ICON: a randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. METHODS: ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. DISCUSSION: ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198.

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00145314.

Differential expression of miRNAs in pancreatobiliary type of periampullary adenocarcinoma and its associated stroma.

Periampullary adenocarcinomas can be of two histological subtypes, intestinal or pancreatobiliary. The latter is more frequent and aggressive, and characterized by a prominent desmoplastic stroma, which is tightly related to the biology of the cancer, including its poor response to chemotherapy. Whereas miRNAs are known to regulate various cellular processes and interactions between cells, their exact role in periampullary carcinoma remains to be characterized, especially with respect to the prominent stromal component of pancreatobiliary type cancers. The present study aimed at elucidating this role by miRNA expression profiling of the carcinomatous and stromal component in twenty periampullary adenocarcinomas of pancreatobiliary type. miRNA expression profiles were compared between carcinoma cells, stromal cells and normal tissue samples. A total of 43 miRNAs were found to be differentially expressed between carcinoma and stroma of which 11 belong to three miRNA families (miR-17, miR-15 and miR-515). The levels of expression of miRNAs miR-17, miR-20a, miR-20b, miR-223, miR-10b, miR-2964a and miR-342 were observed to be higher and miR-519e to be lower in the stromal component compared to the carcinomatous and normal components. They follow a trend where expression in stroma is highest followed by carcinoma and then normal tissue. Pathway analysis revealed that pathways regulating tumor-stroma interactions such as ECM interaction remodeling, epithelial-mesenchymal transition, focal adhesion pathway, TGF-beta, MAPK signaling, axon guidance and endocytosis were differently regulated. The miRNA-mRNA mediated interactions between carcinoma and stromal cells add new knowledge regarding tumor-stroma interactions.

AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

Molecular signatures of mRNAs and miRNAs as prognostic biomarkers in pancreatobiliary and intestinal types of periampullary adenocarcinomas.

Periampullary adenocarcinomas include four anatomical sites of origin (the pancreatic duct, bile duct, ampulla and duodenum) and most of them fall into two histological subgroups (pancreatobiliary and intestinal). Determining the exact origin of the tumor is sometimes difficult, due to overlapping histopathological characteristics. The prognosis depends on the histological subtype, as well as on the anatomical site of origin, the former being the more important. The molecular basis for these differences in prognosis is poorly understood. Whole-genome analyses were used to investigate the association between molecular tumor profiles, pathogenesis and prognosis. A total of 85 periampullary adenocarcinomas were characterized by mRNA and miRNA expressions profiling. Molecular profiles of the tumors from the different anatomical sites of origin as well as of the different histological subtypes were compared. Differentially expressed mRNAs and miRNAs between the two histopathological subtypes were linked to specific molecular pathways. Six miRNA families were downregulated and four were upregulated in the pancreatobiliary type as compared to the intestinal type (P < 0.05). miRNAs and mRNAs associated with improved overall and recurrence free survival for the two histopathological subtypes were identified. For the pancreatobiliary type the genes ATM, PTEN, RB1 and the miRNAs miR-592 and miR-497, and for the intestinal type the genes PDPK1, PIK3R2, G6PC and the miRNAs miR-127-3p, miR-377* were linked to enriched pathways and identified as prognostic markers. The molecular signatures identified may in the future guide the clinicians in the therapeutic decision making to an individualized treatment, if confirmed in other larger datasets.

Plasma microRNAs predicting clinical outcome in metastatic colorectal cancer patients receiving first-line oxaliplatin-based treatment.

The conventional first-line chemotherapy for metastatic colorectal cancer (mCRC) consists of fluorouracil (5-FU) in combination with either oxaliplatin or irinotecan. We have explored microRNAs (miRNAs) in plasma as potential predictive markers to oxaliplatin-based chemotherapy. The expression of 742 miRNAs was examined in plasma samples from 24 mCRC patients (12 responders and 12 non-responders) before onset and after four cycles of 5-FU/oxaliplatin. The top differentially expressed miRNAs between responders and non-responders were selected for further analysis in a validation cohort of 150 patients. In the validation cohort, there was a significant overrepresentation of miRNAs with higher mean expression in the non-responder group than in the responder group before treatment (p < 0.002). Moreover, we found three miRNAs (miR-106a, miR-484, and miR-130b) to be significantly differentially expressed before treatment (p = 0.008, 0.008, and 0.008, respectively). All three miRNAs were upregulated in non-responders. High expression of miR-27b, miR-148a, and miR-326 were associated with decreased progression-free survival (Hazard ratios (HR) of 1.4 (95% CI 1.1-1.8, p = 0.004), 1.3 (95% CI 1.1-1.6, p = 0.007), and 1.4 (95% CI 1.1-1.8, p = 0.008), respectively). miR-326 was also associated with decreased overall survival (HR 1.5 (95% CI 1.1-2.0, p = 0.003)). There were no significantly differentially expressed miRNAs in association with clinical outcome after four cycles of chemotherapy. The present study demonstrates that plasma miRNAs analyzed before treatment may serve as non-invasive markers predicting outcome in mCRC patients treated with 5-FU and oxaliplatin-based chemotherapy.

