence of adverse events (AEs) and the estimation of the factors that potentially impact the treatment outcome and patient survival. METHODS: Patients treated in national drug programme were enrolled into this retrospective cohort study. Evaluation of the treatment efficacy was performed according to CT/MRI scans and by the response evaluation criteria in solid tumours (RECIST) 1.1. The safety evaluation was performed according to the Common Terminology Criteria for Adverse Events v. 5.0 (CTCAE) classification and severity assessment. RESULTS: The median duration of treatment was 14 months (range 1-94 months). The median progression-free survival reached 30.5 months (95% CI; 24.8-36.3), and the progression-free survival rate after 6, 12 and 24-months were 92%, 78% and 61%, respectively. The median overall survival was 41.5 months (95% CI; 31.6-51.3), and the overall survival rate after 1, 2 and 3 years accordingly 86%, 73% and 60%. The univariant and multivariant analysis indicated that the female gender is an independent positive prognostic factor of progression-free survival. CONCLUSIONS: The response to treatment is the prognostic factor for response maintenance and better overall survival. The therapy was well tolerated with the safety profile consistent in general with known from previous studies.

Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma.

BACKGROUND: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy. PATIENTS AND METHODS: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers. RESULTS: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Current landscape of ESMO/ASCO Global Curriculum adoption and medical oncology recognition: a global survey.

BACKGROUND: With the implementation of multidisciplinary treatment and development of multiple novel anticancer drugs in parallel with expanding knowledge of supportive and palliative care, a need for separate training and specialisation in medical oncology emerged. A Global Curriculum (GC) in medical oncology, developed and updated by a joint European Society for Medical Oncology/American Society of Clinical Oncology (ESMO/ASCO) GC Task Force/Working Group (GC WG), greatly contributed to the recognition of medical oncology worldwide. MATERIAL AND METHODS: ESMO/ASCO GC WG carried out a global survey on medical oncology recognition and GC adoption in 2019. RESULTS: Based on our survey, medical oncology is recognised as a separate specialty or sub-specialty in 47/62 (75%) countries participating in the survey; with a great majority of them (39/47, 83%) recognising medical oncology as a standalone specialty. Additionally, in 9 of 62 (15%) countries, medical oncology is trained together with haematology as a specialty in haemato-oncology or together with radiotherapy as a specialty in clinical oncology. As many as two-thirds of the responding countries reported that the ESMO/ASCO GC has been either fully or partially adopted or adapted in their curriculum. It has been adopted in a vast majority of countries with established training in medical oncology (28/41; 68%) and adapted in 12 countries with mixed training in haemato-oncology, clinical oncology or other specialty responsible for training on systemic anticancer treatment. CONCLUSIONS: With 75% of participating countries reporting medical oncology as a separate specialty or sub-specialty and as high as 68% of them reporting on GC adoption, the results of our survey on global landscape are reassuring. Despite a lack of data for some regions, this survey represents the most comprehensive and up-to-date information about recognition of medical oncology and GC adoption worldwide and will allow both societies to further improve the dissemination of the GC and global recognition of medical oncology, thus contributing to better cancer care worldwide.

The Extent of Task Specificity for Visual and Tactile Sequences in the Auditory Cortex of the Deaf and Hard of Hearing.

It has been proposed that the auditory cortex in the deaf humans might undergo task-specific reorganization. However, evidence remains scarce as previous experiments used only two very specific tasks (temporal processing and face perception) in visual modality. Here, congenitally deaf/hard of hearing and hearing women and men were enrolled in an fMRI experiment as we sought to fill this evidence gap in two ways. First, we compared activation evoked by a temporal processing task performed in two different modalities, visual and tactile. Second, we contrasted this task with a perceptually similar task that focuses on the spatial dimension. Additional control conditions consisted of passive stimulus observation. In line with the task specificity hypothesis, the auditory cortex in the deaf was activated by temporal processing in both visual and tactile modalities. This effect was selective for temporal processing relative to spatial discrimination. However, spatial processing also led to significant auditory cortex recruitment which, unlike temporal processing, occurred even during passive stimulus observation. We conclude that auditory cortex recruitment in the deaf and hard of hearing might involve interplay between task-selective and pluripotential mechanisms of cross-modal reorganization. Our results open several avenues for the investigation of the full complexity of the cross-modal plasticity phenomenon.SIGNIFICANCE STATEMENT Previous studies suggested that the auditory cortex in the deaf may change input modality (sound to vision) while keeping its function (e.g., rhythm processing). We investigated this hypothesis by asking deaf or hard of hearing and hearing adults to discriminate between temporally and spatially complex sequences in visual and tactile modalities. The results show that such function-specific brain reorganization, as has previously been demonstrated in the visual modality, also occurs for tactile processing. On the other hand, they also show that for some stimuli (spatial) the auditory cortex activates automatically, which is suggestive of a take-over by a different kind of cognitive function. The observed differences in processing of sequences might thus result from an interplay of task-specific and pluripotent plasticity.

Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

BACKGROUND: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. METHODS: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. DISCUSSION: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. TRIAL REGISTRATION: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆.

BACKGROUND: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. PATIENTS AND METHODS: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. RESULTS: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. CONCLUSIONS: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

The role of the superior parietal lobule in lexical processing of sign language: Insights from fMRI and TMS.

There is strong evidence that neuronal bases for language processing are remarkably similar for sign and spoken languages. However, as meanings and linguistic structures of sign languages are coded in movement and space and decoded through vision, differences are also present, predominantly in occipitotemporal and parietal areas, such as superior parietal lobule (SPL). Whether the involvement of SPL reflects domain-general visuospatial attention or processes specific to sign language comprehension remains an open question. Here we conducted two experiments to investigate the role of SPL and the laterality of its engagement in sign language lexical processing. First, using unique longitudinal and between-group designs we mapped brain responses to sign language in hearing late learners and deaf signers. Second, using transcranial magnetic stimulation (TMS) in both groups we tested the behavioural relevance of SPL's engagement and its lateralisation during sign language comprehension. SPL activation in hearing participants was observed in the right hemisphere before and bilaterally after the sign language course. Additionally, after the course hearing learners exhibited greater activation in the occipital cortex and left SPL than deaf signers. TMS applied to the right SPL decreased accuracy in both hearing learners and deaf signers. Stimulation of the left SPL decreased accuracy only in hearing learners. Our results suggest that right SPL might be involved in visuospatial attention while left SPL might support phonological decoding of signs in non-proficient signers.

Which medical disciplines diagnose and treat melanoma in Europe in 2019? A survey of experts from melanoma centres in 27 European countries.

BACKGROUND AND OBJECTIVES: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe. MATERIALS AND METHODS: A web-based survey of experts from melanoma centres in 27 European countries was conducted from 1 February to 1 August 2019. Data on diagnostic techniques, surgical and medical treatment, organization of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at P < 0.05. RESULTS: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons (SURG) per million inhabitants. In these countries, GPs and dermatologists (DER) were involved in melanoma detection; high percentage of DER used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists (ONC) and dermato-oncologists administered systemic treatments; and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards. CONCLUSION: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained DER in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, SURG, DER and ONC are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries will be needed to more accurately evaluate these first insights.

Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study.

BACKGROUND: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

Lipoxin (LTX A4 5S, 6R, 15R) levels drastically decrease after 5 years of hemodialysis treatment.

The increased risk of atherosclerosis in patients with chronic kidney disease (CKD) is associated with the increased concentration of fatty acids from the omega-6 family. Products of arachidonic acid oxidation, including prostaglandins, thromboxanes, hydroxyleicosa-tetraenoic acids (HETES) and hydroxyoctadecadienoic acids (HODES) are involved in the pathogenesis of cancer and cardiovascular diseases due to increased oxidative stress. The aim of our study was to determine the relations resulting from the duration of CKD treatment. One of our main concerns is, whether and when the cascade of synthesis of inflammatory mediators may be insufficient in patients with CKD during many years of treatment. The study involved 121 patients with CKD and 87 healthy volunteers. Eicosanoid profiles 9(S)-HODE, 13(S)-HODE, 5(S)-HETE, 12(S)-HETE, 15(S)-HETE, 5(S)-oxoETE, 16(RS)-HETE, and 5(S),6(R)-lipoxinA4, 5(S),6(R),15(R)-lipoxinA4 were extracted in plasma. The HPLC separations were performed by means of 1260 liquid chromatography. Patients with CKD have a significantly higher concentration of the following inflammatory mediators: 13(S)-HODE, 5(S)-HETE, 12(S)-HETE, 15(S)-HETE, 5(S)-oxoETE, 16(RS)-HETE, and 5(S),6(R), 15(R)-lipoxinA4 relative to the control group. However, the concentrations of 9(S)-HODE were lower in the CKD group. The comparison of sexes did not show significant differences in terms of CKD. A tendency for lower concentrations of HETE and HODE were observed in the group of men. 15LOX, 12LOX and 5LOX pathways in chronic kidney disease are increased, while COX are suppressed (9-HODE). The analysis of the treatment time of patients with CKD shows that incorrect levels of 5(S), 6(R) and 15(R)-lipoxinA4 are developed. We present a new evidence of possible concepts and future clinical interventions in patients suffering from chronic kidney disease for many years. These data for the first time demonstrate that lipoxin levels drastically decrease in the course of CKD. Therefore, synthetic LXA4 analogues may be used as an antioxidant therapy in CKD, which requires further research.