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Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.
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Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/imunologia , Feminino , Masculino , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Pessoa de Meia-Idade , Comunicação Parácrina , Idoso , Regulação Neoplásica da Expressão Gênica , ImunomodulaçãoRESUMO
BACKGROUND: Peritoneal sarcomatosis (PS) is a difficult entity to treat with limited options and guarded prognosis. We aimed to determine if the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) could offer superior local recurrence-free survival in patients with retroperitoneal sarcoma at high risk of developing PS as opposed to extended resection alone. METHODS: This is a single arm, phase II intervention study where all patients with recurrent localized retroperitoneal sarcoma considered at high risk of developing PS were considered for enrolment (ClinicalTrials.gov identifier: NCT03792867). Upon enrolment, patients underwent vigorous preoperative testing to ensure fitness for the procedure. During surgery, patients underwent extended resection and HIPEC with doxorubicin. Patients were followed-up every 2 weeks (± 10 days) for the first month and subsequently every three months (± 1 month) up to a year post-surgery, and were assessed for potential chemotherapy toxicity and post-treatment complications. After a year from resection and HIPEC, patients were followed-up either during routine clinic review or contacted via telephone every year (± 1 month) for 3 years. RESULTS: Six patients were recruited but one patient dropped out due to adverse and unexpected intraoperative events. The remaining patients completed the procedure uneventfully. Post-HIPEC, all patients recurred with a disease-free interval ranging from six to 24 months. Three patients died due to complications from recurrent disease whereas the remaining three patients are alive as of their last visit. The overall survival at time at reporting ranged between 22 to 56 months. CONCLUSION: The procedure is feasible with no major morbidity to patients. However, we are unable to recommend for it to be implemented as a routine procedure at this current stage due to lack of improved survival outcomes. Further multi-institutional studies may be conducted to yield better results.
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Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Retroperitoneais , Sarcoma , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida/métodos , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneais/cirurgia , Projetos Piloto , Neoplasias Retroperitoneais/cirurgia , Sarcoma/tratamento farmacológico , Sarcoma/cirurgiaAssuntos
Meios de Contraste , Obstrução Intestinal , Neoplasias Peritoneais , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Neoplasias Peritoneais/secundário , Meios de Contraste/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Solubilidade , IdosoRESUMO
Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD). Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence. Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported. Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results. Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.
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The use of open cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown improved oncological survival in terms of treating peritoneal surface malignancies (PSM). However, this procedure often comes with associated morbidity. The move towards use of laparoscopic surgery in this field is postulated to lead to a reduction in morbidity and earlier return to function, but literature on its use for CRS and HIPEC has been scarce. We performed a retrospective review of 6 patients with PSM who underwent laparoscopic CRS and HIPEC in our institution and analysed the patient characteristics, oncological history, perioperative and postoperative outcomes. Median peritoneal cancer index (PCI) score was 0 (IQR 0-1.25). All 6 patients had appendiceal primaries. Median operative time was 285 min (IQR 228.8-300); median length of stay was 7.5 days (IQR 5-8.8). All patients achieved complete cytoreduction, and there was no conversion to open surgery. One patient developed port site infection and another 2 patients subsequently developed adhesions. Median follow-up time was 35 (IQR 17.5-41) months. No patients had developed recurrence at the time of data collection. We conclude that in patients with limited PCI sore (< 2), laparoscopic CRS and HIPEC are safe and feasible. With increasing experience, a select group of patients with limited PSM may be treated via minimally invasive surgery, minimising the morbidity of a traditional laparotomy.
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Background: Peritoneal surface malignancies (PSM) present insidiously and often pose diagnostic challenges. There is a paucity of literature quantifying the frequency and extent of therapeutic delays in PSM and its impact on oncological outcomes. Methods: A review of a prospectively maintained registry of PSM patients undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy (CRS-HIPEC) was conducted. Causes for treatment delays were identified. We evaluate the impact of delayed presentation and treatment delays on oncological outcomes using Cox proportional hazards models. Results: 319 patients underwent CRS-HIPEC over a 6-years duration. 58 patients were eventually included in this study. Mean duration between symptom onset and CRS-HIPEC was 186.0 ± 37.1 days (range 18-1494 days) and mean duration of between patient-reported symptom onset and initial presentation was 56.7 ± 16.8 days. Delayed presentation (> 60 days between symptom onset and presentation) was seen in 20.7% (n=12) of patients and 50.0% (n=29) experienced a significant treatment delay of > 90 days between 1st presentation and CRS-HIPEC. Common causes for treatment delays were healthcare provider-related i.e. delayed or inappropriate referrals (43.1%) and delayed presentation to care (31.0%). Delayed presentation was a significantly associated with poorer disease free survival (DFS) (HR 4.67, 95% CI 1.11-19.69, p=0.036). Conclusion: Delayed presentation and treatment delays are common and may have an impact on oncological outcomes. There is an urgent need to improve patient education and streamline healthcare delivery processes in the management of PSM.
