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The purpose of this study was to examine the factors influencing the efficacy and safety of the ultrasound-guided radiofrequency ablation of renal tumors. Between January 2010 and December 2018, 159 patients with renal tumors treated with ultrasound-guided percutaneous radiofrequency ablation at our institution were included in this study. Biopsies were performed for histopathological analysis prior to each ablation. Patients underwent computed tomography follow-ups at 3, 6, and 12 months and were subsequently observed on an annual basis. The primary efficacy rate (i.e., residual tumor), local tumor progression, morbidity and mortality, and possible outcome predictors (age, body mass index, gender, tumor size, tumor location, tumor characteristics, ablation temperature, and reported technical problems) were analyzed using binary logistic regression. At the first follow-up, 3 months after ablation, the primary efficacy rate was 79%. Two percent of the tumors showed local tumor progression during the whole follow-up. Tumor proximity to the collecting system and the final temperature in the ablation region were associated with the occurrence of residual tumor (OR = 2.85, p = 0.019 and OR = 4.23, p = 0.006, respectively). A similar trend was shown for tumors larger than 3 cm (p = 0.066). A short distance to the collecting system and the ablation temperature were significantly related to the occurrence of residual tumors after the radiofrequency ablation of small renal masses. The ultrasound guidance used in our study has a lower primary efficacy rate than the computed tomography guidance used in comparable studies.

Background and objective: There is an unmet need to avoid long-term morbidity associated with standard cytotoxic treatment for low-volume metastatic seminoma. Our aim was to assess the oncological efficacy and surgical safety of retroperitoneal lymph node dissection (RPLND) as treatment in a population-based cohort of metastatic seminoma patients with limited retroperitoneal lymphadenopathy. Methods: Sixty-two seminoma patients in Norway and Sweden were included in the cohort from 2019 to 2022. Patients with lymphadenopathy ≤3 cm, having primary clinical stage (CS) IIA/B or CS I with a relapse, were operated with uni- or bilateral template RPLND, open or robot assisted. The outcome measures included surgical complications as per Clavien-Dindo, and Kaplan-Meier survival estimates for 24-mo progression-free survival (PFS) and overall survival (OS). Key findings and limitations: In the cohort, 33 (53%) had CS I with a relapse during surveillance, six (10%) CS I with a relapse following adjuvant chemotherapy, and 23 (37%) initial CS IIA/B. Metastatic seminoma was verified in 58 patients (94%) with a median largest diameter of 18 mm (interquartile range [IQR] 13–24). Robot-assisted RPLND was performed in 40 patients (65%). Clavien-Dindo III complications were observed in three patients (5%); no grade ≥IV complications occurred. Eighteen patients (29%) received adjuvant chemotherapy after surgery. The median follow-up was 23 mo (IQR 16–30), and recurrence occurred in six patients (10%) after a median of 8 mo (IQR 4–14). PFS was 90% (95% confidence interval: 0.86–1) and OS was 100% at 24 mo. Conclusions and clinical implications: RPLND as primary treatment is an option for selected low-stage seminomas with a limited burden of disease, showing low complications and low relapse rates, with the potential to reduce long-term morbidity. Patient summary: In seminoma patients with limited metastatic spread, surgery is a treatment option offering an alternative to chemotherapy or radiation. This paper covers the first 62 patients operated in Norway and Sweden.

The purpose of this study is to evaluate the treatment safety of thermal ablation compared to surgical treatment of T1a tumors (small renal masses) at a high-volume center. We conducted an observational single-center study based on data collected form the National Swedish Kidney Cancer Register (NSKCR) between 2015 and 2021. In total, 444 treatments of T1a tumors were included. Patients underwent surgery (partial or total nephrectomy) or ablative treatment—radiofrequency ablation (RFA) or microwave ablation (MWA). Patient characteristics were retrieved from patient records, and tumor complexity was estimated from pre-interventional CT scans. The odds ratio (OR) of suffering from a severe surgical complication following ablative treatment was estimated using a logistic regression model adjusted for age, BMI, ASA physical status classification, smoking status and RENAL nephrometry score. The frequency of severe surgical complications was 6.3% (16/256 treatments) after surgical intervention and 2.1% (4/188 treatments) following ablative treatment. Our primary hypothesis that ablative treatment is associated with a lower risk of severe surgical complications is supported by the results (OR 0.39; 0.19–0.79; p = 0.013). When adjusting for age, smoking status, ASA score, BMI score and RENAL nephrometry score, we see an even greater difference between the two groups (OR 0.34; 0.17–0.68; p = 0.002). Our study was limited by the differences in patient and tumor characteristics between the two compared groups and the study design. If oncological outcomes are found to be comparable, ablative treatment should be considered as a first-line treatment for all small renal masses.

