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Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor -subunits (HIF-) and their downstream targets. HIF-2 expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2 protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2 protein and mRNA. Depletion of other PHD family members had no effect on HIF-2 expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2 protein expression. Accordingly, PHD3 knockdown decreased HIF-2 target gene expression in ccRCC cells and expression was restored upon forced HIF-2 expression. The effect of PHD3 depletion was pinpointed to HIF2A mRNA stability. In line with these in vitro results, a strong positive correlation of PHD3 and HIF2A mRNA expression in ccRCC tumors was detected. Our results suggest that in contrast to the known negative regulation of HIF-2 in most cell types, high PHD3 expression in ccRCC cells maintains elevated HIF-2 expression and that of its target genes, which may enhance kidney cancer aggressiveness.

Oxaliplatin, combined with capecitabine (CAPOX) or infused 5-fluorouracil (FOLFOX), is standard of care in the adjuvant treatment of colorectal cancer (CRC). Prospective data on prevalence of oxaliplatin induced acute and long-term neuropathy in a real-life patient population and its effects on quality of life (QOL) and survival is limited, and scarce in CAPOX versus FOLFOX treated, especially in a subarctic climate.One hundred forty-four adjuvant CRC patients (all 72 CAPOX cases and 72 matched FOLFOX controls) were analyzed regarding oxaliplatin induced sensory neuropathy, which was graded according to NCI-CTCAEv3.0. Ninety-two long-term survivors responded to the QOL (EORTC QLQ-C30) and Chemotherapy-Induced Peripheral Neuropathy (EORTC CIPN20) questionnaires and were interviewed regarding long-term neuropathy.Acute neurotoxicity was present in 94% (136/144) during adjuvant therapy and there was a significant association between acute neurotoxicity and long-term neuropathy (p .001). Long-term neuropathy was present in 69% (grade 1/2/3/4 in 36/24/8/1%) at median 4.2 years. Neuropathy grades 2-4 did not influence global health status, but it was associated with decreased physical functioning (p = .031), decreased role functioning (p = .040), and more diarrhea (p = .021) in QLQ-C30 items. There were no differences in acute neurotoxicity, long-term neuropathy, or in QOL between CAPOX and FOLFOX treated. Neuropathy showed no pattern of variation according to starting and stopping month or treatment during winter.Neuropathy following oxaliplatin containing adjuvant chemotherapy is present in two-thirds, years after cessation, and impairs some QOL scales. There is no difference in severity of acute or long-term neuropathy between CAPOX and FOLFOX treated and QOL is similar. No seasonal variation in neuropathy was noted.

Colorectal carcinomas that are mismatch repair (MMR)‐deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch‐like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000–2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer‐relevant genes. Among 107 MMR‐deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E‐negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP‐positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population‐based study design. Significantly more frequent CIMP‐positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1‐methylated colorectal carcinomas with CIMP‐positive phenotype. peerReviewed

Background Daylight photodynamic therapy (DL-PDT) with methyl-5-aminolaevulinate (MAL) is an effective treatment for mild and moderate actinic keratosis (AK). Objectives To assess the clinical efficacy, tolerability and cost-effectiveness of 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) compared with MAL in DL-PDT for grade I-II AKs. Methods This nonsponsored, prospective randomized double-blind multicentre trial included 69 patients with 767 grade I-II AKs located symmetrically on the face or scalp. A single DL-PDT was given in a randomized split-face design. The primary outcome was clearance of the AKs at 12 months as assessed by a blinded observer. The secondary outcomes were pain, treatment reactions, cosmetic outcome and the cost-effectiveness of the therapy. Results In the per-patient (half-face) analysis, clearance was better for the BF-200 ALA sides than for those treated with MAL (P = 0·008). In total, BF-200 ALA cleared 299/375 AKs (79·7%) and MAL 288/392 (73·5%) (P = 0·041). The treatment was practically painless with both photosensitizers, the mean pain visual analogue scale being 1·51 for BF-200 ALA and 1·35 for MAL (P = 0·061). Twenty-six patients had a stronger skin reaction on the BF-200 ALA side, seven on the MAL side and 23 displayed no difference (P = 0·001). The cosmetic outcome was excellent or good in > 90% of cases with both photosensitizers (P = 1·000). The cost-effectiveness plane showed that the costs of DL-PDT were similar for both photosensitizers, but the effectiveness was slightly higher for BF-200 ALA. Conclusions Our results indicate that BF-200 ALA is more effective than MAL in DL-PDT for grade I-II AKs. BF-200 ALA provides slightly better value for money than MAL.