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BACKGROUND: The COVID-19 pandemic has led to a decrease in cancer screening due to the redeployment of health care resources and public avoidance of health care facilities. Breast cancer is the most common cancer diagnosed in female individuals, with improved survival rates from early detection. An avoidance of screening, resulting in late detection, greatly affects survival and increases health care resource burden and costs. OBJECTIVE: This study aimed to evaluate if a sustained decrease in public interest in screening occurred and to evaluate other search terms, and hence interest, associated with that. METHODS: This study used Google Trends to analyze public interest in breast cancer screening and symptoms. We queried search data for 4 keyword terms ("mammogram," "breast pain," "breast lump," and "nipple discharge") from January 1, 2019, to January 1, 2022. The relative search frequency metric was used to assess interest in these terms, and related queries were retrieved for each keyword to evaluate trends in search patterns. RESULTS: Despite an initial drastic drop in interest in mammography from March to April 2020, this quickly recovered by July 2020. After this period, alongside the recovery of interest in screening, there was a rapid increase in interest for arranging for mammography. Relative search frequencies of perceived breast cancer-related symptoms such as breast lump, nipple discharge, and breast pain remained stable. There was increase public interest in natural and alternative therapy of breast lumps despite the recovery of interest in mammography and breast biopsy. There was a significant correlation between search activity and Breast Cancer Awareness Month in October. CONCLUSIONS: Online search interest in breast cancer screening experienced a sharp decline at the beginning of the COVID-19 pandemic, with a subsequent return to baseline interest in arranging for mammography followed this short period of decreased interest.
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BACKGROUND: Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. METHODS: We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. RESULTS: SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. CONCLUSIONS: Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.
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Transformação Celular Neoplásica , Linfoma Extranodal de Células T-NK , Humanos , Transformação Celular Neoplásica/metabolismo , Oncogenes , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , RNA Interferente Pequeno/metabolismo , Células Matadoras Naturais/patologia , Linhagem Celular Tumoral , Proteínas HMGB/genética , Proteínas HMGB/metabolismoRESUMO
BACKGROUND: Immunonutrition has been shown to reduce hospital stay and postoperative morbidity in patients undergoing gastrointestinal, and head and neck surgery. However, its use has not been demonstrated in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). This study aims to determine the effectiveness of perioperative immunonutrition on patients undergoing CRS-HIPEC in reducing length of hospitalization and postoperative complications. PATIENTS AND METHODS: From April 2017 to December 2018, patients undergoing CRS-HIPEC for peritoneal metastases in a single center were enrolled in a randomized controlled trial. Patients with evidence of intestinal obstruction or with diabetes mellitus were excluded. Patients were randomly assigned in a 1:1 fashion to receive perioperative oral immunonutrition or standard nutritional feeds. Length of hospital stay and rates of wound infection and complications were recorded and compared between the two groups in an intention-to-treat manner. RESULTS: A total of 62 patients were recruited and randomized into two groups. Compliance to nutritional feeds in the preoperative period was significantly higher in the standard nutrition group (95.2% versus 75.4%, p = 0.004). There was no difference in postoperative compliance rates. Length of hospital stay and rates of wound infection and postoperative complications were higher in the standard nutrition group when compared with patients on immunonutrition (15.5 versus 11.1 days, p = 0.186; 19% versus 9.7%, p = 0.473; 16% versus 9.7%, p = 0.653; respectively). CONCLUSIONS: Patients undergoing CRS-HIPEC who received perioperative immunonutrition had shorter hospitalization and less wound infections and postoperative complications, although the differences with the standard nutrition group were not statistically significant. Potential benefits of perioperative immunonutrition need to be further evaluated in larger studies.