IntroductionRecently developed prismatic loupes may mitigate the high physical workload and risk of neck disorders associated with traditional surgical loupes among surgeons. However, research in this area, particularly among surgeons, is sparse. This study examines the impact of prismatic loupes on surgeons’ physical workload, musculoskeletal discomfort, and performance during simulated surgical tasks.Materials and methodsNineteen out of twenty recruited surgeons performed three tasks in a fixed-order with their own loupes and both low-tilt (LT) and high-tilt (HT) prismatic loupes, in a randomized order. The primary outcomes were the median inclination angles and velocities of the head, trunk, and upper arms, along with the median muscle activity of the cervical erector spinae (CES), upper trapezius (UT), and lumbar erector spinae (LES) for each pair of loupes. The secondary outcomes included performance (completion time and errors), perceived body-part discomfort, and subjective evaluation of the three pairs of loupes.ResultsUsing prismatic loupes, either LT or HT, compared with the surgeons’ own loupes yielded lower head inclinations (all p

Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design, setting, and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients). Outcome measurements and statistical analysis: The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests. Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42–1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy. Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.

Abstract Recent studies suggest that metabolic changes and oxygen deficiency in the central nervous system play an important role in the pathophysiology of multiple sclerosis (MS). In our present study, we investigated the changes in oxygenation and analyzed the vascular perfusion of the spinal cord in a rodent model of MS. We performed multispectral optoacoustic tomography of the lumbar spinal cord before and after an oxygen enhancement challenge in mice with experimental autoimmune encephalomyelitis (EAE), a model for MS. In addition, mice were transcardially perfused with lectin to label the vasculature and their spinal columns were optically cleared, followed by light sheet fluorescence microscopy. To analyze the angioarchitecture of the intact spine, we used VesSAP, a novel deep learning-based framework. In EAE mice, the spinal cord had lower oxygen saturation and hemoglobin concentration compared to healthy mice, indicating compromised perfusion of the spinal cord. Oxygen administration reversed hypoxia in the spinal cord of EAE mice, although the ventral region remained hypoxic. Additionally, despite the increased vascular density, we report a reduction in length and complexity of the perfused vascular network in EAE. Taken together, these findings highlight a new aspect of neuroinflammatory pathology, revealing a significant degree of hypoxia in EAE in vivo that is accompanied by changes in spinal vascular perfusion. The study also introduces optoacoustic imaging as a tractable technique with the potential to further decipher the role of hypoxia in EAE and to monitor it in MS patients.

Abstract Background Follicular thyroid carcinomas (FTCs) rarely metastasize to regional lymph nodes, and descriptions of synchronous lateral lymph node metastases of FTC and papillary thyroid carcinoma (PTC) are lacking. Case Presentation We describe a 43-year-old female with a preoperative cytology indicating a right-sided PTC with lateral lymph node metastases. She underwent a total thyroidectomy and central and lateral lymph node dissection, and histopathology confirmed a multifocal tall cell variant PTC together with a 12 mm minimally invasive FTC in the ipsilateral lobe. While the central compartment demonstrated metastatic PTC, the lateral compartment contained PTC metastases alongside a 15 mm large follicular-patterned mass in a separate lymph node. As the cells lacked PTC associated nuclear changes, the possibility of a lateral lymph node metastasis of FTC was considered, with the possibility of ectopic thyroid tissue as a differential diagnosis. By utilizing next-generation sequencing, a Q61R NRAS mutation was pinpointed, thus proving the tissue as tumorous. The patient underwent radioiodine treatment and is currently monitored following a negative whole-body scan. Conclusions This is probably the first case report of a patient with co-existing lateral lymph node PTC and FTC metastases. Consulting previous publications, there is currently a gap of knowledge in terms of how patients with regional FTC metastases should be followed-up and treated, especially when co-occurring with spread high-risk PTC subtypes. Moreover, what guides a seemingly indolent FTC to spread via the lymphatic system remains to be defined from a molecular standpoint.