Cancer cachexia is a multifactorial syndrome characterized by anorexia, body wasting, and muscle and adipose tissue loss, impairing patient's tolerance to anticancer treatments and survival. The aim of the present study was to compare the effects induced in mice by tumor growth alone (C26) or in combination with chemotherapy [C26 oxaliplatin and 5-fluorouracil (oxfu)] and to evaluate the potential of moderate exercise. Oxfu administration to C26 mice exacerbated muscle wasting and triggered autophagy or mitophagy, decreased protein synthesis, and induced mitochondrial alterations. Exercise in C26 oxfu mice counteracted the loss of muscle mass and strength, partially rescuing autophagy and mitochondrial function. Nevertheless, exercise worsened survival in C26 oxfu mice in late stages of cachexia. In summary, chemotherapy further impinges on cancer-induced alterations, worsening muscle wasting. An ideal multifactorial and early intervention to prevent cancer cachexia could take advantage of exercise, improving patient's energy metabolism, mobility, and quality of life.-Ballaro, R., Beltra, M., De Lucia, S., Pin, F., Ranjbar, K., Hulmi, J. J., Costelli, P., Penna, F. Moderate exercise in mice improves cancer plus chemotherapy-induced muscle wasting and mitochondrial alterations.

Cancer is an exceptionally confounding disease that demands the development of powerful drug/drugs, without inducing heavy adverse side effects. Thus, different approaches have been applied to improve the targeted delivery of cancer drugs: for example by using nanocarriers. However, nanocarriers are foreign materials, which need further validation for their biocompatibility and biodegradability. In this study, we have chemically conjugated the hydrophilic anticancer drug doxorubicin (DOX) with the hydrophobic drug paclitaxel (PTX) through a redox-sensitive disulfide bond, abbreviated to DOX-S-S-PTX. Subsequently, due to its amphiphilic characterization, the prodrug can self-assemble into nanoparticles under microfluidic nanoprecipitation. These novel prodrug nanoparticles have a super-high drug loading degree of 89%, which is impossible to achieve by any nanocarrier systems, and can be tailored to 180 nm to deliver themselves to the target, and release DOX and PTX under redox conditions, which are often found in cancer cells. By evaluating cell viability in MDA-MB-231, MDA-MB-231/ADR and MEF cell lines, we observed that the prodrug nanoparticles effectively killed the cancer cells, and selectively conquered the MDA-MB-231/ADR. Meanwhile, MEF cells were spared due to their lack of a redox condition. The cell interaction results show that the reduced intermediate of the prodrug can also bind to parent drug biological targets. The hemolysis results show that the nanoparticles are biocompatible in blood. Computer modelling suggested that the prodrug is unlikely to bind to biological targets that parent drugs still strongly interact with. Finally, we confirm that the prodrug nanoparticles have no therapeutic effect in blood or healthy cells, but can selectively eliminate the cancer cells that meet the redox conditions to cleave the disulfide bond and release the drugs DOX and PTX.

The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-κB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy.

