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Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-gamma response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.

Background Malignant pleural mesothelioma (MPM) is a rare but fatal cancer, which is largely caused by exposure to asbestos. Reliable information about the incidence of MPM prior the influence of asbestos is lacking. The nationwide regional incidence trends for MPM remain poorly characterized. We use nationwide MPM data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to assess incidence, mortality and survival trends for MPM in these countries. Methods We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1958 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization. Results The lowest incidence that we recorded for MPM was 0.02/100,000 for NO women and 0.05/100,000 for FI men in 1953–57, marking the incidence before the influence of asbestos. The highest rate of 1.9/100,000 was recorded for DK in 1997. Female incidence was much lower than male incidence. In each country, the male incidence trend for MPM culminated, first in SE around 1990. The regional incidence trends matched with earlier asbestos-related industrial activity, shipbuilding in FI and SE, cement manufacturing and shipbuilding in DK and seafaring in NO. Relative 1-year survival increased from about 20 to 50% but 5-year survival remained at or below 10%. Conclusion In the Nordic countries, the male incidence trends for MPM climaxed and started to decrease, indicating that the prevention of exposure was beneficial. Survival in MPM has improved for both sexes but long-term survival remains dismal.

In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer., SorLA interacts with HER2 and HER3 and positively regulates their oncogenic signaling. Here, we report that SorLA‐targeting antibody synergizes with trastuzumab to inhibit proliferation of HER2‐amplified, trastuzumab‐resistant breast cancer cells. In addition, SorLA ab monotherapy inhibits proliferation of breast cancer patient‐derived explant cultures. These results provide proof of principle that SorLA is a druggable target in breast cancer.

Dendritic cells (DC), the classic antigen-presenting cells of the immune system, switch from an adhesive, phagocytic phenotype in tissues, to a mature, nonadhesive phenotype that enables migration to lymph nodes to activate T cells and initiate antitumor responses. Monocyte-derived DCs are used in cancer immunotherapy, but their clinical efficacy is limited. Here, we show that cultured bone marrow–derived DCs (BM-DC) expressing dysfunctional β2-integrin adhesion receptors displayed enhanced tumor rejection capabilities in B16.OVA and B16-F10 melanoma models. This was associated with an increased CD8+ T-cell response. BM-DCs expressing dysfunctional β2-integrins or manipulated to disrupt integrin adhesion or integrin/actin/nuclear linkages displayed spontaneous maturation in ex vivo cultures (increased costimulatory marker expression, IL12 production, and 3D migration capabilities). This spontaneous maturation was associated with an altered DC epigenetic/transcriptional profile, including a global increase in chromatin accessibility and H3K4me3/H3K27me3 histone methylation. Genome-wide analyses showed that H3K4me3 methylation was increased on DC maturation genes, such as CD86, Il12, Ccr7, and Fscn1, and revealed a role for a transcription factor network involving Ikaros and RelA in the integrin-regulated phenotype of DCs. Manipulation of the integrin-regulated epigenetic landscape in wild-type ex vivo–cultured BM-DCs enhanced their functionality in tumor rejection in vivo. Thus, β2-integrin–mediated adhesion to the extracellular environment plays an important role in restricting DC maturation and antitumor responses through regulation of the cellular epigenetic and transcriptional landscape. Targeting β2-integrins could therefore be a new strategy to improve the performance of current DC-based cancer immunotherapies.

Background and Objective: The European Association for Palliative Care (EAPC) published recommendations for postgraduate education in palliative medicine in 2009. However, it is currently unknown how the EAPC remommendations are implemented in national programs, as audits of them are lacking. In Finland, the national society of palliative medicine has been organizing postgraduate palliative medicine training for experienced physicians since 2008, but the program has not been audited. The aim of this study was to perform a comprehensive analysis of the program. Design: In 2018-2019, a questionnaire on the Finnish Training Program for Palliative Medicine Competence was sent to past participants and delivered in person to current trainees. Learning outcomes were assessed with validated instruments for received skills and attitudes. All available educational archives were examined as well. Results: Forty-five (32 %) out of 155 specialists and 13 (38 %) out of 34 trainees responded. According to their assessments, the training provided them well with most skills required to work as palliative care specialists, but poorly with research capabilities. However, the Finnish program covers the EAPC guidelines well. Problem-based education, group work, and clinical excursions have been added to the latest curriculum. Maturation through work is needed for administrative and consultant competences. Conclusion: The EAPC guidelines can be included in a national course. The course had an important positive influence on the attitudes and learning of physicians in palliative medicine. The development of the education would benefit from pedagogical consultation. Uniform standards for auditing national programs should be developed.