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Hipertermia Induzida , Neoplasias Peritoneais , Infecção dos Ferimentos , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Dieta de Imunonutrição , Neoplasias Peritoneais/secundário , Hipertermia Induzida/efeitos adversos , Complicações Pós-Operatórias/etiologia , Infecção dos Ferimentos/complicaçõesRESUMO
OBJECTIVE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) represent a mainstay of treatment for peritoneal malignancies. There is evidence that HIPEC using high intra-abdominal pressure (IAP) results in increased tissue penetration, although its safety profile remains relatively unknown. We thus aim to evaluate differences in intra- and post-operative outcomes in patients undergoing CRS-HIPEC with different levels of IAP. METHODS: This pilot prospective cohort study was conducted from January 2020 to February 2021 with patients undergoing CRS-HIPEC. Low IAP during HIPEC was defined as <18 mmHg and high IAP as ≥18 mmHg. Data was collected on patient and tumor characteristics, intra-operative clinical and biochemical parameters, and immediate post-operative outcomes. RESULTS: 40 patients underwent CRS-HIPEC (n low = 20, n high = 20). Median IAP in the low and high IAP groups were 12.0 and 19.0 mmHg respectively. During HIPEC, both groups experienced increase in heart rate, central venous pressure, end tidal CO2, temperature, and serum glucose, with decrease in mean arterial pressure and base excess. There were no significant differences in hemodynamics between the 2 groups. Mild electrolyte derangements and a decrease in hemoglobin were noted in the high IAP group but were of small magnitude. Post-operatively, high IAP did not result in increased rate of complications, time to full feeds, ICU or total hospital stay. CONCLUSIONS: High IAP in HIPEC is well tolerated and did not result in additional adverse events.
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Hipertermia Induzida , Neoplasias Peritoneais , Procedimentos Cirúrgicos de Citorredução/métodos , Humanos , Hipertermia Induzida/efeitos adversos , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Estudos ProspectivosRESUMO
Retroperitoneal liposarcomas (RPLPSs) are a rare tumor group for which current guidelines recommend aggressive en bloc resection to attain microscopically negative (R0) margins. To ensure R0 margins, resection of adherent or adjacent organs is often required. However, it is still unclear if R0 margins confer any additional benefit to patients over a grossly negative but microscopically positive (R1) margin. We performed a systematic search of PubMed and Embase databases for studies including patients receiving R0 or R1 resection for RPLPS. Nine retrospective cohort studies, one prospective cohort study, and 49 case reports/case series were included. A total of 552 patients with RPLPS were evaluated: 346 underwent R0 resection and 206 underwent R1 resection. In the R0 group, 5-year overall survival (OS) ranged from 58.3% to 85.7%; local recurrence (LR) ranged from 45.5% to 52.3%. In the R1 group, 5-year OS ranged from 35% to 55.3%; LR ranged from 66.7% to 91.7%. Among cohort studies, OS, disease-free survival (DFS), LR rate, and LR-free survival (LRFS) were significantly associated with R0 resections. Assessment of case series and reports suggested that the R0 margin led to a slightly higher morbidity than that of R1. In conclusion, this review found the R0 margin to be associated with reductions in LR rates and improved OS when compared with the R1 margins, though accompanied by slight increases in morbidity. The roles of tumor histotype and perioperative chemotherapy or radiotherapy were not well-elucidated in this review.
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Clinically relevant animal models are crucial for effective development of therapeutics for peritoneal carcinomatosis (PC). This protocol describes the generation of patient-derived ascites-dependent xenograft (PDADX) models from the cellular component of ascites. The use of routine intraperitoneal injection of the fluid component of ascites is analogous to the biological events occurring intra-abdominally in patients with PC. By serving as a proxy, PDADX models represent a valuable tool for preclinical testing of new therapeutics for PC. For complete details on the use and execution of this protocol, please refer to Hendrikson et al. (2022).
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Neoplasias Peritoneais , Animais , Ascite/tratamento farmacológico , Modelos Animais de Doenças , Xenoenxertos , Humanos , Injeções Intraperitoneais , Camundongos , Neoplasias Peritoneais/tratamento farmacológicoRESUMO
Objectives: Peritoneal cancer index (PCI) score is a common prognostication tool in peritoneal metastases (PM). We hypothesize that the distribution of PCI score and involvement of specific regions affects survival and morbidity outcomes. Methods: Data was collected from a prospective database of patients who underwent CRS and HIPEC for PM at the National Cancer Centre Singapore. We evaluate the relationship between PCI, PCI distribution, and survival and morbidity outcomes. Results: One hundred and fifty-two patients underwent CRS and HIPEC with a median PCI score of nine (range 0-31). Median overall survival (OS) and progression free survival (PFS) were 43 and 17 months, respectively. Region six (pelvis) was most commonly involved and had the highest frequency of heavy disease burden. Presence of PM in the lower abdomen, flanks, and small bowel were associated with poorer OS (p=0.01, 0.03, <0.001) and PFS (p=0.04, 0.02, <0.001). Involvement of porta hepatitis predicted poorer OS but not PFS (p=0.03). Involvement of the gastric antrum resulted in higher rates of postoperative complications. Conclusions: The pattern of PCI distribution may be associated with varying survival and morbidity outcomes.