Purpose The aim of this retrospective single-center analysis was to evaluate the feasibility of fluorine-18 fluorodeoxyglucose (FDG)-PET imaging in evaluating metabolic response of preoperative chemotherapy in the treatment of locally advanced operable gastroesophageal adenocarcinoma and to investigate the association between histopathologic and FDG-PET response and overall survival. Methods Patients with locally advanced adenocarcinoma of distal esophagus, gastroesophageal junction or stomach were assessed for the study during 2008–2012. After evaluation with endoscopy, computed tomography and FDG-PET, patients with clinical stage II or III disease were assigned for perioperative EOX (epirubicin-oxaliplatin-capecitabine) treatment targeted at three cycles both pre- and postoperatively, if possible. Metabolic response was evaluated by repeated FDG-PET during or right after the second chemotherapy cycle. Becker tumor regression grade (TRG) was used to evaluate histopathologic response. For statistical purposes, the clinically significant cut-off for tumor maximum standardized uptake value (SUVmax) change (SUVδ%) was set at −35%. Results 54 patients were included in the study. 53 PET images were obtained before chemotherapy, 11 (21%) of those were PET negative. A major metabolic response was detected in 19 patients and major histopathologic response in 14 patients. No statistically significant association was observed between SUVδ% and histopathological responses. Median overall survival (OS) time of the patients was 49.9 months. No association between OS and PET response was found in our study. The administration of all six cycles of perioperative EOX was associated with improved OS. Conclusions Follow-up PET during or right after second preoperative chemotherapy cycle did not assist in identifying patients with favorable histopathological response or OS.

Myeloid cell leukemia 1 (Mcl1), is an antiapoptotic member of the Bcl-2 family proteins, has gained considerable importance due to its overexpression activity prevents the oncogenic cells to undergo apoptosis. This overexpression activity of Mcl1 eventually develops strong resistance to a wide variety of anticancer agents. Therefore, designing novel inhibitors with potentials to elicit higher binding affinity and specificity to inhibit Mcl1 activity is of greater importance. Thus, Mcl1 acts as an attractive cancer target. Despite recent experimental advancement in the identification and characterization of benzothiophene and benzofuran scaffold-merged compounds, the molecular mechanisms of their binding to Mcl1 are yet to be explored. The current study demonstrates an integrated approach – pharmacophore-based 3D-QSAR, docking, molecular dynamics (MD) simulation and free-energy estimation – to access the precise and comprehensive effects of current inhibitors targeting Mcl1 together with its known activity values. The pharmacophore – ANRRR.240 – based 3D-QSAR model from the current study provided high confidence (R2=0.9154, Q2=0.8736 and RMSE = 0.3533) values. Furthermore, the docking correctly predicted the binding mode of highly active compound 42. Additionally, the MD simulation for docked complex under explicit-solvent conditions together with free-energy estimation exhibited stable interaction and binding strength over the time period. Also, the decomposition analysis revealed potential energy contributing residues – M231, M250, V253, R265, L267 and F270 – to the complex stability. Overall, the current investigation might serve as a valuable insight, either to (i) improve the binding affinity of the current compounds or (ii) discover new generation anticancer agents that can effectively downregulate Mcl1 activity. Communicated by Ramaswamy H. Sarma

Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR. Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n 49) and MMR-proficient (MMR-P, n 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing. Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (1612, NEUROGI,CRABP1, and CDKN2A) and TSGs (SERPI and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas. Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. Fund: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid juselius Foundation, and HiL1FE. (C) 2019 Published by Elsevier B.V.

Background Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate? Methods To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease‐specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39‐year period (1977‐2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958‐1976). All patients received stage‐specific therapy according to the latest national guidelines, irrespective of the mode of detection. Results The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34‐0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44‐0.63) compared with the corresponding risks for nonparticipants. Conclusions Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated., After 20 years of follow‐up, women who participate in mammography screening have a 47% lower risk of dying from breast cancer. Although all patients with breast cancer potentially can benefit from advances in breast cancer therapy, women who participate in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than those who do not participate.