Background Bone fractures are a global public health issue; however, to date, no comprehensive study of their incidence and burden has been done. We aimed to measure the global, regional, and national incidence, prevalence, and years lived with disability (YLDs) of fractures from 1990 to 2019. Methods Using the framework of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we compared numbers and age-standardised rates of global incidence, prevalence, and YLDs of fractures across the 21 GBD regions and 204 countries and territories, by age, sex, and year, from 1990 to 2019. We report estimates with 95% uncertainty intervals (UIs). Findings Globally, in 2019, there were 178 million (95% UI 162-196) new fractures (an increase of 33.4% [30.1-37.0] since 1990), 455 million (428-484) prevalent cases of acute or long-term symptoms of a fracture (an increase of 70.1% [67.5-72.5] since 1990), and 25.8 million (17.8-35.8) YLDs (an increase of 65.3% [62.4-68.0] since 1990). The age-standardised rates of fractures in 2019 were 2296.2 incident cases (2091.1-2529.5) per 100 000 population (a decrease of 9.6% [8.1-11.1] since 1990), 5614.3 prevalent cases (5286.1-5977.5) per 100 000 population (a decrease of 6.7% [5.7-7.6] since 1990), and 319.0 YLDs (220.1-442.5) per 100 000 population (a decrease of 8.4% [7.2-9.5] since 1990). Lower leg fractures of the patella, tibia or fibula, or ankle were the most common and burdensome fracture in 2019, with an age-standardised incidence rate of 419.9 cases (345.8-512.0) per 100 000 population and an age-standardised rate of YLDs of 190.4 (125.0-276.9) per 100 000 population. In 2019, age-specific rates of fracture incidence were highest in the oldest age groups, with, for instance, 15 381.5 incident cases (11 245.3-20 651.9) per 100 000 population in those aged 95 years and older. Interpretation The global age-standardised rates of incidence, prevalence, and YLDs for fractures decreased slightly from 1990 to 2019, but the absolute counts increased substantially. Older people have a particularly high risk of fractures, and more widespread injury-prevention efforts and access to screening and treatment of osteoporosis for older individuals should help to reduce the overall burden. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.

Background Metaplastic breast cancer (MpBC) is a heterogeneous subtype of invasive mammary carcinoma associated with epithelial-mesenchymal transition (EMT) and cancer stem cell characteristics. Data regarding prognostic markers and potentially actionable targets for therapy are still limited. The present study aimed to characterize the immunohistochemical landscape of this rare malignancy and to identify potential prognostic factors and targets for therapy. Material and methods A total of 75 patients diagnosed with MpBC over a 15-year period were included in the study. We performed immunohistochemical analyses for Ki-67 (MIB-1), epidermal growth factor receptor (EGFR), cytokeratin 5/6, vimentin, CD44, and androgen receptor (AR) and correlated their expression with clinicopathologic features and clinical outcomes. The p-values for survival analyses were corrected for multiple testing (threshold 0.01). Results Most tumors expressed CK5/6 (73%), EGFR (59%), CD44 (81%), and vimentin (87%). Eighty-nine percent had a high Ki-67 index. Eighty-four percent were classified as basal-like (CK 5/6 or EGFR positive). AR was expressed in 21% of the tumors. The basal-like phenotype was significantly (p = 0.009) associated with inferior disease-free (DFS) and breast-cancer-specific overall survival (BCOS) with borderline significance (p = 0.01). In addition, a low Ki-67 index was associated with improved DFS (p = 0.033) and BCOS (p = 0.03). Conclusion Most MpBCs express basal markers (CK5/6, EGFR), epithelial-mesenchymal transition marker vimentin, and the stem cell marker CD44. Expression of basal-like markers was significantly related to inferior DFS. All the 11 patients with a lack of expression of basal markers survived without relapse.

While the abundance and phenotype of tumor-infiltrating lymphocytes are linked with clinical survival, their spatial coordination and its clinical significance remain unclear. Here, we investigated the immune profile of intratumoral and peritumoral tissue of clear cell renal cell carcinoma patients (n = 64). We trained a cell classifier to detect lymphocytes from hematoxylin and eosin stained tissue slides. Using unsupervised classification, patients were further classified into immune cold, hot and excluded topographies reflecting lymphocyte abundance and localization. The immune topography distribution was further validated with The Cancer Genome Atlas digital image dataset. We showed association between PBRM1 mutation and immune cold topography, STAG1 mutation and immune hot topography and BAP1 mutation and immune excluded topography. With quantitative multiplex immunohistochemistry we analyzed the expression of 23 lymphocyte markers in intratumoral and peritumoral tissue regions. To study spatial interactions, we developed an algorithm quantifying the proportion of adjacent immune cell pairs and their immunophenotypes. Immune excluded tumors were associated with superior overall survival (HR 0.19, p = 0.02) and less extensive metastasis. Intratumoral T cells were characterized with pronounced expression of immunological activation and exhaustion markers such as granzyme B, PD1, and LAG3. Immune cell interaction occurred most frequently in the intratumoral region and correlated with CD45RO expression. Moreover, high proportion of peritumoral CD45RO+ T cells predicted poor overall survival. In summary, intratumoral and peritumoral tissue regions represent distinct immunospatial profiles and are associated with clinicopathologic characteristics.

Objectives Acquired von Willebrand syndrome (AVWS) is a rare and frequently underdiagnosed bleeding disorder with an unknown prevalence. The diagnosis of AVWS is made based on laboratory investigations and the presence of clinical symptoms. Evaluation and management of affected patients are complex due to the need for multiple laboratory assays. Materials and Methods Here, we describe the clinical and laboratory data of seven patients with a diagnosis of AVWS. All patients met the criteria for AVWS based on laboratory findings, bleeding symptoms, and the absence of any previous history of a bleeding disorder. Results In all cases, the laboratory findings, lack of bleeding anamnesis, and family history suggested the presence of AVWS. Von Willebrand factor multimeric analysis showed decreased high-molecular weight (HMW) multimers in six cases. Patients with lower HMW multimers experienced more severe bleeding complications. Conclusions The diagnosis of AVWS is complex and requires extensive laboratory evaluation. Interdisciplinary collaboration and complex laboratory evaluations are of paramount importance for the early recognition of AVWS and optimal AVWS diagnosis as well as successful clinical management.

