Norwegian Radium Hospital Research Articles

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer.

To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.

Translation and cross-cultural adaptation of the Gynecologic Cancer Lymphedema Questionnaire and the Lower Extremity Lymphedema Screening Questionnaire

ObjectiveThere is a paucity of international data regarding self-reported lower extremity lymphedema and quality of life after surgery for gynecological cancer. Validated questionnaires are emerging, but translated versions are lacking....

Documentation for Assessing Pain in Postoperative Pain Management Pre- and Post-intervention

PurposeAlthough Norwegian law requires the documentation of patients’ care processes, including pain assessment, research has shown that the quality of postoperative documentation for assessing pain does not meet an acceptable standard and requires improvement. The purpose of this study was to investigate whether an educational intervention can increase nurses’ documentation of postoperative pain assessments, alter patients’ opioid consumption, and ensure that patients have at least one documented Numeric Rating Scale (NRS) ≤3 at rest before being discharged. A secondary aim was to investigate whether the nurses’ education and experience influenced their pain assessments. DesignAn observational study with a pre-post intervention. MethodsThe study following a pre-post design involved documenting pain assessments of 304 patients undergoing cancer surgeries in a postoperative unit at the Norwegian Radium Hospital, Oslo University Hospital. In an educational intervention, two 45-minutes teaching sessions within two weeks, addressed validated pain assessment tools and the documentation of pain assessment. Descriptive frequency analysis and partial correlation with Pearson's r - value were used, with P < .05 indicating significance. FindingsPostintervention, pain assessments in general increased significantly from a mean of two times per patient to three times. Overall, the use of assessment tool Critical -Care Pain Observation Tool increased from 6.1% to 25.8%, opioid consumption increased in mean from 3.34 to 4.79 in milligram and the documentation at discharge increased from 81.4% to 91.4%. The documentation of nurses with more than 10 years’ experience in the unit especially improved from 17.5% to 31.7%. ConclusionsEducational intervention and reminders about basic systematic pain assessment and the evaluation of pain measures improved nurses’ documentation of postoperative pain management and documentation at discharge. The findings underscore the importance of regularly ensuring the quality of patients’ treatment by systematically documenting nurses’ clinical tasks and the outcome of patients’ care.

Early referral to a palliative team improves end-of-life care among gynecological cancer patients: a retrospective, population-based study

ObjectiveTo assess end-of-life care among patients with gynecological cancer, and to describe the association between timing of palliative care referral and patterns of care.MethodsAll women with residence in Oslo, Norway,...

Long-term oncological outcomes and recurrence patterns in early-stage cervical cancer treated with minimally invasive versus abdominal radical hysterectomy: The Norwegian Radium Hospital experience

ObjectiveTo compare long-term oncological outcomes in early-stage cervical cancer (CC) patients treated with minimally invasive radical hysterectomy (MIRH) versus abdominal radical hysterectomy (ARH), with a focus on recurrence patterns, tumor sizes, and conization. MethodsThis single-institution, retrospective study consisted of stage IA1-IB1 (FIGO 2009) squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma of the cervix, who underwent radical hysterectomy between 2000 and 2017. ResultsOf the 582 patients included, 353 (60.7%) underwent ARH, and 229 (39.3%) MIRH. The median follow-up was 14.4 years in the ARH group and 6.1 years in the MIRH group (p < 0.0001). Among the 96 stage IA patients, only 3 (3.1%) experienced recurrence. Among stage IB1 patients, the risk of recurrence, after adjusting for standard prognostic variables, was twofold higher in the MIRH group versus the ARH group (HR 2.73, 95% CI: 1.56–4.80), and the relative difference was similar in terms of risk of cancer-specific survival (CSS) (HR 3.04, 95% CI: 1.28–7.20) and overall survival (OS) (HR 2.35, 95% CI: 1.21–4.59). In stage IB1 ≤ 2 cm patients without conization MIRH was associated with reduced time to recurrence (TTR) (HR 4.00, 95% CI: 1.67–9.57), CSS (HR 3.71, 95% CI: 1.19–11.58) and OS (HR 3.02, 95% CI: 1.24–7.34). Intraperitoneal combined recurrences accounted for 12 of 30 (40.0%) recurrences in the MIRH group but were not identified after ARH (p = 0.0001). ConclusionsMIRH was associated with reduced TTR, CSS and OS versus ARH in stage IB1 CC patients. The risk of peritoneal recurrence was high, even for tumors ≤2 cm without conization.

