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Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 22189

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Dr. Per J. Nilsson

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Guest Editor

Department of Molecular Medicine and Surgery, Karolinska Institutet, SE 171 77 Stockholm, Sweden
Interests: colorectal cancer; anal cancer; surgery; radiotherapy non-operative management

Special Issue Information

Dear Colleagues,

Prof. Bengt Glimelius (born 1946) is currently a Senior Professor of Oncology at Uppsala University, Sweden. After finishing studies at Lund University medical school, he entered the field of pathology and presented his PhD thesis in Uppsala in 1977. This was followed by post-doctoral studies at University of Oregon, Eugene, USA until his return to Sweden in 1979. Prof. Glimelius widened his sphere of interest to include oncology and, after first becoming Associate Professor in Pathology in 1980, also gained this title in Oncology two years later. Dr. Glimelius was awarded full Professorship in Oncology at Uppsala University in 1998. From 1999 and onwards, he also, in parallel, served as Guest Professor of Oncology at the Karolinska Institute until 2013. After formal retirement in 2017, Prof. Glimelius has continued to pursue research tirelessly.

Prof. Glimelius has authored well over 750 papers in peer-reviewed journals and several book chapters, and he served as Editor-in-Chief for Acta Oncologica for almost two decades. His research has been focused on colorectal cancer, covering all aspects from pre-clinical molecular research to multi-center international randomized trials. In addition, he has published on other GI-cancers and also in the field of Hematology. Over his career, Prof Glimelius has been awarded several distinctions such as the ESTRO Lifetime Award and the Hamilton Fairley Award (ESMO). Prof. Glimelius has supervised and guided more than 40 PhD candidates to successful examinations.

Based on Prof. Glimelius's outstanding contributions to the field of Colorectal cancer, and being a former PhD student of his, it is my privilege to serve as Guest Editor for this Special Issue in his honour. The primary goal of this issue is to highlight the significant achievements in the field of colorectal cancer reflecting the critical role played by his work. I am therefore pleased to invite all collaborators, peers, and previous students to submit a publication to this Special Issue.

Dr. Per J. Nilsson
Guest Editor

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Keywords

rectal cancer
colon cancer
neoadjuvant therapy
adjuvant therapy
radiotherapy
proton therapy
immunotherapy
imaging

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Published Papers (10 papers)

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Research

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12 pages, 1438 KiB

Open AccessArticle

Clinical Significance of Circulating Tumor Cells in Epithelial Appendiceal Neoplasms with Peritoneal Metastases

by Petter Frühling, Louice Moberg, Lana Ghanipour, Helgi Birgisson, Wilhelm Graf, Christer Ericsson and Peter H. Cashin

Cancers 2024, 16(13), 2441; https://doi.org/10.3390/cancers16132441 - 2 Jul 2024

Cited by 1 | Viewed by 1362

Abstract

Appendiceal tumors are uncommon and, at times, discovered incidentally during histological examination. The histopathological classification of the disease is complex and has generated some controversy. The analysis of circulating tumor cells can be used for the early detection of metastatic potential. The aim of the present study was to examine the prognostic value of circulating tumor cells in patients with appendiceal tumors and peritoneal metastases. To our knowledge, this is the first study to examine CTCs in appendiceal tumors. We performed a prospective cohort study of consecutive patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between 2015 and 2019 at a HIPEC referral center. In total, 31 patients were included in the analysis, and circulating tumor cells were detected in 15 patients (48%). CTC positivity was not associated with overall or recurrence-free survival, nor was it correlated with PCI score or histopathological grading. Surprisingly, however, CTCs were found in almost half the patients. The presence or quantities of these cells did not, on their own, predict systemic metastatic potential during the observed time, and they did not appear to significantly correlate with the oncological outcomes recorded. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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11 pages, 2264 KiB

Open AccessArticle

CD10 Expression Correlates with Earlier Tumour Stages and Left-Sided Tumour Location in Colorectal Cancer but Has No Prognostic Impact in a European Cohort

by Julia-Kristin Grass, Katharina Grupp, Martina Kluth, Claudia Hube-Magg, Ronald Simon, Marius Kemper, Jakob R. Izbicki, Guido Sauter and Nathaniel Melling

