Publications by authors named "T Joensuu"

131 Publications

The Clip Approach: A Visual Methodology to Support the (Re)Construction of Life Narratives.

Qual Health Res 2021 Mar;31(4):789-803

Aalto University, Espoo, Finland.

Major life changes may cause an autobiographical rupture and a need to work on one's narrative identity. This article introduces a new qualitative interview methodology originally developed to facilitate 10 prostate cancer patients and five spouses in the (re)creation of their life narratives in the context of a series of interventive interviews conducted over a timespan of several months. In "The Clip Approach" the interviewees' words, phrases, and metaphors are reflected back in a physical form ("the Clips") as visual artifacts that allow the interviewees to re-enter and re-consider their experience and life and re-construct their narratives concerning them. Honoring the interviewees as authors facilitates autobiographical reasoning, building a bridge between the past and the future, and embedding the illness experience as part of one's life narrative. The Clip Approach provides new tools for both research and practice-potentially even a low-threshold psychosocial support method for various applicability areas.
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http://dx.doi.org/10.1177/1049732320982945DOI Listing
March 2021

A Retrospective Comparative Study of Sodium Fluoride (NaF-18)-PET/CT and Fluorocholine (F-18-CH) PET/CT in the Evaluation of Skeletal Metastases in Metastatic Prostate Cancer Using a Volumetric 3-D Radiomics Analysis.

Diagnostics (Basel) 2020 Dec 24;11(1). Epub 2020 Dec 24.

Department of Nuclear Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.

Bone metastases are common in prostate cancer (PCa). Fluorocholine-18 (FCH) and sodium fluoride-18 (NaF) have been used to assess PCa associated skeletal disease in thousands of patients by demonstrating different mechanism of uptake-cell membrane (lipid) synthesis and bone mineralization. Here, this difference is characterized quantitatively in detail. Our study cohort consisted of 12 patients with advanced disease (> 5 lesions) (M) and of five PCa patients with no skeletal disease (N). They had routine PET/CT with FCH and NaF on consecutive days. Skeletal regions in CT were used to co-register the two PET/CT scans. Bone 3-D volume of interest (VOI) was defined on the CT of PET with a threshold of HU > 150, and sclerotic/dense bone as HU > 600, respectively. Additional VOIs were defined on PET uptake with the threshold values on both FCH (SUV > 3.5) and NaF (SUV > 10). The pathologic skeletal volumes for each technique (CT, HU > 600), NaF (SUV > 10) and FCH (SUV > 3.5) were developed and analyzed. The skeletal VOIs varied from 5.03 L to 7.31 L, whereas sclerotic bone VOIs were from 0.88 L to 2.99 L. Total choline kinase (cell membrane synthesis) activity for FCH (TCA) varied from 0.008 to 4.85 [kg] in M group and from 0.0006 to 0.085 [kg] in N group. Total accelerated osteoblastic (bone demineralization) activity for NaF (TBA varied from 0.25 to 13.6 [kg] in M group and varied from 0.000 to 1.09 [kg] in N group. The sclerotic bone volume represented only 1.86 ± 1.71% of the pathologic FCH volume and 4.07 ± 3.21% of the pathologic NaF volume in M group, and only 0.08 ± 0.09% and 0.18 ± 0.19% in N group, respectively. Our results suggest that CT alone cannot be used for the assessment of the extent of active metastatic skeletal disease in PCa. NaF and FCH give complementary information about the activity of the skeletal disease, improving diagnosis and disease staging.
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http://dx.doi.org/10.3390/diagnostics11010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824105PMC
December 2020

A Deep Learning-Based Automated CT Segmentation of Prostate Cancer Anatomy for Radiation Therapy Planning-A Retrospective Multicenter Study.

Diagnostics (Basel) 2020 Nov 17;10(11). Epub 2020 Nov 17.

Turku University Hospital, Department of Oncology and Radiotherapy, Hämeentie 11, FI-20521 Turku, Finland.

A commercial deep learning (DL)-based automated segmentation tool (AST) for computed tomography (CT) is evaluated for accuracy and efficiency gain within prostate cancer patients. Thirty patients from six clinics were reviewed with manual- (MC), automated- (AC) and automated and edited (AEC) contouring methods. In the AEC group, created contours (prostate, seminal vesicles, bladder, rectum, femoral heads and penile bulb) were edited, whereas the MC group included empty datasets for MC. In one clinic, lymph node CTV delineations were evaluated for interobserver variability. Compared to MC, the mean time saved using the AST was 12 min for the whole data set (46%) and 12 min for the lymph node CTV (60%), respectively. The delineation consistency between MC and AEC groups according to the Dice similarity coefficient (DSC) improved from 0.78 to 0.94 for the whole data set and from 0.76 to 0.91 for the lymph nodes. The mean DSCs between MC and AC for all six clinics were 0.82 for prostate, 0.72 for seminal vesicles, 0.93 for bladder, 0.84 for rectum, 0.69 for femoral heads and 0.51 for penile bulb. This study proves that using a general DL-based AST for CT images saves time and improves consistency.
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http://dx.doi.org/10.3390/diagnostics10110959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697786PMC
November 2020

Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS.