A bibliometric review of top 50 cited articles published in the Photodiagnosis and Photodynamic Therapy from 2004 to 2019.

The aim of the article was to identify the top 50 cited articles in the journal of Photodiagnosis and Photodynamic Therapy during 2004-2019. The online search was conducted on Scopus database to retrieve all the articles published during 2004-2019 in the journal of Photodiagnosis and Photodynamic Therapy. The papers were identified and ranked as per the citation counts >42. Additionally the authors; institute and country of origin; type of study and availability of funding in these highly cited articles was identified. VOS viewer software was used to analyze the occurrence of most commonly used keywords by the authors. Majority of the highly cited studies published during last 15 years were literature reviews (n = 34) followed by the qualitative/quantitative studies (n = 15). The largest number of articles published were single nations without any collaborations (n = 45). The institutes publishing highest number of top cited articles included Massachusetts General Hospital, East Carolina University, 21 st Century Oncology, The Norwegian Radium Hospital and Trinity College Dublin. The country with largest number of top cited articles was USA. The keyword most commonly associated with the 50 top cited articles was 'Photodynamic therapy'. Extensively, various specialties of medicine and dentistry have been explored in the last 15 years in the journal of Photodiagnosis and Photodynamic Therapy. Based on citatations, we have highlighted those that can be considered as classic research.

PSA status after neoadjuvant androgen deprivation therapy before high-dose-rate brachytherapy as biomarker for prediction of long-term outcome in high-risk prostate cancer patients.

301 Background: The aim is to investigate the clinical significance of biochemical response after Androgen Deprivation Therapy (ADT) prior to high-dose-rate brachytherapy (HDR-BT) for early identification of patients at increased risk of recurrence. Measured outcomes included biochemical relapse free survival (bRFS), distant metastasis free survival (DMFS) and overall survival (OS). Methods: A total of 324 patients with high-risk Prostate Cancer (PCa) were identified in the Norwegian Radium Hospital brachytherapy database. Neo-adjuvant ADT was administered for 3-6 months, followed by two 10 Gy HDR-BT treatments to the prostate, each spaced by two weeks, followed by conformal external beam radiation to 50 Gy to the prostate gland and seminal vesicles. Total length of ADT ranged from 12 to 36 months. PSA (ng/mL) and testosterone values (T, nmol/L) after 3-6 months of neo-adjuvant ADT were measured. Kaplan Meier and Cox regression analyses were performed. Results: Median age at diagnosis was 66 years and median follow-up was 10 years. At last follow-up, 277 patients (85,2%) were alive, 10 patients (3.1%) had died of prostate cancer and 37 patients (11.4%) died of other causes. 24 patients (7.4%) had biochemical relapse and 9 patients (2.8%) had distant metastasis within the first 5 years. Patients with PSA &gt; 1 after neo-adjuvant therapy had 4.3 (95%CI 1.7 to 11.1) higher odds of biochemical relapse within 5 years compared to patients with PSA &lt; 1 (p = 0.002). ROC analysis confirmed that PSA &lt; 1 had a prediction accuracy of 0.76 (sensitivity 68% and specificity 67%). T &lt; 0.7 and PSA &lt; 1 after neo-adjuvant therapy were associated with improved bRFS, DMFS and OS (p &lt; 0.001). Neither the length of neo-adjuvant nor total ADT treatment impacted outcomes (p &gt; 0.05). Conclusions: Dose intensification with 2 HDR-BT boosts resulted in excellent survival in our cohort. PSA &gt; 1 after neo-adjuvant ADT may be able to predict patients at increased risk of relapse and worse OS and identify patients in whom increased monitoring and/or intervention is warranted. ADT &gt; 1 year did not improve outcome, indicating that shorter course of ADT may be used.

