Rune Smaaland

Stavanger University Hospital · Department of Hematology and Oncology

Background Although pancreatic ductal adenocarcinoma (PDAC) rarely metastasizes to the skeleton, disseminated tumor cells have been detected in bone marrow samples from patients with this disease. The prognostic value of such findings is currently unclear. Thus, the current study aimed to clarify the prognostic information associated with dissemina...

Background It was recently demonstrated that the size of cell-free DNA (cfDNA) fragments that originates from tumor cells are shorter than cfDNA fragments that originates from non-malignant cells. We investigated whether cfDNA fragment size and cfDNA levels might have prognostic value in patients with advanced pancreatic cancer. Methods Blood samp...

Purpose: To investigate the prognostic value of cell-free DNA (cfDNA) fragment size and cfDNA levels in patients with advanced pancreatic cancer. Methods: Blood samples were acquired from patients with locally advanced or metastatic pancreatic cancer at baseline (n = 61) and one month (n = 48) after initiation of chemotherapy. All samples were proc...

Background: Regional lymph node (LN) metastasis is a strong and well-established prognostic factor in colon cancer, and recent data suggest a prognostic value of detecting micrometastases and isolated tumor cells in regional LNs. The aim of the study was to investigate the clinical relevance of detecting sentinel lymph node (SLN) metastases in col...

Background The primary function of the intestines is the absorption of water and nutrients. Although our knowledge about these processes on the cellular level is extensive, a number of important intracellular elements remain unknown. Here, we characterize the novel proline-, histidine-, glycine-rich 1 (PHGR1) mRNA and protein on the molecular level...

Background: Pancreatic cancer is the fourth leading cause of cancer-related death. While surgical resection remains the foundation for potentially curative treatment, survival benefit is achieved with adjuvant oncological treatment. Thus, completion of multimodality treatment (surgical resection and (neo)adjuvant chemotherapy) to all patients and...

Background: Single-cell analysis of the transcriptional heterogeneity of circulating tumor cells have the prospect of better understanding the biology of these cells and their involvement in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms leading to chemotherapy resistance and tumor progression in pa...

Background Single-cell mRNA profiling of circulating tumour cells may contribute to a better understanding of the biology of these cells and their role in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms underlying chemotherapy resistance and tumour progression in patients with cancer. Methods Single...

Most current methods of circulating tumour cell (CTC) enrichment target the epithelial protein EpCAM, which is commonly expressed in adenocarcinoma cells. However, such methods will not recover the fraction of CTCs that have a non-epithelial phenotype due to epithelial–mesenchymal transition. For phenotype-independent CTC enrichment, we developed a...

We used KRAS mutations to investigate the clinical relevance of circulating tumor DNA (ctDNA) measurements in patients with advanced pancreatic cancer. Fifty‐three blood samples were collected from 14 prospectively recruited patients prior to chemotherapy (gemcitabine or FOLFIRINOX) and subsequently every month during treatment. Samples were proces...

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Circulating tumor DNA (ctDNA) may originate from necrotic or apoptotic tumor cells in the primary tumor, metastatic lesions or in the circulation. There is evidence that the ctDNA level may reflect the total tumor burden in a patient. We wanted to investig...

Objective: We sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer. Methods: We sought to investigate various molecular subtypes defined by instability at microsatellites (MSI), changes in methylation patterns (CpG island methylator phenotype, CIMP) or c...

Aim: Regional and hospital payers increasingly require analyses assessing the cost-benefit profile of new drugs. This analysis evaluates the cost profile in Nordic countries of nano albumin-bound paclitaxel (nab-paclitaxel [nab-P]) in pancreatic cancer vs other drugs per gained month in OS and PFS in high-unmet need solid tumour indications. Method...

Background: Disseminated tumor cells (DTCs) have potential to predict the effect of adjuvant treatment. The purpose of this study was to compare two methods, reverse transcription quantitative PCR (RT-qPCR) and immunocytochemisty (ICC), for detecting breast cancer DTCs in bone marrow (BM) from early breast cancer patients. Methods: We investigat...

