Digitally assessed lymphocyte infiltration in rectal cancer biopsies is associated with pathological response to neoadjuvant therapy.

A frequently used treatment strategy in locally advanced rectal cancer (RC) is neoadjuvant therapy followed by surgery. Patients treated with neoadjuvant therapy achieve varying pathological response, and currently, predicting the degree of response is challenging. This study examined the association between digitally assessed histopathological features in the diagnostic biopsies and pathological response to neoadjuvant therapy, aiming to find potential predictive biomarkers. 50 patients with RC treated with neoadjuvant chemotherapy and/or radiotherapy followed by surgery were included. Deep learning-based digital algorithms were used to assess the epithelium tumor area percentage (ETP) based on H&E-stained slides, and to quantify the density of CD3+ and CD8+ lymphocytes, as well as the CD8+/CD3+ lymphocyte percentage, based on immunohistochemically stained slides, from the diagnostic tumor biopsies. Pathological response was assessed according to the Mandard method. A good pathological response was defined as tumor regression grade (TRG) 1-2, and a complete pathological response was defined as Mandard TRG 1. Associations between the ETP and lymphocyte densities in the diagnostic biopsies and the pathological response were examined. The density of CD8+ lymphocytes, and the CD8+/CD3+ lymphocyte percentage, were associated with both good and complete response to neoadjuvant therapy, while the density of CD3+ lymphocytes was associated with complete response. The ETP did not correlate with response to neoadjuvant therapy. It is well-known that infiltration of lymphocytes in colorectal cancer is a prognostic biomarker. However, assessment of CD8+ and CD3+ lymphocytes in the diagnostic tumor biopsies of patients with RC may also be useful in predicting response to neoadjuvant therapy.

The role of immunotherapy in the treatment of colorectal cancer.

In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch-repair deficient (dMMR) metastatic CRC, which accounts for 10-15% of patients. Recent studies indicate high rates of pathologic response in dMMR CRC treated with pre-operative immunotherapy while large-scale studies on novel immunotherapy combinations are ongoing.

Myocardial injury and long-term oncological outcomes in patients undergoing surgery for colorectal cancer.

PURPOSE: Myocardial injury after noncardiac surgery (MINS) is associated with increased mortality and postoperative complications. In patients with colorectal cancer (CRC), postoperative complications are a risk factor for cancer recurrence and disease-free survival. This study investigates the association between MINS and long-term oncological outcomes in patients with CRC in an ERAS setting. METHODS: This retrospective cohort study was conducted at Zealand University Hospital, Denmark, between June 2015 and July 2017. Patients undergoing CRC surgery were included if troponin was measured twice after surgery. Outcomes were all-cause mortality, recurrence, and disease-free survival within five years of surgery. RESULTS: Among 586 patients, 42 suffered MINS. After five years, 36% of patients with MINS and 26% without MINS had died, p = 0.15. When adjusted for sex, age and UICC, the hazard ratio (aHR) for 1-year all-cause mortality, recurrence, and disease-free survival were 2.40 [0.93-6.22], 1.47 [0.19-11.29], and 2.25 [0.95-5.32] for patients with MINS compared with those without, respectively. Further adjusting for ASA status, performance status, smoking, and laparotomies, the aHR for 3- and 5-year all-cause mortality were 1.05 [0.51-2.15] and 1.11 [0.62-1.99], respectively. Similarly, the aHR for 3- and 5-year recurrence were 1.38 [0.46-4.51], and 1.49 [0.56-3.98] and for 3- and 5-year disease-free survival the aHR were 1.19 [0.63-2.23], and 1.19 [0.70-2.03]. CONCLUSION: In absolute numbers, we found no difference in all-cause mortality and recurrence in patients with and without MINS. In adjusted Cox regression analyses, the hazard was increased for all-cause mortality, recurrence, and disease-free survival in patients with MINS without reaching statistical significance.

The Matrix Reloaded-The Role of the Extracellular Matrix in Cancer.

