Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, Jan 10, 1992
A major problem in the treatment of cancer is clinical resistance to chemotherapeutic drugs. Mult... more A major problem in the treatment of cancer is clinical resistance to chemotherapeutic drugs. Multi-drug resistance (MDR) is a well-studied experimental phenomenon which seems to play an important role in clinical resistance to drugs. Tumour cells selected for resistance to a "natural product" anticancer drug display crossresistance to a variety of structurally and functionally unrelated anticancer drugs. Such resistant cells accumulate and retain less drug than retained by their drug sensitive counterparts. This lower grade of accumulation is most likely mediated by P-glycoprotein, an integral membrane protein which functions as an energy-dependent efflux pump. It has now become clear that several lipophilic agents can reverse MDR both in vitro and in vivo. Clinical trials with such modulators (chemosensitizers) have already given promising results.
Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic ... more Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76–81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with eit...
Purpose: Cancer immune therapy has revolutionized patient outcome for the small mCRC subgroup wit... more Purpose: Cancer immune therapy has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS with inherently low susceptibility to immune therapy. In our ongoing METIMMOX study (NCT03388190), MSS-mCRC patients are randomized to oxaliplatin-based immunogenic chemotherapy followed by ICI (experimental study arm) or the oxaliplatin-based standard-of-care (control arm). A subgroup of experimental arm patients has obtained durable major partial or complete responses. Such remarkable outcomes call for biomarkers that may help identifying MSS-mCRC patients who will benefit from such sequential therapy. Experimental procedures: Study enrollment began August 2018. Patients with unresectable, previously untreated MSS-mCRC have been randomized to the Nordic FLOX regimen (standard-of-care) or repeat sequential 2 FLOX cycles and 2 cycles of nivolumab (240 mg Q2W). At analysis October 2020, 48 patients were evaluable f...
Quality of life data from randomized trials are lacking in older patients with metastatic colorec... more Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 7...
3556 Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the smal... more 3556 Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS without innate ICB susceptibility. In our ongoing METIMMOX study, we hypothesize that MSS mCRC can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy (FLOX), enabling patients with unresectable, previously untreated metastases to obtain durable disease control when adding ICB therapy. Here we present the protocol-planned interim analysis. Methods: Eligibility criteria include infradiaphragmatic metastasis and C-reactive protein < 60 mg/L. At analysis 15 January 2021, 54 patients stratified according to primary tumor sidedness and mutational status and evaluable for the primary end point (progression-free survival; PFS) had been randomly assigned to a standard-of-care schedule of 8 FLOX cycles Q2W (control arm) or repeat sequential 2 FLOX cycles and 2 nivolu...
Background Colorectal cancer (CRC) is the third most common cancer worldwide, and a large proport... more Background Colorectal cancer (CRC) is the third most common cancer worldwide, and a large proportion of the patients receive adjuvant oxaliplatin-based chemotherapy. Most of these experience chemotherapy-induced peripheral neuropathy (CIPN), affecting quality of life. Evidence to advise exercise to reduce CIPN is limited. The primary aim of this study was to investigate the feasibility of an exercise intervention and data collection among CRC patients during adjuvant chemotherapy. Material and methods This non-randomized feasibility study included CRC patients admitted to adjuvant chemotherapy to an intervention consisting of supervised aerobic endurance, resistance, and balance exercises twice a week at the hospital in addition to home-based exercise once a week. A physiotherapist supervised the patients, and the intervention lasted throughout the period of adjuvant chemotherapy (12–24 weeks). Participants performed physical tests and filled in questionnaires at baseline, 3, 6, 9, ...
Figure S5. Expression of F. nucleatum and EBV miRNA in TCGA data and correlation with clinical pa... more Figure S5. Expression of F. nucleatum and EBV miRNA in TCGA data and correlation with clinical parameters across data sets. The p-values in Fig. S5E-L are calculated using an unpaired two-tailed Student's t-test. A) Expression of F. nucleatum in TCGA small RNA data. Left: All tumor samples compared to the eight normal samples. Right: The 8 paired tumor and normal samples. The p-values are calculated using an unpaired and paired two-tailed Student's t-test for the left and right boxplot, respectively. B) Expression of F. nucleatum in TCGA colon samples. C) Expression of EBV miRNAs in TCGA colon samples. The figure shows the sum of all detected EBV miRNA for each sample as log2 and is normalized based on library sizes of mature miRNAs in the corresponding samples. D) Correlation between F. nucleatum and EBV miRNA in Neerincx et al., Sun et al., TCGA, and our datasets. The correlation is calculated using the cor() function in R with pearson correlation. E) F. nucleatum expressi...