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Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has recently emerged as a palliative alternative for patients with unresectable peritoneal metastasis (PM). Quality of life (QoL) has increasingly been used as an endpoint to evaluate treatment outcomes. This review aims to identify evidence on how PIPAC would impact the QoL of PM patients. Content: A systematic review was performed on articles identified from Medline, EMBASE, PsycInfo, and Web of Sciences. A meta-analysis was conducted on further selected studies. ACROBAT-NRSI was attempted to assess the risk of bias (RoB). Summary: Nine studies using the EORTC QLQ-C30 questionnaire to assess QoL after repeated PIPAC cycles were identified. Majority was found to be moderately biased and a great extent of heterogeneity was observed. Four studies on PM from either gastric cancer (GC) or epithelial ovarian cancer (EOC) were included for meta-analysis. In 31 GC patients and 104 EOC patients, QoL remained stable in 13/14 and 11/14 EORTC QLQ-C30 scales. PIPAC was inferior to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in global QoL and functioning but superior in symptom reduction. Outlook: PIPAC is a well-tolerated option for most GC and EOC patients with irresectable PM. Future trials are warranted to confirm the findings.
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Objectives: Various studies have shown that good quality of life (QoL) can be achieved after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is prognostic value of baseline QoL in post-operative outcome in Western setting. Our prospective study aims to validate these observations and elucidate clinical factors that predict poorer QoL in Asian peritoneal carcinomatosis patients. Methods: European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire was administered to patients before CRS and HIPEC and thereafter at 3, 6 and 12 months. Results: A total of 151 patients underwent 155 surgeries. Four hundred and seventy two questionnaires were completed. Median disease-free survival (DFS) was 16.5 months. Three year DFS and overall survival (OS) were 24.0% and 73.0% respectively. Post-operative global health status significantly increased at 3, 6 and 12 months. The decreases in functional scales recovered to baseline by 1-year post-surgery. Peritoneal carcinomatosis index (PCI), presence of stoma, peritonectomy duration, death within one year, post-operative complication and length of SICU stay negatively influenced QoL. Complication rates were higher in patients with lower global health status, physical and role functioning scores and higher symptom summary scores at baseline. Lower social functioning score, and higher pain, dyspnoea and symptom summary scores at baseline were significantly associated with poorer OS. Conclusions: Various clinical factors can help us predict a patient's QoL after surgery. Several baseline factors were also able to predict morbidity and survival. Going forward, we can use these factors to help us better select patients who will have a greater benefit from CRS and HIPEC.
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Background: The performance of MRI versus CT in the detection and evaluation of peritoneal surface malignancies (PSM) remains unclear in the current literature. Our study is the first prospective study in an Asian center comparing the two imaging modalities, validated against intra-operative findings. Methods: A total of 36 patients with PSM eligible for CRS-HIPEC underwent both MRI and CT scans up to 6 weeks before the operation. The scans were assessed for the presence and distribution of PSM and scored using the peritoneal cancer index (PCI), which were compared against PCI determined at surgery. Results: Both MRI and CT were 100% sensitive and specific in detecting the overall presence of PSM. Across all peritoneal regions, the sensitivity and specificity for PSM detection was 49.1% and 93.0% for MRI, compared to 47.8% and 95.1% for CT (p = 0.76). MRI was more sensitive than CT for small bowel disease, although the difference did not reach statistical significance. Comparing PCI on imaging with intra-operative PCI, the mean difference was found to be −3.4 ± 5.4 (p < 0.01) for MRI, and −3.9 ± 4.1 (p < 0.01) for CT. The correlation between imaging and intra-operative PCI was poor, with a concordance coefficient of 0.76 and 0.79 for MRI and CT, respectively. Within individual peritoneal regions, there was also poor agreement between imaging and intra-operative PCI for both modalities, other than in regions 1 and 3. Conclusion: MRI and CT are comparable in the detection and evaluation of PSM. While sensitive in the overall detection of PSM, they are likely to underestimate the true disease burden.
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The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined 'IMF' classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F).