Effect of pentoxifylline on colon cancer patients treated with chemotherapy (Part I)

BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. MAIN OBJECTIVE: To evaluate PTX effects on colon cancer patients treated with chemotherapy. PATIENTS and METHODS: Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). RESULTS: Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. CONCLUSIONS: PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence –all important parameters of cachexia.

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he effects of NETosis on fibrinolysis in colon cancer patients

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2021-4-25-31 ◽

2022 ◽

Vol 20 (4) ◽

pp. 25-31

Author(s):

A. A. Parshina ◽

N. N. Tsybikov ◽

P. P. Tereshkov ◽

T. M. Karavaeva ◽

M. V. Maksimenya

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Cell Activation ◽

Fluorescent Microscopy ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Metastatic Colon Cancer ◽

The Given ◽

Experimental Group ◽

Pai 1

Aim. To investigate formation of neutrophil extracellular traps (NETs) and their impact on fibrinolysis in patients with colon cancer.Materials and methods. The study was performed in two groups. The experimental group consisted of patients with stage 2–3 non-metastatic colon cancer (n = 17, average age – 67 years). The control group included healthy volunteers matched by sex and age (n = 30, average age – 68 years). An experimental model was created from the whole blood. It included platelet-poor plasma and an isolated culture of neutrophils, previously induced to NETosis by adding 100 nmol PMA. The samples were incubated for 4 hours, then the test tubes were centrifuged to pellet cells and their remnants, and the plasma was transferred for subsequent examination. The plasma incubated with intact neutrophils was used as a control. The levels of interleukin-8 (IL-8) and P-selectin glycoprotein ligand-1 (PSGL-1) were used to determine the degree of cell activation. NETosis was confirmed by enzyme-linked immunosorbent assay (ELISA) and fluorescent microscopy. Fibrinolysis was assessed using the thrombodynamics test. The results were compared with the levels of fibrinolytic system components measured by flow cytometry.Results. In the control group, NETosis induction contributed to pronounced neutrophil activation that was accompanied by an increase in the IL-8, PSGL-1, and plasminogen levels, a decrease in PAI-1, and enhancement of fibrinolysis, compared with the intact samples. Higher levels of IL-8, PSGL-1, plasminogen, and PAI-1 and intensified fibrinolysis were detected in the intact samples. However, PMA-induced NETosis did not result in an increase in the degree of activation and significant changes in the given parameters.Conclusion. NETosis promotes both formation and lysis of fibrin clots. However, in cancer patients, suicidal NETosis does not contribute to fibrinolysis due to intracellular protease depletion, which may be one of the mechanisms causing hypercoagulation and insufficient fibrinolysis in cancer.

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VEGFR2 expressions in Th1 and CD8+ cytotoxic T lymphocytes (CTL) in colon cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15535 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15535-e15535

Author(s):

Mehmet Artac ◽

Ayca Ceylan ◽

Melek Karakurt Eryılmaz ◽

Murat Araz ◽

Mustafa Karaagac ◽

...

Keyword(s):

