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  • Vakkilainen, Svetlana; Taskinen, Mervi; Klemetti, Paula; Pukkala, Eero; Mäkitie, Outi (2019)
    Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95% CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95% CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95% CI = 9.5-130). Mortality associated with birth length below-4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95% CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio= 3.9, 95% CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95% CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95% CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95% CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
  • Esterhuizen, Karien; Lindeque, J. Zander; Mason, Shayne; van der Westhuizen, Francois H.; Suomalainen, Anu; Hakonen, Anna H.; Carroll, Christopher J.; Rodenburg, Richard J.; de Laat, Paul B.; Janssen, Mirian C. H.; Smeitink, Jan A. M.; Louw, Roan (2019)
    We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A > G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.
  • Lassfolk, Robert; Rahkila, Jani; Johansson, Mikael Peter; Ekholm, Filip Sebastian; Wärnå, Johan; Leino, Reko (2019)
    Acetylated oligosaccharides are common in nature. While they are involved in several biochemical and biological processes, the role of the acetyl groups and the complexity of their migration has largely gone unnoticed. In this work, by combination of organic synthesis, NMR spectroscopy and quantum chemical modeling, we show that acetyl group migration is a much more complex phenomenon than previously known. By use of synthetic oligomannoside model compounds, we demonstrate, for the first time, that the migration of acetyl groups in oligosaccharides and polysaccharides may not be limited to transfer within a single monosaccharide moiety, but may also involve migration over a glycosidic bond between two different saccharide units. The observed phenomenon is not only interesting from the chemical point of view, but it also raises new questions about the potential biological role of acylated carbohydrates in nature.
  • Pollari, Marjukka; Pellinen, Teijo; Karjalainen-Lindsberg, Marja-Liisa; Kellokumpu-Lehtinen, Pirkko-Liisa; Leivonen, Suvi-Katri; Leppä, Sirpa (2020)
    Objectives Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival. Methods We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T-cells (CTLs; CD8(+), OX40(+), Granzyme B+, Ki-67(+), LAG-3(+), TIM-3(+), PD-1(+)), CD4(+)T-cells (CD3(+), CD4(+), TIM-3(+), LAG-3(+)), regulatory T-cells (Tregs; CD3(+), CD4(+), FoxP3(+)), and T helper 1 cells (Th1; CD3(+), CD4(+), T-bet(+)) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome. Results We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8(+)TILs were Ki-67(+)and TIM-3(+)CTLs, whereas the most prominent CD4(+)TILs were FoxP3(+)Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet(+)FoxP3(+)Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features. Conclusions Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.
  • Murphy, Natalie A.; Arthur, Karissa C.; Tienari, Pentti J.; Houlden, Henry; Chio, Adriano; Traynor, Bryan J. (2017)
    A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
  • Laaksovirta, Hannu; Launes, Jyrki; Jansson, Lilja; Traynor, Bryan J.; Kaivola, Karri; Tienari, Pentti J. (2022)
    Background and Objectives To analyze the frequencies of major genetic variants and the clinical features in Finnish patients with amyotrophic lateral sclerosis (ALS) with or without the C9orf72 hexanucleotide repeat expansion. Methods A cohort of patients with motor neuron disease was recruited between 1993 and 2020 at the Helsinki University Hospital and 2 second-degree outpatient clinics in Helsinki. Finnish ancestry patients with ALS fulfilled the diagnosis according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined FALS-A if at least 1 first- or second-degree family member had ALS, and FALS-NP, if family members had additional neurologic or psychiatric endophenotypes. Results Of the 815 patients, 25% had FALS-A and 45% FALS-NP. C9orf72 expansion (C9pos) was found in 256 (31%) of all patients, in 58% of FALS-A category, in 48% of FALS-NP category, and in 23 or 17% of sporadic cases using the FALS-A or FALS-NP definition. C9pos or SOD1 p.D91A homozygosity was found in 328 (40%) of the 815 patients. We compared demographic and clinical characteristics between C9pos and patients with unknown cause of ALS (Unk). We found that the age at onset was significantly earlier and survival markedly shorter in the C9pos vs Unk patients with ALS. The shortest survival was found in bulbar-onset male C9pos patients, whereas the longest survival was found in Unk limb-onset males. Older age at onset associated consistently with shorter survival in C9pos and Unk patients in both limb-onset and bulbaronset groups. There were no significant differences in the frequencies of bulbar-onset and limbonset patients in C9pos and Unk groups. ALS-frontotemporal dementia (FTD) was more common in C9pos (17%) than in Unk (4%) patients, and of all patients with ALS-FTD, 70% were C9pos. Discussion These results provide further evidence for the short survival of C9orf72-associated ALS. A prominent role of the C9orf72 and SOD1 variants was found in the Finnish population. An unusually high frequency of C9pos was also found among patients with sporadic ALS. The enrichment of these 2 variants likely contributes to the high incidence of ALS in Finland.