Introduction: Predicting the bleeding phenotype is crucial for the management of patients with moderate haemophilia. Global coagulation assays evaluate haemostasis more comprehensively than conventional methods. Aim: To explore global coagulation assays and the bleeding phenotype of patients with moderate haemophilia A (MHA) and B (MHB). Methods: The MoHem study is a cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Thromboelastometry in whole blood and thrombin generation (TG) in platelet-poor plasma (1, 2.5 and 5 pM tissue factor (TF)) were compared with joint health (Haemophilia Joint Health Score (HJHS)) and treatment modality. Results: We report on 61 patients from Oslo and Helsinki: 24 MHA and 37 MHB. By TG (2.5 pM TF), patients who had been without replacement therapy during the previous 12 months depicted higher endogenous thrombin potential (P =.03). In contrast, those who had low ETP (< median) captured higher HJHS (P =.02). Patients who had undergone orthopaedic surgery generated least thrombin (P =.02). By thromboelastometry, those without the need of factor consumption had short clotting times, and quick times to maximum velocity (< median values) (P =.03). Factor VIII/factor IX activity (FVIII/FIX:C) did not align with the bleeding phenotype, but FIX:C ≤ 3 IU/dL was associated with lower peak thrombin (P =.03). Conclusion: TG differentiated patients with moderate haemophilia according to HJHS, annual factor consumption, and whether orthopaedic surgery had been performed. Thromboelastometry differentiated according to factor consumption only. Global coagulation assays may assist predicting the bleeding phenotype in moderate haemophilia. (Less)

Purpose To investigate clinical and radiological factors predicting worse outcome after (chemo)radiotherapy ([C]RT) in oropharyngeal squamous cell carcinoma (OPSCC) with a focus on apparent diffusion coefficient (ADC). Methods This retrospective study included 67 OPSCC patients, treated with (C)RT with curative intent and diagnosed during 2013–2017. Human papilloma virus (HPV) association was detected with p16 immunohistochemistry. Of all 67 tumors, 55 were p16 positive, 9 were p16 negative, and in 3 the p16 status was unknown. Median follow-up time was 38 months. We analyzed pretreatment magnetic resonance imaging (MRI) for factors predicting disease-free survival (DFS) and locoregional recurrence (LRR), including primary tumor volume and the largest metastasis. Crude and p16-adjusted hazard ratios were analyzed using Cox proportional hazards model. Interobserver agreement was evaluated. Results Disease recurred in 13 (19.4%) patients. High ADC predicted poor DFS, but not when the analysis was adjusted for p16. A break in RT (hazard ratio, HR = 3.972, 95% confidence interval, CI 1.445–10.917, p = 0.007) and larger metastasis volume (HR = 1.041, 95% CI 1.007–1.077, p = 0.019) were associated with worse DFS. A primary tumor larger than 7 cm3 was associated with increased LRR rate (HR = 4.861, 1.042–22.667, p = 0.044). Among p16-positive tumors, mean ADC was lower in grade 3 tumors compared to lower grade tumors (0.736 vs. 0.883; p = 0.003). Conclusion Low tumor ADC seems to be related to p16 positivity and therefore should not be used independently to evaluate disease prognosis or to choose patients for treatment deintensification.

The KIT D816V mutation is found in >80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor, and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, a US Food and Drug Administration–approved angiokinase inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the adenosine triphosphate binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V–targeted therapy of advanced SM.

The role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000–2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group (p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively (p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group (p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting.

Introduction Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). Aim To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. Methods PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). Results Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. Conclusion The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.

Background Metastasectomy is probably underused in metastatic colorectal cancer. The aim of this study was to investigate the effect of centralized repeated assessment on resectability rate of liver metastases. Methods The prospective RAXO study was a nationwide study in Finland. Patients with treatable metastatic colorectal cancer at any site were eligible. This planned substudy included patients with baseline liver metastases between 2012 and 2018. Resectability was reassessed by the multidisciplinary team at Helsinki tertiary referral centre upfront and twice during first-line systemic therapy. Outcomes were resectability rates, management changes, and survival. Results Of 812 patients included, 301 (37.1 per cent) had liver-only metastases. Of these, tumours were categorized as upfront resectable in 161 (53.5 per cent), and became amenable to surgery during systemic treatment in 63 (20.9 per cent). Some 207 patients (68.7 per cent) eventually underwent liver resection or ablation. At baseline, a discrepancy in resectability between central and local judgement was noted for 102 patients (33.9 per cent). Median disease-free survival (DFS) after first resection was 20 months and overall survival (OS) 79 months. Median OS after diagnosis of metastatic colorectal cancer was 80, 32, and 21 months in R0–1 resection, R2/ablation, and non-resected groups, and 5-year OS rates were 68, 37, and 9 per cent, respectively. Liver and extrahepatic metastases were present in 511 patients. Of these, tumours in 72 patients (14.1 per cent) were categorized as upfront resectable, and 53 patients (10.4 per cent) became eligible for surgery. Eventually 110 patients (21.5 per cent) underwent liver resection or ablation. At baseline, a discrepancy between local and central resectability was noted for 116 patients (22.7 per cent). Median DFS from first resection was 7 months and median OS 55 months. Median OS after diagnosis of metastatic colorectal cancer was 79, 42, and 17 months in R0–1 resection, R2/ablation, and non-resected groups, with 5-year OS rates of 65, 39, and 2 per cent, respectively. Conclusion Repeated centralized resectability assessment in patients with colorectal liver metastases improved resection and survival rates.

