In vitro chemotherapy-associated muscle toxicity is attenuated with nutritional support, while treatment efficacy is retained.

PURPOSE: Muscle-wasting and treatment-related toxicities negatively impact prognosis of colorectal cancer (CRC) patients. Specific nutritional composition might support skeletal muscle and enhance treatment support. In this in vitro study we assess the effect of nutrients EPA, DHA, L-leucine and vitamin D3, as single nutrients or in combination on chemotherapy-treated C2C12-myotubes, and specific CRC-tumor cells. MATERIALS AND METHODS: Using C2C12-myotubes, the effects of chemotherapy (oxaliplatin, 5-fluorouracil, oxaliplatin+5-fluorouracil and irinotecan) on protein synthesis, cell-viability, caspase-3/7-activity and LDH-activity were assessed. Addition of EPA, DHA, L-leucine and vitamin D3 and their combination (SNCi) were studied in presence of above chemotherapies. Tumor cell-viability was assessed in oxaliplatin-treated C26 and MC38 CRC cells, and in murine and patient-derived CRC-organoids. RESULTS: While chemotherapy treatment of C2C12-myotubes decreased protein synthesis, cell-viability and increased caspase-3/7 and LDH-activity, SNCi showed improved protein synthesis and cell viability and lowered LDH activity. The nutrient combination SNCi showed a better overall performance compared to the single nutrients. Treatment response of tumor models was not significantly affected by addition of nutrients. CONCLUSIONS: This in vitro study shows protective effect with specific nutrition composition of C2C12-myotubes against chemotherapy toxicity, which is superior to the single nutrients, while treatment response of tumor cells remained

Specialized nutrition improves muscle function and physical activity without affecting chemotherapy efficacy in C26 tumour-bearing mice

Background: Skeletal muscle wasting and fatigue are commonly observed in cancer patients receiving chemotherapy and associated with reduced treatment outcome and quality of life. Nutritional support may mitigate these side effects, but potential interference with chemotherapy efficacy could be of concern. Here, we investigated the effects of an ω-3 polyunsaturated fatty acid (eicosapentaenoic acid and docosahexaenoic acid), leucine-enriched, high-protein (100% whey), additional vitamin D, and prebiotic fibres ‘specific nutritional composition’ (SNC) and chemotherapy on state-of-the-art tumour organoids and muscle cells and studied muscle function, physical activity, systemic inflammation, and chemotherapy efficacy in a mouse model of aggressive colorectal cancer (CRC). Methods: Tumour-bearing mice received a diet with or without SNC. Chemotherapy treatment consisted of oxaliplatin and 5-fluorouracil. Tumour formation was monitored by calliper measurements. Physical activity was continuously monitored by infrared imaging. Ex vivo muscle performance was determined by myography, muscle fatty acid composition by gas chromatography, and plasma cytokine levels by Luminex xMAP technology. Patient-derived CRC organoids and C2C12 myotubes were used to determine whether SNC affects chemotherapy sensitivity in vitro. Results: Specific nutritional composition increased muscle contraction capacity of chemotherapy-treated tumour-bearing mice (P < 0.05) and enriched ω-3 fatty acid composition in muscle without affecting treatment efficacy (P < 0.0001). Mice receiving SNC maintained physical activity after chemotherapy and showed decreased systemic inflammation. Therapeutic response of CRC organoids was unaffected by SNC nutrients, while cell viability and protein synthesis of muscle cells significantly improved. Conclusions: The results show that specialized nutritional support can be used to maintain muscle function and physical activity levels during chemotherapy without increasing tumour viability. Therefore, nutritional strategies have potential value in promoting cancer and chemotherapy tolerance

DPA shows comparable chemotherapy sensitizing effects as EPA upon cellular incorporation in tumor cells

Dietary supplementation with ω-3 polyunsaturated fatty acids (PUFAs) has been reported to enhance the sensitivity of tumor cells towards chemotherapy. Most enhancing effects are described for ω-3 PUFAs EPA and DHA; less evidence is available with the intermediate DPA. We studied the chemotherapy enhancing effects of EPA, DPA and DHA in murine colon C26 adenocarcinoma cells and showed that DPA displayed similar chemosensitizing effects as EPA. Moreover, EPA supplementation increased cellular DPA content. In a C26 tumor-bearing mouse model, we studied the incorporation of ω-3 PUFA in tumor and skeletal muscle after a diet with different ω-3 PUFA sources. Although little DPA was present in the fatty acid food sources, in those that contained considerable EPA concentrations, DPA levels were higher in tumor and muscle tissue. From these studies, we conclude that EPA and DPA show chemosensitizing effects and that intake of EPA or EPA-containing nutrition leads to increased cellular DPA content by elongation. These findings support the use of ω-3 PUFA containing nutritional supplementations in cancer patients during chemotherapy treatment.</p