Abstract MicroRNA-371a-3p (miR371) has been suggested as a sensitive biomarker in testicular germ cell cancer (TGCC). We aimed to compare miR371 with the classical biomarkers α-fetoprotein (AFP) and β-human chorionic gonadotropin (hCGβ). Overall, 180 patients were prospectively enrolled in the study, with serum samples collected before and after orchiectomy. We compared the use of digital droplet PCR (RT-ddPCR) with the quantitative PCR used by others for detection of miR371. The novel RT-ddPCR protocol showed high performance in detection of miR371 in serum samples. In the study cohort, miR371 was measured using RT-ddPCR. MiR371 detected CS1 of the seminoma and the non-seminoma sub-types with a sensitivity of 87% and 89%, respectively. The total sensitivity was 89%. After orchiectomy, miR371 levels declined in 154 of 159 TGCC cases. The ratio of miR371 pre- and post-orchiectomy was 20.5 in CS1 compared to 6.5 in systemic disease. AFP and hCGβ had sensitivities of 52% and 51% in the non-seminomas. MiR371 is a sensitive marker that performs better than the classical markers in all sub-types and clinical stages. Especially for the seminomas CS1, the high sensitivity of miR371 in detecting TGCC cells may have clinical implications.

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required.

Abstract Background Cancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. Careful isolation, identification, and characterisation of CAF heterogeneity is thus necessary for ex vivo validation and future implementation of CAF-targeted strategies in cancer. Methods Murine 4T1 (metastatic) and 4T07 (poorly/non-metastatic) orthotopic triple negative breast cancer tumours were collected after 7, 14, or 21 days. The tumours were analysed via flow cytometry for the simultaneous expression of six CAF markers: alpha smooth muscle actin (αSMA), fibroblast activation protein alpha (FAPα), platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ), CD26/DPP4 and podoplanin (PDPN). All non-CAFs were excluded from the analysis using a lineage marker cocktail (CD24, CD31, CD45, CD49f, EpCAM, LYVE-1, and TER-119). In total 128 murine tumours and 12 healthy mammary fat pads were analysed. Results We have developed a multicolour flow cytometry strategy based on exclusion of non-CAFs and successfully employed this to explore the temporal heterogeneity of freshly isolated CAFs in the 4T1 and 4T07 mouse models of triple-negative breast cancer. Analysing 128 murine tumours, we identified 5–6 main CAF populations and numerous minor ones based on the analysis of αSMA, FAPα, PDGFRα, PDGFRβ, CD26, and PDPN. All markers showed temporal changes with a distinct switch from primarily PDGFRα+ fibroblasts in healthy mammary tissue to predominantly PDGFRβ+ CAFs in tumours. CD26+ CAFs emerged as a large novel subpopulation, only matched by FAPα+ CAFs in abundance. Conclusion We demonstrate that multiple subpopulations of CAFs co-exist in murine triple negative breast cancer, and that the abundance and dynamics for each marker differ depending on tumour type and time. Our results form the foundation needed to isolate and characterise specific CAF populations, and ultimately provide an opportunity to therapeutically target specific CAF subpopulations.

Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988–1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.

Koguchi-Yoshioka et al. demonstrate that functional activities and diversity of T cells are highly maintained in the skin of elderly people when compared with those in the blood regardless of the ethnicity of the participants or the experimental procedures. They also find the accumulation of epidermal T cells with maintained cytokine production in the elderly participants.

Abstract Background Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. Case presentation At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient’s medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. Conclusions For the first time, we report the detection of HPV45 in a case of ANEC. To our belief, PIK3CA mutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or the PIK3CA mutation may have contributed to the favorable outcome.