In-hospital deaths attributable to healthcare-associated infections.

It is estimated that approximately one-third of in-hospital deaths in Norway are attributable to adverse events, while the proportion caused by infection is unknown. Oslo University Hospital provides a full range of medical specialties on a national and regional level while serving as a local hospital for a population of approximately 300 000. We wished to investigate in-hospital deaths associated with fatal adverse events, and healthcare-associated infections in particular. The study is based on a review of the medical records for all patients who died in Oslo University Hospital's somatic units in 2011. Infections were classified according to the criteria of the Centers for Disease Control and Prevention, USA. Out of a total of 82 341 admitted patients, 1 126 died while in hospital. We identified life-shortening adverse events in 128 (11.4%) of these. The 87patients at Ullevål hospital had a mean age of 73 years, while the 41patients at Rikshospitalet/the Norwegian Radium Hospital had a mean age of 62 years. A total of 108patients (9.6%) died from a healthcare-associated infection, 49 of whom had a predicted survival of more than four weeks (4.4% of the fatalities). Fifty-eight patients had pneumonia. The proportion of deaths that were attributable to adverse events was lower than previously estimated in Norway. Oslo University Hospital, with its combined functions and broad patient base, can provide representative figures for healthcare-associated infections with fatal outcome in Norwegian hospitals.

The Long Term Oncological Follow up Results After Robot-Assisted Radical Hysterectomy (RARH) as Compared to Open Radical Hysterectomy (ORH) in the Management of Early-Stage (ST IB1) Cervical Cancer (ESCC)

<h3>Study Objective</h3> To investigate the long term oncological follow up results and the relevant clinicopathologic prognostic factors for early stage (St IB1) cervical carcinoma patients who were surgically treated with Robot Assisted Radical Hysterectomy (RARH) or Open Radical Hysterectomy (ORH) from 2005 to 2012 at The Norwegian Radium Hospital. <h3>Design</h3> Prospectively collected and non-randomized retrospective controlled study. <h3>Setting</h3> Single institution (A university teaching hospital). <h3>Patients or Participants</h3> All early-stage cervical cancer patients who underwent radical hysterectomy at the Norwegian Radium Hospital within that time period. <h3>Interventions</h3> Patients underwent RARH or ORH. <h3>Measurements and Main Results</h3> 193 stage IB1 patients were identified within the study period. None of the RARH cases was converted either conventional laparoscopy or laparotomy. 19 cases were excluded due to preoperative neoadjuvant chemotherapy and total 174 patients were included. 110 patients underwent ORH and 64 patients RARH. RARH were performed with using the first generation da Vinci surgical platform by the same surgeon (MBS). The two groups were comparable in terms of age, body mass index (BMI) and follow-up time. The ORH group had shorter mean operation time (p<0.001) while RARH group have less estimated mean blood loss (<0.001) and shorter mean length of hospital stay (LOS) (p<0.001). The tumor size, positive lymph-vascular space invasion (LVSI), positive surgical margins were comparable between the groups. The frequency of perioperative complications were similar, but post- operative complications were higher in the ORH group (p<0.005). Recurrence rate 12% in the RARH group and 9% in the ORH group (p:0.48). Mean recurrence-free interval and 5 years survival rate were comparable in the both groups even-thought hematogenous metastasis was more likely (5.4%) in RARH group. <h3>Conclusion</h3> This long follow up study provides that RARH reduces EBL and LOS and post-operative complications without significant poorer oncological outcomes even-thought distant organ metastasis were almost double in the RARH arm which should be further investigated with larger prospective randomized clinical studies.

Survival according to mutations in BRAF, KRAS, or microsatellite instability (MSI-H) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases from colorectal cancer.