More people are living with the long-term effects of cancer owing to improvements in cancer treatments and an aging population. Many people diagnosed with cancer report a negative impact on sexual identity, sexual functioning, and their sexual relationship. Gynecologic cancer survivors are often the most severely affected. These cancers involve cancers of the ovaries, uterus, cervix, vagina, and vulva. The impact of these cancers on sexual health results not only from the disease process itself, but may also be due to the necessary treatments required. These can have a profound impact on psychological, physiological, and social well-being both in the short and long term, which may result in negative impact on the quality of life of the patient as well as her partner. Although most patients express that they would like to be more informed about sexual health and would like to have the opportunity to discuss these issues with their therapeutic team, sexual health is often not discussed with the patient.

Aim Immunotherapies blocking the CD47‐SIRPα pathway by targeting CD47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRPα exhibits relatively restricted tissue expression, SIRPα antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies (mAbs) against CD47 and/or SIRPα on gastroenterological tumors in syngeneic immunocompetent mouse models. Methods We used in vitro and in vivo phagocytosis assays in C57BL/6J (B6) mice to investigate anti‐CD47/SIRPα mAb effects on Hepa1‐6 and CMT93 originating from B6 mice. The influence of these mAbs on macrophage transmigration was also assessed. To investigate anti‐SIRPα mAb therapy‐induced inhibitory effects on sporadic colon cancer growth, we used a CDX2P9.5‐NLS Cre;APC + /FLOX (CPC‐APC) mouse model. Results Systemic anti‐SIRPα mAb administration significantly increased Hepa1‐6 and CMT93 cell susceptibility to macrophage phagocytosis, both in vitro and in vivo. Conversely, similarly administered anti‐CD47 mAb did not promote macrophage phagocytosis of target cells, whereas cells incubated with anti‐CD47 mAb prior to inoculation were more susceptible to macrophage phagocytosis. In vitro cell migration assays revealed that binding with anti‐CD47 mAb inhibited macrophage transmigration. Anti‐SIRPα mAb treatment inhibited tumor progression in CPC‐APC mice and significantly improved overall survival. Anti‐CD47 mAb administration in vivo eliminated the phagocytosis‐promoting CD47 blockade effect, probably by inhibiting macrophage transmigration/chemotaxis. In contrast, anti‐SIRPα mAb exhibited enhanced macrophage phagocytic activity and marked anti‐tumor effects against gastroenterological malignancies. Conclusion SIRPα mAb augmentation of macrophage phagocytic activity may represent an effective treatment strategy for human gastrointestinal tumors.

Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a network-based approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWS-FLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.

Background and purpose - Metal-on-metal (MoM) total hip arthroplasty (THA) and hip resurfacing arthroplasty (HRA) have been widely used during the early 21st century. We assessed the midterm risk of cancer of patients treated with modern MoM hip implants compared with patients with non-MoM hip implants and the general Finnish population with special interest in soft tissue sarcomas and basalioma due to the findings of our previous report. Patients and methods - All large-diameter head MoM THAs and hip resurfacings performed in Finland between 2001 and 2010 were extracted from the Finnish Arthroplasty Register (10,728 patients). Patients who underwent conventional THA formed the non-MoM reference cohort (18,235 patients). Data on cancer cases up to 2014 were extracted from the Finnish Cancer Registry. The relative risk of cancer in the general population was expressed as the ratio of observed to expected number of cases, i.e., standardized incidence ratio (SIR). Poisson regression analysis was used to compare the cancer risk between the cohorts. The mean follow-up was 7.4 years (1-14) in the MoM cohort and 8.4 years (1-14) in the non-MoM cohort. Results - The overall risk of cancer in the MoM cohort was comparable to the general Finnish population (SIR 0.9, 95% CI 0.9-1.0). Risk of basalioma in the MoM cohort was higher than in the general Finnish population (SIR 1.2, CI 1.1-1.4) and higher than in the non-MoM cohort in the stratified regression analysis (RR 1.2, CI 1.0-1.4, p = 0.02). The SIR of soft-tissue sarcoma in the MoM cohort was 1.4 (CI 0.6-2.8); the incidence was same as in the non-MoM cohort. Interpretation - Metal-on-metal hip implants are not associated with an increased overall risk of cancer during midterm follow-up.