BackgroundFew studies have focused on patient-related factors in analyzing long-term functional outcome and health-related quality of life (HRQoL) in patients with postoperative lower extremity soft tissue sarcoma (STS).ObjectiveThe purpose of this study was to investigate factors associated with postoperative functional outcome and HRQoL in patients with lower extremity STS.MethodsThis cross-sectional study was performed in a tertiary referral center using the Toronto Extremity Salvage Score (TESS), Quality-of-Life Questionnaire (QLQ)-C30 and 15 Dimension (15D) measures. Functional outcome and HRQoL data were collected prospectively. All patients were treated by a multidisciplinary team according to a written treatment protocol.ResultsA total of 141 patients who had undergone limb-salvage surgery were included. Depending on the outcome measure used, 19–51% of patients were completely asymptomatic and 13–14% of patients had an unimpaired HRQoL. The mean score for TESS, 15D mobility score, and QLQ-C30 Physical Functioning scale were 86, 0.83, and 75, respectively, while the mean score for 15D was 0.88, and 73 for QLQ-C30 QoL. Lower functional outcome was statistically significantly associated with higher age, higher body mass index (BMI), and the need for reconstructive surgery and radiotherapy, while lower HRQoL was statistically significantly associated with higher age, higher BMI, and reconstructive surgery.ConclusionFunctional outcome and HRQoL were generally high in this cross-sectional study of patients with STS in the lower extremity. Both tumor- and treatment-related factors had an impact but patient-related factors such as age and BMI were the major determinants of both functional outcome and HRQoL.

Background Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM). Methods For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM. Results MM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis. Conclusions Esterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.

Background Second primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce. Objective In this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks. Design, setting, and participants Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register. Outcome measurements and statistical analysis We employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC. Results and limitations We identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC. Conclusions The bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits. Patient summary Close to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer., Take Home Message The study results recommend considering strategies for early detection and prevention of second primary cancer. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits.

Background/Aim: Preclinical studies on metformin use and endometrial cancer have been promising but epidemiological studies have reported variable results. This study aimed to assess if metformin use is associated with endometrial cancer aggressiveness and survival in women with type 2 diabetes (T2D). Patients and methods: This retrospective hospital-based cohort consisted of women with T2D who were treated for endometrial cancer at the Oulu University Hospital, Finland, between 2007 and 2014. Results: The sample size was 121 patients: 58 metformin users and 63 metformin non-users. Intriguingly, type 2 histology, deep myometrial invasion and the presence of lymphovascular invasion were more common in the metformin user group. However, metformin use showed no association with overall survival and progression-free survival. Conclusion: Metformin use was associated with poorer prognostic factors in endometrial cancer patients with T2D.

Medir la vacunación infantil de rutina es crucial para informar las políticas mundiales de vacunación y la implementación de programas, y para hacer un seguimiento del progreso hacia los objetivos establecidos por el Plan de Acción Mundial sobre Vacunas (GVAP) y la Agenda de Inmunización 2030. Se necesitan estimaciones sólidas de la cobertura de vacunación de rutina para identificar los éxitos pasados ​​y persistentes. vulnerabilidades. A partir del Estudio de la carga global de enfermedades, lesiones y factores de riesgo (GBD) 2020, versión 1, realizamos un análisis sistemático de las tendencias de cobertura de vacunas a nivel mundial, regional y nacional utilizando un marco estadístico, por vacuna y a lo largo del tiempo. Métodos Para este análisis recopilamos 55 326 observaciones específicas del país, de la cohorte, del año, de la vacuna y de la dosis de la cobertura de vacunación infantil de rutina entre 1980 y 2019. Utilizando el proceso de regresión gaussiana espaciotemporal, Estimaciones específicas por año de 11 indicadores de cobertura de vacunación infantil de rutina para 204 países y territorios desde 1980 hasta 2019, ajustando los sesgos en los datos informados por los países y reflejando los desabastecimientos informados y las interrupciones en el suministro. Analizamos las tendencias mundiales y regionales en la cobertura y el número de niños con dosis cero (definidos como aquellos que nunca recibieron una dosis de vacuna contra la difteria, el tétanos y la tos ferina [DTP]), el progreso hacia los objetivos del GVAP y la relación entre la cobertura de la vacuna y el desarrollo sociodemográfico. Recomendaciones Para 2019, la cobertura mundial de la tercera dosis de DTP (DTP3; 81,6 % [intervalo de incertidumbre del 95 % 80,4–82,7]) se duplicó con creces con respecto a los niveles estimados en 1980 (39,9 % [37,5–42 ·1]), al igual que la cobertura mundial de la vacuna antisarampionosa de primera dosis (MCV1; del 38,5 % [35,4–41,3] en 1980 al 83,6 % [82,3–84,8 ] en 2019). La cobertura de la vacuna antipoliomielítica de tercera dosis (Pol3) también aumentó, del 42,6 % (41,4–44,1) en 1980 al 79,8 % (78,4–81,1) en 2019, y la cobertura mundial de vacunas más nuevas Las vacunas aumentaron rápidamente entre 2000 y 2019. La cantidad mundial de niños que recibieron dosis cero se redujo en casi un 75 % entre 1980 y 2019, de 56,8 millones (52,6–60,9) a 14,5 millones (13,4– 15·9). Sin embargo, durante la última década, la cobertura mundial de vacunas se estabilizó en general; 94 países y territorios registraron una disminución de la cobertura de DTP3 desde 2010. Se estimó que solo 11 países y territorios alcanzaron el objetivo nacional del GVAP de al menos una cobertura del 90 % para todas las vacunas evaluadas en 2019. Interpretación Después de lograr grandes avances en la cobertura de vacunación infantil en todo el mundo, en gran parte del mundo este progreso se estancó o se revirtió de 2010 a 2019. Estos hallazgos subrayan la importancia de revisar las estrategias de inmunización de rutina y los enfoques programáticos, centrando la prestación de servicios en torno a la equidad y las poblaciones desatendidas. Fortalecer los datos de vacunas y los sistemas de monitoreo es crucial para estas actividades, ahora y hasta 2030, para garantizar que todos los niños tengan acceso y puedan beneficiarse de las vacunas que salvan vidas. Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dose-specific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in country-reported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. Findings By 2019, global coverage of third-dose DTP (DTP3; 81·6% [95% uncertainty interval 80·4–82·7]) more than doubled from levels estimated in 1980 (39·9% [37·5–42·1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38·5% [35·4–41·3] in 1980 to 83·6% [82·3–84·8] in 2019). Third-dose polio vaccine (Pol3) coverage also increased, from 42·6% (41·4–44·1) in 1980 to 79·8% (78·4–81·1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56·8 million (52·6–60·9) to 14·5 million (13·4–15·9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. Interpretation After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines.

