Kjersti Flatmark

Oslo University Hospital · Department of Gastroenterological Surgery

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigne...

The objective of this study was to analyze the expression and prognostic role of methylthioadenosine phosphorylase (MTAP) in mesothelioma. MTAP protein expression by immunohistochemistry was analyzed in 113 mesotheliomas (60 pleural and 53 peritoneal), consisting of 36 effusions and 77 surgical specimens. MTAP expression was fully lost in 38 tumors...

Background This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. Patients and Methods Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and comp...

Background We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Methods Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental...

Background: Pseudomyxoma peritonei (PMP) is a rare cancer originating from appendiceal mucinous tumors, which may spread to encompass the entire peritoneal cavity. Complete surgical removal and hyperthermic intraperitoneal chemotherapy cures approximately half of the patients, but patients with recurrent or non-resectable disease have no efficaciou...

Objective: Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) have inferior prognosis and respond poorly to chemotherapy compared to other metastatic locations. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Design: Tumor samples from a No...

Purpose: Most CRC patients harbor primarily non-immunogenic MSS tumor. The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab) repeatedly. Half of...

Introduction: The peritoneum is a common metastatic site for several abdominal cancers, including ovarian and colorectal cancer. Peritoneal metastasis is associated with poor prognosis and poor response to therapy. A potentially curative treatment is cytoreductive surgery (CRS) to remove all visible tumor tissue, followed by perfusion with hyperthe...

150 Background: The anti-tumor activity of ICB in MSS/pMMR-CRC is limited. However, recent studies have highlighted the possibility of inducing ICB responsiveness by oxaliplatin-based chemotherapy. The understanding of underlying mechanisms and identification of rational biomarkers are major focus areas in immuno-oncology. Methods: Patients with pr...

Aim Rectal cancers requiring beyond total mesorectal excision (bTME) are traditionally operated using an open approach, but the use of minimally invasive robot-assisted procedures is increasing. Introduction of minimal invasive surgery for complex cancer cases could be associated with compromised surgical margins or increased complication rates. Th...

Background: In some surgical disciplines, navigation-assisted surgery has become standard of care, but in rectal cancer, indications for navigation and the utility of different technologies remain undetermined. Methods: The NAVI-LARRC prospective study (NCT04512937; IDEAL Stage 2a) evaluated feasibility of navigation in patients with locally adv...

Appendiceal adenocarcinomas (AA) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology...

3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplat...

Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX study (NCT03388190) explored an unconventional concept, that patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivo...

Objectives Pseudomyxoma peritonei (PMP) is a rare cancer currently affecting over 11,736 patients across Europe. Since PMP is so uncommon, collaboration between scientific centers is key to discovering the mechanisms behind the disease, efficient treatments, and targets pointing to a cure. To date, no consensus has been reached on the minimum data...

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, and in part because of this AA remains an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in wh...

Disease recurrence and drug resistance are major challenges in the clinical management of patients with colorectal cancer liver metastases (CLM), and because tumors are generally microsatellite stable (MSS), responses to immune therapies are poor. The mesenchymal phenotype is overrepresented in treatment-resistant cancers and is associated with an...

Colorectal and ovarian cancers frequently develop peritoneal metastases with few treatment options. Intraperitoneal chemotherapy has shown promising therapeutic effects, but is limited by rapid drug clearance and systemic toxicity. We therefore encapsulated the cabazitaxel taxane in poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs), designed to...

Background: Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite-stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumor-infiltrating T cells, which has been associated with improved resp...

Alginate hydrogels have been broadly investigated for use in medical applications due to their biocompatibility and the possibility to encapsulate cells, proteins, and drugs. In the treatment of peritoneal metastasis, rapid drug clearance from the peritoneal cavity is a major challenge. Aiming to delay drug absorption and reduce toxic side effects,...

Background: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. Methods: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assig...

Background Precision cancer medicine (PCM), frequently used for the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges healthcare resources. We compared the health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comp...