Neuroendocrine tumours (NETs) comprise a heterogenous group of malignancies with an often unpredi... more Neuroendocrine tumours (NETs) comprise a heterogenous group of malignancies with an often unpredictable course, and with limited treatment options. Thus, new diagnostic, prognostic, and therapeutic markers are needed. To shed new lights into the biology of NETs, we have by cDNA transcript profiling, sought to identify genes that are either up- or downregulated in NE as compared with non-NE tumour cells. A panel of six NET and four non-NET cell lines were examined, and out of 12 743 genes examined, we studied in detail the 200 most significantly differentially expressed genes in the comparison. In addition to potential new diagnostic markers (NEFM, CLDN4, PEROX2), the results point to genes that may be involved in the tumorigenesis (BEX1, TMEPAI, FOSL1, RAB32), and in the processes of invasion, progression and metastasis (MME, STAT3, DCBLD2) of NETs. Verification by real time qRT-PCR showed a high degree of consistency to the microarray results. Furthermore, the protein expression of...
American Journal of Physiology-Endocrinology and Metabolism, 2001
In the present study, we explore the role of cAMP-responsive (CRE) promoter elements in gastrin-m... more In the present study, we explore the role of cAMP-responsive (CRE) promoter elements in gastrin-mediated gene activation. By using the minimal CRE promoter reporter plasmid, pCRELuc, we show that gastrin can activate CRE. This activation is blocked by H-89 and GF 109203x, which inhibit protein kinases A and C, respectively. Moreover, Ca2+-activated pathways seem to be involved, because the calmodulin inhibitor W-7 reduced gastrin-mediated activation of pCRELuc. Deletion of CRE from the c- fos promoter rendered this promoter completely unresponsive to gastrin, indicating that CRE plays a central role in c- fos transactivation. Interestingly, gastrin-induced expression of the inducible cAMP early repressor (ICER), a gene that is known to be regulated by CRE promoter elements, was not reduced by H-89, W-7, or GF 109203x. Furthermore, bandshift analyses indicated that the region of the ICER promoter containing the CRE-like elements CARE 3–4 binds transcription factors that are not membe...
Ki-67 Proliferative Index Predicts Response to Chemotherapy and Survival in 252 Patients with Hig... more Ki-67 Proliferative Index Predicts Response to Chemotherapy and Survival in 252 Patients with High-Grade Gastrointestinal Neuroendocrine Carcinoma (WHO G3)
Figure S4. MicroRNAs and isomiRs correlated with clinicopathological characteristics. A) Differen... more Figure S4. MicroRNAs and isomiRs correlated with clinicopathological characteristics. A) Differentially expressed isomiRs in our dataset and the dataset of Neerincx et al. between right and left normal colon tissue. The comparison is Right-Left such that a positive fold change indicates that the corresponding miRNA is upregulated in right normal colon compared to left normal colon. B) Differentially expressed isomiRs in our data and the dataset of Neerincx et al. and TCGA comparing right and left tumor colon tissue. The statistical comparison is described in A). C) Differentially expressed miRNAs between right and left tumor tissue (x-axis) compared with differentially expressed miRNAs between right and left normal tissue (y-axis), for the datasets Mjelle et al. and Neerincx et al. D) Similar comparison as in C), for isomiRs. E) Differentially expressed isomiRs in our data and the dataset and TCGA comparing MSS and MSI. The comparison is MSS-MSI such that a positive fold change indi...