Publisher Copyright: © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Background: The association between frailty and specialized healthcare utilization is not well studied. We, therefore, examined the utilization of specialized healthcare services among frail Finnish older adults. Methods: A sub-sample of 1060 participants of the Helsinki Birth Cohort Study were followed prospectively for specialized healthcare utilization from nationwide registers between the years 2013 and 2017. The participants’ frailty status was assessed according to Fried’s criteria at a mean age of 71.0 (2.7 SD) years between the years 2011 and 2013. A negative binomial regression model was used to examine the association between frailty and the total number of visits, emergency visits, outpatient appointments separating the first outpatient appointments and the follow-up appointments, inpatient care including elective and non-elective hospital admissions and the total number of hospital days. We also calculated average length of stay (ALOS) and used the Kruskal–Wallis test to examine the differences between the groups. Results: After adjusting for covariates, frailty was significantly associated with the number of specialized healthcare visits (IRR 1.50, 95% CI = 1.04–2.15) and all subgroups of visits apart from follow-up outpatient appointments. Frailty was particularly strongly associated with the number of hospital days (IRR 5.24, 95% CI = 2.35–11.7) and notably with emergency visits (IRR = 2.26, 95% CI = 1.45–3.51) and hospital admissions (IRR 2.23, 95% CI = 1.39–3.56). Frail older adults had also higher ALOS compared to non-frail participants (p =.009). Conclusions: Frailty increases the use of most specialized healthcare services. Preventative interventions against frailty are needed to decrease the burden on specialized healthcare systems.KEY MESSAGE Frailty is associated with the utilization of most specialized healthcare services, the most expensive part of the healthcare in most high-income countries. The association of frailty with inpatient care is particularly strong. Preventative interventions against frailty are needed to decrease the burden on specialized healthcare systems.

Background: Patient-reported outcomes (PROS) are widely accepted measures for evaluating outcomes of surgical interventions. As patient-reported information is stored in electronic health records, it is essential that there are valid electronic PRO (ePRO) instruments available for clinicians and researchers. The aim of this study was to evaluate the validity of electronic versions of five widely used foot and ankle specific PRO instruments. Methods: Altogether 111 consecutive elective foot/ankle surgery patients were invited face-to-face to participate in this study. Patients completed electronic versions of the Foot and Ankle Ability Measure (FAAM), the Foot and Ankle Outcome Score (FAOS), the modified Lower Extremity Function Scale (LEFS), the Manchester-Oxford Foot Questionnaire (MOXFQ), and the Visual Analogue Scale Foot and Ankle (VAS-FA) on the day of elective foot and/or ankle surgery. Construct validity, coverage, and targeting of the scales were assessed. Results: Based on general and predefined thresholds, construct validity, coverage, and targeting of the ePRO versions of the FAAM, the FAOS, the MOXFQ, and the VAS-FA were acceptable. Major issues arose with score distribution and convergent validity of the modified LEFS instrument. Conclusions: The ePRO versions of the FAAM, the FAOS, the MOXFQ and the VAS-FA provide valid scores for foot and ankle patients. However, our findings do not support the use of the modified LEFS as an electronic outcome measure for patients with orthopedic foot and/or ankle pathologies. (C) 2020 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10–90th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49–61%), which increases to 84% (71–97%) with a high PRS ( > 90th percentile), and decreases to 49% (30–68%) with a low PRS (, Identifying women at high risk of breast cancer has important implications for screening. Here, the authors demonstrate that polygenic risk scores improve breast cancer risk prediction in the population, in women with mutations in high-risk genes and in women with close relatives with the disease.

Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings The global TFR decreased from 2.72 (95% uncertainty interval [UI] 2.66-2.79) in 2000 to 2.31 (2.17-2.46) in 2019. Global annual livebirths increased from 134.5 million (131.5-137.8) in 2000 to a peak of 139.6 million (133.0-146.9) in 2016. Global livebirths then declined to 135.3 million (127.2-144.1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2.1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27.1% (95% UI 26.4-27.8) of global livebirths. Global life expectancy at birth increased from 67.2 years (95% UI 66.8-67.6) in 2000 to 73.5 years (72.8-74.3) in 2019. The total number of deaths increased from 50.7 million (49.5-51.9) in 2000 to 56.5 million (53.7-59.2) in 2019. Under-5 deaths declined from 9.6 million (9.1-10.3) in 2000 to 5.0 million (4.3-6.0) in 2019. Global population increased by 25.7%, from 6.2 billion (6.0-6.3) in 2000 to 7.7 billion (7.5-8.0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58.6 years (56.1-60.8) in 2000 to 63.5 years (60.8-66.1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.