As the core component of all organs, the extracellular matrix (ECM) is an interlocking macromolecular meshwork of proteins, glycoproteins, and proteoglycans that provides mechanical support to cells and tissues. In cancer, the ECM can be remodelled in response to environmental cues, and it controls a plethora of cellular functions, including metabolism, cell polarity, migration, and proliferation, to sustain and support oncogenesis. The biophysical and biochemical properties of the ECM, such as its structural arrangement and being a reservoir for bioactive molecules, control several intra- and intercellular signalling pathways and induce cytoskeletal changes that alter cell shapes, behaviour, and viability. Desmoplasia is a major component of solid tumours. The abnormal deposition and composition of the tumour matrix lead to biochemical and biomechanical alterations that determine disease development and resistance to treatment. This review summarises the complex roles of ECM in cancer and highlights the possible therapeutic targets and how to potentially remodel the dysregulated ECM in the future. Furthering our understanding of the ECM in cancer is important as the modification of the ECM will probably become an important tool in the characterisation of individual tumours and personalised treatment options.

Metabolic switch in cancer - Survival of the fittest.

Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring of cancer cell metabolism. Driver gene mutations direct malignant cells away from oxidation to maximise energy production and biosynthesis while tumour-secreted factors degrade peripheral tissues to fuel disease progression and initiate metastasis. As it is vital to understand cancer cell metabolism and survival mechanisms, this review discusses the metabolic switch and current drug targets and clinical trials. In the future, metabolic markers may be included when phenotyping individual tumours to improve the therapeutic opportunities for personalised therapy.

Electroporation and Immunotherapy-Unleashing the Abscopal Effect.

The discovery of electroporation in 1968 has led to the development of electrochemotherapy (ECT) and irreversible electroporation (IRE). ECT and IRE have been established as treatments of cutaneous and subcutaneous tumors and locally advanced pancreatic cancer, respectively. Interestingly, the treatment modalities have been shown to elicit immunogenic cell death, which in turn can induce an immune response towards the tumor cells. With the dawn of the immunotherapy era, the potential of combining ECT and IRE with immunotherapy has led to the launch of numerous studies. Data from the first clinical trials are promising, and new combination regimes might change the way we treat tumors characterized by low immunogenicity and high levels of immunosuppression, such as melanoma and pancreatic cancer. In this review we will give an introduction to ECT and IRE and discuss the impact on the immune system. Additionally, we will present the results of clinical and preclinical trials, investigating the combination of electroporation modalities and immunotherapy.

Neutrophils and polymorphonuclear myeloid-derived suppressor cells: an emerging battleground in cancer therapy.

Neutrophils are central mediators of innate and adaptive immunity and first responders to tissue damage. Although vital to our health, their activation, function, and resolution are critical to preventing chronic inflammation that may contribute to carcinogenesis. Cancers are associated with the expansion of the neutrophil compartment with an escalation in the number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the peripheral circulation and tumor microenvironment. Although phenotypically similar to classically activated neutrophils, PMN-MDSC is pathologically activated and immunosuppressive in nature. They dynamically interact with other cell populations and tissue components and convey resistance to anticancer therapies while accelerating disease progression and metastatic spread. Cancer-associated neutrophilia and tumor infiltration of neutrophils are significant markers of poor outcomes in many cancers. Recently, there has been significant progress in the identification of molecular markers of PMN-MDSC providing insights into the central role of PMN-MDSC in the local tumor microenvironment as well as the systemic immune response in cancer. Further advances in sequencing and proteomics techniques will improve our understanding of their diverse functionalities and the complex molecular mechanisms at play. Targeting PMN-MDSC is currently one of the major focus areas in cancer research and several signaling pathways representing possible treatment targets have been identified. Positive results from preclinical studies clearly justify the current investigation in drug development and thus novel therapeutic strategies are being evaluated in clinical trials. In this review, we discuss the involvement of PMN-MDSC in cancer initiation and progression and their potential as therapeutic targets and clinical biomarkers in different cancers.

Tumor-Infiltrating Lymphocytes as Biomarkers of Treatment Response and Long-Term Survival in Patients with Rectal Cancer: A Systematic Review and Meta-Analysis.