Ann Neurol 2021 02 5;89(2):402-407. Epub 2020 Nov 5.

Genetics Department, Lyon Civil Hospices, Lyon, France.

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402-407.
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http://dx.doi.org/10.1002/ana.25941DOI Listing
February 2021

Eye Symptoms in a Patient With Prostate Cancer.

Clin Nucl Med 2020 May;45(5):370-371

Ophthalmic Pathology and Oncology Service, St Eriks Eye Hospital, Karolinska Institutet, Stockholm, Sweden.

A 66-year-old man with castration-resistant prostate cancer was evaluated with F-prostate-specific membrane antigen (PSMA) 1007 PET/CT, which revealed extensive PSMA-positive skeletal metastases in the skull, thorax, spine, pelvis, and extremities. He was then treated Lu-PSMA-617 therapy. Twenty-four-hour SPECT/CT revealed additional activity not seen with F-PSMA adjacent to his left eye. The lesion was biopsied after the first cycle due to pain. This activity was not visible on SPECT/CT after the second treatment cycle, and his eye pain has resolved.
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http://dx.doi.org/10.1097/RLU.0000000000002982DOI Listing
May 2020

Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension.

Eur Urol 2019 11 30;76(5):586-595. Epub 2019 Jul 30.

Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; Docrates Cancer Center, Helsinki, Finland; Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland. Electronic address:

Background: It remains unclear whether patients with positive surgical margins or extracapsular extension benefit from adjuvant radiotherapy following radical prostatectomy.

Objective: To compare the effectiveness and tolerability of adjuvant radiotherapy following radical prostatectomy.

Design, Setting, And Participants: This was a randomised, open-label, parallel-group trial. A total of 250 patients were enrolled between April 2004 and October 2012 in eight Finnish hospitals, with pT2 with positive margins or pT3a, pN0, M0 cancer without seminal vesicle invasion.

Intervention: A total of 126 patients received adjuvant radiotherapy at 66.6Gy.

Outcome Measurements And Statistical Analysis: The primary endpoint was biochemical recurrence-free survival, which we analysed using the Kaplan-Meier method and Cox proportional hazard regression. Overall survival, cancer-specific survival, local recurrence, and adverse events were secondary endpoints.

Results And Limitations: The median follow-up time for patients who were alive when the follow-up ended was 9.3yr in the adjuvant group and 8.6yr in the observation group. The 10-yr survival for biochemical recurrence was 82% in the adjuvant group and 61% in the observation group (hazard ratio [HR] 0.26 [95% confidence interval {CI} 0.14-0.48], p<0.001), and for overall survival 92% and 87%, respectively (HR 0.69 [95% CI 0.29-1.60], p=0.4). Two and four metastatic cancers occurred, respectively. Out of the 43 patients with biochemical recurrence in the observation group, 37 patients received salvage radiotherapy. In the adjuvant group, 56% experienced grade 3 adverse events, versus 40% in the observation group (p=0.016). Only one grade 4 adverse event occurred (adjuvant group). A limitation of this study was the number of patients.

Conclusions: Adjuvant radiotherapy following radical prostatectomy is generally well tolerated and prolongs biochemical recurrence-free survival compared with radical prostatectomy alone in patients with positive margins or extracapsular extension.

Patient Summary: Radiotherapy given immediately after prostate cancer surgery prolongs prostate-specific antigen progression-free survival, but causes more adverse events, when compared with surgery alone.
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http://dx.doi.org/10.1016/j.eururo.2019.07.001DOI Listing
November 2019

Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer.

Oncotarget 2019 Mar 29;10(25):2451-2461. Epub 2019 Mar 29.

Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Bad Berka, Germany.