Colon Cancer ◽

T Cell ◽

Cancer Patients ◽

Study Groups ◽

T Cell Subsets ◽

Control Group ◽

Study Group ◽

Metastatic Colon Cancer ◽

Vegf Receptors ◽

Cancer History

e15535 Background: VEGF receptors have an important role for inhibiting adaptive immun response in colon cancer. Therefore, we analyzed VEGF receptors in circulating T cell subsets according to stage in colon cancer patients. Methods: The prospective study group consisted of 50 patients with histologically confirmed colon cancer and 30 person without any cancer history as a control group. Peripheral blood specimens were collected from the patients after the diagnosis before inducing chemotherapy and radiotherapy. Patients with active infections or autoimmune disorders, who were treated with steroids and antibiotics in the last four weeks before the study enrollment were excluded from the study group. VEGFR2 expressions in circulating T cell subsets (Th1, Th2, Th17, CTL) were analyzed by flow cyctometry. Results: Age and gender were not different between the all study groups. Mean circulating CD4+ folicullar cells were less in colon cancer patients (9.54%±3.99) than the control group (12.03%±4.34), (p < 0.01). Mean circulating CD8+ follicular cells were higher in metastatic colon cancer (n = 26) 2.48% ± 1.68, than the non-metastatic colon cancer patients (n = 24) 1.63% ± 1.37, (p = 0.02). Mean VEGFR2 expressions in Th1 cells were higher in colon cancer patients 248.8 (Mean Flourescein intensity-MFI) than the control group 224.6, (P = 0.006). Mean VEGFR2 expressions in CTL were higher in colon cancer patients (381.8) than the control group (284.7), (p < 0.001). PD-1 expressions were not different between the colon cancer patients and the control group in all circulating T cell subsets. Mean VEGFR2 expressions in Th17 cells were higher non-metastatic colon cancer patients than the metastatic colon cancer patients (326.5 and 268.4 MFI, respectively, p = 0.02). Conclusions: VEGFR2 expressions are increased in circulating Th1 and CTL subsets in colon cancer patients. Whereas PD-1 expressions were not different in circulating T cell subsets than the control. VEGFRs may play an important role for the inhibition of circulating T cell subsets in colon cancer.

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Association of chemotherapy with survival in stage II colon cancer patients who received radical surgery: a retrospective cohort study

BMC Cancer ◽

10.1186/s12885-021-08057-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhihao Lv ◽

Yuqi Liang ◽

Huaxi Liu ◽

Delong Mo

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Prediction Models ◽

Radical Surgery ◽

Survival Rates ◽

Stage Ii ◽

Survival Prediction ◽

Stage Ii Colon Cancer ◽

Overall Survival Rates

Abstract Background It remains controversial whether patients with Stage II colon cancer would benefit from chemotherapy after radical surgery. This study aims to assess the real effectiveness of chemotherapy in patients with stage II colon cancer undergoing radical surgery and to construct survival prediction models to predict the survival benefits of chemotherapy. Methods Data for stage II colon cancer patients with radical surgery were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (1:1) was performed according to receive or not receive chemotherapy. Competitive risk regression models were used to assess colon cancer cause-specific death (CSD) and non-colon cancer cause-specific death (NCSD). Survival prediction nomograms were constructed to predict overall survival (OS) and colon cancer cause-specific survival (CSS). The predictive abilities of the constructed models were evaluated by the concordance indexes (C-indexes) and calibration curves. Results A total of 25,110 patients were identified, 21.7% received chemotherapy, and 78.3% were without chemotherapy. A total of 10,916 patients were extracted after propensity score matching. The estimated 3-year overall survival rates of chemotherapy were 0.7% higher than non- chemotherapy. The estimated 5-year and 10-year overall survival rates of non-chemotherapy were 1.3 and 2.1% higher than chemotherapy, respectively. Survival prediction models showed good discrimination (the C-indexes between 0.582 and 0.757) and excellent calibration. Conclusions Chemotherapy improves the short-term (43 months) survival benefit of stage II colon cancer patients who received radical surgery. Survival prediction models can be used to predict OS and CSS of patients receiving chemotherapy as well as OS and CSS of patients not receiving chemotherapy and to make individualized treatment recommendations for stage II colon cancer patients who received radical surgery.