  • Jacob, Laurent; Boisserand, Ligia Simoes Braga; Geraldo, Luiz Henrique Medeiros; Neto, Jose de Brito; Mathivet, Thomas; Antila, Salli; Barka, Besma; Xu, Yunling; Thomas, Jean-Mickael; Pestel, Juliette; Aigrot, Marie-Stephane; Song, Eric; Nurmi, Harri; Lee, Seyoung; Alitalo, Kari; Renier, Nicolas; Eichmann, Anne; Thomas, Jean-Leon (2019)
    Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO(+)-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.
  • Milatovic, B.; Saponjski, J.; Huseinagic, H.; Moranjkic, M.; Medenica, S. Milosevic; Marinkovic, I.; Nikolic, Milos; Marinkovic, S. (2018)
    Background: Identification and anatomic features of the feeding arteries of the arteriovenous malformations (AVMs) is very important due to neurologic, radiologic, and surgical reasons. Materials and methods: Seventy-seven patients with AVMs were examined by using a digital subtraction angiographic (DSA) and computerised tomographic (CT) examination, including three-dimensional reconstruction of the brain vessels. In addition, the arteries of 4 human brain stems and 8 cerebral hemispheres were microdissected. Results: The anatomic examination showed a sporadic hypoplasia, hyperplasia, early bifurcation and duplication of certain cerebral arteries. The perforating arteries varied from 1 to 8 in number. The features of the leptomeningeal and choroidal vessels were presented. The radiologic examination revealed singular (22.08%), double (32.48%) or multiple primary feeding arteries (45.45%), which were dilated and elongated in 58.44% of the patients. The feeders most often originated from the middle cerebral artery (MCA; (23.38%), less frequently from the anterior cerebral artery (ACA; 12.99%), and the posterior cerebral artery (PCA; 10.39%). Multiple feeders commonly originated from the ACA and MCA (11.69%), the MCA and PCA (10.39%), the ACA and PCA (7.79%), and the ACA, MCA and PCA (5.19%). The infratentorial feeders were found in 9.1% of the AVMs. Contribution from the middle meningeal and occipital arteries was seen in 3.9% angiograms. Two cerebral arteries had a saccular aneurysm. The AVM haemorrhage appeared in 63.6% of patients. Conclusions: The knowledge of the origin and anatomic features of the AVMs feeders is important in the explanation of neurologic signs, and in a decision regarding the endovascular embolisation, neurosurgical and radiosurgical treatments.
  • Palmerini, Emmanuela; Leithner, Andreas; Windhager, Reinhard; Gosheger, Georg; Boye, Kjetil; Laitinen, Minna; Hardes, Jendrik; Traub, Frank; Jutte, Paul; Willegger, Madeleine; Casanova, Jose; Setola, Elisabetta; Righi, Alberto; Picci, Piero; Donatih, Davide Maria; Ferrari, Stefano (2020)
    Angiosarcoma of bone (B-AS) is a rare malignant tumor of vascular origin. The aim of this retrospective study is to report on treatments and prognosis. Data were collected from the EMSOS website. 80 patients in 9 centers included: 51 male/29 female; median age 54 years (range 17 to 92); 56% with localized disease, 44% metastatic. Primary tumor surgery: 76% (30% amputation, 26% intralesional margins); radiotherapy (RT): 41%; chemotherapy (CT): 47% (56% in metastatic, 41% in localized cases). With a median follow-up of 31 months (range 40 to 309), 5-year overall survival (OS) was 27% (95%CI 16-30): 41% (95%CI 25-56) for localized patients, and 8% (95%CI 0-20) for metastatic (p = 0.002). In metastatic patients, 1 year OS was significantly influenced by chemotherapy response: 67% (95CI% 29-100) for those who responded or had stable disease (n = 7), and 18% (95CI% 0-41) for patients with progressive disease (n = 11), p 0.002. The surgical complete remission (SCR) status was pivotal in localized patients (5-year OS 45% for SCR, 17% no SCR, p = 0.03); also 5-year OS was significantly influenced by age and site of the tumor. After multivariate analysis, the addition of radiotherapy to surgery significantly influenced the disease-free survival (DFS) rate, whereas the use of chemotherapy lost the significance showed at the univariate analysis. Overall, patients with metastatic B-AS have a dismal prognosis, with a prolonged survival in case with a response to chemotherapy. Experimental trials with more active systemic treatment regimens are needed. In patients with localized disease, the patient's age and site of the tumor are prognostic factors and any effort must be made to achieve an SCR status. No definitive conclusions can be drawn from our data on the use of adjuvant chemotherapy, while the use of adjuvant radiotherapy might improve DSF in patients surgically free of disease.