3565 Background: Patients with metastatic colorectal cancer (mCRC) and mutations in BRAF V600E (mutBRAF) or KRAS (mutKRAS) have a worse prognosis after liver or lung surgery/ablation, whereas the impact of microsatellite instability (MSI-H) has not been well studied. Few patients with mutBRAF receive liver or lung surgery (1-4%), whereas mutBRAF is present in 5-12% of mCRC trial patients and in up to 20% of the general mCRC population. The frequency and prognostic role of mutBRAF, mutKRAS and MSI has not been well studied after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases from colorectal cancer. Methods: The Norwegian Radium Hospital is the only center offering CRS and HIPEC in Norway. From 2004 to 2015 257 patients with histology proven peritoneal metastasis from colorectal cancer, appendiceal cancer excluded, was consecutively enrolled. Molecular analyses of KRAS, BRAF and MSS/MSI in mutBRAF were done. Fourteen patients were excluded due to missing tumour blocks (7), unsuccessful analysis (4) and other malignant disease (1). Results: 180 of 243 patients obtained complete cytoreductive surgery and received HIPEC for 90 minutes with Mitomycin C (45-70mg). Median survival for the 180 patients was 47 months and 5-year survival rate 40.1%. Median disease-free survival was 10 months. mutBRAF was found in 23.4% of cases, mutKRAS 35.1% and double-wild type 41.5%. mutBRAF with MSS was found in 16.4%, mutBRAF with MSI-H in 7.0%. 3-year disease free survival (DFS) and median overall survival (OS) was 38.9% and 59 months with mutBRAF with MSI-H, significantly higher compared to 24.2% and 30 months in patients with double wild type, 13.2 % and 41 months in mutKRAS and 17.9% and 22 months in mutBRAF with MSS. Conclusions: A surprisingly high frequency of mutBRAF was seen in mCRC patients after CRS and HIPEC for peritoneal metastatic disease. Patients with mutBRAF and MSI-H had a significantly better DFS and OS after CRS and HIPEC. DFS for patients with mutBRAF and MSS was numerically lower but not statistically different from patients with mutKRAS or double wild type.

Abstract 5713: Promising predictive biomarkers for immunotherapy in metastatic melanoma

Abstract Aim: to explore biomarkers in order to predict outcome in patients with metastatic melanoma who have had immunotherapy with ipilimumab in a real-world setting. Metastatic melanoma is a very aggressive, incurable cancer with historically few therapeutic options and poor survival. Immunotherapy represents a revolution for metastatic melanoma treatment but there is a lack of biomarkers to predict treatment response. Material and methods: In the Norwegian National Phase 4 Multicenter Study, IPI4, 150 patients were included to receive ipilimumab (anti-CTLA3). A subgroup of 73 patients (4 screening failure) was included at Oslo University Hospital -The Norwegian Radium Hospital. Serum was available from 56 patients of this subgroup and were examined before and during ipilimumab treatment concerning possible predictive biomarkers. Expression of a panel of 17 inflammatory markers reflecting different inflammatory pathways including extra cellular matrix remodeling and fibrosis, vascular inflammation, notch signaling, inflammation in general and monocyte/macrophage activation were measured at baseline and at the 2nd and/or 3rd treatment with ipilimumab. Results: During an average 33.7 months follow-up, 33 (59%) patients died. Six promising candidates (endostatin, osteoprotegerin, C-reactive protein, pulmonary and activation-regulated chemokine and galectin-3 binding-protein) were higher in non-survivors. In particular, high endostatin and galectin-3 binding protein levels were independently associated with poor long time survival also in adjusted analysis (age, gender, lactate dehydrogenase). A 1 standard deviation (SD) increase in Gal3BP gave a 1.8 x times higher risk of death (95% CI 1.10-2.95, p=0.019) while a 1 SD increase in endostatin was associated with a 2x higher risk of death (95% CI 1.12-3.64, p=0.020) in the final model. Conclusion: Endostatin and galectin-3 binding protein may represent biomarkers for prognosis during immunotherapy with ipilimumab and should be further evaluated. Citation Format: Marta Nyakas, Elin Aamdal, Tormod Guren, Steinar Aamdal, Kari Dolven Jacobsen, Paal Brunsvig, Kristin Austlid Tasken, Gunhild Mælandsmo, Arne Yndestad, Bente Halvorsen, Paal Aukrust, Thor Ueland. Promising predictive biomarkers for immunotherapy in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5713.

