Analysis of Expression of Programmed Cell Death Ligand 1 (PD-L1) and BRAFV600E Mutation in Thyroid Cancer.

In thyroid cancer, it has been suggested that PD-L1 overexpression is associated with some clinicopathological factors and prognosis. The aim of this study is to characterize the expression of PD-L1, the presence of the BRAFV600E mutation, as well as cellular and humoral immunity in thyroid cancer, and to investigate the factors that predict the effectiveness of anti-PD-L1 antibody therapy. Blood samples were collected from 33 patients who were newly diagnosed with thyroid cancer after surgery or biopsy. PD-L1 expression, BRAFV600E mutation, and CD8+ expression were examined by immunohistological staining using clinical thyroid cancer specimens. With a PD-L1 staining cut-off value of 1%, 13 (39.4%) patients were classified as PD-L1 positive. Stimulation Index (SI) is an indicator of T cell activation. PD-L1 expression was significantly correlated with low SI level (p = 0.046). Moreover, BRAFV600E mutation was detected in 24 of the 33 (72.7%) patients, and was significantly associated with PD-L1 expression (p = 0.047). In addition, enhanced CD8+ expression was significantly associated with PD-L1 expression (p = 0.003). Multivariate analyses confirmed that high CRP levels (p = 0.039) were independently and significantly associated with poor progression-free survival. These findings suggest that elevated PD-L1 status can be a prognostic indicator for survival in patients with thyroid cancer when comprehensively assessed using the expression of CD8+, the presence of BRAFV600E mutation and the patient's immune status.

U-to-C RNA editing by synthetic PPR-DYW proteins in bacteria and human culture cells.

Programmable RNA editing offers significant therapeutic potential for a wide range of genetic diseases. Currently, several deaminase enzymes, including ADAR and APOBEC, can perform programmable adenosine-to-inosine or cytidine-to-uridine RNA correction. However, enzymes to perform guanosine-to-adenosine and uridine-to-cytidine (U-to-C) editing are still lacking to complete the set of transition reactions. It is believed that the DYW:KP proteins, specific to seedless plants, catalyze the U-to-C reactions in mitochondria and chloroplasts. In this study, we designed seven DYW:KP domains based on consensus sequences and fused them to a designer RNA-binding pentatricopeptide repeat (PPR) domain. We show that three of these PPR-DYW:KP proteins edit targeted uridine to cytidine in bacteria and human cells. In addition, we show that these proteins have a 5' but not apparent 3' preference for neighboring nucleotides. Our results establish the DYW:KP aminase domain as a potential candidate for the development of a U-to-C editing tool in human cells.

Rapid repair of human disease-specific single-nucleotide variants by One-SHOT genome editing.

Many human diseases ranging from cancer to hereditary disorders are caused by single-nucleotide mutations in critical genes. Repairing these mutations would significantly improve the quality of life for patients with hereditary diseases. However, current procedures for repairing deleterious single-nucleotide mutations are not straightforward, requiring multiple steps and taking several months to complete. In the current study, we aimed to repair pathogenic allele-specific single-nucleotide mutations using a single round of genome editing. Using high-fidelity, site-specific nuclease AsCas12a/Cpf1, we attempted to repair pathogenic single-nucleotide variants (SNVs) in disease-specific induced pluripotent stem cells. As a result, we achieved repair of the Met918Thr SNV in human oncogene RET with the inclusion of a single-nucleotide marker, followed by absolute markerless, scarless repair of the RET SNV with no detected off-target effects. The markerless method was then confirmed in human type VII collagen-encoding gene COL7A1. Thus, using this One-SHOT method, we successfully reduced the number of genetic manipulations required for genome repair from two consecutive events to one, resulting in allele-specific repair that can be completed within 3 weeks, with or without a single-nucleotide marker. Our findings suggest that One-SHOT can be used to repair other types of mutations, with potential beyond human medicine.

The Clinicopathological Results of Thyroid Cancer With BRAFV600E Mutation in the Young Population of Fukushima.

BACKGROUND: Thyroid ultrasound screening for children aged 0 to 18 years was performed in Fukushima following the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases were detected. To explore the carcinogenic mechanisms of these cancers, we analyzed their clinicopathological and genetic features. METHODS: We analyzed 138 cases (52 males and 86 females) who had undergone surgery between 2013 and 2016 at Fukushima Medical University Hospital. Postoperative pathological diagnosis revealed 136 (98.6%) cases of papillary thyroid cancer (PTC). RESULTS: The BRAFV600E mutation was detected using direct DNA sequencing in 96 (69.6%) of the thyroid cancer cases. In addition, oncogenic rearrangements were detected in 23 cases (16.7%). Regarding chromosomal rearrangements, 8 (5.8%) RET/PTC1, 6 (4.3%) ETV6(ex4)/NTRK3, 2 (1.4%) STRN/ALK, and 1 each of RET/PTC3, AFAP1L2/RET, PPFIBP/RET, KIAA1217/RET, ΔRFP/RET, SQSTM1/NTRK3 and TPR/NTRK1 were detected. Tumor size was smaller in the BRAFV600E mutation cases (12.8 ±â€…6.8 mm) than in wild-type BRAF cases (20.9 ±â€…10.5 mm). In the BRAFV600E mutation cases, 83 (86.5%) showed lymph node metastasis, whereas 26 (61.9%) of the wild-type BRAF cases showed lymph node metastasis. CONCLUSIONS: The BRAFV600E mutation was mainly detected in residents of Fukushima, which was different from post-Chernobyl PTC cases with RET/PTC3 rearrangement. PTC with the BRAFV600E mutation was smaller but was shown in the high rate of central cervical lymph node metastasis than the wild-type BRAF PTC in the young population of Fukushima.