Comparison of the Agilent, ROMA/NimbleGen and Illumina platforms for classification of copy number alterations in human breast tumors.

BACKGROUND: Microarray Comparative Genomic Hybridization (array CGH) provides a means to examine DNA copy number aberrations. Various platforms, brands and underlying technologies are available, facing the user with many choices regarding platform sensitivity and number, localization, and density distribution of probes. RESULTS: We evaluate three different platforms presenting different nature and arrangement of the probes: The Agilent Human Genome CGH Microarray 44 k, the ROMA/NimbleGen Representational Oligonucleotide Microarray 82 k, and the Illumina Human-1 Genotyping 109 k BeadChip, with Agilent being gene oriented, ROMA/NimbleGen being genome oriented, and Illumina being genotyping oriented. We investigated copy number changes in 20 human breast tumor samples representing different gene expression subclasses, using a suite of graphical and statistical methods designed to work across platforms. Despite substantial differences in the composition and spatial distribution of probes, the comparison revealed high overall concordance. Notably however, some short amplifications and deletions of potential biological importance were not detected by all platforms. Both correlation and cluster analysis indicate a somewhat higher similarity between ROMA/NimbleGen and Illumina than between Agilent and the other two platforms. The programs developed for the analysis are available from http://www.ifi.uio.no/bioinf/Projects/. CONCLUSION: We conclude that platforms based on different technology principles reveal similar aberration patterns, although we observed some unique amplification or deletion peaks at various locations, only detected by one of the platforms. The correct platform choice for a particular study is dependent on whether the appointed research intention is gene, genome, or genotype oriented.

Predicting survival from microarray data--a comparative study.

MOTIVATION: Survival prediction from gene expression data and other high-dimensional genomic data has been subject to much research during the last years. These kinds of data are associated with the methodological problem of having many more gene expression values than individuals. In addition, the responses are censored survival times. Most of the proposed methods handle this by using Cox's proportional hazards model and obtain parameter estimates by some dimension reduction or parameter shrinkage estimation technique. Using three well-known microarray gene expression data sets, we compare the prediction performance of seven such methods: univariate selection, forward stepwise selection, principal components regression (PCR), supervised principal components regression, partial least squares regression (PLS), ridge regression and the lasso. RESULTS: Statistical learning from subsets should be repeated several times in order to get a fair comparison between methods. Methods using coefficient shrinkage or linear combinations of the gene expression values have much better performance than the simple variable selection methods. For our data sets, ridge regression has the overall best performance. AVAILABILITY: Matlab and R code for the prediction methods are available at http://www.med.uio.no/imb/stat/bmms/software/microsurv/.

Relatives' distress and patients' symptoms and behaviours: a prospective study of patients with schizophrenia and their relatives.

OBJECTIVE: The aim of this study is to explore the relationship between relatives' distress and patients' symptoms and behaviours. METHOD: Fifty relatives in close contact with 36 patients with schizophrenia DSM-III-R filled in the General Health Questionnaire (GHQ) and the Perceived Family Burden Scale (PFBS) at the patient's hospital admission, 4.5 and 9 months post-discharge. The patients were assessed by means of the Positive and Negative Syndrome Scale (PANSS). RESULTS: The PFBS anxiety-depression cluster was at all three assessments positively correlated with relative's distress (GHQ), not with PANSS anxiety and depression measurements. In multiple regression analysis PFBS, but not PANSS, was related to relatives' distress. CONCLUSION: Relatives' distress was related to their reports of problematic patient behaviours, especially anxiety-depressive behaviour, not to symptoms as measured by clinical interviews. High distress is related to high expressed emotion, suggesting that relatives' report of patient's behaviour should be addressed to improve patient's outcome.

Personality structure in patients with winter depression, assessed in a depression-free state according to the five-factor model of personality.