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Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00581-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jiao Wu ◽

Sai-Ching Jim Yeung ◽

Sicheng Liu ◽

Aiham Qdaisat ◽

Dewei Jiang ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Weight Loss ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Progression ◽

Colorectal Cancer Patient ◽

Nutrition Support ◽

Immunodeficient Mice ◽

The Impact

AbstractWeight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

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Sequential Therapies and the Cost-Effectiveness of Treating Metastatic Colon Cancer Patients

Journal of Managed Care & Specialty Pharmacy ◽

10.18553/jmcp.2016.22.6.628 ◽

2016 ◽

Vol 22 (6) ◽

pp. 628-639 ◽

Cited By ~ 3

Author(s):

Andinet Woldemichael ◽

Eberechukwu Onukwugha ◽

Brian Seal ◽

Nader Hanna ◽

C. Daniel Mullins

Keyword(s):

Colon Cancer ◽

Cost Effectiveness ◽

Cancer Patients ◽

Metastatic Colon Cancer ◽

The Cost

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Blood cytokine analysis suggests that SARS-CoV-2 infection results in a sustained tumour promoting environment in cancer patients

10.1101/2021.10.29.21265511 ◽

2021 ◽

Author(s):

Fien HR De Winter ◽

An Hotterbeekx ◽

Manon Huizing ◽

Angelina Konnova ◽

Erik Fransen ◽

...

Keyword(s):

Cancer Patients ◽

Cancer Progression ◽

Haematological Malignancy ◽

Control Group ◽

Haematological Malignancies ◽

Angiogenic Growth Factors ◽

Cytokine Analysis ◽

Care Workers ◽

Tnf Α ◽

Infected Control Group

Cytokines, chemokines and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n=54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n=42). Of the 35 CCGs, 19 were common to both solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-α, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n=52). Of these TNF-α, IFN-β, TSLP and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data urge for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.

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ASO Visual Abstract: Timing of Primary Tumor Resection in Synchronous Metastatic Colon Cancer Patients Undergoing Hepatic Arterial Infusion Pump Placement

Annals of Surgical Oncology ◽

10.1245/s10434-021-11106-7 ◽

2022 ◽

Author(s):

Floris S. Verheij ◽

Kevin C. Soares ◽

Geerard L. Beets ◽

Niels F. M. Kok ◽

Jonathan B. Yuval ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Primary Tumor ◽

Infusion Pump ◽

Tumor Resection ◽

Hepatic Arterial Infusion ◽

Primary Tumor Resection ◽

Metastatic Colon Cancer ◽

Arterial Infusion ◽

Pump Placement

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GDF15 expression in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.116 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 116-116

Author(s):

Priya Jayachandran ◽

Joanne Xiu ◽

Shivani Soni ◽

Richard M. Goldberg ◽

Benjamin Adam Weinberg ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Nk Cells ◽

Chromatin Remodeling ◽

Cancer Progression ◽

Cd8 T Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Metastatic Colon Cancer ◽