Prospective study on clinical characteristics of Japanese diabetic patients with chronic limb-threatening ischemia presenting Fontaine stage IV.

The aim of this prospective cross-sectional study was to reveal clinical characteristics of Japanese diabetic patients with chronic limb-threatening ischemia (CLTI) presenting ischemic unhealed ulcer/gangrene (Fontaine stage IV) in the real-world settings. The present study included 132 Japanese diabetic patients who underwent endovascular therapy for CLTI presenting Fontaine stage IV. The prevalence of diabetes-related complications, as well as prior history of ankle-brachial index (ABI) measurement before CLTI onset, was evaluated adopting multiple imputation (50 times). Duration of diabetes was referred to as time from diagnosis. The patients were aged 70 ± 10 years, with duration of diabetes 23 ± 12 years. The diabetes-related complications were so common that only 17% (95% confidence interval: 11-24%) and 25% (17-33%) of the population were free from advanced micro- and macroangiopathies, respectively. The clustering of advanced macroangiopathies was not significantly associated with duration of diabetes (P = 0.62). On the other hand, that of advanced microangiopathies was significantly positively associated with duration of diabetes (P = 0.004). However, even in patients with duration of diabetes < 10 years, as many as 63% (38-87%) of patients had at least one advanced microangiopathy. Only 31% (22-39%) of the patients had prior history of ABI measurement before CLTI onset. The history was inversely associated with age (P = 0.005). In conclusion, the advanced diabetes-related complications were highly prevalent, even in those whose diabetes was diagnosed less than a decade before. In addition, only a few patients had ever undergone ABI measurement before CLTI onset.

Improvement in diagnostic performance of breast cancer: comparison between conventional digital mammography alone and conventional mammography plus digital breast tomosynthesis.

BACKGROUND: The aim of this study was to determine if the diagnostic performance of breast lesion examinations could be improved using both digital breast tomosynthesis (DBT) and conventional digital mammography (CDM). METHODS: Our institutional review board approved the protocol, and patients were provided the opportunity to opt out of the study. A total of 628 patients aged 22-91 years with abnormal screening results or clinical symptoms were consecutively enrolled between June 2015 and March 2016. All patients underwent DBT and CDM, and 1164 breasts were retrospectively analyzed by three radiologists who interpreted the results based on the Breast Imaging Reporting and Data System. Categories 4 and 5 were considered positive, and pathological results were the gold standard. The diagnostic performance of CDM and CDM plus DBT was compared using the mean areas under the receiver operating characteristic (ROC) curves. RESULTS: A total of 100 breast cancer cases were identified. The areas under the ROC curves were 0.9160 (95% confidence interval 0.8779-0.9541) for CDM alone and 0.9376 (95% confidence interval 0.9019-0.9733) for CDM plus DBT. The cut-off values for both CDM alone and CDM plus DBT measurements were 4, with sensitivities of 61.0% (61/100) and 83.0% (83/100), respectively, and specificities of 99.1% (1054/1064) and 98.9% (1052/1064), respectively. CDM yielded 39 false-negative diagnoses, while CDM plus DBT identified breast cancer in 22 of those cases (56.4%). CONCLUSION: The combination of DBT and CDM for the diagnosis of breast cancer in women with abnormal examination findings or clinical symptoms proved effective and should be used to improve the diagnostic performance of breast cancer examinations.

A Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi-Tyrosine Kinase Inhibitor Lenvatinib.

Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor α, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib.

CDX2 is involved in microRNA-associated inflammatory carcinogenesis in gastric cancer.

The development of gastric cancer is significantly associated with chronic inflammation, such as caused by Helicobacter pylori (H. pylori) infection. Caudal-type homeobox 2 (CDX2) is a homeobox protein involved in intestinal differentiation in normal and in aberrant locations, and is associated with inflammation. The authors of the present study have previously reported that CDX2 may have a suppressive role in the progression and carcinogenesis of gastric carcinoma. In the present study, the authors initially confirmed that a decreased expression of CDX2, as detected by immunohistochemistry, is associated with poor cancer-specific survival in 210 gastric cancer cases, which is consistent with several previously published studies. To elucidate the potential mechanisms underlying this association, the authors investigated the mechanism of CDX2 suppression, which included interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) and p53 signaling pathways. The present study confirmed that CDX2 was suppressed by activation of the IL-6/STAT3 signaling pathway via miR-181b in vitro. It was further revealed that gastric cancer with negative CDX2 expression is associated with negative p53 staining, and this association was particularly significant in undifferentiated gastric cancer. The activation of the IL-6/STAT3 signaling pathway suppressed miR-34a, which is induced by p53. This suggests that the activation of the IL-6/STAT3 signaling pathway inflammation signaling pathway suppresses the p53 signaling pathway in tumors without TP53 mutation, which results in poor prognostic outcomes. In conclusion, CDX2 may be a useful prognostic biomarker for gastric cancer and is associated with p53 inactivation.