Nanobody-based cancer therapy of solid tumors

The development of tumor-targeted therapies using monoclonal antibodies has been successful during the last 30 years. Nevertheless, the efficacy of antibody-based therapy is still limited and further improvements are eagerly awaited. One of the promising novel developments that may overcome the drawbacks of monoclonal antibody-based therapies is the employment of nanobodies. Current nanobody-based therapeutics can be divided into three different platforms with nanobodies functioning as: receptor antagonists; targeting moieties of effector domains; or targeting molecules on the surface of nanoparticles. In this article, we describe factors that affect their performance at three different stages: their systemic circulation upon intravenous injection; their extravasation and tumor penetration; and, finally, their interaction with target molecules

Etiological Role of Viruses in Outbreaks of Acute Gastroenteritis in The Netherlands from 1994 through 2005

Acute gastroenteritis is one of the most common diseases worldwide. In developed countries, viruses, particularly noroviruses, are recognized as the leading cause. In The Netherlands, the surveillance of gastroenteritis outbreaks with suspected viral etiologies (as determined by Kaplan criteria) was established by the National Institute for Public Health and the Environment in 1994. This paper presents an overview of viral gastroenteritis outbreaks reported from 1994 through 2005. A minimum epidemiological data set consisting of the associated setting(s), the probable transmission mode, the date of the first illness and the date of sampling, the number of persons affected, and the number of hospitalizations was requested for each reported outbreak. Stool samples were tested for the presence of norovirus, sapovirus, rotavirus, astrovirus, adenovirus, and Aichi virus by electron microscopy, enzyme-linked immunosorbent assay, and/or reverse transcription-PCR. A total of 6,707 stool samples from 941 gastroenteritis outbreaks were investigated. Noroviruses were detected as the causative agent in 735 (78.1%) of the outbreaks, and rotaviruses, adenoviruses, and astroviruses were found to be responsible for 46 (4.9%), 9 (1.0%), and 5 (0.5%) outbreaks, respectively. Among the gastroenteritis outbreaks in which a mode of transmission was identified, most outbreaks (38.1%) were associated with person-to-person transmission, and the majority (54.9%) of the outbreaks investigated were reported by residential institutions. Since 2002, the total number of outbreaks reported and the number of unexplained outbreaks have increased. Furthermore, the number of rotavirus-associated outbreaks has increased, especially in nursing homes. Despite thorough testing, 115 (12.2%) outbreaks suspected of having viral etiologies remain unexplained. Increases in numbers of reported outbreaks may indicate undefined changes in the criteria for reporting or the emergence of new pathogens

Trajectory of body mass and skeletal muscle indices and disease progression in metastatic colorectal cancer patients

BACKGROUND: Knowledge of the evolution of BMI and skeletal muscle index (SMI) measurements during advanced cancer and their relationships with disease progression (PD) is relevant to improve the timing of interventions that may improve cachexia-associated outcomes. OBJECTIVES: We investigated BMI and SMI trajectories and their associations with PD in metastatic colorectal cancer (mCRC) patients during consecutive palliative systemic regimens. METHODS: In a secondary analysis of the primary CAIRO3 trial, we included 533 mCRC patients with BMI measurements repeated every 3 wk and 95 randomly selected patients with SMI measurements repeated every 9 wk. We studied 2 periods: p1, during first-line maintenance capecitabine + bevacizumab or observation until the first progression of disease (PD1); and p2, during capecitabine + oxaliplatin + bevacizumab or another reintroduction treatment from PD1 until the second progression of disease (PD2). BMI and SMI trajectories were modeled separately throughout both periods, and joint longitudinal-survival modeling was used to investigate the relationships between slopes in BMI and SMI with PD at 9 and 3 wk pre-PD. A multivariate longitudinal joint model was used to investigate the association between the BMI trajectory and PD at time of PD, independent of SMI. RESULTS: During p1, the slopes in BMI and SMI were associated with early PD1 [HRs for 9-wk BMI: 1.54 (95% CI: 1.33, 1.76); 9-wk SMI: 1.38 (95% CI: 0.87, 1.89), NS; 3-wk BMI: 1.74 (95% CI: 1.48, 1.99); 3-wk SMI: 2.65 (95% CI: 1.97, 3.32)]. During p2, only the slope in SMI was related to PD2 [9-wk BMI: 1.09 (95%: CI: 0.73, 1.45), NS; 9-wk SMI: 1.64 (95% CI: 1.25, 2.04); 3-wk BMI: 1.17 (95% CI: 0.77, 1.57); 3-wk SMI: 1.11 (95% CI: 0.70, 1.53)]. In models mutually adjusting for BMI and SMI, SMI was associated with PD in p1 [p1 ( n = 95), HR BMI: 1.32 (95% CI: 0.74, 2.39), NS; p1, HR SMI: 1.50 (95% CI: 1.04, 2.14); p2 ( n = 50), BMI: 0.98 (95% CI: 0.55, 1.75), NS; p2, HR SMI: 1.11 (95% CI: 0.61, 2.05), NS]. CONCLUSIONS: In mCRC patients during palliative systemic treatment, SMI losses, irrespective of BMI losses, may be a marker for the early initiation of cachexia interventions

Trajectory of body mass and skeletal muscle indices and disease progression in metastatic colorectal cancer patients