BACKGROUND: Only a small fraction of patients with colorectal liver metastases (CLM) is eligible for curative resection, and novel treatment options are highly needed. The high linear-energy transfer of short-ranged alpha particles can induce complex double-stranded DNA breaks, leading to cell death. With no known resistance mechanism, alpha-partic...

Background: Colorectal liver metastasis (CLM) is a leading cause of cancer-related mortality in the industrialized world, and only a small fraction of patients are eligible for curative resections. While immune checkpoint inhibition (ICI) has resulted in major breakthroughs in some cancers, the response in microsatellite stable (MSS) colorectal can...

Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ from efficacy measures of directly cytotoxic chemotherapies. Hence, the selection of patients for experimental ICI schedules, for instance in MSS-mCRC, calls for applicable and reliable signals of activity or early failure that enable treatment adaptation...

PURPOSE In GI cancers, anaplastic lymphoma kinase ( ALK) rearrangements are extremely less frequent than in non–small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce. MATERIALS AND METHODS We assembled a...

Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published next-generation sequencing (NGS) datasets generated from 268 sampl...

Background Tumor delineation is time- and labor-intensive and prone to inter- and intraobserver variations. Magnetic resonance imaging (MRI) provides good soft tissue contrast, and functional MRI captures tissue properties that may be valuable for tumor delineation. We explored MRI-based automatic segmentation of rectal cancer using a deep learning...

Background Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mut BRAF ) or KRAS mutation (mut KRAS ) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less inv...

Background Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer with no efficacious treatment options in non-resectable and recurrent cases. Otherwise, rare activating mutations in the GNAS oncogene are remarkably frequent in PMP and the mutated gene product, guanine nucleotide-binding protein α subunit (Gsα), is a potential tumor...

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...

Background The subtype, density and location of tumor infiltrating T-cells are being explored as prognostic and predictive biomarkers in primary colorectal cancer (pCRC) and colorectal liver metastases (CLM). Very limited data exist comparing findings in pCRC and matched CLM. Patients and methods Fifty-eight patients with available pCRC and matche...

Simple Summary Patients with pseudomyxoma peritonei that are not cured by the standard treatment (cytoreductive surgery and hyperthermic intraperitoneal chemotherapy) have no efficacious treatment options. Drugs that inhibit formation of new vessels (anti-angiogenic drugs) could be a therapeutic option for these patients. Using patient samples and...

Background: Despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), most patients with resectable peritoneal metastases from colorectal cancer experience disease relapse. MOC31PE immunotoxin is being explored as a novel treatment option for these patients. MOC31PE targets the cancer-associated epithelial...

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...

Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R...

Background In colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk. Methods We measured 84...

A correction to this paper has been published: https://doi.org/10.1007/s10585-021-10084-0

Background The main cause of mortality in locally advanced rectal cancer (LARC) is metastatic progression. The aim of the present study was to describe frequency, pattern and outcome of metastatic disease in a cohort of LARC patients after curative resection. Methods This was a single-centre cohort study of 628 LARC cases after neoadjuvant chemora...

High-throughput "-omics" analysis may provide a broader and deeper understanding of cancer biology to define prognostic and predictive biomarkers and identify novel therapy targets. In this review we provide an overview of studies where the peritoneal tumor component of peritoneal metastases from colorectal cancer (PM-CRC) and pseudomyxoma peritone...

Oncolytic peptides represent a novel, promising cancer treatment strategy with activity in a broad spectrum of cancer entities, including colorectal cancer (CRC). Cancer cells are killed by immunogenic cell death, causing long-lasting anticancer immune responses, a feature of particular interest in non-immunogenic CRC. Oncolytic peptides DTT-205 an...

Background The multidisciplinary perioperative and anaesthetic management of patients undergoing pelvic exenteration is essential for good surgical outcomes. No clear guidelines have been established, and there is wide variation in clinical practice internationally. This consensus statement consolidates clinical experience and best practice collect...

Background: Despite the recent worldwide dissemination of laparoscopic liver surgery, no high-level evidence supports the oncologic safety of this approach. Objective: To evaluate long-term oncologic outcomes after laparoscopic versus open liver resection in patients with colorectal metastases. Design: A single-center, assessor-blinded, randomize...