Figure S2. MicroRNA clusters and isomiRs. A) A scatterplot of genomic clustered miRNAs showing lo... more Figure S2. MicroRNA clusters and isomiRs. A) A scatterplot of genomic clustered miRNAs showing log fold change values between tumor and normal (y-axis) for each individual miRNA within the clusters. The clusters are indicated with a unique ID on each facet of the plot. The figure only includes miRNAs that are significantly differentially expressed between tumor and normal. B) Illustrations of the main types of isomiRs analyzed in the current study, exemplified for hsa-miR-10b. C) Scatterplot comparing fold-change values for isomiRs between our dataset and the Neerincx, Röhr, and Sun datasets. (PDF 1751 kb)
Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, Jan 10, 1992
A major problem in the treatment of cancer is clinical resistance to chemotherapeutic drugs. Mult... more A major problem in the treatment of cancer is clinical resistance to chemotherapeutic drugs. Multi-drug resistance (MDR) is a well-studied experimental phenomenon which seems to play an important role in clinical resistance to drugs. Tumour cells selected for resistance to a "natural product" anticancer drug display crossresistance to a variety of structurally and functionally unrelated anticancer drugs. Such resistant cells accumulate and retain less drug than retained by their drug sensitive counterparts. This lower grade of accumulation is most likely mediated by P-glycoprotein, an integral membrane protein which functions as an energy-dependent efflux pump. It has now become clear that several lipophilic agents can reverse MDR both in vitro and in vivo. Clinical trials with such modulators (chemosensitizers) have already given promising results.
Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic ... more Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76–81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with eit...
Purpose: Cancer immune therapy has revolutionized patient outcome for the small mCRC subgroup wit... more Purpose: Cancer immune therapy has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS with inherently low susceptibility to immune therapy. In our ongoing METIMMOX study (NCT03388190), MSS-mCRC patients are randomized to oxaliplatin-based immunogenic chemotherapy followed by ICI (experimental study arm) or the oxaliplatin-based standard-of-care (control arm). A subgroup of experimental arm patients has obtained durable major partial or complete responses. Such remarkable outcomes call for biomarkers that may help identifying MSS-mCRC patients who will benefit from such sequential therapy. Experimental procedures: Study enrollment began August 2018. Patients with unresectable, previously untreated MSS-mCRC have been randomized to the Nordic FLOX regimen (standard-of-care) or repeat sequential 2 FLOX cycles and 2 cycles of nivolumab (240 mg Q2W). At analysis October 2020, 48 patients were evaluable f...
Quality of life data from randomized trials are lacking in older patients with metastatic colorec... more Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 7...
3556 Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the smal... more 3556 Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS without innate ICB susceptibility. In our ongoing METIMMOX study, we hypothesize that MSS mCRC can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy (FLOX), enabling patients with unresectable, previously untreated metastases to obtain durable disease control when adding ICB therapy. Here we present the protocol-planned interim analysis. Methods: Eligibility criteria include infradiaphragmatic metastasis and C-reactive protein < 60 mg/L. At analysis 15 January 2021, 54 patients stratified according to primary tumor sidedness and mutational status and evaluable for the primary end point (progression-free survival; PFS) had been randomly assigned to a standard-of-care schedule of 8 FLOX cycles Q2W (control arm) or repeat sequential 2 FLOX cycles and 2 nivolu...
Background Colorectal cancer (CRC) is the third most common cancer worldwide, and a large proport... more Background Colorectal cancer (CRC) is the third most common cancer worldwide, and a large proportion of the patients receive adjuvant oxaliplatin-based chemotherapy. Most of these experience chemotherapy-induced peripheral neuropathy (CIPN), affecting quality of life. Evidence to advise exercise to reduce CIPN is limited. The primary aim of this study was to investigate the feasibility of an exercise intervention and data collection among CRC patients during adjuvant chemotherapy. Material and methods This non-randomized feasibility study included CRC patients admitted to adjuvant chemotherapy to an intervention consisting of supervised aerobic endurance, resistance, and balance exercises twice a week at the hospital in addition to home-based exercise once a week. A physiotherapist supervised the patients, and the intervention lasted throughout the period of adjuvant chemotherapy (12–24 weeks). Participants performed physical tests and filled in questionnaires at baseline, 3, 6, 9, ...
Figure S5. Expression of F. nucleatum and EBV miRNA in TCGA data and correlation with clinical pa... more Figure S5. Expression of F. nucleatum and EBV miRNA in TCGA data and correlation with clinical parameters across data sets. The p-values in Fig. S5E-L are calculated using an unpaired two-tailed Student's t-test. A) Expression of F. nucleatum in TCGA small RNA data. Left: All tumor samples compared to the eight normal samples. Right: The 8 paired tumor and normal samples. The p-values are calculated using an unpaired and paired two-tailed Student's t-test for the left and right boxplot, respectively. B) Expression of F. nucleatum in TCGA colon samples. C) Expression of EBV miRNAs in TCGA colon samples. The figure shows the sum of all detected EBV miRNA for each sample as log2 and is normalized based on library sizes of mature miRNAs in the corresponding samples. D) Correlation between F. nucleatum and EBV miRNA in Neerincx et al., Sun et al., TCGA, and our datasets. The correlation is calculated using the cor() function in R with pearson correlation. E) F. nucleatum expressi...