Telomere maintenance is a critical requirement for enabling replicative immortality and tumour development. Here, telomerase expression and activity, telomere length (TL) and potential regulatory factors that can underlie telomerase machinery alterations in small intestinal neuroendocrine tumours (SI-NETs) were analyzed. Telomerase activity assessed by TRAP assay was increased in SI-NETs compared to normal ileum (P < 0.001). The telomerase reverse transcriptase gene (TERT) was over-expressed in SI-NETs vs. normal ileal samples (P = 0.01). Furthermore, relative TL assessed by qPCR was found shorter in tumours compared with normal ileum (P = 0.02) and in distant metastasis samples compared to primary tumours and local metastases (P= 0.02). TERT promoter hotspot mutations were not present and TERT copy number gain was only observed in 3/70 tumour samples. TERT or chromosome 18 copy number alterations were not associated with telomerase expression and activity or TL. However, hypermethylation of TERT promoter in Region B – in the proximity of the transcription start site – was inversely correlated with TERT expression and telomerase activity and positively correlated with TL. Global LINE1 methylation was positively correlated with TERT promoter Region B methylation and was inversely correlated with telomerase activity, TERT expression and the upstream Region A methylation. The results show that telomerase activation, TERT expression and shorter telomeres are commonly found in SI-NETs. Aberrant DNA methylation of TERT promoter and of LINE1 can be implicated in abnormal regulation of TERT in SI-NETs.

Mode-locked lasers find their use in a large number of applications, for instance, in spectroscopic sensing, distance measurements, and optical communication. To enable widespread use of mode-locked lasers, their on-chip integration is desired. In recent years, there have been multiple demonstrations of monolithic III-V and heterogeneous III-V-on-silicon mode-locked lasers. However, the pulse energy, noise performance, and stability of these mode-locked lasers are limited by the relatively high linear and nonlinear waveguide loss, and the high temperature sensitivity of said platforms. Here, we demonstrate a heterogeneous III-V-on-silicon-nitride (III-V-on-SiN) electrically pumped mode-locked laser. SiN’s low waveguide loss, negligible two-photon absorption at telecom wavelengths, and small thermo-optic coefficient enable low-noise mode-locked lasers with high pulse energies and excellent temperature stability. Our mode-locked laser emits at a wavelength of 1.6 μm, has a pulse repetition rate of 3 GHz, a high on-chip pulse energy of ≈2 pJ, a narrow RF linewidth of 400 Hz, and an optical linewidth

Lipid nanoparticles (LNPs) are potential platforms for RNA-based therapeutics, but the fate of LNP-RNAs upon internalization into the cell is unclear. Here, the authors show that LNP-mRNAs and ionizable lipids escape the endosomes and are re-released via extracellular vesicles which could deliver the functional mRNA to other cells.

The STRIPAK complex has been linked to a variety of biological processes taking place during embryogenesis and development, but its role in cancer has only just started to be defined. Here, we expand on previous work indicating a role for the scaffolding protein STRIP1 in cancer cell migration and metastasis. We show that cell cycle arrest and decreased proliferation are seen upon loss of STRIP1 in MDA-MB-231 cells due to the induction of cyclin dependent kinase inhibitors, including p21 and p27. We demonstrate that p21 and p27 induction is observed in a subpopulation of cells having low DNA damage response and that the p21high/γH2AXlow ratio within single cells can be rescued by depleting MST3&4 kinases. While the loss of STRIP1 decreases cell proliferation and tumor growth, cells treated with low dosage of chemotherapeutics in vitro paradoxically escape therapy-induced senescence and begin to proliferate after recovery. This corroborates with already known research on the dual role of p21 and indicates that STRIP1 also plays a contradictory role in breast cancer, suppressing tumor growth, but once treated with chemotherapeutics, allowing for possible recurrence and decreased patient survival.

Background: With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation). Methods: We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded. Results: Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/ normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure. Conclusion: Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving.

Abstract Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff. This study investigates a hypothetical clinical scenario of pre-operative PET imaging, combined with intra-operative MMUS imaging, implemented in a sentinel lymph node (SLN) rat model. At one-hour post injection of 68Ga-labelled magnetic nanoparticles, six animals were imaged with combined PET/CT. After two or four days, the same animals were imaged with MMUS. In addition, ex-vivo MRI was used to evaluate the amount of nanoparticles in each single SLN. All SLNs were detectable by PET. Four out of six SLNs could be detected with MMUS, and for these MMUS and MRI measurements were in close agreement. The MRI measurements revealed that the two SLNs undetectable with MMUS contained the lowest nanoparticle concentrations. This study shows that MMUS can complement standard pre-operative imaging by providing bedside real-time images with high spatial resolution.