BACKGROUND: Depressive disorders are often associated with abnormalities of personality. This has also been found in Seasonal Affective Disorder, Winter Depression type (W-SAD), although relatively few and small studies have been done on this disorder so far, and mainly in the depressed phase. The aim of this study was to explore the personality structure and its possible background and clinical correlates in a larger group of patients with W-SAD, assessed in a non-depressed state, in the Five-Factor (or "Big Five") model of personality paradigm. METHODS: 82 persons (87% of those asked) with diagnosed W-SAD, most of them originally self-referred, who had previously received light treatment at our unit, completed a Norwegian version of an inventory yielding the personality factors Agreeableness, Surgency, Conscientiousness, Emotional stability, and Openness to experience. RESULTS: Compared to a Norwegian reference group, the mean scores of the W-SAD patients were significantly lower on the factors agreeableness, surgency and emotional stability, and significantly higher on conscientiousness. However, very few patients had scores outside the reference range. The personality factors do not seem to be associated with the core physiological manifestations of winter depression, but rather with the psychic aspects, and are poor predictors of response to light treatment. LIMITATIONS: Some reservations should be made as to the generalisability of the findings to SAD patients in general. Thus, increased conscientiousness may reflect help-seeking behaviour. CONCLUSIONS: Personality structure does not seem to predict occurrence of physiological reactions to lack of adequate daylight in autumn/winter, and is a poor predictor of improvement after light treatment, but may predict the associated psychic symptomatology.

Effects of various anions on serotonin transport in human platelets.

A survey is given of some results from the author's studies on serotonin (5HT) uptake in human blood platelets in vitro. These findings are relevant also for serotonin reuptake at serotonergic synapses, since it has been shown that the serotonin transporter (5HTT) in platelets is identical to that in the brain. The main findings: 5HT uptake is dependent on the presence of Cl-, which shows simple saturation kinetics in relation to 5HT uptake rate, probably by acting on a hypothetical "anion site". Chloride can, however, be partly replaced by other small anions like bromide, iodide and nitrite. Unexpectedly, increasing concentrations of nitrite gives a sigmoidal 5HT uptake curve, indicating a double effect: being able to replace chloride in the "anion site", and exerting an allosteric effect by being bound to a separate "activating site". It was later found that the monocarboxylic acids acetate, lactate and pyruvate, which can not replace chloride, have an allosteric stimulatory effect on 5HT uptake in the presence of chloride, presumably by acting at the same activating site as shown for nitrite. The chloride concentration, as well as lactate and puruvate, may exert a regulatory effect on serotonin reuptake in the brain.

Winter depression with spring exacerbation: A frequent occurrence in women with seasonal affective disorder.

Winter depression (WD) usually starts in October/November and remits in February/March, but some experience a relatively short depressive exacerbation in spring. To further characterize this spring exacerbation (SE), 84 previously diagnosed WD patients rated in retrospect whether they had experienced SE after their otherwise typical WD in the years before receiving active treatment. Thirty-nine percent of the women and 12% of the men reported to have experienced SE many times or practically every year; another 28 and 29%, respectively, had experienced SE a few times. In general, the symptomatology during SE was about the same as during WD. Female patients who had experienced SE many times or practically every year were marginally older (p = 0.05) and had suffered many more previous WD episodes (p = 0.0005) than female patients having experienced SE only a few times or never.

Characteristics of patients with otherwise typical winter depression, but with incomplete summer remission.

BACKGROUND: Seasonal affective disorder, winter depression type (WD-SAD), is characterized by recurring autumn/winter depression with full remission or hypomania/mania in summer. However, some patients have an otherwise typical WD but with incomplete summer remission. We wanted to elucidate in what other respects such patients differ from typical WD-SAD patients. METHODS: 14 patients meeting DSM-III-R criteria for Seasonal Pattern except for incomplete summer remission (ISR), were compared with 144 patients meeting the full criteria, including complete summer remission (CSR), with regard to demography, illness history, clinical symptoms, and response to light treatment. RESULTS: In comparison with the CSR group, the ISR group had a longer duration of illness, more often used antidepressants, and improved significantly less after treatment with bright light for 6 days, whereas the symptomatology in winter (Montgomery-Asberg Depression Rating Scale plus hypersomnia, hyperphagia, and carbohydrate craving) was similar in the two groups. LIMITATIONS: The ISR group was small, and the severity of their summer depression could only be assessed retrospectively. CONCLUSIONS: Patients with otherwise typical WD but with incomplete summer remission respond poorly to light treatment. Full summer remission should be retained as a criterion for WD-SAD.

What predicts the course of expressed emotion in relatives of patients with schizophrenia or related psychoses?

The expressed emotion (EE) index may not be as stable as it was once believed to be. The aim of this study was to identify variables associated with spontaneous change from low to high and from high to low levels of EE and EE subscales--critical comments (CC), hostility (H), emotional overinvolvement (EOI). Using a longitudinal, prospective study design, of 59 relatives having at least weekly face-to-face contact with 40 patients with an acute episode or relapse into schizophrenia (DSM-III-R) were interviewed by means of the Camberwell Family Interview (CFI) at admission and at 4 1/2 months after discharge. The results showed that high-high or unstable levels of CC, H or EE were associated with the patient not working or studying prior to admission. Relatives with low-high and high-high EOI patterns had more weekly face-to-face contact with the patient prior to admission than relatives with a low-low EOI pattern. Patients whose relatives had low-high CC and EE patterns were less ill at admission than patients whose relatives had low-low patterns. Higher perceived family burden was associated with, at admission, an unstable pattern of CC, and at follow-up, high-high EOI or EE patterns rather than low-low patterns. Our study suggests that it is possible to identify which relatives will have a stable and which a changing EE level, allowing for more focused intervention.