Neuroendocrine tumours (NETs) comprise a heterogenous group of malignancies with an often unpredi... more Neuroendocrine tumours (NETs) comprise a heterogenous group of malignancies with an often unpredictable course, and with limited treatment options. Thus, new diagnostic, prognostic, and therapeutic markers are needed. To shed new lights into the biology of NETs, we have by cDNA transcript profiling, sought to identify genes that are either up- or downregulated in NE as compared with non-NE tumour cells. A panel of six NET and four non-NET cell lines were examined, and out of 12 743 genes examined, we studied in detail the 200 most significantly differentially expressed genes in the comparison. In addition to potential new diagnostic markers (NEFM, CLDN4, PEROX2), the results point to genes that may be involved in the tumorigenesis (BEX1, TMEPAI, FOSL1, RAB32), and in the processes of invasion, progression and metastasis (MME, STAT3, DCBLD2) of NETs. Verification by real time qRT-PCR showed a high degree of consistency to the microarray results. Furthermore, the protein expression of...
American Journal of Physiology-Endocrinology and Metabolism, 2001
In the present study, we explore the role of cAMP-responsive (CRE) promoter elements in gastrin-m... more In the present study, we explore the role of cAMP-responsive (CRE) promoter elements in gastrin-mediated gene activation. By using the minimal CRE promoter reporter plasmid, pCRELuc, we show that gastrin can activate CRE. This activation is blocked by H-89 and GF 109203x, which inhibit protein kinases A and C, respectively. Moreover, Ca2+-activated pathways seem to be involved, because the calmodulin inhibitor W-7 reduced gastrin-mediated activation of pCRELuc. Deletion of CRE from the c- fos promoter rendered this promoter completely unresponsive to gastrin, indicating that CRE plays a central role in c- fos transactivation. Interestingly, gastrin-induced expression of the inducible cAMP early repressor (ICER), a gene that is known to be regulated by CRE promoter elements, was not reduced by H-89, W-7, or GF 109203x. Furthermore, bandshift analyses indicated that the region of the ICER promoter containing the CRE-like elements CARE 3–4 binds transcription factors that are not membe...
Ki-67 Proliferative Index Predicts Response to Chemotherapy and Survival in 252 Patients with Hig... more Ki-67 Proliferative Index Predicts Response to Chemotherapy and Survival in 252 Patients with High-Grade Gastrointestinal Neuroendocrine Carcinoma (WHO G3)
Figure S4. MicroRNAs and isomiRs correlated with clinicopathological characteristics. A) Differen... more Figure S4. MicroRNAs and isomiRs correlated with clinicopathological characteristics. A) Differentially expressed isomiRs in our dataset and the dataset of Neerincx et al. between right and left normal colon tissue. The comparison is Right-Left such that a positive fold change indicates that the corresponding miRNA is upregulated in right normal colon compared to left normal colon. B) Differentially expressed isomiRs in our data and the dataset of Neerincx et al. and TCGA comparing right and left tumor colon tissue. The statistical comparison is described in A). C) Differentially expressed miRNAs between right and left tumor tissue (x-axis) compared with differentially expressed miRNAs between right and left normal tissue (y-axis), for the datasets Mjelle et al. and Neerincx et al. D) Similar comparison as in C), for isomiRs. E) Differentially expressed isomiRs in our data and the dataset and TCGA comparing MSS and MSI. The comparison is MSS-MSI such that a positive fold change indi...
Figure S2. MicroRNA clusters and isomiRs. A) A scatterplot of genomic clustered miRNAs showing lo... more Figure S2. MicroRNA clusters and isomiRs. A) A scatterplot of genomic clustered miRNAs showing log fold change values between tumor and normal (y-axis) for each individual miRNA within the clusters. The clusters are indicated with a unique ID on each facet of the plot. The figure only includes miRNAs that are significantly differentially expressed between tumor and normal. B) Illustrations of the main types of isomiRs analyzed in the current study, exemplified for hsa-miR-10b. C) Scatterplot comparing fold-change values for isomiRs between our dataset and the Neerincx, Röhr, and Sun datasets. (PDF 1751 kb)
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