Abstract CT094: Novel treatment with intraperitoneal MOC31PE immunotoxin in colorectal peritoneal metastasis: Long-term outcome from the ImmunoPeCa phase I/II trial

Abstract Background. Peritoneal metastasis (PM) from colorectal cancer (CRC) is associated with poor outcome, but in patients with resectable disease long-term survival through cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be achieved. The dual rationale for applying intraperitoneal therapy in PM-CRC is dose intensification because of the peritoneal-plasma barrier and the conception of PM as a localized disease within the peritoneal cavity. Outcome following CRS-HIPEC is however highly variable and most patients will experience disease recurrence, illustrating the need for improved treatment. MOC31PE immunotoxin, composed of the monoclonal antibody MOC31 and pseudomonas exotoxin A (PE), was developed by researchers at the Norwegian Radium Hospital to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule (EpCAM), which is highly expressed in CRC. In the ImmunoPeCa trial we investigated the use of intraperitoneal MOC31PE as a novel therapeutic principle to target PM-CRC. Methods. The ImmunoPeCa trial was a dose-escalating phase I trial to evaluate the safety and tolerability (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC. Overall survival (OS) and disease-free survival (DFS) were also examined (secondary endpoints). Fifteen patients received the study drug at four dose levels (2.5 (n=3), 5.0 (n=3), 7.5 (n=3) and 10 (n=6) µg kg). Additional 6 patients, constituting an expansion cohort, were treated on dose level 4 (10 µg/kg). Results. There was no major toxicity, and the maximum tolerated dose was not reached. The systemic drug exposure was low, and MOC31PE in peritoneal fluid samples retained cytotoxic capacity, suggesting that the drug is very stable under physiological conditions. With a median follow-up of 29 months (95% CI 22-35 months), the median OS was not reached and the estimated 3-year OS was 85%. Estimated median DFS was 20 months (95% CI 8-33 months) and the estimated 3-year DFS was 36%, with a median follow-up of 25 months (95% CI 19-31 months). Although very encouraging, the results may reflect the selection of the cohort, and investigation in a larger cohort would be necessary to study efficacy. Conclusions. Intraperitoneal, perioperative administration of MOC31PE was safe and well tolerated. The promising long-term outcome combined with the low systemic uptake and retained cytotoxic activity in peritoneal fluid samples support further clinical testing. Citation Format: Ida S. Froysnes, Yvonne Andersson, Stein Larsen, Ben Davidson, Janne-Merete T. Oien, Kari H. Olsen, Karl-Erik Giercksky, Lars Julsrud, Oystein Fodstad, Svein Dueland, Kjersti Flatmark. Novel treatment with intraperitoneal MOC31PE immunotoxin in colorectal peritoneal metastasis: Long-term outcome from the ImmunoPeCa phase I/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT094.

Identification of genetic variants for clinical management of familial colorectal tumors

BackgroundThe genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines.MethodsThe Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays.ResultsWe identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing.ConclusionsAmong high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.

RETRACTED ARTICLE: The BRCA2 variant c.68-7 T>A is associated with breast cancer

BackgroundBRCA2 c.68-7T>A has been demonstrated to cause aberrant splicing and is possibly pathogenic. The population prevalence of the variant is 0.2%, which higher than usual for pathogenic BRCA2 variants. The pathogenicity of the variant is discussed.MethodsThe outpatient genetic clinic at The Norwegian Radium Hospital, part of Oslo University Hospital, has invited breast cancer kindreds for genetic examinations and prospective follow-up of high risk patients since 1988. We have complete files of all activities and results, and we examined the files for association between BRCA2 c.68-7T>A and breast cancer.ResultsSeventeen out of 714 (2.4%) breast cancer kindreds sequenced for BRCA2 carried the variant BRCA2 c.68-7T>A (p < 0.0001 compared to population controls). Segregation analysis was inconclusive (likelihood ratio 0.36) for pathogenicity. Two breast cancers were prospectively observed during 134 observation years (annual incidence rate 1.5% (95% CI 0.15% to 5.4%) and one additional breast cancer was diagnosed at first (prevalence) round.ConclusionBRCA2 c.68-7T>A is associated with breast cancer. In the families selected due to aggregation of breast cancer, carriers of the BRCA2 c.68-7T>A variant have increased risk for breast cancer. It is, however, possible that the variant has lower penetrance than the average pathogenic BRCA2 variants, and that in the families selected for having known aggregation of breast cancer other (modifying) factors contributed to the observed results.