Mucinous peritoneal metastases (PM) generally respond poorly to systemic treatment, and there is a clear unmet need for new treatment strategies to improve survival and quality of life for patients with PM. In this work, the growth inhibitory effect of five drugs (oxaliplatin (OXA; 5 mg/kg), irinotecan (IRI; 60 mg/kg), cabazitaxel (CBZ; 15 or 30 mg...

Background Although microRNAs (miRNAs) are involved in all hallmarks of cancer, miRNA dysregulation in the metastatic process remains poorly understood. We investigated the role of miRNAs in metastatic evolution of colorectal cancer (CRC) by analyzing smallRNA-seq datasets from primary CRC, metastatic locations (liver, lung and peritoneum), and cor...

Background The determination of the incidence and prevalence of rare diseases is important for economists and health-care providers. Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer that represents a substantial burden on both patients and health-care systems. The incidence rate was previously approximated at 1–2 people per mil...

Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer death in the Western world. Up to 50% of CRC patients develop metastatic disease and the liver is the most common site. The recently identified consensus molecular subtypes (CMS1-4) based on analyses of primary CRC have prognostic and therapeutic implications, b...

Background: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA seq...

Objective High rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity. Methods We analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 we...

Patients with colorectal liver metastases (CLM) commonly receive neoadjuvant chemotherapy (NACT) prior to surgical resection. NACT may induce immunogenic cell death with subsequent recruitment of T-cells to the tumor microenvironment, which could be exploited by immune checkpoint inhibition (ICI). In theory, this could expand the use of ICI to obta...

Background: A total of 15-20% of patients with rectal cancer patients have liver metastases on presentation. The management of these patients is controversial. Heterogeneity in management strategies is considerable, and often dependent on local resources and available expertise. Methods: members of the PelvEx Collaborative were invited to partic...

Introduction: In a recent phase I trial in a heterogeneous group of carcinoma patients with advanced disease, we did not observe objective responses by CT at 8 weeks in patients treated with either the anti-EpCAM immunotoxin MOC31PE alone or administered in combination with the immunosuppressor cyclosporin (CsA). We have now assessed overall surviv...

Pseudomyxoma peritonei (PMP) is a rare cancer commonly originating from appendiceal neoplasms that presents with mucinous tumor spread in the peritoneal cavity. Patients with PMP are treated with curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The value of adding HIPEC to CRS has not been proven...

Background and purpose: We investigated how features relating to pelvic cavity anatomy and tumor hemodynamic factors may influence systemic failure in rectal cancer. Materials and methods: Rectal cancer patients (207 women, 343 men), who had been prospectively enrolled onto six cohorts and given curative-intent therapy, were analyzed for the fir...

Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are special because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguish bona fide miRNAs from the myriad o...

Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are unique because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguish bona fide miRNAs from the myriad ot...

As many as 30% to 40% of locally advanced rectal cancer (LARC) patients experience metastatic progression of the disease. Recognizing the potential of the genetic cargo in tumor-derived exosomes, we hypothesized that plasma exosomal microRNA (miRNA) may reflect biological aggressiveness in LARC and provide new markers for rectal cancer aggressivene...

Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D)ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lym...

Purpose: Systemic failure remains a challenge in rectal cancer. Our recent data from a prospective study of intensified treatment in locally advanced rectal cancer indicated that neoadjuvant chemotherapy (NACT) and sequential long-course chemoradiotherapy (CRT), both modalities containing oxaliplatin, may have eradicated hypoxic tumor components an...

Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer death in the Western world. Up to 50% of CRC patients develop metastatic disease and the liver is the most common site. The recently identified consensus molecular subtypes (CMS1-4) based on analyses of primary CRC have prognostic and therapeutic implications, b...

Purpose: Systemic failure remains a challenge in rectal cancer. Our recent data from a prospective study of intensified treatment in locally advanced rectal cancer indicated that neoadjuvant chemotherapy (NACT) and sequential long-course chemoradiotherapy (CRT), both modalities containing oxaliplatin, may have eradicated hypoxic tumor components an...