  • Ng, Wai Tong; But, Barton; Choi, Horace C. W.; de Bree, Remco; Lee, Anne W. M.; Lee, Victor H. F.; Lopez, Fernando; Mäkitie, Antti A.; Rodrigo, Juan P.; Saba, Nabil F.; Tsang, Raymond K. Y.; Ferlito, Alfio (2022)
    Introduction: Nasopharyngeal carcinoma (NPC) is endemic to Eastern and South-Eastern Asia, and, in 2020, 77% of global cases were diagnosed in these regions. Apart from its distinct epidemiology, the natural behavior, treatment, and prognosis are different from other head and neck cancers. With the growing trend of artificial intelligence (AI), especially deep learning (DL), in head and neck cancer care, we sought to explore the unique clinical application and implementation direction of AI in the management of NPC. Methods: The search protocol was performed to collect publications using AI, machine learning (ML) and DL in NPC management from PubMed, Scopus and Embase. The articles were filtered using inclusion and exclusion criteria, and the quality of the papers was assessed. Data were extracted from the finalized articles. Results: A total of 78 articles were reviewed after removing duplicates and papers that did not meet the inclusion and exclusion criteria. After quality assessment, 60 papers were included in the current study. There were four main types of applications, which were auto-contouring, diagnosis, prognosis, and miscellaneous applications (especially on radiotherapy planning). The different forms of convolutional neural networks (CNNs) accounted for the majority of DL algorithms used, while the artificial neural network (ANN) was the most frequent ML model implemented. Conclusion: There is an overall positive impact identified from AI implementation in the management of NPC. With improving AI algorithms, we envisage AI will be available as a routine application in a clinical setting soon.
  • Niinikoski, Laura; Hukkinen, Katja; Leidenius, Marjut H. K.; Ståhls, Anders; Meretoja, Tuomo J. (2018)
    Objectives: This study aims to evaluate the feasibility of Breast Lesion Excision System (BLES) in the treatment of intraductal papillomas. Material and methods: All patients with a needle biopsy-based suspicion of an intraductal papilloma who consequently underwent a BLES procedure at Helsinki University Hospital between 2011 and 2016 were included in this retrospective study. The purpose of the BLES procedure was either to excise the entire lesion or in few cases to achieve better sampling. Results: In total, 74 patients underwent 80 BLES procedures. Pathological diagnosis after the BLES biopsy confirmed an intraductal papilloma without atypia in 43 lesions, whereas 10 lesions were upgraded to high-risk lesions (HRL) with either atypical ductal hyperplasia or lobular carcinoma in situ. Five cases were upgraded to malignancy, two were invasive ductal carcinomas and three were ductal carcinoma in situ. Additionally, 18 lesions were diagnosed as other benign lesions. Four procedures failed. Complete excision with BLES was achieved in 19 out of 43 intraductal papillomas, 6 out of 10 HRL and two out of five malignant lesions. No major complications occurred. The BLES procedure was adequate in the management of the 71 breast lesions. Conclusion: The BLES procedure is an acceptable method for the management of small benign and high-risk breast lesions such as intraductal papillomas in selected patients. Thus, a great amount of diagnostic surgical biopsies can be avoided. (C) 2017 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