Objective: High heparin doses during cardiopulmonary bypass (CPB) have been suggested to reduce thrombin activation and consumption coagulopathy and consequently bleeding complications. The authors investigated the effect of a high heparin dose during CPB on point-of-care measurements of coagulation. The authors hypothesized that during CPB a high heparin dose compared with a lower heparin dose would reduce thrombin generation and platelet activation and tested whether this would be reflected in the results of rotational thromboelastometry (TEM) and platelet aggregation, measured with multiple electrode aggregometry (MEA). Design: Prospective, randomized, controlled, open single-center study. Setting: University teaching hospital. Participants: Sixty-three consecutive patients undergoing elective coronary artery bypass grafting with CPB were enrolled. Interventions: Patients were randomly assigned to receive either a high (600 IU/kg, n = 32) or a low (300 IU/kg, n = 31) initial dose of heparin. Target levels of activated clotting time during CPB were >600 seconds in the high heparin dose group and >400 seconds in the low heparin dose group. Measurements and Main Results: Blood samples were collected (1) preoperatively after induction of anesthesia, (2) 10 minutes after aortic declamping, (3) 30 minutes after protamine administration, and (4) 3 hours after protamine administration. TEM and MEA were then measured. There was no difference in blood loss up to 18 hours postoperatively (median 735 mL for high dose v 610 mL for low dose; p

Background Many cancers are increased in immunosuppressed patients and evidence is accumulating that immune dysfunction may be a contributing risk factor for second primary cancers (SPCs). The aim of this study was to explore the potential influence of immune mechanisms in SPC. Methods We used the Swedish Cancer Registry (1990‐2015) to select 13 male and 14 female first primary cancers (FPCs) that are known to be related to immune suppression. We assessed relative risks (RRs) for any of these as concordant (same first and second cancer) and discordant FPC‐SPC pairs. Hierarchical clustering of significant RRs was performed for cancers as FPC and SPC. Results Concordant risks for SPCs were excessive in men and women for nasal (RRs 59.3 for men and 150.6 for women), tongue/mouth (51.7 and 100.8), and lip (32.4 and 61.2) cancers. Heatmaps showed that some cancers, such as skin cancer, tongue/mouth cancers, and non‐Hodgkin lymphoma had multiple bidirectional associations as FPC and SPC. Nasal cancer and chronic lymphocytic leukemia had associations mainly as FPC while liver and kidney cancers showed most associations as SPC. Conclusions Immune dysfunction may be a plausible contributing factor for most of the associations, which calls for experimental verification., Relative risks for a single second primary cancer after any first primary cancer (top), and RRs for any second primary cancer after a single first primary cancer (bottom). Male data are blue and female data in yellow symbols. The vertical bars show 95%CIs. NHL, non‐Hodgkin lymphoma, CLL, chronic lymphocytic leukemia.

Oncolytic adenoviruses are promising cancer therapeutic agents. Clinical data have shown adenoviruses’ ability to transduce tumors after systemic delivery in human cancer patients, despite antibodies. In the present work, we have focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and human erythrocytes. Ad5/3 binding with human lymphocytes and erythrocytes was observed to occur in a reversible manner, which allowed viral transduction of tumors, and oncolytic potency of Ad5/3 in vitro and in vivo, with or without neutralizing antibodies. Immunodeficient mice bearing xenograft tumors showed enhanced tumor transduction following systemic administration, when Ad5/3 virus was bound to lymphocytes or erythrocytes (P

Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients withTP53missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 andTP53status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression andTP53mutations on survival (hazard ratio of 3 center dot 1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Glioblastomas and brain metastases (BM) of solid tumours are the most common central nervous system neoplasms associated with very unfavourable prognosis. In this study, we report the association of prostate-specific membrane antigen (PSMA) with various clinical parameters in a large cohort of primary and secondary brain tumours. A tissue microarray containing 371 cases of ascending grades of gliomas pertaining to astrocytic origin and samples of 52 cases of primary lung carcinomas with matching BM with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in BM arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumour cell expression. This result correlated with the results obtained from the in silico (cancer genome databases) analyses. In gliomas, only the vascular expression of PSMA associated with poor overall survival but not the tumour cell expression. In the matched primary lung cancers and their BM (n = 52), vascular PSMA expression in primary tumours associated with significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report that the vascular expression of PSMA in the primary and secondary brain tumours globally associates with the malignant progression and poor outcome of the patients.

Background Although statements on the competencies required from physicians working within palliative care exist, these requirements have not been described within different levels of palliative care provision by multi-professional workshops, comprising representatives from working life. Therefore, the aim of this study was to describe the competencies required from physicians working within palliative care from the perspectives of multi-professional groups of representatives from working life. Methods A qualitative approach, using a workshop method, was conducted, wherein the participating professionals and representatives of patient organizations discussed the competencies that are required in palliative care, before reaching and documenting a consensus. The data (n = 222) was collected at workshops held in different parts of Finland and it was analyzed using a qualitative content analysis method. Results The description of the competencies required of every physician working within palliative care at the general level included 13 main categories and 50 subcategories in total. ‘Competence in advanced care planning and decision-making’ was the main category which was obtained from the highest number of reduced expressions from the original data (f = 125). Competence in social interactions was another strong main category (f = 107). In specialist level data, six main categories with 22 subcategories in total were found. ‘Competence in complex symptom management’ was the main category which was obtained from the biggest number of reduced expressions (f = 46). A notable association between general level and specialist level data was related to networking, since one of the general level categories was ‘Competence in consultations and networking’ (f = 34) and one of the specialist level categories was ‘Competence to offer consultative and educational support to other professionals’ (f = 30). Moreover, part of the specialist level results were subcategories which belonged to the main categories produced from the general level data. Conclusions The competencies described in this study emphasize decision-making, social interactions and networking. It is important to listen to the voices of the working-life representatives when planning curricula. Moreover, the views of the working-life representatives inform how the competencies gained during their education meet the challenges of the ordinary work.