The poor prognosis of pancreatic cancer patients is associated with the frequent and early dissemination of the disease, as well as late detection due to unspecific and late symptoms from the primary tumor. Pancreatic cancers frequently spread to the liver, lung, and skeletal system, suggesting that pancreatic tumor cells must be able to intravasat...

Lymph node (LN) harvest is influenced by several factors, including tumor genetics. Microsatellite instability (MSI) is associated with improved node harvest, but the association to other genetic factors is largely unknown. Prospective series of stage I-III colon cancer patients undergoing ex-vivo sentinel-node sampling. The presence of MSI, KRAS m...

Background: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the...

Recent evidence suggests that microscopic lymph node metastases and circulating tumor cells may have clinical importance in lung cancer. The purpose of this study was to identify new molecular markers for tumor cells in regional lymph nodes (LNs) and peripheral blood (PB) from patients with non-small cell lung cancer (NSCLC). Candidate markers were...

The proliferation factors: mitotic activity index (MAI), phosphohistone H3 (PPH3) and Ki67 have strong prognostic value in early breast cancer but their independent value to each other and other prognostic factors has not been evaluated. In 237 T1-2N0M0 breast cancers without systemic adjuvant treatment, formalized MAI assessment and strictly stand...

There is a need for new biomarkers to more correctly identify node-negative breast cancer patients with a good or bad prognosis. Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) is a membrane-bound protein that is associated with cell spreading, integrin activation and exocytosis. Three hundred and five operable T1,2N0M0 lymph node-n...

To investigate the prognostic value of occult metastases detected by quantitative measurements of candidate biomarkers in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer. Resection specimens from consecutive patients undergoing surgery for localized colon cancer were subjected to ex vivo SLN mapping. SLNs were examine...

Background Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer.Patients and methodsA meta-analysis was performed using individual data from three international P...

BACKGROUND: Lymph node (LN) metastasis status is among the strongest prognostic factors in colon cancer. Despite this, 20-30% of LN negative patients experience disease recurrence. These patients may have occult LN metastases that are not detected by routine microscopy. The aim of the present study was to investigate the prognostic value of occult...

To investigate the prognostic significance of disseminated tumor cells (DTCs) in bone marrow (BM) from non-metastatic breast cancer patients before and after surgery. Patients with non-metastatic breast cancer were consecutively recruited to this project during the years 1998-2000. Real-time RT-PCR quantification of a DTC multimarker panel consisti...

Aims: The proliferation factor Ki67 is prognostic in breast cancer and included in international therapy guidelines, but measurement procedures differ between laboratories. We compared the reproducibility and prognostic value of different Ki67 sampling and measurement methods. Methods and results: In 237 T(1,2) N(0) M(0) breast cancers without a...

To identify micro RNA (miRNA) biomarker candidates for early detection of breast cancer and detection of minimal residual breast cancer, we performed miRNA expression profiling in pooled RNA samples from breast tumors, and from bone marrow mononuclear cells, peripheral blood mononuclear cells and plasma from healthy controls. We found substantially...

Point mutations in the K-ras gene have been shown to confer resistance against epidermal growth factor receptor-directed therapy of metastatic colorectal cancer. Accordingly, K-ras mutation testing has become mandatory in hospitals offering such treatment. We compared the performance and reagent costs of 2 sensitive methods for detection of K-ras m...

71 Background: The Norwegian Gastrointestinal Cancer Group (NGICG) conducted a phase II randomized study comparing the efficacy and safety of FLOX and FLIRI as first line treatment in metastatic or locally advanced gastric cancer. At progression or unacceptable drug related toxicity, a crossover to the other treatment arm should be done, if second...

Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreat...

The existence of circadian oscillations in the level of hormones, in numerous physiological parameters, in toxicity and in behavior is now fully recognized in all living organisms. In contrast, the synchronisation and regulation of cell proliferation by circadian rhythms in vivo is only starting to be appreciated. This article reviews the experimen...