  • Traenka, Christopher; Dougoud, Daphne; Simonetti, Barbara Goeggel; Metso, Tiina Maria; Debette, Stephanie; Pezzini, Alessandro; Kloss, Manja; Grond-Ginsbach, Caspar; Majersik, Jennifer J.; Worrall, Bradford B.; Leys, Didier; Baumgartner, Ralf; Caso, Valeria; Bejot, Yannick; Compter, Annette; Reiner, Peggy; Thijs, Vincent; Southerland, Andrew M.; Bersano, Anna; Brandt, Tobias; Gensicke, Henrik; Touze, Emmanuel; Martin, Juan J.; Chabriat, Hugues; Tatlisumak, Turgut; Lyrer, Philippe; Arnold, Marcel; Engelter, Stefan T. (2017)
    Objective: In a cohort of patients diagnosed with cervical artery dissection (CeAD), to determine the proportion of patients aged >= 60 years and compare the frequency of characteristics (presenting symptoms, risk factors, and outcome) in patients aged = 60 years. Methods: We combined data from 3 large cohorts of consecutive patients diagnosed with CeAD (i. e., Cervical Artery Dissection and Ischemic Stroke Patients-Plus consortium). We dichotomized cases into 2 groups, age >= 60 and Results: Among 2,391 patients diagnosed with CeAD, we identified 177 patients (7.4%) aged >= 60 years. In this age group, cervical pain (ORadjusted 0.47 [0.33-0.66]), headache (ORadjusted 0.58 [0.42-0.79]), mechanical trigger events (ORadjusted 0.53 [0.36-0.77]), and migraine (ORadjusted 0.58 [0.39-0.85]) were less frequent than in younger patients. In turn, hypercholesterolemia (ORadjusted 1.52 [1.1-2.10]) and hypertension (ORadjusted 3.08 [2.25-4.22]) were more frequent in older patients. Key differences between age groups were confirmed in secondary analyses. In multivariable, adjusted analyses, favorable outcome (i. e., modified Rankin Scale score 0-2) was less frequent in the older age group (ORadjusted 0.45 [0.25, 0.83]). Conclusion: In our study population of patients diagnosed with CeAD, 1 in 14 was aged >= 60 years. In these patients, pain and mechanical triggers might be missing, rendering the diagnosis more challenging and increasing the risk ofmissed CeAD diagnosis in older patients.
  • Nicoli, Taija K; Saat, Riste; Tarkkanen, Jussi; Kinnunen, Ilpo; Mäkitie, Antti A.; Jero, Jussi (2022)
    Plexiform variants of neurofibromas and schwannomas are rare and typically arise in superficial soft tissues in the head and neck region. The treatment of these tumors is challenging and no generally accepted guidelines exist for their optimal management. The purpose of this study was to review the management and longterm prognosis of head and neck plexiform neurofibromas and schwannomas at 2 tertiary care academic hospitals in Finland over a 31-year period. The pathology files were searched for plexiform neurofibromas and schwannomas between the years 1990 and 2020. The case notes were reviewed for full management details. Two plexiform schwannomas and 6 plexiform neurofibromas were identified. Five of the 6 plexiform neurofibromas were managed operatively. All patients with a surgically managed plexiform neurofibroma underwent multiple operations. Sclerotherapy abolished 1 patient's cutaneous plexiform neurofibromas. The management of plexiform neurofibromas and plexiform schwannomas remains challenging. Sclerotherapy may offer a promising management option for cutaneous plexiform neurofibromas.