BACKGROUND Autologous stem cell transplantation is an established treatment option for patients with multiple myeloma (MM) or non-Hodgkin?s lymphoma (NHL). STUDY DESIGN AND METHODS In this prospective multicenter study, 147 patients with MM were compared with 136 patients with NHL regarding the mobilization and apheresis of blood CD34+ cells, cellular composition of infused blood grafts, posttransplant recovery, and outcome. RESULTS Multiple myeloma patients mobilized CD34+ cells more effectively (6.3???106/kg vs. 3.9???106/kg, p?=?0.001). The proportion of poor mobilizers (peak blood CD34+ cell count 100?days) nonrelapse mortality (NRM; 6% vs. 0%, p?=?0.003). CONCLUSIONS Non-Hodgkin?s lymphoma and MM patients differ in terms of mobilization of CD34+ cells, graft cellular composition, and posttransplant recovery. Thus, the optimal graft characteristics may also be different.

BACKGROUND AND PURPOSE Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. METHODS Trial participation required a recent embolic stroke of undetermined source. Patients' history of cancer was recorded at the time of study entry. During a mean follow-up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. RESULTS Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78-1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71-2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67-9.96; P for interaction 0.95). All-cause mortality was similar in both groups. CONCLUSIONS Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909).

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC(0-infinity)) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P

Contains fulltext : 248798.pdf (Publisher’s version ) (Open Access) Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.

Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus"). Virus was given intratumorally (to one of the two tumors only) and aPD-1 monoclonal antibody systemically. We evaluated both tumors' response to treatment, overall survival, metastasis development, and immunological mechanisms involved with response. Consistent tumor control was observed in both injected and non-injected tumors, including complete response in all treated animals receiving aPD-1+ virus therapy. Mechanistically, virus injections enabled potent effector lymphocyte response locally, with systemic effects in non-injected tumors facilitated by aPD-1 treatment. Moreover, adenovirus therapy demonstrated immunological memory formation. Virus therapy was effective in preventing metastasis development. Local treatment with TNFa and IL-2 coding adenovirus enhanced systemic response to aPD-1 therapy, by re-shaping the microenvironment of both injected and non-injected tumors. Therefore, our pre-clinical data support the rationale for a trial utilizing a combination of aPD-1 plus virus for the treatment of human cancer.

Interest in functional outcome (FO) and health-related quality of life (HRQL) in extremity soft-tissue sarcoma (STS) patients has increased. The aim of this study was to validate two FO questionnaires for upper extremity STS patients: the Toronto Extremity Salvage Score (TESS) and short version of the Disability of Arm, Shoulder and Hand (QuickDASH), based on Finnish population data. A multi-center study was conducted at two academic sarcoma centers. Surgically treated upper extremity STS patients were invited to participate. Patients completed the TESS and the QuickDASH with HRQL questionnaires the 15D and the QLQ-C30. The scores were analyzed and compared. Fifty-five patients with a mean follow-up period of 4.7 years were included. Mean age was 63 years (standard deviation [SD] 14.6). The mean score for TESS was 88.5 (SD 15.1) and for QuickDASH 17.8 (SD 19.6). The QuickDASH had a statistically significantly better score coverage. A ceiling effect was noted, 27% and 20% for TESS and QuickDASH, respectively. The TESS and QuickDASH scores were strongly correlated ( r =-0.89). The TESS score strongly correlated with the QLQ-C30 ( r = 0.79) and the 15D score ( r = 0.70). The QuickDASH score correlated strongly with the QLQ-C30 score ( r =-0.71) and moderately with the 15D score ( r =-0.56). The TESS score had a statistically significantly stronger correlation with the 15D score than QuickDASH ( p < 0.005). Both the TESS and the QuickDASH provide reliable scores for assessing FO in upper extremity STS patients. The QuickDASH has a better coverage, whereas TESS showed a stronger correlation to HRQL scores. (c) 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Mantle cell lymphoma (MCL) is a rare, often aggressive type of B-cell lymphoma with poor survival and no cure. Cancer and cancer treatment has a negative impact on health-related quality of life (HRQOL) both during active disease and in the long term, and improvement of HRQOL is a crucial objective of cancer therapy in older patients and no curative intent. Baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Here, we explored HRQOL, and its association with survival, by the EORTC QLQ-C30 questionnaire, before, during and after chemotherapy in a patient cohort with mantle cell lymphoma, treated within the NLG-MCL4 trial, designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment. Fifty-one patients were enrolled, median age was 71 years (range 62-84), 37 were men (73%). Pre-treatment HRQOL was similar to scores from the reference population with healthy individuals. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. There was a correlation between physical function (p=0.001) and role function (p=0.006) at baseline and WHO performance status, but not with other clinical or genetic prognostic factors. None of the baseline factors were predictive for treatment related to HRQOL in this cohort. Pre-treatment physical (p=0.011) and role function (p=0.032) were independent factors associated with overall survival, and physical function (p=0.002) was also associated with progression free survival. These findings may possibly be used to design support during treatment and improve rehabilitation. Further investigations are needed for assessment of long-term HRQOL. This article is protected by copyright. All rights reserved.