John Acquavella,1 Vera Ehrenstein,1 Morten Schiødt,2 Uffe Heide-Jørgensen,1 Anders Kjellman,3,4 Svein Hansen,5 Cecilia Larsson Wexell,6,7 Bente Brokstad Herlofson,8 Sven Erik Noerholt,9 Haijun Ma,10 Katarina Öhrling,11 Rohini K Hernandez,12 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen, Denmark; 3Department of Urology, Karolinska University Hospital, 4Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; 5Cancer Registry of Norway, Oslo University Hospital, Oslo, Norway; 6Department of Oral and Maxillofacial Surgery, Södra Älvsborg Hospital, Borås, Sweden; 7Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 8Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo, Norway; 9Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Aarhus, Denmark; 10Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA; 11Clinical Development, Amgen Inc., Thousand Oaks, CA, USA; 12Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA Objective: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies. Methods: As part of a comprehensive pharmacovigilance plan, developed with regulators’ input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Follow-up will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naïve patients, zoledronic acid-naïve patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA® clinical trials program. Conclusion: This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies. Keywords: cohort study, osteonecrosis of the jaw, pharmacovigilance, postmarketing drug surveillance, denosumab, zoledronic acid

Endo-β-N-acetylglucosaminidase (EndoS) is a family 18 glycosyl hydrolase secreted by Streptococcus pyogenes. Recombinant EndoS hydrolyzes the β-1,4-di-N-acetylchitobiose core of the N-linked complex type glycan on the asparagine 297 of the γ-chains of IgG. Here, we report that EndoS and IgG hydrolyzed by EndoS induced suppression of local immune complex (IC)-mediated arthritis. A small amount (1 µg given i.v. to a mouse) of EndoS was sufficient to inhibit IgG-mediated arthritis in mice. The presence of EndoS disturbed larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen-antibody binding per se were affected. Thus, EndoS could potentially be used for treating patients with IC-mediated pathology.

This article contains a presentation of experiences gained of research circles as a participant-based method for the development of knowledge and the creation of change in practice. The starting point is two international projects whose aim is to develop knowledge about the professional work being done with young people who exhibit violent behavior. In the Swedish sub-studies, research circles are used as a method for developing such knowledge as well as for creating change in practice. The research circle as a method has its theoretical starting point in action research and participant-oriented research. The results of the study illustrate how research circles can contribute to the creation of a knowledge process through the dialogue in the group and the facilitation of reflection over different work approaches in one’s own work, even if it is a method that does not suit everyone. The results also show that the research circle can lead to a change process in the actual work by enhancing transprofessional collaboration and leading to an increase in the participants’ awareness and evaluation of their work with violent children and young people. Este artigo contém uma apresentação de experiências adquiridas com círculos de investigação como método participante capaz de gerar conhecimento e mudança de práticas. Dois projetos internacionais constituem o nosso ponto de partida, cujo objetivo foi o de produzir conhecimento sobre o trabalho profissional que está a ser feito com os jovens que apresentam comportamento violento. Nos sub-estudos suecos, os círculos de investigação são usados como um método para o desenvolvimento de tais conhecimentos, bem como para proporcionar mudança de práticas. O círculo de investigação como método tem o seu ponto de partida teórico na investigação-ação e na investigação participante. Os resultados do estudo demonstram como os círculos de investigação podem contribuir para a criação de um processo de conhecimento através do diálogo no grupo e a facilitação da reflexão sobre as diferentes abordagens de intervenção no próprio trabalho, mesmo que seja um método que não sirva a todos. Os resultados mostram também que o círculo de investigação pode conduzir a um processo de mudança no trabalho concreto e ao reforço da colaboração transprofissional levando ainda a um aumento da consciencialização dos participantes e da avaliação do seu trabalho com crianças e jovens violentos. Este artículo contiene una presentación de experiencias de los círculos de investigación como método participante capaz de generar conocimientos y cambio de prácticas. Dos proyectos internacionales constituyen nuestro punto de partida, cuya finalidad era producir conocimiento sobre el trabajo profesional qué está haciendo con los jóvenes que exhiben un comportamiento violento. En los sub-estudios suecos, los círculos de investigación se utilizan como un método para el desarrollo de tales conocimientos, así como para proporcionar cambio de prácticas. El círculo de investigación como método tiene su punto de partida teórico en la investigación-acción y la investigación participativa. Los resultados del estudio demuestran cómo los círculos de investigación pueden contribuir a la creación de un proceso de conocimiento a través del diálogo en el grupo y la facilitación de la reflexión sobre los diferentes abordajes de intervención en su trabajo, incluso si se trata de un método que no sirve para todos. Los resultados también muestran que el círculo de investigación puede conducir a un proceso de cambio en el trabajo concreto y el fortalecimiento de la colaboración sigue transprofesional lo que aumenta la conciencia de los participantes y la evaluación de su trabajo con los niños y los jóvenes violentos. Cet article contient une présentation des expériences des cercle de recherche en tant que méthode de participant capable de générer des connaissances et changement des pratique. Deux projets internationaux constituent notre point de départ, le but était de produire des connaissances sur le travail professionnel accompli avec les jeunes qui manifestent un comportement violent. Dans les sous-études suédoises, milieux de la recherche sont utilisés comme une méthode pour le développement de ces connaissances ainsi que pour la changement des pratique. Le cercle de recherche comme méthode a son point de départ théorique dans la recherche-action et la recherche participative. Les résultats de l'étude montrent comment les milieux de la recherche peut contribuer à la création d'un processus de connaissance par le dialogue dans le groupe et la facilitation de la réflexion sur les différentes approches d'intervention dans leur travail, même si ce est une méthode qui ne convient pas à tous. Les résultats montrent également que le cercle de recherche peut conduire à un processus de changement dans le présent ouvrage et le renforcement de la collaboration transprofessional toujours en tête à une sensibilisation accrue des participants et de l'évaluation de leur travail avec les enfants et les jeunes violents.