Neoadjuvant chemoradiotherapy (NCRT) is indicated in locally advanced rectal cancer (LARC) to downstage tumors before surgery. Watchful waiting may be a treatment option to avoid surgery in patients, obtaining a complete clinical response. However, biomarkers predictive of treatment response and long-term prognosis are lacking. Here we investigated tumor-infiltrating lymphocytes (TILs) in pretherapeutic biopsies as predictive and prognostic biomarkers. A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. In total, 429 articles were identified, of which 19 studies were included in the systematic review and 14 studies in the meta-analysis. Patients with high pretherapeutic CD8+ TILs density had an increased likelihood of achieving a pathological complete response (RR = 2.71; 95% CI: 1.58-4.66) or a complete or near-complete pathological treatment response (RR = 1.86; 95% CI: 1.50-2.29). Furthermore, high CD8+ TILs density was a favorable prognostic factor for disease-free survival (HR = 0.57; 95% CI: 0.38-0.86) and overall survival (HR = 0.43; 95% CI: 0.27-0.69). CD3+, CD4+, and FOXP3+ TILs were not identified as predictive or prognostic biomarkers. Thus, assessing pretherapeutic CD8+ TILs density may assist in identifying patients with increased sensitivity to NCRT and favorable long-term prognosis.

Myocardial Injury After Colorectal Cancer Surgery and Postoperative 90-Day Mortality and Morbidity: A Retrospective Cohort Study.