Lu-PSMA radioligand therapy (LuPRLT) is mainly used for patients with metastatic castration-resistant prostate cancer who are resistant to established drugs. This study describes LuPRLT, either LuPSMA I&T or LuPSMA RLT-617, for 45 patients with predominant lymph node metastatic prostate cancer (LNM PC). Thirty-five patients had LNM and ten patients had LNM and one or two bone metastases. Before LuPRLT, the patients had prostate specific antigen (PSA) of median 18 µg/l (interquartile range (IQR): 3.3-39). LuPRLT was given with a cumulative injected Lu activity of median 14.5 GBq (IQR: 12.2-20.4). Maximum percentage decline of PSA was median 92% (IQR: 70-99). Thirty-five patients with only LNM had a better overall survival (OS) than ten patients with LNM and one or two bone metastases. Thirty-three docetaxel-naïve patients had a longer PSMA PET/CT progression-free survival than twelve patients who were resistant to docetaxel. Twenty-two patients who received LuPRLT with a cumulative injected Lu activity ≥ 14.8 GBq had a better PSMA PET/CT progression-free survival than 23 patients who received LuPRLT with a lower cumulative injected Lu activity. Seventeen patients with relapse after LuPRLT who received rechallenge LuPRLT or ActPRLT had a better OS than five patients who received other forms for relapse treatment. LuPRLT gave mild and transitory adverse effects. The findings of the present study suggest that LuPRLT of patients with LNM may be effective and safe. The promising results motivate randomized phase II trials to further quantify the impact of LuPRLT as treatment of patients with LNM.
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http://dx.doi.org/10.18632/oncotarget.26789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497435PMC
March 2019

Oncograms Visualize Factors Influencing Long-Term Survival of Cancer Patients Treated with Adenoviral Oncolytic Immunotherapy.

Mol Ther Oncolytics 2018 Jun 22;9:41-50. Epub 2018 Apr 22.

Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as "oncograms." Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-8], HMGB1, anti-viral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy.
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http://dx.doi.org/10.1016/j.omto.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035494PMC
June 2018

Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases.

Neuropediatrics 2018 08 25;49(4):256-261. Epub 2018 May 25.

PEDEGO Research Unit, University of Oulu, Finland.

Alexander disease (AxD) is a genetic leukodystrophy caused by mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel missense mutation and a splice site mutation segregating with the BFNE phenotype in the family. The mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.
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http://dx.doi.org/10.1055/s-0038-1649500DOI Listing
August 2018

The clinical impact of using complex molecular profiling strategies in routine oncology practice.

Oncotarget 2018 Apr 17;9(29):20282-20293. Epub 2018 Apr 17.

Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10-50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice.
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http://dx.doi.org/10.18632/oncotarget.24757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945513PMC
April 2018

Interleukin 8 activity influences the efficacy of adenoviral oncolytic immunotherapy in cancer patients.

Oncotarget 2018 Jan 5;9(5):6320-6335. Epub 2018 Jan 5.

Cancer Gene Therapy Group, University of Helsinki, Faculty of Medicine, Helsinki, Finland.

After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy. We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses. We found high baseline serum IL-8 concentration to be independently associated with poor prognosis (p<0.001). Further, normal baseline IL-8 was associated with improved prognostic potential of calculation of the neutrophil-to-lymphocyte ratio (p<0.001). Interestingly, a decrease in IL-8 concentration after treatment with oncolytic adenovirus predicted better overall survival (p<0.001) and higher response rate, although this difference was not significant (p=0.066). We studied the combination of adenovirus and IL-8 neutralizing antibody in single cell suspensions and in co-cultures of tumor-associated CD15+ neutrophils and CD3+ tumor-infiltrating lymphocytes derived from fresh patient tumor samples. These results indicate a role for IL-8 as a biomarker in oncolytic virotherapy, but additionally provide a rationale for targeting IL-8 to improve treatment efficacy. In conclusion, curtailing the activity of IL-8 systemically or locally in the tumor microenvironment could improve anti-tumor immune responses resulting in enhanced efficacy of adenoviral immunotherapy of cancer.
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http://dx.doi.org/10.18632/oncotarget.23967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814215PMC
January 2018

Accuracy and precision of patient positioning for pelvic MR-only radiation therapy using digitally reconstructed radiographs.

Phys Med Biol 2018 03 2;63(5):055009. Epub 2018 Mar 2.

Philips MR Therapy, Äyritie 4, FI-01510, Vantaa, Finland. Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Rakentajanaukio 2 C, FI-02150 Espoo, Finland.

Background And Purpose: Magnetic resonance imaging (MRI) has in recent years emerged as an imaging modality to drive precise contouring of targets and organs at risk in external beam radiation therapy. Moreover, recent advances in MRI enable treatment of cancer without computed tomography (CT) simulation. A commercially available MR-only solution, MRCAT, offers a single-modality approach that provides density information for dose calculation and generation of positioning reference images. We evaluated the accuracy of patient positioning based on MRCAT digitally reconstructed radiographs (DRRs) by comparing to standard CT based workflow.

Materials And Methods: Twenty consecutive prostate cancer patients being treated with external beam radiation therapy were included in the study. DRRs were generated for each patient based on the planning CT and MRCAT. The accuracy assessment was performed by manually registering the DRR images to planar kV setup images using bony landmarks. A Bayesian linear mixed effects model was used to separate systematic and random components (inter- and intra-observer variation) in the assessment. In addition, method agreement was assessed using a Bland-Altman analysis.