BACKGROUND: Current nodal staging for salivary gland cancer (SGC) is extrapolated from mucosal head and neck squamous cell carcinoma. However, given their unique biology and clinical behavior, it is possible that a SGC-specific nodal staging system would be more accurate. METHODS: Patients from the National Cancer Database with non-metastatic SGC of the head and neck diagnosed from 2004 to 2013 and undergoing surgical resection and neck dissection removing at least 10 lymph nodes (LN) were included. Multivariable models were constructed to assess the association between survival and nodal factors, including number of metastatic LN, extranodal extension, LN size, and lower LN involvement. RESULTS: Overall, 4,520 patients met inclusion criteria. Increasing number of metastatic LN was strongly associated with worse survival without plateau. The risk of death increased more rapidly up to 4 LN (HR=1.34, 95% confidence interval (CI) 1.27-1.41, P

Background: In Finland, selective internal radiation therapy (SIRT) is at present the preferred first-line loco-regional therapy for uveal melanoma patients with hepatic metastases not suitable for surgery. We retrospectively evaluate the outcome and safety of SIRT in this group of patients.Material and methods: Yttrium-90 microspheres were delivered via the hepatic artery into the circulation of metastases from uveal melanoma in 18 patients with a predicted life expectancy of more than three months in three Finnish tertiary referral centers between November 2010 and December 2015. Progression-free survival (PFS), toxicity and overall survival (OS) were evaluated. Patients with historical uveal melanoma without extrahepatic metastases, who had received systemic chemotherapy as first-line treatment for their hepatic metastases at the Helsinki University Hospital between January 2006 and May 2010, were used as a historical control group.Results: Partial response and stable disease were observed in three (17%) and eight (44%) patients, respectively; one patient was not evaluable for response. Median PFS after SIRT was 5.6 (range, 1.3-40.8) months. Median OS after SIRT was 13.5 (range, 3.6-44.8) months compared with 10.5 (range, 3.0-16.5; p=.047) months for the historical chemotherapy group. Among patients who received SIRT as first-line treatment, the median OS was 18.7 (range, 8.2-44.8) months, significantly longer than that of the chemotherapy group (10.5 months, p=.017). There were no treatment-related deaths. Toxicity was mainly WHO grade 1-2 and self-limited.Conclusion: SIRT is a feasible and safe treatment for liver metastases in patients with uveal melanoma.

Objective:Post-operative bleeding in the head and neck area is potentially fatal. This ‘real world’ study sought to assess factors that increase the risk of re-operation for post-operative bleeding in head and neck cancer surgery.Methods:A total of 456 patients underwent surgery for head and neck cancer (591 operations). The primary endpoint was re-operation for bleeding.Results:The rate of re-operation for bleeding was 5 per cent of all operations. Re-operation for bleeding was an independent risk factor for 30-day mortality (odds ratio = 5.27, p = 0.014). Risk factors for re-operation because of bleeding included excessive (more than 4000 ml) fluid administration (over 24 hours) (p < 0.001), heavy alcohol consumption (p = 0.014), pre-operative oncological treatment (p = 0.017), advanced disease stage (p = 0.020) and higher tumour (T) classification (p = 0.034). Operations with more excessive bleeding (700 ml or more) were associated with an increased risk (p = 0.001) of re-operation for post-operative bleeding. Moreover, the risk of re-operation was significantly higher in patients undergoing microvascular surgery compared to those who had no oncological treatment pre-operatively (18 vs 6 per cent, p = 0.001).Conclusion:The 30-day mortality risk increased over 5-fold in patients undergoing re-operation for bleeding.