In laparoscopy, novel three-dimensional laparoscopic vision systems (3D LVS) without glasses (3D−) have been invented. While standard 3D LVS with glasses (3D+) have shown advantages over original two-dimensional systems, quantitative comparisons of surgical performance between 3D− and 3D+ systems are still lacking. The aim is to compare the systems in simulated robotic surgery tasks. In a crossover study, 18 medical students performed four basic laparoscopic tasks in the validated Simball Box simulator with authentic surgical instruments by using the 3D+ and 3D− systems. Performance was measured by the number of errors and the task’s duration. Subjective ratings of perceptions and preference were assessed after each test. There were significant, but still minor, advantages for the conventional 3D+ system regarding spatial orientation and sense of depth. Overall, ten and eight subjects preferred 3D+ and 3D− systems, respectively. No significant differences were found in performance, post-operative physicals or eye symptoms. The novel 3D− system was similar to the conventional 3D+ system regarding performance and overall preference, while there were minor advantages for the 3D+ system in the subjective ratings. Since the 3D− system is a new invention, it should have a higher potential of usability improvements.

Rosacea is a field within dermatology with new insight within immunological research and new treatment-algorithm. Patient education on rosacea and appropriate treatments is an important aspect in helping patients succeed with therapy. Treatment should be tailored to each individual patient, taking into account: symptoms, trigger factors, patients’ wishes, most bothersome symptoms, psychological aspect, individual needs. A combination of clinical therapies to treat different symptoms concomitantly may offer the best possible outcomes for the patient. In this review article we describe these aspects.

This report deals with the special resources given to several school districts in Sweden for dealing with problems concerning the coordination of leisure activities and pupil welfare, with emphasis on the planning in Malmo. Three models are applied: (a) an educational planning model, where planning, process, and results stages are emphasized; (b) a sociological model, dealing with organizational aspects and interpersonal cooperation; and (c) a psychological study, with emphasis on barriers and conflicts. The study ends with a discussion of some special problems arising in activities attempting the integration of different community services. (Author/MB)

Recently, integrin alpha10 was described as a collagen type II-binding integrin expressed mainly in chondrocytes. However, by array studies we detected integrin alpha10 also to be upregulated in malignant melanoma compared to primary melanocytes. Subsequent analysis of melanoma cell lines and melanoma tumor samples confirmed this finding. Further, we demonstrated that expression of integrin alpha10 is controlled by AP-2 and Ets-1, two transcription factors known to be involved in melanoma development and progression. To investigate the functional relevance of integrin alpha10, expression was downregulated via stable antisense transfection. Proliferation assays and colony forming assays revealed no differences comparing antisense integrin alpha10 cell clones with control and wild type melanoma cells, respectively. However, antisense integrin alpha10 cell clones and Mel Im cells treated with an inhibitory antibody against integrin alpha10 showed a reduced migratory potential.