  • Ruonala, Verneri; Pekkonen, Eero; Airaksinen, Olavi; Kankaanpää, Markku; Karjalainen, Pasi A.; Rissanen, Saara M. (2022)
    Objective Deep brain stimulation (DBS) is an effective treatment for motor symptoms of advanced Parkinson's disease (PD). Currently, DBS programming outcome is based on a clinical assessment. In an optimal situation, an objectively measurable feature would assist the operator to select the appropriate settings for DBS. Surface electromyographic (EMG) measurements have been used to characterise the motor symptoms of PD with good results; with proper methodology, these measurements could be used as an aid to program DBS. Methods Muscle activation measurements were performed for 13 patients who had advanced PD and were treated with DBS. The DBS pulse voltage, frequency, and width were changed during the measurements. The measured EMG signals were analysed with parameters that characterise the EMG signal morphology, and the results were compared to the clinical outcome of the adjustment. Results The EMG signal correlation dimension, recurrence rate, and kurtosis changed significantly when the DBS settings were changed. DBS adjustment affected the signal recurrence rate the most. Relative to the optimal settings, increased recurrence rates (median ± IQR) 1.1 ± 0.5 (-0.3 V), 1.3 ± 1.1 (+0.3 V), 1.7 ± 0.4 (-30 Hz), 1.7 ± 0.8 (+30 Hz), 2.0 ± 1.7 (+30 μs), and 1.5 ± 1.1 (DBS off) were observed. With optimal stimulation settings, the patients' Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) score decreased by 35% on average compared to turning the device off. However, the changes in UPRDS-III arm tremor and rigidity scores did not differ significantly in any settings compared to the optimal stimulation settings. Conclusion Adjustment of DBS treatment alters the muscle activation patterns in PD patients. The changes in the muscle activation patterns can be observed with EMG, and the parameters calculated from the signals differ between optimal and non-optimal settings of DBS. This provides a possibility for using the EMG-based measurement to aid the clinicians to adjust the DBS.
  • Makinen, Netta; Kampjarvi, Kati; Frizzell, Norma; Butzow, Ralf; Vahteristo, Pia (2017)
    Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.
  • Kaimio, Mirja; Malkamäki, Sanna; Kaukonen, Maria; Ahonen, Saija; Hytönen, Marjo K.; Rantala, Merja; Lohi, Hannes; Saijonmaa-Koulumies, Leena; Laitinen-Vapaavuori, Outi (2021)
    American Cocker Spaniels (ACSs) develop aural ceruminous gland hyperplasia and ectasia more often than dogs of other breeds. Data on the cause and development of these breed characteristic histopathological changes are lacking. We performed video-otoscopic examinations and dermatological work-up on 28 ACSs, obtained aural biopsies from each dog and assessed the statistical associations between the presence of ceruminous gland hyperplasia and ectasia and disease history, clinical or microbiological findings and underlying cause of otitis externa (OE). Histological lesions of ceruminous gland hyperplasia and ectasia were observed in aural biopsies from 6/13 clinically healthy ears and 13/15 ears with OE from 19/28 examined dogs. Nine of 28 dogs had histologically normal ceruminous glands (odds ratio [OR] 6.2, 95% confidence interval [CI] 1.1-36.6). Bacterial growth in microbiological culture of aural exudate (OR 14.1, 95% CI 2.1-95.3) was associated with ceruminous glandular changes, whereas previous history of OE, cutaneous findings or underlying allergies were not. Pedigree analysis and a genome-wide association study (GWAS) were performed on 18 affected and eight unaffected dogs based on histopathological diagnosis. While the GWAS indicated a tentative, but not statistically significant, association of ceruminous gland hyperplasia and ectasia with chromosome 31, a larger cohort is needed to confirm this preliminary result. Based on our results, ceruminous gland hyperplasia and ectasia may also precede clinical signs of OE in ACSs and a genetic aetiological component is likely Further studies with larger cohorts are warranted to verify our preliminary results. (C) 2021 The Authors. Published by Elsevier Ltd.
  • Passador-Santos, F.; Gronroos, M.; Irish, J.; Gilbert, R.; Gullane, P.; Perez-Ordonez, B.; Makitie, A.; Leivo, I. (2016)
    Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).
  • Alabi, Rasheed Omobolaji; Mäkitie, Antti A.; Pirinen, Matti; Elmusrati, Mohammed; Leivo, Ilmo; Almangush, Alhadi (2021)
    Background: The prediction of overall survival in tongue cancer is important for planning of personalized care and patient counselling. Objectives: This study compares the performance of a nomogram with a machine learning model to predict overall survival in tongue cancer. The nomogram and machine learning model were built using a large data set from the Surveillance, Epidemiology, and End Results (SEER) program database. The comparison is necessary to provide the clinicians with a comprehensive, practical, and most accurate assistive system to predict overall survival of this patient population. Methods: The data set used included the records of 7596 tongue cancer patients. The considered machine learning algorithms were logistic regression, support vector machine, Bayes point machine, boosted decision tree, decision forest, and decision jungle. These algorithms were mainly evaluated in terms of the areas under the receiver operating characteristic (ROC) curve (AUC) and accuracy values. The performance of the algorithm that produced the best result was compared with a nomogram to predict overall survival in tongue cancer patients. Results: The boosted decision-tree algorithm outperformed other algorithms. When compared with a nomogram using external validation data, the boosted decision tree produced an accuracy of 88.7% while the nomogram showed an accuracy of 60.4%. In addition, it was found that age of patient, T stage, radiotherapy, and the surgical resection were the most prominent features with significant influence on the machine learning model's performance to predict overall survival. Conclusion: The machine learning model provides more personalized and reliable prognostic information of tongue cancer than the nomogram. However, the level of transparency offered by the nomogram in estimating patients' outcomes seems more confident and strengthened the principle of shared decision making between the patient and clinician. Therefore, a combination of a nomogram - machine learning (NomoML) predictive model may help to improve care, provides information to patients, and facilitates the clinicians in making tongue cancer management-related decisions.