The cost of cancer and outcomes of cancer care have been discussed a lot since cancer represents 3-6% of total healthcare costs and cost estimations have indicated growing costs. There are studies considering the cost of all cancers, but studies focusing on the cost of disease and outcomes in most common cancer sites are limited. The objective of this study was to analyze the development of the costs and outcomes in Finland between 2009 and 2014 per cancer site.The National cost, episode and outcomes data were obtained from the National register databases based on International Statistical Classification of Diseases (ICD)-10 diagnosis codes. Cost data included both the direct and indirect costs. Two hospitals were used to validate the costs of care. The outcome measures included relative survival rate, mortality, sick leave days per patient and number of new disability pensions.The outcomes of cancer care in most common cancer sites have improved in Finland between 2009-2014. The real costs per new cancer patient decreased in seven out of ten most common cancer sites. The significance of different cost components differ significantly between the different cancer sites. The share of medication costs of the total cost of all cancers increased, but decreased for the five most common cancer sites.The changes in the cost components indicate that the length of stay has shortened in special care and treatment methods have developed towards outpatient care. This partially explains the decrease of costs. Also, at the same time outcomes improved, which indicates that decrease in costs did not come at the expense of treatment quality. As the survival rates increase, the relevance of mortality measures decreases and the relevance of other, patient-relevant outcome measures increases. In the future, the outcomes and costs of health care systems should be assessed routinely for the most common patient groups.

Objective We compared the self-sampling performance of the newly designed HerSwab™ device with a physician-collected cervical sample and another self-sample using the cobas® PCR Female swab for the detection of cervical intraepithelial neoplasia (CIN) and cancer. Methods Women referred for colposcopy at McGill University affiliated hospital clinics collected two consecutive self-samples, one with HerSwab™ and one with cobas® swab, after receiving instructions. The order of sampling was randomized. The colposcopist then collected a cervical sample and conducted a colposcopic examination. Samples were tested for human papillomavirus (HPV) DNA. Sensitivity and specificity to detect CIN2+ and respective 95% confidence intervals (CI) were calculated to compare sampling approaches. The HPV testing agreement between samples was measured using the Kappa statistic. Results Of 1217 women enrolled, 1076 had complete results for HPV and cytology; 148 (13.8%) had CIN1, 147 (13.7%) had CIN2/3, and 5 (0.5%) had cancer. There was very good agreement between methods for HPV detection (HerSwab™ versus physician: kappa=0.84; cobas® swabs versus physician: kappa=0.81; HerSwab™ versus cobas® swabs: kappa=0.87). The sensitivity of HPV detection for CIN2+ was 87.6% (95%CI: 79.8–93.2) with self-sampling using HerSwab™, 88.6% (95%CI: 80.9–94.0) with self-sampling using the cobas® swab, and 92.4% (95%CI: 85.5–96.7) with physician sampling. Corresponding estimates of specificity were 58.1% (95%CI: 54.1–62.1), 55.0% (95%CI: 50.9–59.0) and 58.7% (95%CI: 54.6–62.6). Cytology (ASC-US or more severe) done on the physician-collected specimen was 80.2% (95%CI: 70.8–87.6) sensitive and 61.4% (95%CI: 57.2–65.5) specific for CIN2+. Conclusions The HerSwab™ had good agreement with physician sampling in detecting HPV, and adequate performance in detecting high-grade lesions among women referred to colposcopy for abnormal cytology.

AIMS Oral tongue squamous cell carcinoma (OTSCC) has a relatively poor outcome, and there is a need to identify better prognostic factors. Recently, tumour-stroma ratio (TSR) has been associated with prognosis in several cancers. The aim of this multi-institutional study was to evaluate the prognostic value of TSR from original haematoxylin and eosin (HE)-stained tumour-resection slides in a series of early-stage (cT1-2N0) OTSCC patients. METHODS AND RESULTS A TSR cutoff value of 50% was used to divide the patients into stroma-rich (≥50%) and stroma-poor (