Cancers 2024, 16(8), 1473; https://doi.org/10.3390/cancers16081473 - 11 Apr 2024

Viewed by 1609

Abstract

The role of CD10 expression in colorectal cancer has been controversially discussed in the literature. Some data suggest a predictive capacity for lymph node and liver metastases, thus influencing overall survival (OS) and disease-free survival (DFS). This study aims to analyse the relationship between CD10 expression and overall survival (OS) in a European cohort. To determine the association of CD10 expression with tumour phenotype, molecular features, and prognosis, a tissue microarray of 1469 colorectal carcinomas was analysed using immunohistochemistry and was compared with matched clinicopathologic data. CD10 expression correlated with earlier tumour stages (p = 0.017) and left-sided colon cancer (p < 0.001). However, no correlation was found between CD10 expression and lymph node involvement (p = 0.711), tumour grading (p = 0.397), or overall survival (p = 0.562). Even in the subgroup analysis of tumour or nodal stage, CD10 did not affect overall survival, although it was significantly associated with p53 and nuclear β-catenin expression (p = 0.013 and p < 0.001, respectively). CD10 expression correlates with earlier tumour stages, colon cancer location, and indicators of aggressive CRC subtypes. However, we can exclude CD10 as a relevant independent prognosticator for CRC. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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22 pages, 5322 KiB

Open AccessArticle

Impact of Primary Tumor Location on Demographics, Resectability, Outcomes, and Quality of Life in Finnish Metastatic Colorectal Cancer Patients (Subgroup Analysis of the RAXO Study)

by Sonja Aho, Emerik Osterlund, Ari Ristimäki, Lasse Nieminen, Jari Sundström, Markus J. Mäkinen, Teijo Kuopio, Soili Kytölä, Annika Ålgars, Raija Ristamäki, Eetu Heervä, Raija Kallio, Päivi Halonen, Leena-Maija Soveri, Arno Nordin, Aki Uutela, Tapio Salminen, Hanna Stedt, Annamarja Lamminmäki, Timo Muhonen, Juha Kononen, Bengt Glimelius, Helena Isoniemi, Juho T. Lehto, Kaisa Lehtomäki and Pia Osterlund Show full author list Hide full author list

Cancers 2024, 16(5), 1052; https://doi.org/10.3390/cancers16051052 - 5 Mar 2024

Viewed by 2344

Abstract

The primary tumor location (PTL) is associated with the phenotype, metastatic sites, mutations, and outcomes of metastatic colorectal cancer (mCRC) patients, but this has mostly been studied according to sidedness (right vs. left sided). We studied right colon vs. left colon vs. rectal PTL in a real-life study population (n = 1080). Health-related quality of life (HRQoL) was assessed multi-cross-sectionally with QLQ-C30, QLQ-CR29, EQ-5D, and 15D. A chi-square, Kaplan–Meier, and Cox regression were used to compare the groups. The PTL was in the right colon in 310 patients (29%), the left colon in 396 patients (37%), and the rectum in 375 patients (35%). The PTL was associated with distinct differences in metastatic sites during the disease trajectory. The resectability, conversion, and resection rates were lowest in the right colon, followed by the rectum, and were highest in the left colon. Overall survival was shortest for right colon compared with left colon or rectal PTL (median 21 vs. 35 vs. 36 months), with the same trends after metastasectomy or systemic therapy only. PTL also remained statistically significant in a multivariable model. The distribution of symptoms varied according to PTL, especially between the right colon (with general symptoms of metastases) and rectal PTL (with sexual- and bowel-related symptoms). mCRC, according to PTL, behaves differently regarding metastatic sites, resectability of the metastases, outcomes of treatment, and HRQoL. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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16 pages, 2210 KiB

Open AccessArticle

Short- and Long-Term Survival among Elderly Colorectal Cancer Patients in Finland, 2006–2015: A Nationwide Population-Based Registry Study

by Tanja Hukkinen, Tobias Olenius, Selja Koskensalo, Anna Lepistö, Laura Koskenvuo and Camilla Böckelman