BACKGROUND: Myocardial injury after noncardiac surgery is a strong predictor of 30-day mortality and morbidity. OBJECTIVE: The purpose of this study was to examine the incidence of myocardial injury in patients undergoing colorectal cancer surgery in an enhanced recovery after surgery protocol and its association with 90-day mortality and morbidity. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted at Zealand University Hospital, Denmark, between June 2015 and July 2017. PATIENTS: Adult patients undergoing colorectal cancer surgery were included if troponin was measured at least twice during the first 7 days after surgery. The patients were followed for 90 days. MAIN OUTCOME MEASURES: Myocardial injury was defined as an elevated troponin I measurement (>45 ng/L) without evidence of a nonischemic origin causing the elevation. Ninety-day mortality and complications were assessed. RESULTS: A total of 586 patients were included of which 42 were diagnosed with myocardial injury. Thirteen patients (2%) died within 90 days of surgery. There was no significant difference in 90-day mortality between patients with and without myocardial injury (5% (2/42) versus 2% (11/544); p = 0.24). We found a higher incidence of postoperative complications within 90 days of surgery in the myocardial injury group than in the nonmyocardial injury group (43% (18/42) versus 20% (107/544); p < 0.01). We found a significant difference between the myocardial injury group and nonmyocardial injury group in terms of medical complications (33% (14/42) versus 9% (50/544); p < 0.01) but not surgical complications (19% (8/42) versus 16% (85/544); p = 0.56). Myocardial injury was an independent predictor of postoperative complications within 90 days of surgery (adjusted OR, 2.69; 95% CI, 1.31-5.55). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Myocardial injury occurs frequently in patients undergoing colorectal cancer surgery in an enhanced recovery after surgery protocol. Patients with myocardial injury did not have a significantly higher 90-day mortality but had higher risk of 90-day postoperative complications than patients without myocardial injury. Future research should examine the prevention and treatment of myocardial injury. See Video Abstract at http://links.lww.com/DCR/B692. LESIN MIOCRDICA DESPUS DE LA CIRUGA DE CNCER COLORRECTAL Y MORTALIDAD Y MORBILIDAD POSOPERATORIAS A LOS DAS UN ESTUDIO DE COHORTE RETROSPECTIVE: ANTECEDENTES:La lesión del miocardio después de una cirugía no cardíaca es un fuerte predictor de mortalidad y morbilidad a los 30 días.OBJETIVO:El propósito fue examinar la incidencia de lesión miocárdica en pacientes sometidos a cirugía de cáncer colorrectal en un protocolo de recuperación mejorada después de la cirugía y su asociación con la mortalidad y morbilidad a los 90 días.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Realizado en el Hospital Universitario de Zelanda, Dinamarca, entre junio de 2015 y julio de 2017.PACIENTES:Se incluyeron pacientes adultos sometidos a cirugía de cáncer colorrectal, si la troponina se midió al menos dos veces durante los primeros siete días después de la cirugía. Los pacientes fueron seguidos durante 90 días.PRINCIPALES MEDIDAS DE RESULTADO:La lesión miocárdica se definió como una medición de troponina I elevada (> 45 ng / l) sin evidencia de una etiología no isquémica que causara la elevación. Se evaluaron la mortalidad y las complicaciones a los noventa días.RESULTADOS:Se incluyeron un total de 586 pacientes, de los cuales 42 fueron diagnosticados de lesión miocárdica. Trece pacientes (2%) murieron dentro de los 90 días posteriores a la cirugía. No hubo diferencias significativas en la mortalidad a 90 días entre los pacientes con y sin lesión del miocardio, 5% [2/42] versus 2% [11/544], p = 0,24. Encontramos una mayor incidencia de complicaciones posoperatorias dentro de los 90 días de la cirugía en el grupo de lesión miocárdica en comparación con el grupo de lesión no miocárdica, 43% [18/42] versus 20% [107/544], p <0,01. Encontramos una diferencia significativa entre el grupo de lesión miocárdica y el grupo de lesión no miocárdica en términos de complicaciones médicas (33% [14/42] versus 9% [50/544]; p <0,01) pero no complicaciones quirúrgicas (19% [8/42] versus 16% [85/544]; p = 0,56). La lesión miocárdica fue un predictor independiente de complicaciones posoperatorias dentro de los 90 días posteriores a la cirugía (razón de probabilidades ajustada: 2,69; intervalo de confianza del 95%: 1,31 - 5,55).LIMITACIONES:Limitado por su diseño retrospectivo.CONCLUSIÓN:La lesión del miocardio ocurre con frecuencia en pacientes sometidos a cirugía de cáncer colorrectal en un protocolo de recuperación mejorada después de la cirugía. Los pacientes con lesión miocárdica no tuvieron una mortalidad significativamente mayor a los 90 días, pero tuvieron un mayor riesgo de complicaciones posoperatorias a los 90 días en comparación con los pacientes sin lesión miocárdica. Las investigaciones futuras deben examinar la prevención y el tratamiento de la lesión miocárdica. Consulte Video Resumen en http://links.lww.com/DCR/B692.

Natural Killer Cells in Cancer and Cancer Immunotherapy.

The detection and killing of neoplastic cells require coordination of a variety of antitumor effector cells. Natural killer (NK) cells of the innate immune system are at the forefront of the body's defense systems and evidence suggests that the infiltration and cytotoxicity of NK cells in the cancer tissue influence treatment efficacy and survival. As powerful effectors in the anticancer immune response, NK cells rapidly recognize and kill transformed cells with little reactivity against healthy self-tissues, which highlights their potential role in cancer immunotherapy. Modern immunotherapeutic approaches include immune checkpoint inhibitors to revitalize dysfunctional T cells and adoptive cell transfer using CD8+ T cells with chimeric antigen receptors to enhance their functionality. However, treatment responses may be short-lived and risk of discontinuation due to adverse effects necessitates the development of safer immuno-oncologic therapies with improved outcomes. To this end, novel combinatorial interventions using T cells and NK cells and strategies for overcoming associated challenges are currently being investigated. This review summarizes the advances in the research on NK cells in cancer and cancer immunotherapy and discusses the possible implications for future cancer treatment.

Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy.