The purpose of this article is to investigate the prognostic value of the mitotic activity index (MAI) and the presence of disseminated tumor cells (DTCs) in bone marrow (BM), in clinically operable breast cancer patients. We compared routinely assessed MAI, classic prognosticators and BM DTCs, detected by a real-time RT-PCR multimarker assay inclu...

K-ras mutations predict resistance against epidermal growth factor receptor (EGFR)-directed therapy of metastatic colorectal cancer (CRC). The purpose of this study was to analyze the distribution of K-ras mutations in primary tumors and corresponding sentinel lymph nodes (SLNs) from colon cancer patients. Tumor biopsies and SLNs from 158 patients...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL PURPOSE: Lung cancer retains its status as the most common cancer in the world, with an estimated 1.5 million cases diagnosed in 2007, accounting for about 12% of all cancers. Identifying microscopic lynph-node metastases, could have clinical importance in selecting patients...

In breast cancer, different tools are used for prognostication and adjuvant systemic therapy selection. We compared the accuracy of the online program Adjuvant!, the Norwegian Breast Cancer Group (NBCG) guidelines, and the proliferation factor mitotic activity index (MAI) in patients with lymph node (LN) -negative disease (pN0). Adjuvant! and MAI t...

454 Background: Circadian clocks control cellular proliferation and drug metabolism over 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronoFLO4) offered no survival benefit as compared to the non-time stipulated FOLFOX2 in an international randomized trial involving patients (pts) with prev...

A binational, population-based treatment protocol was established to prospectively treat and follow patients with seminomatous testicular cancer. The aim was to standardize care for all patients with seminoma to further improve the good results expected for this disease. From 2000 to 2006, a total of 1,384 Norwegian and Swedish patients were includ...

PURPOSE: To investigate the prognostic value of Mitotic Activity Index (MAI) in lymph node negative and lymph node positive operable breast cancer patients in an unselected population and to compare it to bone marrow (BM) micrometastatis status. PATIENTS AND METHODS: Analysis of MAI assessed using a strict protocol with proven strong prognostic va...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC BACKGROUND: Mutations in the K-ras oncogene occur in 30-50% of colorectal cancers and have been described as an early event in colorectal tumorigenesis. K-ras mutations have recently gained renewed interest due to their well-documented prediction of resistance against EG...

To investigate the association of high-dose preoperative chemoradiotherapy (CRT) and dose-volume histogram (DVH) parameters of lungs with incidence of postoperative pulmonary complications and to identify predictive clinical factors of pulmonary complications. Data of 65 patients were collected retrospectively. Thirty-five patients underwent transt...

To investigate the prognostic relevance of disseminated tumor cells (DTCs) in bone marrow (BM) assessed by a multimarker mRNA panel consisting of TWIST1, cytokeratin 19 (CK19) and human mammaglobin A (hMAM) mRNA, in patients with early breast cancer. TWIST1 (gene name: TWIST1), CK19 (gene name: KRT19), and hMAM (gene name: SCGB2A2) mRNA was quantit...

We aimed to assess whether high-dose preoperative chemoradiotherapy (CRT) improves outcome in esophageal cancer patients compared to surgery alone and to define possible prognostic factors for overall survival. Hundred-and-seven patients with disease stage IIA - III were treated with either surgery alone (n = 45) or high-dose preoperative CRT (n =...

To identify colon cancer patients with occult lymph node metastases. The prognostic value of regional lymph node (LN) metastases in colorectal cancer patients is well established. The disease recurrences nevertheless experienced by 20% to 30% of the LN negative patients suggest a potential for improvement in current LN diagnostics. We suspect that...

4531 Background: From 2000-2007, 1,380 Norwegian and Swedish patients (pts) with seminomatous germ cell testicular cancer (SGCT) were followed prospectively according to a nationwide community-based treatment protocol, SWENOTECA V. The main objectives were to register all pts within the multicenter setting of the SWENOTECA in order to maintain and...