Validation of a Mitotic Index Cutoff as a Prognostic Marker in Undifferentiated Uterine Sarcomas

Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutoff of 25 mitoses/10 high-power fields (corresponding to 11.16 mitotic figures/mm) could successfully divide tumors into 2 prognostic groups with significantly different overall survival. The goals of the current study were to (1) validate this mitotic index cutoff in an independent, multicenter cohort and (2) explore the prognostic value of the mitotic index groups in relation to other clinicopathologic variables. Cases were included from 3 independent institutions: The Norwegian Radium Hospital, The Mayo Clinic, and Skåne University Hospital. A total of 40 tumors were included after central review. All cases were negative for the YWHAE-FAM22A/B and JAZF1-JJAZ1 translocations. Survival data were available on all patients. In this study, one-third of patients with UUS survived beyond 5 years. The crude (unadjusted) Cox Proportional Hazards model revealed a number of parameters that significantly impacted overall survival, including mitotic index group, patient age, stage, and the presence of tumor necrosis. Classification into the uniform and pleomorphic types was not prognostic. Combining these parameters into an adjusted model revealed that only the mitotic index group and stage were prognostic. On the basis of these findings, it is proposed that UUS be subdivided into "mitogenic" and "not otherwise specified" types.

Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families.

To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS (BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families.

Changes in the body image of bone sarcoma survivors following surgical treatment--A qualitative study.

Background and ObjectivesAmong several long‐term effects, people treated for cancer may experience an altered appearance. Our study aims to identify how visible body changes following surgical treatment affect the life and identity of primary bone sarcoma survivors 3–10 years after diagnosis. A qualitative, phenomenological, and hermeneutic design was applied.MethodsSarcoma survivors (n = 18) who were previously treated at Norwegian Radium Hospital, Oslo University Hospital, participated in the study. In‐depth and semi‐structured interviews were conducted and analyzed using inductive thematic analysis.ResultsThe main finding of this study concerned how altered appearance after bone cancer treatment in the hip/pelvis or lower extremities affected the participants’ self‐esteem. Half of the participants expressed concerns about their visible differences, particularly those with functional impairment. They felt that it is important to hide the bodily signs of changes to appear as normal as possible, as well as attractive and healthy. They describe, with specific examples, how these changes influence their self‐realization, especially their social life.ConclusionsHealthcare providers who guide bone sarcoma survivors during follow‐up should develop a comprehensive understanding of what it means to cope with a changed and challenging body. J. Surg. Oncol. 2016;113:229–234. © 2015 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc.

A tribute to Sjur: Sjur Olsnes, 1939-2014.

In the summer of 2014, the community of scientists studying bacterial protein toxins lost one of its pioneers and most prolific members, Sjur Olsnes. Sjur was a valued friend and colleague to those of us who knew and worked with him, and his passing was a deep loss. Sjur was born in Bergen, Norway, in 1939 and grew up on a farm nearby. He studied medicine in Bonn and after a short period at the University of Bergen moved to Oslo, where he did doctoral research in the Institute for Cancer Research at the Norwegian Radium Hospital. Except for brief periods as visiting scientist at institutions abroad, Sjur spent his entire career performing fundamental biochemical and cell biological research at the Radium Hospital. He progressed there from Senior Scientist (1972) to Head of Biochemistry (1990) and also held professorial appointments at the University of Oslo in Biochemistry and Tumor Biology. The research group he headed at the Radium Hospital was internationally recognized for their work on the actions of toxins at the molecular and cellular levels and became a mecca in the field. Sjur's scientific contributions, documented in more than 280 papers, include major discoveries that form the foundation of our current understanding of how protein toxins act at a biochemical and cellular level. While much of his research focused on protein toxins of plant or bacterial origin, his studies also extended to animal viruses and growth factors. The questions he addressed were primarily of a fundamental nature, but he always had an eye on relevance to cancer therapy. Below I briefly describe a few of Sjur's major contributions. Sjur's doctoral research on protein synthesis, mRNA and polyribosomes formed the context for his first major discovery in the toxin field. He reported in 1972, in a paper coauthored by his …