BACKGROUND: Knowledge of the evolution of BMI and skeletal muscle index (SMI) measurements during advanced cancer and their relationships with disease progression (PD) is relevant to improve the timing of interventions that may improve cachexia-associated outcomes. OBJECTIVES: We investigated BMI and SMI trajectories and their associations with PD in metastatic colorectal cancer (mCRC) patients during consecutive palliative systemic regimens. METHODS: In a secondary analysis of the primary CAIRO3 trial, we included 533 mCRC patients with BMI measurements repeated every 3 wk and 95 randomly selected patients with SMI measurements repeated every 9 wk. We studied 2 periods: p1, during first-line maintenance capecitabine + bevacizumab or observation until the first progression of disease (PD1); and p2, during capecitabine + oxaliplatin + bevacizumab or another reintroduction treatment from PD1 until the second progression of disease (PD2). BMI and SMI trajectories were modeled separately throughout both periods, and joint longitudinal-survival modeling was used to investigate the relationships between slopes in BMI and SMI with PD at 9 and 3 wk pre-PD. A multivariate longitudinal joint model was used to investigate the association between the BMI trajectory and PD at time of PD, independent of SMI. RESULTS: During p1, the slopes in BMI and SMI were associated with early PD1 [HRs for 9-wk BMI: 1.54 (95% CI: 1.33, 1.76); 9-wk SMI: 1.38 (95% CI: 0.87, 1.89), NS; 3-wk BMI: 1.74 (95% CI: 1.48, 1.99); 3-wk SMI: 2.65 (95% CI: 1.97, 3.32)]. During p2, only the slope in SMI was related to PD2 [9-wk BMI: 1.09 (95%: CI: 0.73, 1.45), NS; 9-wk SMI: 1.64 (95% CI: 1.25, 2.04); 3-wk BMI: 1.17 (95% CI: 0.77, 1.57); 3-wk SMI: 1.11 (95% CI: 0.70, 1.53)]. In models mutually adjusting for BMI and SMI, SMI was associated with PD in p1 [p1 ( n = 95), HR BMI: 1.32 (95% CI: 0.74, 2.39), NS; p1, HR SMI: 1.50 (95% CI: 1.04, 2.14); p2 ( n = 50), BMI: 0.98 (95% CI: 0.55, 1.75), NS; p2, HR SMI: 1.11 (95% CI: 0.61, 2.05), NS]. CONCLUSIONS: In mCRC patients during palliative systemic treatment, SMI losses, irrespective of BMI losses, may be a marker for the early initiation of cachexia interventions

Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients

Background: Observational studies suggest that loss of skeletal muscle mass (SMM) is associated with chemotherapy-related toxicity, poor quality of life, and poor survival in metastatic colorectal cancer (mCRC) patients. Little is known about the evolution of SMM during palliative systemic therapy. We investigated changes in SMM during various consecutive palliative systemic treatment regimens using repeated abdominal computed tomography scans of mCRC patients who participated in the randomized phase 3 CAIRO3 study. Methods: In the CAIRO3 study, mCRC patients with stable disease or better after 6 cycles of first-line treatment with capecitabine + oxaliplatin + bevacizumab (CAPOX-B) were randomized between maintenance treatment with capecitabine + bevacizumab (CAP-B) or observation. Upon first disease progression, in both groups, CAPOX-B or other treatment was reintroduced until the second disease progression, which was the primary study endpoint. We analysed 1355 computed tomography scans of 450 (81%) CAIRO3 patients (64 ± 9.0 years, CAP-B n = 223; observation n = 227) for SMM at four time points (i.e. prior to the start of pre-randomization initial treatment, at randomization, and at first and at second disease progression) using the Slice-o-matic software and single slice evaluation at the lumbar 3 level. By using accepted and widely used formulas, whole body SMM was calculated. A linear mixed effects model, adjusted for relevant confounders, was used to assess SMM changes for the total group and within and between study arms. Results: During 6 cycles of initial treatment with CAPOX-B prior to randomization, SMM decreased significantly in all patients [CAP-B arm: −0.53 kg (95% CI −1.12; −0.07) and observation arm: −0.85 kg (−1.45; −0.25)]. After randomization, SMM recovered during CAP-B treatment by 1.32 kg (0.73; 1.90) and observation by 1.20 kg (0.63; 1.78) (median time from randomization to first disease progression 8.6 and 4.1 months for CAP-B arm and observation arm, respectively). After first progression and during reintroduction treatment with CAPOX-B or other treatment, SMM again decreased significantly and comparable in both arms, CAP-B: −2.71 kg (−3.37; −2.03), and observation: −2.01 kg (−2.64; −1.41) (median time from first progression until second progression CAP-B arm: 4.7 months and observation arm: 6.6 months). Conclusions: This longitudinal study provides a unique insight in SMM changes in mCRC patients during palliative systemic treatment regimens, including observation. Our data show that muscle loss is reversible and may be influenced by the intensity of systemic regimens. Although studies have shown prognostic capacity for SMM, the effects of subsequent changes in SMM are unknown and may be clues for new future therapeutic interventions