Results: The systematic difference between MRCAT and CT based patient positioning, averaged over the study population, were found to be (mean [95% CI])  -0.49 [-0.85 to  -0.13] mm, 0.11 [-0.33 to  +0.57] mm and  -0.05 [-0.23 to  +0.36] mm in vertical, longitudinal and lateral directions, respectively. The increases in total random uncertainty were estimated to be below 0.5 mm for all directions, when using MR-only workflow instead of CT.

Conclusions: The MRCAT pseudo-CT method provides clinically acceptable accuracy and precision for patient positioning for pelvic radiation therapy based on planar DRR images. Furthermore, due to the reduction of geometric uncertainty, compared to dual-modality workflow, the approach is likely to improve the total geometric accuracy of pelvic radiation therapy.
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http://dx.doi.org/10.1088/1361-6560/aaad21DOI Listing
March 2018

Third-line treatment and Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review.

Eur J Nucl Med Mol Imaging 2018 03 16;45(3):496-508. Epub 2017 Dec 16.

Docrates Cancer Center, Helsinki, Finland.

Aims: There is a controversy as to the relative efficacy of Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743).

Methods: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model.

Results: Twelve studies including 669 patients reported Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with Lu-PSMA RLT. The treatment with Lu-PSMA-617 and Lu-PSMA for imaging and therapy (I&T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ test). Median survival was longer after Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ test).

Conclusions: As for patients with mCRPC, treatment with Lu-PSMA-617 RTL and Lu-PSMA I&T gave better effects and caused fewer adverse effects than third-line treatment.
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http://dx.doi.org/10.1007/s00259-017-3895-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787223PMC
March 2018

Validity of Digital Imaging of Fiber-Optic Transillumination in Caries Detection on Proximal Tooth Surfaces.

Int J Dent 2017 1;2017:8289636. Epub 2017 Oct 1.

Research Unit of Oral Health Sciences, Department of Cariology, Endodontology and Paediatric Dentistry, University of Oulu, Oulu, Finland.

Objective: The aim of our study was to evaluate the validity of the digital imaging fiber-optic transillumination (DIFOTI) method in comparison with clinical visual examination (CV) and bitewing (BW) radiography on detecting caries lesions on proximal surfaces of teeth.

Materials And Methods: Proximal tooth surfaces of premolars and molars ( = 2,103) of 91 voluntary university students aged from 18 to 30 years were examined with CV, BW radiography, and the DIFOTI method.

Results: DIFOTI detected more initial and manifested caries lesions compared with CV and BW. Of the analyzed tooth surfaces, 69.8% were classified as sound by DIFOTI, 80.3% by BW, and 91.6% by CV. Initial caries lesions were found in 21.2% of the surfaces by DIFOTI, in 14.1% by BW, and in 6.2% by CV, whereas the proportions for manifested dental caries lesions were 9.0%, 5.6%, and 2.2%, respectively. The interexaminer agreement regarding the DIFOTI findings between an experienced clinician and a fifth-year dental student was high: = 0.67 for initial and = 0.91 for manifested caries lesions.

Conclusions: The noninvasive DIFOTI method seems to offer a potential tool for everyday clinical practice. In clinical use, DIFOTI finds well even initial caries lesions on proximal surfaces, thus providing an instrument for detecting lesions potential for arresting as well as for monitoring the outcome after preventive measures.
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http://dx.doi.org/10.1155/2017/8289636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642884PMC
October 2017

Lu-PSMA-617 radioligand therapy for a patient with lymph node metastatic prostate cancer.

Oncotarget 2017 Sep 2;8(39):66112-66116. Epub 2017 Aug 2.

Department of Nuclear Medicine, Innsbruck University Hospital, Innsbruck, Austria.

Prostate specific membrane antigen (PSMA) is expressed in unfavorable prostate cancer. PSMA is basis for new diagnostics and theranostics. PET/CT using PSMA is more sensitive than choline PET/CT. Lu-PSMA radioligand therapy is mainly used for patients with end-stage prostate cancer. This report describes a patient with a third recurrence in lymph nodes. The recurrence was treated with Lu-PSMA radioligand therapy instead of chemotherapy with docetaxel. The effect was in part evaluated relative to that of two established salvage treatments. Prior salvage radiotherapy and abiraterone of the first and second recurrence in lymph nodes had given only a partial reduction of PSA. Nevertheless within five months of follow-up, Lu-PSMA radioligand therapy of the third recurrence in lymph nodes reduced PSA for a period to unmeasurable levels. Lu-PSMA radioligand therapy gave only mild adverse effects. In conclusion, for a patient with lymph node metastatic prostate cancer, Lu-PSMA-617 radioligand therapy had an attractive therapeutic profile. A follow-up study of similar patients is being planned.
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http://dx.doi.org/10.18632/oncotarget.19805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630396PMC
September 2017

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.