Cancers 2024, 16(1), 135; https://doi.org/10.3390/cancers16010135 - 27 Dec 2023

Cited by 1 | Viewed by 1252

Abstract

This population-based registry study aimed to report 30-day and one-year postoperative survival, five-year overall survival (OS), and disease-specific survival (DSS) among elderly (≥75 years old) colorectal cancer (CRC) patients. All new colorectal cancer cases from 2006–2015 were included and followed until death or the end of follow-up (end of 2016). Among 27,088 CRC patients, 11,306 patients were ≥75 years old. Among patients ≥ 75 years, 36.8% (n = 4160) had right-sided colon cancer, 21.9% (n = 2478) left-sided colon cancer, and 32.3% (n = 3650) rectal cancer. In this study population, 932 patients were aged ≥ 90. The 30-day postoperative OS for patients aged 75–79 was 96.1% (95% confidence interval [CI] 95.3–96.9) falling to 93.2% (95% CI 92.0–94.4) for patients aged 80–84. The one-year postoperative OS among patients aged 75–79 was 86.3% (95% CI 84.7–87.9) compared with 80.5% (95% CI 78.7–82.3) among patients aged 80–84. Five-year OS among patients aged 75–79 was 47.6% (95% CI 46.0–49.2) and 36.6% (95% CI 34.8–38.4) among patients aged 80–84, compared with 61.7% (95% CI 60.9–62.5) among younger patients (<75 years old). Survival among elderly CRC patients (≥75 years old) was in general fairly good when compared with younger patients, especially among patients aged 75–79 and 80–84 with localized or locally advanced disease. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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18 pages, 3728 KiB

Open AccessArticle

Enhanced Therapeutic Effects of ¹⁷⁷Lu-DOTA-M5A in Combination with Heat Shock Protein 90 Inhibitor Onalespib in Colorectal Cancer Xenografts

by Tabassom Mohajershojai, Douglas Spangler, Saloni Chopra, Fredrik Y. Frejd, Paul J. Yazaki and Marika Nestor

Cancers 2023, 15(17), 4239; https://doi.org/10.3390/cancers15174239 - 24 Aug 2023

Viewed by 1969

Abstract

Carcinoembryonic antigen (CEA) has emerged as an attractive target for theranostic applications in colorectal cancers (CRCs). In the present study, the humanized anti-CEA antibody hT84.66-M5A (M5A) was labeled with ¹⁷⁷Lu for potential CRC therapy. Moreover, the novel combination of ¹⁷⁷Lu-DOTA-M5A with the heat shock protein 90 inhibitor onalespib, suggested to mediate radiosensitizing properties, was assessed in vivo for the first time. M5A antibody uptake and therapeutic effects, alone or in combination with onalespib, were assessed in human CRC xenografts and visualized using SPECT/CT imaging. Although both ¹⁷⁷Lu-DOTA-M5A and onalespib monotherapies effectively reduced tumor growth rates, the combination therapy demonstrated the most substantial impact, achieving a fourfold reduction in tumor growth compared to the control group. Median survival increased by 33% compared to ¹⁷⁷Lu-DOTA-M5A alone, and tripled compared to control and onalespib groups. Importantly, combination therapy yielded comparable or superior effects to the double dose of ¹⁷⁷Lu-DOTA-M5A monotherapy. ¹⁷⁷Lu-DOTA-M5A increased apoptotic cell levels, indicating its potential to induce tumor cell death. These findings show promise for ¹⁷⁷Lu-DOTA-M5A as a CRC therapeutic agent, and its combination with onalespib could significantly enhance treatment efficacy. Further in vivo studies are warranted to validate these findings fully and explore the treatment’s potential for clinical use. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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12 pages, 2003 KiB

Open AccessArticle

Prognostic Values of Tissue and Serum Angiogenic Growth Factors Depend on the Phenotypic Subtypes of Colorectal Cancer

by Jussi Herman Kasurinen, Jaana Hagström, Tuomas Kaprio, Sirpa Jalkanen, Marko Salmi, Camilla Böckelman and Caj Haglund

Cancers 2023, 15(15), 3871; https://doi.org/10.3390/cancers15153871 - 29 Jul 2023

Cited by 1 | Viewed by 1620

Abstract

We classified colorectal cancer (CRC) patients into four phenotypic subgroups and investigated the prognostic value of angiogenic growth factors across subgroups. Preoperative serum concentrations and tissue expressions of VEGF, bFGF, and PDGF-bb were determined among 322 CRC patients. We classified patients into phenotypic subgroups (immune, canonical, metabolic, and mesenchymal) according to a method described in our earlier work. Among the metabolic subgroup, patients with high serum concentrations of VEGF, bFGF, or PDGF-bb exhibited a significantly improved prognosis. Moreover, those with high VEGF tissue expressions exhibited a significantly improved prognosis among patients in the metabolic subgroup. Among immune patients, a high VEGF serum expression is associated with a worse prognosis. A high serum bFGF concentration is associated with a favorable prognostic factor among patients with a canonical tumor phenotype. A high PDGF-bb tissue expression is associated with non-metastasized disease and with the immune, canonical, and metabolic subtypes. To our knowledge, this is the first study to show that the prognostic value of angiogenic growth factors differs between phenotypic subtypes. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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Review