This study is a retrospective analysis of high-dose definitive concomitant chemoradiotherapy in locally advanced esophageal cancer in a single institution. The aim of the study was to identify and quantify the toxicity associated with the high-dose treatment and to analyze the outcome of this treatment. Forty-six patients (41 men and 5 women, media...

Time-dependent variations in clock gene expression have recently been observed in mouse hematopoietic cells, but the activity of these genes in human bone marrow (BM) has so far not been investigated. Since such data can be of considerable clinical interest for monitoring the dynamics in stem/progenitor cells, the authors have studied mRNA expressi...

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In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, le...

Proapoptotic drugs such as docetaxel displayed least toxicity and highest antitumor efficacy following dosing during the circadian rest phase in mice, suggesting that cell cycle and apoptotic processes could be regulated by the circadian clock. In study 1, mouse bone marrow and/or tumor were obtained every 4 h for 24 h in C3H/HeN mice with or witho...

Recent advances in radiotherapy (RT) are founded on the enhanced tumour visualisation capabilities of new imaging modalities and the precise deposition of individualised radiation dose distributions made possible with the new systems for RT planning and delivery. These techniques have a large potential to also improve the results of RT of urinary b...

A major challenge in conformal radiotherapy of bladder cancer is to determine adequate treatment margins. For this purpose, we therefore quantified the internal motion of the urinary bladder as well as the external patient set-up variation during a course of fractionated radiotherapy. In the light of the recently introduced ICRU-62 concept, the pla...

In 24h studies of bone marrow (BM), circadian stage-dependent variations were demonstrated in the proliferative activity of BM cells from subsets of 35 healthy diurnally active men. On an average, the percentage of total BM cells in deoxyribonucleic acid (DNA) synthesis phase was 188% greater at midday than at midnight (circadian rhythm: p = 0.018;...

Partially wedged beams (PWBs) having wedge in one part of the field only, can be shaped using dynamic jaw intensity modulation. The possible clinical benefit of PWBs was tested in treatment plans for muscle-infiltrating bladder cancer. Three-dimensional treatment plans for 25 bladder cancer patients were analyzed. The originally prescribed standard...

Fifteen bone marrow (BM) and venous blood circadian profiles were obtained from 13 diurnally-active, healthy men sampled every 4–5 h for 24 h. Peripheral blood (PB) was also sampled in subsets of 5 men either for 24 h immediately preceding the BM procedure or 5–6 months afterwards. Cortisol and white and red cell parameters were determined in PB. B...

We measured plasma total homocysteine (tHcy) in 14 patients (13 patients with colorectal cancer and 1 patient with breast cancer) during their first treatment with 5-fluorouracil (5-FU) plus leucovorin [LV (5-FULV)]. Eight of these patients were investigated a second time after 3-10 cycles (median, 4 cycles) with 5-FULV. Each cycle consisted of two...

Variations in cell yield and proliferative activity of human bone marrow (BM) progenitor cells were determined with flow cytometry along the 24-h (circadian) time scale. Equal volumes of BM were aspirated every 5 h, altogether 5 times in 5 healthy men. An average 6-fold higher yield of positive selected CD34+ cells occurred in each subject when BM...

Variations in cell yield and proliferative activity of human bone marrow (BM) progenitor cells were determined with flow cytometry along the 24-h (circadian) time scale. Equal volumes of BM were aspirated every 5 h, altogether 5 times in 5 healthy men. An average 6-fold higher yield of positive selected CD34(+) cells occurred in each subject when B...

The use of 5-Fluorouracil and Leucovorin is recommended as palliative chemotherapy in metastatic colorectal cancer in patients under 75 years of age with symptomatic disease or objective progression of disease. However, the oncology units do not have the capacity to cope with this large group of patients and this presents a problem. The chemotherap...