Background: In metastatic colorectal cancer, only the microsatellite instable (MSI) subgroup of cases has so far demonstrated major responses to immune checkpoint inhibition. Increased infiltration of T lymphocytes in presumed non-responsive tumors has been shown to facilitate response to immune checkpoint inhibition. Cytotoxic chemotherapy might i...

p>Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer death in the Western world. Up to 50% of CRC patients develop metastatic disease and the liver is the most common site. The recently identified consensus molecular subtypes (CMS1-4) based on analyses of primary CRC have prognostic and therapeutic implications,...

Background Following curative-intent neoadjuvant therapy in locally advanced rectal cancer, metastatic progression is still dominant. We investigated if patients’ circulating 25-hydroxyvitamin D [25(OH)D] levels were associated with outcome. Methods Serum 25(OH)D concentration was assessed by liquid chromatography-mass spectrometry in samples coll...

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...

Mutations identified in 21 melanoma lymph node metastases and one PDX by IonTorrent Cancer Hotspot and Oncomine Comprehensive Panel.

Background: Laparoscopic liver resection in the posterosuperior segments is technically challenging. This study aimed to compare the perioperative outcomes for laparoscopic and open resection of colorectal liver metastases located in the posterosuperior segments. Methods: This was a subgroup analysis of the OSLO-COMET randomized controlled trial, w...

Background: The ImmunoPeCa trial investigated the use of intraperitoneal MOC31PE immunotoxin as a novel therapeutic principle for the treatment of peritoneal metastasis from colorectal cancer (PM-CRC). We here report long-term outcome from the trial. Methods: This was a dose-finding trial aiming to evaluate safety and toxicity (primary endpoint)...

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothe...

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are cur...

Most patients whose large bowel cancer has spread to other organs do not respond to immune therapy. We detected a rare gene mutation, termed 9p24.1 copy-number gain (CNG), in an otherwise incurable colorectal cancer that provoked an immune therapy response. We identified this gene mutation by gene-panel sequencing of DNA from a liver metastasis bio...

The effect of poly(2-ethyl-butyl cyanoacrylate) nanoparticles containing the cytotoxic drug cabazitaxel was studied in three breast cancer cell lines and one basal-like patient-derived xenograft model grown in the mammary fat pad of immunodeficient mice. Nanoparticle-encapsulated cabazitaxel had a much better efficacy than similar concentrations of...

Tumor hypoxia contributes to therapy resistance and metastatic progression of locally advanced rectal cancer (LARC). We postulated that the tumor mitochondrial metabolism, manifested by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage, reflects how hypoxic conditions connect to cancer-induced systemic inflammation and poor outcome...

In locally advanced rectal cancer (LARC), local recurrence rates are low due to contemporary multimodal treatment regimens involving neoadjuvant chemoradiotherapy (CRT) and surgery. Metastatic progression however, represents a major challenge and is reported by 30-40% of cases in recent trials. Ongoing effort to combine treatment modalities, includ...

Introduction: The presence of tumor-infiltrating lymphocytes, in particular T-cells in the tumor and its microenvironment, has been shown to be associated with prognosis in primary colorectal cancer (CRC) and CRC liver metastases (CLM). In this study we examined T-cell composition in the immune microenvironment in surgical specimens from 64 cases w...

Colorectal cancer (CRC) is the third most common cancer in the world, and approximately 50% of the patients develop liver metastasis, which is a major cause of disease mortality. New drugs and treatment options are therefore necessary to improve the survival of these patients. Lately, different types of immunotherapy, such as check point inhibitors...

A first-in-man study of the anti-EpCAM immunotoxin MOC31PE with and without parallel immunosuppression with Cyclosporin A (CsA) was performed in metastatic colorectal cancer (CRC) patients. The safety and maximum tolerable doses in patients with EpCAM-positive tumors were determined, and only mild and reversible dose-limiting liver toxicity was see...

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 intensifi...