Our understanding of the tumor microenvironment (TME), including the interplay between tumor cells, stromal cells, immune cells, and extracellular matrix components, is mandatory for the innovation of new therapeutic approaches in cancer. The cell-cell communication within the TME plays a pivotal role in the evolution and progression of cancer. Cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) are major cell populations in the stroma of all solid tumors and often exert protumorigenic functions; however, the origin and precise functions of CAF and TAM are still incompletely understood. CAF and TAM hold significant potential as therapeutic targets to improve outcomes in oncology when combined with existing therapies. The regulation of CAF/TAM communication and/or their differentiation could be of high impact for improving the future targeted treatment strategies. Nevertheless, there is much scope for research and innovation in this field with regards to the development of novel drugs. In this review, we elaborate on the current knowledge on CAF and TAM in cancer and cancer immunotherapy. Additionally, by focusing on their heterogenous functions in different stages and types of cancer, we explore their role as potential therapeutic targets and highlight certain aspects of their functions that need further research.

Cytotoxic CD8+ T cells in cancer and cancer immunotherapy.

The functions of, and interactions between, the innate and adaptive immune systems are vital for anticancer immunity. Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response and form the backbone of current successful cancer immunotherapies. Immune-checkpoint inhibitors are designed to target immune-inhibitory receptors that function to regulate the immune response, whereas adoptive cell-transfer therapies use CD8+ T cells with genetically modified receptors-chimaeric antigen receptors-to specify and enhance CD8+ T-cell functionality. New generations of cytotoxic T cells with genetically modified or synthetic receptors are being developed and evaluated in clinical trials. Furthermore, combinatory regimens might optimise treatment effects and reduce adverse events. This review summarises advances in research on the most prominent immune effectors in cancer and cancer immunotherapy, cytotoxic T cells, and discusses possible implications for future cancer treatment.

The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: a systematic review and meta-analysis.

IMPORTANCE: Tumour-infiltrating lymphocytes (TILs) have previously been found to influence patient prognosis in other gastrointestinal cancers, for instance in colorectal cancer. An immunosuppressive phenotype often characterizes pancreatic cancer with a low degree of immune cell infiltration. Cytotoxic CD8+ T cell infiltration in tumours is found to be the best predictive variable for response to immune checkpoint inhibitor therapy, emphasizing the importance of investigating TILs in pancreatic cancer, especially focussing on CD8+ T cells. OBJECTIVE: Here, we systematically review the literature and perform meta-analyses to examine the prognostic value of TILs in human pancreatic ductal adenocarcinomas (PDAC). Secondarily, we review the literature regarding the histological localization of TILs and the impact on survival in PDAC. EVIDENCE REVIEW: A literature search was conducted on PubMed, Embase, The Cochrane Library and Web of Science. Studies examining patients with PDAC and the impact of high vs. low infiltration of immune cells on long-term oncological survival measures were included. Time-to-event meta-analysis and frequency analysis were conducted using a random effects model. The risk of bias was assessed using the Newcastle-Ottowa Scale. Quality of the cumulative evidence was evaluated using the GRADE approach for prognostic studies. FINDINGS: In total, 1971 articles were screened, of which 43 studies were included in the systematic review and 39 in the meta-analysis. High infiltration of CD8+ lymphocytes was significantly associated with improved overall survival (OS) [hazard ratio (HR) = 0.58, 95% confidence intervals (CIs): 0.50-0.68], disease-free survival (DFS) [HR = 0.64, 95% CI: 0.52-0.78], progression-free survival [HR = 0.66, 95% CI: 0.51-0.86] and cancer-specific survival [HR = 0.56, 95% CI: 0.32-0.99]. A high infiltration of CD3+ T cells was correlated with increased OS [HR = 0.58, 95% CI: 0.50-0.68] and DFS [HR = 0.74, 95% CI: 0.38-1.43]. Infiltration of CD4+ lymphocytes was associated with improved 12-months OS [risk ratio = 0.59, 95% CI: 0.35-0.99] and DFS [risk ratio = 0.68, 95% CI: 0.53-0.88]. High expression of FoxP3+ lymphocytes was associated with poor OS [HR = 1.48, 95% CI: 1.20-1.83]. The greatest impact on survival was observed in the CD8+ T cell and OS group, when infiltration was located to the tumour centre [HR = 0.53, 95% CI: 0.45-0.63]. However, subgroup analysis on the impact of the histological location of infiltration revealed no significant differences between the subgroups (tumour centre, invasive margin, stroma and all locations) in any of the examined cell types and outcomes. CONCLUSIONS AND RELEVANCE: Subsets of TILs, especially CD3+, CD8+ and FoxP3+ T cells are strongly associated with long-term oncological outcomes in patients with PDAC. To our knowledge, this is the first systematic review and meta-analysis on the prognostic value of TILs in pancreatic cancer.