Genomic Alterations

116 Background: Cachexia affects many cancer patients. Growth differentiation factor-15 (GDF15) is a protein that regulates weight and the stress response of cells. The GDF15 gene encodes a ligand of TGF-beta that triggers cachexia and modulates the progression from tumorigenesis to metastasis. Inhibition of GDF15 with an antibody restored muscle mass and fat in animal models. Serum levels rise in proportion to the progression of colon cancer, predict outcome, and have been correlated with CEA. Methods: We retrospectively reviewed 7607 CRC tumors profiled by Caris Life Sciences (Phoenix, AZ) from 2019 to 2020. Profiling included whole transcriptome sequencing (RNA-Seq by NovoSeq). Tumor mutational burden, mismatch repair status, and pathway genomic alterations were evaluated. QuantiSEQ was used to assess immune cell infiltration in the tumor microenvironment. Results: GDF15 expression ranged from 0 to 593 transcripts per million (TPM) with median of 30 (IQR = 15.02). There was no association with age, sex, or primary tumor sidedness. MSI-H/dMMR tumors had higher GDF15 expression (median 37 vs 30, p = 0.0004); TMB > = 17 tumors was seen in 5.9% of bottom quartile (Q1) GDF15 expressors and 8.3% of top quartile (Q4). PDL1 IHC positivity was inversely correlated with GDF15 expression (7.1% in Q1 vs. 2.6% in Q4, p < 0.0001). Genomic alterations associated with higher GDF15 expression (Q4 vs Q1) included genes on TGF-B (SMAD2/4), PI3K (PIK3CA, MTOR), chromatin remodeling (ARID1A, KMT2C), DDR (ATM) and Wnt pathway (APC); those inversely associated included MYC CNA and TP53. Q1 tumors had higher CNA of ERBB2 and FGFR1. Relative neutrophils and NK cells in the TME increased from Q1 to Q4 (p < 0.001). There was a decrease in CD8+ T-cells and Treg cells from Q1 to Q4. Conclusions: GDF15 expression correlates with increased dMMR/MSI-H and TMB, but not with PDL1 expression. Mutations and activated pathways associated with GDF15 expression may explain increased cachexia with more aggressive disease. The association with chromatin remodeling may warrant therapies targeting histone modification and epigenetics. The increase in NK cells but decrease in CD8+ T cells in the TME with increasing GDF15 suggests approaches to treatment. Higher CD8+ lymphocyte counts correlate with PFS with immunotherapy. Anti-PD-L1 therapy reinvigorates the killing function of CD8+ T cells. The decrease in CD8+ T cells and PDL1 positivity with rising GDF15 suggests worse outcome and a lack of response to anti-PDL1 therapy. NK cell checkpoint inhibitors, CARs, and an anti-GFRAL antibody are now in clinical trials and might be utilized in high GDF15 cancers. GDF15 is emerging as a target in the treatment of obesity and cachexia and as a prognostic marker in oncology. Understanding its expression in metastatic colon cancer may reveal which patients could benefit from developing anti-GDF15 targeted therapies against cancer progression.

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Effects of magnanimous therapy on coping, adjustment, and living function in advanced lung cancer

Current Oncology ◽

10.3747/co.26.4126 ◽

2019 ◽

Vol 26 (1) ◽

Cited By ~ 2

Author(s):

X. Huang ◽

A. Yan ◽

Q. Liu ◽

L. Wu

Keyword(s):

Lung Cancer ◽

Survival Rate ◽

Usual Care ◽

Coping Style ◽

Therapy Group ◽

Survival Rates ◽

Advanced Lung Cancer ◽

Control Group ◽

Ctrl Group ◽

Psychological Coping

Objectives We examined the effects of magnanimous therapy on psychological coping, adjustment, living function, and survival rate in patients with advanced lung cancer.Methods Patients with advanced lung cancer (n = 145) matched by demographics and medical variables were randomly assigned to an individual computer magnanimous therapy group (ic-mt), a group computer magnanimous therapy group (gc-mt), or a control group (ctrl). Over 2 weeks, the ic-mt and gc-mt groups received eight 40-minute sessions of ic-mt or gc-mt respectively, plus usual care; the ctrl group received only usual care. The Cancer Coping Modes Questionnaire (ccmq), the Psychological Adjustment Scale for Cancer Patients (pascp), and the Functional Living Index–Cancer (flic) were assessed at baseline and 2 weeks later. The relationships of changes in those indicators were analyzed, and survival rates were compared.Results The psychological coping style, adjustment, and living function of the ic-mt and gc-mt groups improved significantly after the intervention (p < 0.01). After 2 weeks, significant (p < 0.01) differences between the treatment groups and the ctrl group in coping style, adjustment, and living function suggested successful therapy. The changes in living function were correlated with changes in psychological coping and adjustment. No difference in efficacy between ic-mt and gc-mt was observed. The survival rate was 31.84% in the ic-mt group and 9.375% in the ctrl group at 2 years after the intervention.Conclusions In patients with advanced lung cancer, ic-mt and gc-mt were associated with positive short-term effects on psychological coping style, adjustment, and living function, although the magnitude of the effect did not differ significantly between the intervention approaches. The effects on living function are partly mediated by improvements in psychological coping and adjustment.

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