Brain 2017 05;140(5):1267-1279

The Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00290 Helsinki, Finland.

Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.
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http://dx.doi.org/10.1093/brain/awx040DOI Listing
May 2017

Multimodal Primary Treatment of Metastatic Prostate Cancer with Androgen Deprivation and Radiation.

Anticancer Res 2016 12;36(12):6439-6447

Docrates Cancer Center, Helsinki, Finland.

Aim: We combined anti-androgen therapy with radiotherapy in a first-line setting for metastatic prostate cancer aiming to cause maximal cancer-cell death to delay the emergence of castration-resistant disease.

Materials And Methods: In this non-randomized retrospective series of 46 patients, the initial median prostate-specific antigen (PSA) was 98.5 μg/l (range=6.7-15,500), median Gleason score 9 and most men had at least TNM disease. All patients received luteinizing hormone releasing hormone analog or degarelix with bicalutamide. If PSA remained above 1 μg/l, docetaxel was initiated. At PSA nadir, all patients received radical radiotherapy of the prostate.

Results: The median follow-up time was 4.38 years (range=0.36-11.24). Most radiotherapy-related adverse events were grade 1 and transient. There were no grade 4 events. Overall survival (OS) at 5 years was 81.3%.

Conclusion: The feasibility and safety of aggressive multimodality treatment were good resulting in an excellent median OS of 8.35 years.
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http://dx.doi.org/10.21873/anticanres.11242DOI Listing
December 2016

Brain inflammation is accompanied by peripheral inflammation in Cstb mice, a model for progressive myoclonus epilepsy.

J Neuroinflammation 2016 11 28;13(1):298. Epub 2016 Nov 28.

Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00014, Helsinki, Finland.

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited childhood-onset neurodegenerative disorder, characterized by myoclonus, seizures, and ataxia. Mutations in the cystatin B gene (CSTB) underlie EPM1. The CSTB-deficient (Cstb ) mouse model recapitulates key features of EPM1, including myoclonic seizures. The mice show early microglial activation that precedes seizure onset and neuronal loss and leads to neuroinflammation. We here characterized the inflammatory phenotype of Cstb mice in more detail. We found higher concentrations of chemokines and pro-inflammatory cytokines in the serum of Cstb mice and higher CXCL13 expression in activated microglia in Cstb compared to control mouse brains. The elevated chemokine levels were not accompanied by blood-brain barrier disruption, despite increased brain vascularization. Macrophages in the spleen and brain of Cstb mice were predominantly pro-inflammatory. Taken together, these data show that CXCL13 expression is a hallmark of microglial activation in Cstb mice and that the brain inflammation is linked to peripheral inflammatory changes, which might contribute to the disease pathology of EPM1.
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http://dx.doi.org/10.1186/s12974-016-0764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127053PMC
November 2016

Self-Reported Bruxism and Symptoms of Temporomandibular Disorders in Finnish University Students.

J Oral Facial Pain Headache 2016 Fall;30(4):311-317

Aims: To evaluate the prevalence of self-reported bruxism and symptoms of temporomandibular disorders (TMD) and to investigate their association in academic and applied science university students in Finland.

Methods: The data were gathered from 4,403 Finnish students included in the Finnish Student Health Survey 2012. The comprehensive questionnaire included five questions concerning bruxism and TMD symptoms. Bivariate associations between self-reported bruxism and TMD symptoms were evaluated using chi-square tests, and logistic regression model was used with age and gender as factors.

Results: Sleep bruxism was reported by 21.0% of women and by 12.5% of men, awake bruxism by 2.0% of women and by 2.8% of men, and both sleep and awake bruxism by 7.2% of women and by 3.2% of men. TMD pain was reported by 25.9% of women and by 11.4% of men and temporomandibular joint (TMJ) pain on jaw movement by 9.6% of women and by 4.2% of men. Report of sleep bruxism increased the risk for all TMD symptoms in both genders. Among women, report of awake bruxism increased the risk for TMD pain and TMJ pain on jaw movement. Reporting stress as a perpetuating factor for TMD pain increased the risk for both sleep and awake bruxism in both genders. The logistic regression analysis (including age and gender) showed that report of sleep bruxism and/or awake bruxism was associated with TMD pain (Odds Ratio [OR] = 5.71; 95% confidence interval [CI] = 4.86-6.70), TMJ pain on jaw movement (OR = 4.49; 95% CI = 3.54-5.69), and TMJ locking (OR = 2.98; 95% CI = 2.17-4.10).

Conclusion: Bruxism and TMD symptoms are frequent in Finnish university students. Self-reported bruxism is associated with TMD symptoms, confirming earlier findings.
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http://dx.doi.org/10.11607/ofph.1674DOI Listing
August 2017

Health and Behavioral Survey of over 8000 Finnish Cats.