Dawn simulation vs. lightbox treatment in winter depression: a comparative study.

Dawn simulation, with gradually increasing bedside light in the morning, has shown promising results as an alternative to bright light treatment for winter depression. To compare these treatments, 61 out-patients with winter depression (20-70 years of age, 80% women) were randomized to receive either lightbox treatment with 1500-2500 lux white light for 2 h in the morning for 6 days on an out-patient basis (n=34), or dawn simulation treatment in their homes, with 60 or 90 min of light augmentation time to 100-300 lux, for 2 weeks (n=27). Patients' ratings of improvement on a visual analogue scale (correlating strongly with percentage reduction in an extended Montgomery-Asberg Depression Rating Scale (MADRS) score) at the end of treatment showed a mean of 40.0% (SD 27.7%) in the dawn simulation group and 57.4% (SD 29.9%) in the lightbox group (P=0.02). The majority of the patients in both groups maintained their improvement during a 9-week follow-up. Age, sex, current major depression or current use of antidepressants did not predict outcome in either group. No serious side-effects were observed.

Guilt proneness and expressed emotion in relatives of patients with schizophrenia or related psychoses.

OBJECTIVE: Knowledge of what predicts relatives' expressed emotion (EE) may contribute to improved family work in schizophrenia. In the present study we examined guilt proneness as a determinant of EE components. METHOD: In a Norwegian sample of 46 recently hospitalized patients (schizophrenia or schizophreniform disorder) and 69 relatives, relatives' expressed emotion was assessed by means of the Camberwell Family Interview, and guilt proneness by means of the Revised Mosher Guilt Inventory. (RMGI). RESULTS: Confirmatory multiple regression analyses showed that hostility-guilt (RMGI) was negatively related to high levels of criticism and hostility and, for men, positively related to emotional overinvolvement. There was a strong positive relationship between relatives' guilty conscience (RMGI) and emotional overinvolvement if the patient had a diagnosis of schizophrenia. CONCLUSIONS: Our analyses indicate that relatives' guilt proneness may be a determinant of their criticism, hostility and emotional overinvolvement towards a schizophrenic family member. This personality trait should be taken into account in family work which aims at modifying relatives' expressed emotion.

[Local monitoring center for clozapine (Leponex) treatment]. / Lokalt monitoreringssenter for klozapin (Leponex)-behandling.

A local centre for monitoring clozapine therapy has been in operation in the Pharmacy Department at Asgård Hospital in Tromsø since 1994. The centre utilizes an electronic reporting system and is available to clozapine-prescribers in the three northernmost countries in Norway: Nordland, Troms and Finnmark. The system fosters early detection of poor compliance with frequent blood tests and for signs of white blood cell suppression. This is a new concept in Norway and one way of assuring the quality of clozapine treatment. The purpose of the centre is to improve patient safety by facilitating early detection of potentially dangerous white blood cell suppression, thereby avoiding fatal consequences.

Criticism and hostility in relatives of patients with schizophrenia or related psychoses: demographic and clinical predictors.

Relatives' criticism and hostility are important risk factors for relapse in schizophrenia. In order to explain these attitudes, we examined a Norwegian sample of 47 recently hospitalized patients (with schizophrenia or related psychoses) and 72 relatives. Relatives' expressed emotion was assessed by means of the Camberwell Family Interview. Demographic and clinical data were used as predictor variables in confirmatory regression analyses. The most robust predictors of high levels of criticism were, on the part of the patient, lack of paid employment, more than 3 previous hospital admissions, more troublesome behaviours reported by relatives, especially anxiety/depression, and better cognitive functioning at admission. Robust predictors of hostility were lack of employment and more than 3 previous hospitalizations. Interventions to reduce criticism should include employing patients and working with relatives' unrealistic expectations.

Relatives' emotional warmth towards patients with schizophrenia or related psychoses: demographic and clinical predictors.

Despite the importance of relatives' emotional warmth for outcome in schizophrenia, no studies to date have addressed demographic and clinical predictors of warmth. We examined a Norwegian sample of 47 recently hospitalized patients (with schizophrenia or schizophreniform disorder) and 72 key relatives. Relatives' emotional warmth was assessed by means of the Camberwell Family Interview. Regression analyses showed that no substance abuse (especially amphetamines), better premorbid adjustment (12-15 years), a chronic social security status, and the relative not being a parent were the strongest predictors of emotional warmth. Emotional warmth was not related to patients' symptoms.