  • Cowley, Benjamin U.; Korpela, Jussi (2018)
    Existing tools for the preprocessing of EEG data provide a large choice of methods to suitably prepare and analyse a given dataset. Yet it remains a challenge for the average user to integrate methods for batch processing of the increasingly large datasets of modern research, and compare methods to choose an optimal approach across the many possible parameter configurations. Additionally, many tools still require a high degree of manual decision making for, e.g., the classification of artifacts in channels, epochs or segments. This introduces extra subjectivity, is slow, and is not reproducible. Batching and well-designed automation can help to regularize EEG preprocessing, and thus reduce human effort, subjectivity, and consequent error. The Computational Testing for Automated Preprocessing (CTAP) toolbox facilitates: (i) batch processing that is easy for experts and novices alike; (ii) testing and comparison of preprocessing methods. Here we demonstrate the application of CTAP to high-resolution EEG data in three modes of use. First, a linear processing pipeline with mostly default parameters illustrates ease-of-use for naive users. Second, a branching pipeline illustrates CTAP's support for comparison of competing methods. Third, a pipeline with built-in parameter-sweeping illustrates CTAP's capability to support data-driven method parameterization. CTAP extends the existing functions and data structure from the well-known EEGLAB toolbox, based on Matlab, and produces extensive quality control outputs. CTAP is available under MIT open-source licence from https://github.com/bwrc/ctap.
  • Knowler, Susan P.; Kiviranta, Anna-Mariam; McFadyen, Angus K.; Jokinen, Tarja S.; La Ragione, Roberto M.; Rusbridge, Clare (2017)
    Objectives To characterize and compare the phenotypic variables of the hindbrain and craniocervical junction associated with syringomyelia (SM) in the Chihuahua, Affenpinscher and Cavalier King Charles Spaniel (CKCS). Method Analysis of 273 T1-weighted mid-sagittal DICOM sequences of the hindbrain and craniocer-vical junction from 99 Chihuahuas, 42 Affenpinschers and 132 CKCSs. The study compared 22 morphometric features (11 lines, eight angles and three ratios) of dogs with and without SM using refined techniques based on previous studies of the Griffon Bruxellois (GB) using Discriminant Function Analysis and ANOVA with post-hoc corrections. Results The analysis identified 14/22 significant traits for SM in the three dog breeds, five of which were identical to those reported for the GB and suggest inclusion of a common aetiology. One ratio, caudal fossa height to the length of the skull base extended to an imaginary point of alignment between the atlas and supraoccipital bones, was common to all three breeds (p values 0.029 to <0.001). Associated with SM were a reduced occipital crest and two acute changes in angulation i) 'sphenoid flexure' at the spheno-occipital synchondrosis ii) 'cervical flexure' at the foramen magnum allied with medulla oblongata elevation. Comparing dogs with and without SM, each breed had a unique trait: Chihuahua had a smaller angle between the dens, atlas and basioccipital bone (p value <0.001); Affenpinschers had a smaller dis-tance from atlas to dens (p value 0.009); CKCS had a shorter distance between the spheno-occipital synchondrosis and atlas (p value 0.007). Conclusion The selected morphometries successfully characterised conformational changes in the brain and craniocervical junction that might form the basis of a diagnostic tool for all breeds. The severity of SM involved a spectrum of abnormalities, incurred by changes in both angulation and size that could alter neural parenchyma compliance and/or impede cerebrospinal fluid channels.