Front Vet Sci 2016 29;3:70. Epub 2016 Aug 29.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; The Folkhälsan Institute of Genetics, Helsinki, Finland.

A comprehensive feline health survey was conducted to reveal breed-specific inheritable diseases in Finnish pedigree cats for genetic research. Prevalence of 19 disease categories and 227 feline diseases were defined in a study population of 8175 cats belonging to 30 breeds. Dental and oral diseases, with a prevalence of 28%, and dental calculus and gingivitis (21 and 8%, respectively) were the most prevalent disease category and diseases among all cats and in most of the breeds. An exception was Korats, which were more often affected by the diseases of the respiratory tract (23%) and asthma (19%). Other prevalent disease categories affected various organ systems, such as the skin (12%), the urinary system (12%), the digestive tract (11%), eyes (10%), the musculoskeletal system (10%), and genitals of female cats (17%). Prevalent health or developmental issues included repetitive vomiting (4%), tail kink (4%), feline odontoclastic resorption lesion (4%), urinary tract infections (4%), as well as cesarean section (6%) and stillborn kittens (6%) among female cats. We found 57 breed-specific conditions by Fisher's exact tests and logistic regression analyses, including 32 previously described and 19 new breed-specific diseases. The genetic defect has already been found in six of them: polycystic kidney disease, progressive retinal atrophy, hypertrophic cardiomyopathy, and three types of tail malformations. Behavioral profiling revealed breed-specific traits, such as an increased human avoidance in British Short and Longhairs and a higher level of aggression in Turkish vans. Our epidemiological study reveals the overall health profile in Finnish pure and mixed breed cats and identifies many breed-specific conditions without molecular identity for genetic research.
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http://dx.doi.org/10.3389/fvets.2016.00070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002895PMC
September 2016

Gene-Expression Profiling Suggests Impaired Signaling via the Interferon Pathway in Cstb-/- Microglia.

PLoS One 2016 29;11(6):e0158195. Epub 2016 Jun 29.

Folkhälsan Institute of Genetics, Helsinki, Finland.

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1, OMIM254800) is an autosomal recessive neurodegenerative disorder characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic epileptic seizures, and ataxia. Loss-of-function mutations in the gene encoding the cysteine protease inhibitor cystatin B (CSTB) underlie EPM1. The deficiency of CSTB in mice (Cstb-/- mice) generates a phenotype resembling the symptoms of EPM1 patients and is accompanied by microglial activation at two weeks of age and an upregulation of immune system-associated genes in the cerebellum at one month of age. To shed light on molecular pathways and processes linked to CSTB deficiency in microglia we characterized the transcriptome of cultured Cstb-/- mouse microglia using microarray hybridization and RNA sequencing (RNA-seq). The gene expression profiles obtained with these two techniques were in good accordance and not polarized to either pro- or anti-inflammatory status. In Cstb-/- microglia, altogether 184 genes were differentially expressed. Of these, 33 genes were identified by both methods. Several interferon-regulated genes were weaker expressed in Cstb-/- microglia compared to control. This was confirmed by quantitative real-time PCR of the transcripts Irf7 and Stat1. Subsequently, we explored the biological context of CSTB deficiency in microglia more deeply by functional enrichment and canonical pathway analysis. This uncovered a potential role for CSTB in chemotaxis, antigen-presentation, and in immune- and defense response-associated processes by altering JAK-STAT pathway signaling. These data support and expand the previously suggested involvement of inflammatory processes to the disease pathogenesis of EPM1 and connect CSTB deficiency in microglia to altered expression of interferon-regulated genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158195PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927094PMC
July 2017

Oncolytic virotherapy for treatment of breast cancer, including triple-negative breast cancer.

Oncoimmunology 2016 Feb 27;5(2):e1078057. Epub 2015 Aug 27.

University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland; TILT Biotherapeutics Ltd., Helsinki, Finland; Helsinki University Central Hospital, Department of Oncology, Helsinki, Finland.

Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules to boost virus triggered antitumoral immune responses. Cyclophosphamide (CP) is a chemotherapy drug that is associated with cytotoxicity and immunosuppression at higher doses, whereas immunostimulatory and anti-angiogenic properties are observed at low continuous dosage. Therefore, the combination of oncolytic immuno-virotherapy with low-dose CP is an appealing approach. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line and in an orthotopic xenograft mouse model, in combination with low-dose CP or its main active metabolite 4-hydroperoxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data on this virus from the Advanced Therapy Access Program (ATAP). Low-dose CP increased the efficacy of Ad5/3-D24-GMCSF and in a TNBC mouse model. In ATAP, treatments appeared safe and well-tolerated. Thirteen out of 16 breast cancer patients treated were evaluable for possible benefits with modified RECIST 1.1 criteria: 1 patient had a minor response, 2 had stable disease (SD), and 10 had progressive disease (PD). One patient is alive at 1,771 d after treatment. Ad5/3-D24-GMCSF in combination with low-dose CP showed promising efficacy in preclinical studies and possible antitumor activity in breast cancer patients refractory to other forms of therapy. This preliminary data supports continuing the clinical development of oncolytic adenoviruses for treatment of breast cancer, including TNBC.
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http://dx.doi.org/10.1080/2162402X.2015.1078057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801445PMC
February 2016

Predictive and Prognostic Clinical Variables in Cancer Patients Treated With Adenoviral Oncolytic Immunotherapy.