250 patients with clinical stage 1 non-seminomatous germ cell tumours of the testis (NSGCT 1) were included into a prospective multicentre protocol during 1990-1994 and treated according to three risk strata: patients without tumour cell invasion of vascular structures in the testis (VASC-) and elevated serum AFP levels (AFP+) at orchiectomy were c...

By use of a multiparameter flow cytometric method with specific surface markers, circadian (24-h) variations in cell cycle distribution have been studied in 19 healthy male volunteers by sampling bone marrow (BM) every 4-5 h during 24-h periods. Admixture of peripheral blood during the sampling was specifically adjusted for, and the fractions of ce...

  By use of a multiparameter flow cytometric method with specific surface markers, circadian (24-h) variations in cell cycle distribution have been studied in 19 healthy male volunteers by sampling bone marrow (BM) every 4–5 h during 24-h periods. Admixture of peripheral blood during the sampling was specifically adjusted for, and the fractions of...

The bone marrow, an extremely complex tissue comprising approximately 4.5% of an adult’s body weight (a mass comparable to the liver) (Nathan 1988), is found in the ends of flat bones (sternum, ribs, skull, vertebrae and innominates) and contains the haemopoietic stem cells, which give rise to the many developing functional blood cell lineages with...

The relationship between bone marrow (BM) cells with S-phase DNA content and the amount of peripheral blood contamination estimated as percentage lymphocytes+monocytes (L+MO) present in BM samples has been investigated in a total of 136 BM aspirates and biopsy expellates from 35 hematologically healthy individuals. A significant negative correlatio...

  The relationship between bone marrow (BM) cells with S-phase DNA content and the amount of peripheral blood contamination estimated as percentage lymphocytes+monocytes (L+MO) present in BM samples has been investigated in a total of 136 BM aspirates and biopsy expellates from 35 hematologically healthy individuals. A significant negative correlat...

The existence of circadian oscillations in the level of hormones, in numerous physiological parameters, in toxicity and in behavior is now fully recognized in all living organisms. In contrast, the synchronisation and regulation of cell proliferation by circadian rhythms in vivo is only starting to be appreciated. This article reviews the experimen...

A prerequisite for the investigation of cell kinetics, and especially circadian cell kinetics, has been the development from the 1950s and onwards of several methods for studying kinetic parameters in different mammalian tissues. A large number of such studies have subsequently taken place in the rodent, mostly as non-circadian experiments, but als...

Colorectal cancer is the most frequent diagnosed cancer in the western world. Less than 50% of the patients will today be cured of their disease. Thus, many patients will be in need of palliative treatment. The combination of 5-FU and Leucovorin has increased our ability to reduce tumour related symptoms by shrinking the tumour/metastases and not o...

We have extended earlier flow cytometric circadian studies of total bone marrow (BM) cells to also include proliferating BM subpopulations (i.e., myeloid lineage, erythroid lineage, CD34+ cells) with the intent to further optimize cancer chromotherapy with chemotherapeutics or cytokines, taking into account temporal susceptibility rhythms of critic...

Potential life-threatening drug induced side effects to the bone marrow (BM) may be reduced by the proper timing of chemotherapy (chronotherapy) according to circadian stage. Blood and BM samples were obtained concomitantly every 4h for 24h from 16 healthy men (19 series total) to compare circadian patterns in peripheral blood (PB) as reference rhy...

Cytotoxic anti-cancer drugs are meant to interact with tumor cells to impair the replicative and/or transcriptional functions of DNA in order to reduce proliferative rate and cause cell death. These drugs also affect rapidly proliferating healthy tissues such as the bone marrow and the gastrointestinal tract, thereby resulting in toxicity-related d...

In this article, a survey on the concepts and scientific basis for applying chemotherapy against malignant tumors on a circadian schedule is given. The idea is to give the cytostatic drugs at times of the day when optimal effect on the tumor is achieved, but at the same time causing minimal toxic side effects. Following a brief description of the c...