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery.

The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and growth of residual cancer. Human and animal studies show that cancer surgery can increase survival, migration and proliferation of residual tumor cells. To secure the survival and growth of disseminated tumor cells, the formation of premetastatic niches in target organs involves a complex interplay between microenvironment, immune system, circulating tumor cells, as well as chemical mediators and exosomes secreted by the primary tumor. This review describes the current understanding of the early mechanisms of dissemination, as well as how surgery may facilitate disease progression.

Long-Term Outcomes after Use of Perioperative Glucocorticoids in Patients Undergoing Cancer Surgery: A Systematic Review and Meta-Analysis.

The surgical stress response can accelerate clinical metastasis formation. Perioperative glucocorticoids might modulate this response and the metastatic process. We aimed to describe associations between perioperative glucocorticoids and long-term outcomes after cancer surgery. We searched four databases for eligible trials and performed meta-analyses on frequency and time-to-event data. We included sixteen studies that evaluated eight different cancer types. No association was found between perioperative glucocorticoids and recurrence in either the frequency meta-analysis, risk ratio (RR) 1.04, 95% confidence interval (CI) (0.87-1.25), or in the time-to-event meta-analysis, hazard ratio (HR) 1.18, 95% CI (0.78-1.79). Increased 1-year overall survival, RR 0.70, 95% (0.51-0.97), and disease-free survival, RR 0.77, 95% CI (0.60-0.97), was found for the glucocorticoid group, but five years after surgery, overall survival was reduced for the glucocorticoid group, RR 1.64, 95% CI (1.00-2.71). An exploratory subgroup analysis revealed decreased overall survival, HR 1.78, 95% CI (1.57-2.03), for patients undergoing colorectal cancer surgery while receiving glucocorticoids. Perioperative glucocorticoids were not associated with recurrence after cancer surgery. We found neither beneficial or deleterious associations between glucocorticoids and overall survival or disease-free survival. The available evidence remains heterogenous; low in quality and amount; and cancer-specific at present.

The Intestinotrophic Effects of Glucagon-Like Peptide-2 in Relation to Intestinal Neoplasia.

Context: Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone with intestinotrophic and antiapoptotic effects. The hormone's therapeutic potential in intestinal diseases and relation to intestinal neoplasia has raised great interest among researchers. This article reviews and discusses published experimental and clinical studies concerning the growth-stimulating and antiapoptotic effects of GLP-2 in relation to intestinal neoplasia. Evidence Acquisition: The data used in this narrative review were collected through literature research in PubMed using English keywords. All studies to date examining GLP-2's relation to intestinal neoplasms have been reviewed in this article, as the studies on the matter are sparse. Evidence Synthesis: GLP-2 has been found to stimulate intestinal growth through secondary mediators and through the involvement of Akt phosphorylation. Studies on rodents have shown that exogenously administered GLP-2 increases the growth and incidence of adenomas in the colon, suggesting that GLP-2 may play an important role in the progression of intestinal tumors. Clinical studies have found that exogenous GLP-2 treatment is well tolerated for up to 30 months, but the tolerability for even longer periods of treatment has not been examined. Conclusion: Exogenous GLP-2 is currently available as teduglutide for the treatment of short bowel syndrome. However, the association between exogenous GLP-2 treatment and intestinal neoplasia in humans has not been fully identified. This leads to a cause for concern regarding the later risk of the development or progression of intestinal tumors with long-term GLP-2 treatment. Therefore, further research regarding GLP-2's potential relation to intestinal cancers is needed.