Purpose: This study aims to compare the feasibility of VAE and BLES in the treatment of intraductal papillomas. Material and methods: Patients with a suspected intraductal papilloma who underwent a BLES or a VAE procedure were included in this retrospective study. The BLES procedures were performed between November 2011 and June 2016 and the VAE procedures between May 2018 and September 2020 at the Department of Radiology of Helsinki University Hospital (HUH). The procedures were performed with an intent of complete removal of the lesions. Results: In total, 72 patients underwent 78 BLES procedures and 95 patients underwent 99 VAE procedures. Altogether 52 (60%) papillomas with or without atypia were completely removed with VAE, whereas 24 (46%) were completely removed with BLES, p = 0.115. The median radiological size of the high-risk lesions completely removed with BLES was 6 mm (4-12 mm), whereas with VAE it was 8 mm (3-22 mm), p = 0.016. Surgery was omitted in 90 (94.7%) non-malignant breast lesions treated with VAE and in 66 (90.4%) treated with BLES, p = 0.368. Conclusion: Both VAE and BLES were feasible in the treatment of intraductal papillomas. In most non-malignant lesions surgery was avoided, but VAE was feasible in larger lesions than BLES. However, follow-up ultrasound was needed more often after VAE. The histopathologic assessment is more reliable after BLES, as the lesion is removed as a single sample. (C) 2021 The Authors. Published by Elsevier Ltd.

We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. Significance: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR β and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN-α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity. Title in Web of Science: Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study

Simple Summary:& nbsp;gamma delta T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, gamma delta T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of gamma delta T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of gamma delta T-cell transformation, summarising the resulting gamma delta T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies.& nbsp;gamma delta T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional alpha beta T cells, gamma delta T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. gamma delta T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-gamma or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, gamma delta T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of gamma delta T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of gamma delta T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of gamma delta T-cell transformation, summarising the main gamma delta T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.

Although the development of hematopoietic stem cells (HSC) has been studied in great detail, their heterogeneity and relationships to different cell lineages remain incompletely understood. Moreover, the role of Vascular Adhesion Protein-1 in bone marrow hematopoiesis has remained unknown. Here we show that VAP-1, an adhesin and a primary amine oxidase producing hydrogen peroxide, is expressed on a subset of human HSC and bone marrow vasculature forming a hematogenic niche. Bulk and single-cell RNAseq analyses reveal that VAP-1+ HSC represent a transcriptionally unique small subset of differentiated and proliferating HSC, while VAP-1− HSC are the most primitive HSC. VAP-1 generated hydrogen peroxide acts via the p53 signaling pathway to regulate HSC proliferation. HSC expansion and differentiation into colony-forming units are enhanced by inhibition of VAP-1. Contribution of VAP-1 to HSC proliferation was confirmed with mice deficient of VAP-1, mice expressing mutated VAP-1 and using an enzyme inhibitor. In conclusion, VAP-1 expression allows the characterization and prospective isolation of a new subset of human HSC. Since VAP-1 serves as a check point-like inhibitor in HSC differentiation, the use of VAP-1 inhibitors enables the expansion of HSC. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-021-03977-6.

Coagulation disturbances are common in severe COVID-19 infection. We examined laboratory markers in COVID-19 patients during the first wave of the pandemic in Finland. We analysed a wide panel of coagulation tests (IL ACL TOP 750/500) from anonymously collected samples of 78 hospitalized COVID-19 patients in intensive care units (ICUs; n = 34) or medical wards (n = 44) at Helsinki University Hospital in April-May 2020. These coagulation data were supplemented with the laboratory information system results, including complete blood count and C reactive protein (CRP). Coagulation and inflammatory markers were elevated in most: FVIII in 52%, fibrinogen 77%, D-dimer 74%, CRP 94%, platelet count 37%. Anaemia was common, especially in men (73% vs. 44% in women), and overall weakly correlated with FVIII (women R-2 = 0.48, men R-2 = 0.24). ICU patients had higher fibrinogen and D-dimer levels (p < .01). Men admitted to the ICU also had higher platelet count, leukocytes and FVIII and lower haemoglobin than the non-ICU patients. None of the patients met the disseminated intravascular coagulation (DIC) criteria, but 31% had a D-dimer level of at least 1.5 mg/L. Presence of both anaemia and high D-dimer together with FVIII is independently associated with ICU admission. Antithrombin was reduced in 47% of the patients but did not distinguish severity. Overall, CRP was associated with coagulation activation. Elevated FVIII, fibrinogen and D-dimer reflected a strong inflammatory response and were characteristic of hospitalized COVID-19 patients. The patients were often anaemic, as is typical in severe inflammation, while anaemia was also associated with coagulation activity.

Large granular lymphocyte leukemia (LGLL) is characterized by somatic gain-of-function STAT3 mutations. However, the functional effects of STAT3 mutations on primary LGLL cells have not been studied in detail. In this study, we show that CD8+ T cells isolated from STAT3 mutated LGLL patients have high protein levels of epigenetic regulators, such as DNMT1, and are characterized by global hypermethylation. Correspondingly, treatment of healthy CD8+ T cells with IL-6, IL-15, and/or MCP-1 cytokines resulted in STAT3 activation, increased DNMT1, EZH2, c-MYC, l-MYC, MAX, and NFκB levels, increased DNA methylation, and increased oxidative stress. Similar results were discovered in KAI3 NK cells overexpressing gain-of-function STAT3Y640F and STAT3G618R mutants compared to KAI3 NK cells overexpressing STAT3WT. Our results also confirm that STAT3 forms a direct complex with DNMT1, EZH2, and HDAC1. In STAT3 mutated LGLL cells, DNA methyltransferase (DNMT) inhibitor azacitidine abrogated the activation of STAT3 via restored SHP1 expression. In conclusion, STAT3 mutations cause DNA hypermethylation resulting in sensitivity to DNMT inhibitors, which could be considered as a novel treatment option for LGLL patients with resistance to standard treatments.

Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence >6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence >6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).