Mol Ther 2016 08 4;24(7):1323-32. Epub 2016 Apr 4.

Cancer Gene Therapy Group, University of Helsinki, Faculty of Medicine, Helsinki, Finland.

The development of oncolytic viruses has recently made great progress towards being available to cancer patients. With the breakthrough into clinics, it is crucial to analyze the existing clinical experience and use it as a basis for treatment improvements. Here, we report clinical data from 290 patients treated with oncolytic adenovirus. Using clinical variables and treatment characteristics, we constructed statistical models with regard to treatment response and overall survival (OS). Additionally, we investigated effects of neutralizing antibodies, tumor burden, and peripheral blood leucocyte counts on these outcomes. We found the absence of liver metastases to correlate with an improved rate of disease control (P = 0.021). In multivariate evaluation, patients treated with viruses coding for immunostimulatory granulocyte macrophage colony-stimulating factor were linked to better prognosis (hazard ratio (HR) 0.378, P < 0.001), as well as women with any cancer type (HR 0.694, P = 0.017). In multivariate analysis for imaging response, patients treated via intraperitoneal injection were more likely to achieve disease control (odds ratio (OR) 3.246, P = 0.027). Patients with low neutrophil-to-lymphocyte ratio before treatment had significantly longer OS (P < 0.001). These findings could explain some of the variation seen in treatment outcomes after virotherapy. Furthermore, the results offer hypotheses for treatment optimization and patient selection in oncolytic adenovirus immunotherapy.
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http://dx.doi.org/10.1038/mt.2016.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088758PMC
August 2016

Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers.

J Immunother Cancer 2016 15;4:17. Epub 2016 Mar 15.

Docrates Cancer Center, Helsinki, Finland.

Background: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.

Methods: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).

Results: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.

Conclusions: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.

Trial Registration: NCT01598129. Registered 19/04/2012.
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http://dx.doi.org/10.1186/s40425-016-0121-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791966PMC
March 2016

Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT.

Diagnostics (Basel) 2015 Oct 13;5(4):413-27. Epub 2015 Oct 13.

Departments of Radiotherapy and Medical Oncology, Docrates Cancer Center, Saukonpaadenranta 2, Helsinki FI-00180, Finland.

The purpose of this study was to evaluate the outcome after Radium-223-dichloride ((223)RaCl₂) treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body (18)F-Fluoride PET/CT. Sodium (18)F-fluoride [(18)F]-NaF PET/CT was performed prior the treatment of (223)RaCl₂, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [(18)F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [(18)F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during (223)RaCl₂. Our results (although preliminary) suggest that (18)F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.
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http://dx.doi.org/10.3390/diagnostics5040413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728467PMC
October 2015

Evaluation of Alpha-Therapy with Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-the Role of Gamma Scintigraphy in Dosimetry and Pharmacokinetics.

Diagnostics (Basel) 2015 Jul 30;5(3):358-68. Epub 2015 Jul 30.

Radiotherapy, Docrates Cancer Center, Saukonpaadenranta 2, Helsinki FI-00180, Finland.

Radium-223-dichloride ((223)RaCl₂) is a new bone-seeking calcium analogue alpha-emitter, which has obtained marketing authorization for the treatment skeletal metastases of hormone-refractory prostate cancer. The current treatment regimen is based on six consecutive doses of (223)RaCl₂ at 4 week intervals and the administered activity dose, 50 kBq/kg per cycle is based on patient weight. We analyzed two patients using quantitative serial gamma imaging to estimate dosimetry in tumors and see possible pharmacokinetic differences in the treatment cycles. The lesions were rather well visualized in gamma scintigraphy in spite of low gamma activity (<1.1% gamma radiation) at 0, 7 and 28 days using 30-60 min acquisition times. Both our patients analyzed in serial gamma imagings, had two lesions in the gamma imaging field, the mean counts of the relative intensity varied from 27.8 to 36.5 (patient 1), and from 37.4 to 82.2 (patient 2). The half-lives varied from 1.8 days to 4.5 days during the six cycles (patient 1), and from 1.5 days to 3.6 days (patient 2), respectively. In the lesion half-lives calculated from the imaging the maximum difference between the treatment cycles in the same lesion was 2.0-fold (1.8 vs. 3.6). Of these patients, patient 1 demonstrated a serum PSA response, whereas there was no PSA response in patient 2. From our data, there were maximally up to 4.0-fold differences (62.1 vs. 246.6 ) between the relative absorbed radiation doses between patients as calculated from the quantitative standardized imaging to be delivered in only two lesions, and in the same lesion the maximum difference in the cycles was up to 2.3-fold (107.4 vs. 246.6). Our recommendation based on statistical simulation analysis, is serial measurement at days 0-8 at least 3 times, this improve the accuracy significantly to study the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the imaging. Both our patients had originally two metastatic sites in the imaging field; the former patient demonstrated a serum PSA response and the latter demonstrated no PSA response. In these two patients there was no significant difference in the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the quantitative imaging. Our results, although preliminary, suggest that dose monitoring can be included as a part of this treatment modality. On the other hand, from the absorbed radiation doses, the response cannot be predicted because with very similar doses, only the former patient responded.
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http://dx.doi.org/10.3390/diagnostics5030358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665607PMC
July 2015