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13 pages, 777 KiB

Open AccessReview

Surgical Outcomes after Radiotherapy in Rectal Cancer

by Sofieke J. D. Temmink, Koen C. M. J. Peeters, Per J. Nilsson, Anna Martling and Cornelis J. H. van de Velde

Cancers 2024, 16(8), 1539; https://doi.org/10.3390/cancers16081539 - 18 Apr 2024

Cited by 4 | Viewed by 2739

Abstract

Over the past decade, the treatment of rectal cancer has changed considerably. The implementation of TME surgery has, in addition to decreasing the number of local recurrences, improved surgical morbidity and mortality. At the same time, the optimisation of radiotherapy in the preoperative setting has improved oncological outcomes even further, although higher perineal infection rates have been reported. Radiotherapy regimens have evolved through the adjustment of radiotherapy techniques and fields, increased waiting intervals, and, for more advanced tumours, adding chemotherapy. Concurrently, imaging techniques have significantly improved staging accuracy, facilitating more precise selection of advanced tumours. Although chemoradiotherapy does lead to the downsizing and -staging of these tumours, a very clear effect on sphincter-preserving surgery and the negative resection margin has not been proven. Aiming to decrease distant metastasis and improve overall survival for locally advanced rectal cancer, systemic chemotherapy can be added to radiotherapy, known as total neoadjuvant treatment (TNT). High complete response rates, both pathological (pCR) and clinical (cCR), are reported after TNT. Patients who follow a Watch & Wait program after a cCR can potentially avoid surgical morbidity and colostomy. For both early and more advanced tumours, trials are now investigating optimal regimens in an attempt to offer organ preservation as much as possible. Multidisciplinary deliberation should include patient preference, treatment toxicity, and likelihood of end colostomy, but also the burden of intensive surveillance in a W&W program. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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12 pages, 273 KiB

Open AccessReview

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases from Colorectal Cancer—An Overview of Current Status and Future Perspectives

by Wilhelm Graf, Lana Ghanipour, Helgi Birgisson and Peter H. Cashin

Cancers 2024, 16(2), 284; https://doi.org/10.3390/cancers16020284 - 9 Jan 2024

Viewed by 2229

Abstract

Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

15 pages, 455 KiB

Open AccessReview

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies

by Line Schmidt Tarpgaard, Stine Brændegaard Winther and Per Pfeiffer

Cancers 2024, 16(1), 126; https://doi.org/10.3390/cancers16010126 - 26 Dec 2023

Cited by 3 | Viewed by 3003

Abstract

Systemic treatment of metastatic colorectal cancer (mCRC) has improved considerably over the past 20 years. First- and second-line combinations of 5FU, oxaliplatin, and irinotecan, with or without anti-angiogenic and/or anti-EGFR antibodies, were approved shortly after the turn of the millennium. Further triumphs were not seen for almost 10 years, until the approval of initially regorafenib and shortly after trifluridine/tipiracil. A growing understanding of tumor biology through molecular profiling has led to further treatment options. Here, we review the most recent clinical data for late-line treatment options in mCRC, focusing on randomized trials if available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles (e.g., BRAF mutations, KRAS G12C mutations, HER2 amplification, deficient MMR, or NTRK gene fusions). Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

Other

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11 pages, 890 KiB

Open AccessSystematic Review

Does the Gain of Total Neoadjuvant Therapy Outweigh the Harm in Rectal Cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) Phenomenon: A Systematic Review

by Joanna Socha and Krzysztof Bujko

Cancers 2023, 15(4), 1016; https://doi.org/10.3390/cancers15041016 - 5 Feb 2023

Cited by 7 | Viewed by 2691

Abstract

Background: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. Methods: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. Results: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. Conclusion: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM. Full article

(This article belongs to the Special Issue Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius)

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Advance in Colorectal Cancer: A Themed Issue in Honor of Prof. Bengt Glimelius

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