Abstract 5170: The autotaxin-lysophosphatidic acid signaling pathways in ovarian carcinoma

Abstract Ovarian carcinoma ranks as the fifth most common cancer among women. This is attributed to late presentation of the patients. The disease is characterized by widespread intraperitoneal metastases and accumulation of effusion fluids mainly in the peritoneal cavity Lysophosphatidic acid (LPA) is a bioactive phospholipid with mitogenic and growth factor-like activities affecting cell invasion, cancer progression and resistance that act via specific cell-surface receptors present in many transformed cell types. LPA is produced by two main pathways, by PLA-2 and by Autotaxin (LysoPLD). Once its produced, it acts on six specific G protein coupled receptors, LPAR1-6. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. Previous studies have shown high levels of LPA in the effusions of ovarian carcinoma patients. The aim of our study was to examine the role of ATX-LPA signaling in the progression of serous ovarian carcinoma. A total of 230 samples of serous ovarian carcinoma from the three different anatomic sites of the disease, were used .Effusion fluids were frozen and stored separately. All specimens were submitted for routine diagnostic purpose to the Division of Pathology at the Norwegian Radium Hospital during the period 1998-2008. mRNA levels of the six different LPA receptors were measured by RT-PCR, protein levels of Autotaxin were measured by Western blotting. Results show that LPA2R is higher in effusion-derived tumor cells compared to solid lesions (p&amp;lt;0.001), while the opposite was found for LPA3R (p&amp;lt;0.001) and LPA6R (p&amp;lt;0.001). Clinico-pathological analysis showed that LPA3R levels are significantly higher in pre-chemo patients (p = 0.038). LPA2R (p = 0.021) and LPA5R (p = 0.035) were found higher in cases with larger residual disease volume. LPA5R (p = 0.032) was higher in cases with primary chemo-resistance and LPA1R (p = 0.05) was marginally associated with better overall survival. Autotaxin protein levels were lower in effusion-derived tumor cells compared to solid lesions (p&amp;lt;0.001), yet higher levels of Autotaxin were found in peritoneal lesions compared to pleural ones (p = 0.033). In this study we showed significant changes in mRNA LPAR levels and Autotaxin protein levels with the progression of the disease that correlates to clinic-pathological parameters. To our best knowledge, this is the first description of the ATX-LPA signaling pathway in ovarian carcinoma with clinical relevance. Citation Format: Hadil Onalla, Claes Tropé, Reuven Reich, Ben Davidson. The autotaxin-lysophosphatidic acid signaling pathways in ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5170. doi:10.1158/1538-7445.AM2015-5170

Cured of primary bone cancer, but at what cost: a qualitative study of functional impairment and lost opportunities.

Purpose. Our study aims to explore how former cancer patients experience physical and psychosocial late effects 3–7 years after they underwent treatment for primary bone sarcoma in the hip/pelvic region. A qualitative, phenomenological, and hermeneutic design was applied. Methods. Sarcoma survivors (n = 10) previously treated at Oslo University Hospital, Norwegian Radium Hospital were selected to participate. In-depth and semistructured interviews were conducted. The interviews were analysed using inductive thematic analysis. Results. The participants reported that the late effects had three core spheres of impact: “their current daily life,” “their future opportunities,” and “their identity.” They expressed negative changes in activity, increased dependence on others, and exclusion from participation in different areas. Their daily life, work, sports activities, and social life were all affected. Several of their experiences are similar to those described by people with functional impairment or disability. Conclusion. Patients cured of bone cancer in the hip/pelvic region pay a significant price in terms of functional impairment, practical challenges, exclusion from important aspects of life, and loss of previous identity. It is important to appreciate this in order to help bone cancer survivors who struggle to reorient their life and build a secure new identity.