Radiotherapy Boost for the Dominant Intraprostatic Cancer Lesion-A Systematic Review and Meta-Analysis.

Clin Genitourin Cancer 2016 Jun 17;14(3):189-97. Epub 2015 Dec 17.

Docrates Cancer Center, Helsinki, Finland.

External beam radiotherapy (EBRT) for prostate cancer can be performed with a high dose of 86 Gy; however, one-tenth or more of the patients will develop recurrence. Prostate cancer is mainly multifocal, but a dominant intraprostatic lesion (DIL) is often the site of local recurrence after EBRT. We undertook a systematic review and meta-analysis to clarify whether functional imaging might identify the DIL and whether a RT boost to the DIL might be increased to an ultrahigh dose level of ≥ 90 Gy without increased toxicity. Of 62 selected studies, 13 reported the size of the DIL. The mean of the median DIL volumes was 2.4 cm(3) (95% confidence interval, 0.9-4.4 cm(3)). Eighteen diagnostic studies with 1205 patients evaluated the diagnostic accuracy using multiparametric magnetic resonance imaging for intraprostatic cancer lesions. Evaluating 14,654 prostate segments, the diagnostic accuracy was 77%. Eleven therapeutic studies with 988 patients reported a RT boost for the DIL. The summary boost dose for the DIL was a mean of 89 Gy in 5 studies using intensity modulated RT (calculated as the equivalent dose in 2-Gy fractions) and a mean of 141 Gy in 4 studies using a combination of EBRT and brachytherapy (P = .018, t test). In 1 therapeutic study, 239 patients had a 98% 10-year disease-free survival rate. Many of our therapeutic studies used a boost dose to the DIL of > 90 Gy. The reported boost for DIL is effective and safe.
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http://dx.doi.org/10.1016/j.clgc.2015.12.005DOI Listing
June 2016

Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.

J Neurol 2016 Feb 8;263(2):334-343. Epub 2015 Dec 8.

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.
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http://dx.doi.org/10.1007/s00415-015-7984-0DOI Listing
February 2016

Chronic Activation of Innate Immunity Correlates With Poor Prognosis in Cancer Patients Treated With Oncolytic Adenovirus.

Mol Ther 2016 Feb 27;24(1):175-83. Epub 2015 Aug 27.

University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.

Despite many clinical trials conducted with oncolytic viruses, the exact tumor-level mechanisms affecting therapeutic efficacy have not been established. Currently there are no biomarkers available that would predict the clinical outcome to any oncolytic virus. To assess the baseline immunological phenotype and find potential prognostic biomarkers, we monitored mRNA expression levels in 31 tumor biopsy or fluid samples from 27 patients treated with oncolytic adenovirus. Additionally, protein expression was studied from 19 biopsies using immunohistochemical staining. We found highly significant changes in several signaling pathways and genes associated with immune responses, such as B-cell receptor signaling (P < 0.001), granulocyte macrophage colony-stimulating factor (GM-CSF) signaling (P < 0.001), and leukocyte extravasation signaling (P < 0.001), in patients surviving a shorter time than their controls. In immunohistochemical analysis, markers CD4 and CD163 were significantly elevated (P = 0.020 and P = 0.016 respectively), in patients with shorter than expected survival. Interestingly, T-cell exhaustion marker TIM-3 was also found to be significantly upregulated (P = 0.006) in patients with poor prognosis. Collectively, these data suggest that activation of several functions of the innate immunity before treatment is associated with inferior survival in patients treated with oncolytic adenovirus. Conversely, lack of chronic innate inflammation at baseline may predict improved treatment outcome, as suggested by good overall prognosis.
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http://dx.doi.org/10.1038/mt.2015.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754537PMC
February 2016