Association between circulating galectin-3 levels and the immunological, inflammatory and nutritional parameters in patients with colorectal cancer.

Galectin-3, a ß-galactoside-binding lectin, exhibits pleiotropic biological functions and has a role as one of the immunological modulators. However, the associations between circulating galectin-3 and immunological, inflammatory and nutritional parameters have not yet been fully elucidated. The serum concentration of galectin-3 was examined in association with interleukin-10 (IL-10), IL-12 and IL17 production, lymphocyte stimulation, neutrophil/lymphocyte ratio (NLR), white blood cell count (WBC), C-reactive protein (CRP) and rapid turnover proteins, including retinol-binding protein (RBP), prealbumin (PA) and transferrin (TF) in 50 patients with untreated colorectal cancers. Significant increases (P<0.05) were observed in the serum galectin-3 levels in patients with untreated colorectal cancer (9.6±4.5 ng/ml) compared with the normal controls (3.2±1.6 ng/ml). Higher serum galectin-3 concentrations were observed in patients with colon cancer (11.5±4.4 ng/ml) compared to in patients with rectal cancer (8.0±4.0 ng/ml) (P=0.005). The levels of circulating galectin-3 inversely correlated with the production of IL-10 (r=-0.59, P<0.001), and IL-12 (r=-0.69, P<0.001). Galectin-3 concentration also inversely correlated with the lymphocyte stimulation assay stimulation index (r=-0.42, P=0.021). However, the level of serum galectin-3 correlated with IL-17 production (r=0.67, P<0.001). Serum galectin-3 levels exhibited significant correlations with NLR (r=0.41, P=0.009), WBC (r=0.32, P=0.035), and CRP (r=0.63, P<0.001), and statistically significant inverse correlations with RBP (r=-0.45, P=0.002), PA (r=-0.46, P=0.001) and TF (r=-0.72, P<0.001). Galectin-3 may be one of the key factors in the regulation of immunological, inflammatory and nutritional conditions.

The protocol and preliminary baseline survey results of the thyroid ultrasound examination in Fukushima [Rapid Communication].

UNLABELLED: After the Fukushima nuclear power plant accident on March 11, 2011, the public of Japan became particularly concerned about the possibility of an increased risk of childhood thyroid cancer, similar to what was observed after the Chernobyl's accident. Due to serious public health perception, there was an urgency to evaluate the baseline levels of childhood thyroid status in Fukushima prefecture. Therefore we have commenced a thyroid ultrasound examination (TUE) survey of the approximately 360,000 pediatric inhabitants (0 to 18 years of age) who lived in Fukushima at the time of the accident in October 2011. The subjects were divided into three categories according to the standardized diagnostic criteria of ultrasound findings. Category A contained the subjects whose TUE findings were intact or benign. Category B were recommended a confirmatory TUE. Category C was recommended an immediate confirmatory TUE. RESULTS: The survey of 40,302 subjects in the first year was completed in March, 2013. There were 40,097 (99.5%), 205 (0.50%) and 0 subjects in categories A, B and C, respectively. Of the 82 category B subjects who underwent fine needle aspiration cytology (FNAC), 12 were diagnosed with a malignant tumor or were suspected to have malignancy. The 12 subjects received thyroid surgery and 11 thyroid cancers and one benign nodule were confirmed histologically after surgery. This is the first large-scaled TUE survey to employ sophisticated ultrasound screening and aim to evaluate the baseline frequency of childhood thyroid nodules and cysts. The results will become the golden standard of future comparative TUE in Fukushima, Japan.

Inappropriate Suppression of Thyrotropin Concentrations in Young Patients with Thyroid Nodules Including Thyroid Cancer: The Fukushima Health Management Survey.

BACKGROUND: Serum thyroid hormone concentration is regulated through the hypothalamic-pituitary-thyroid axis. This study aimed to clarify the relationships between thyroid hormone regulation and ultrasonographic findings in subjects with thyroid nodules detected during thyroid ultrasound examination for the Fukushima Health Management Survey. METHODS: As of October 31, 2014, a total of 296,253 subjects, who had been living in Fukushima Prefecture at the time of the Fukushima nuclear power plant accident and were aged ≤18 years on March 11, 2011, participated in two concurrent screening programs. In the primary screening, thyroid nodules were detected in 2241 subjects. A secondary confirmatory thyroid ultrasound examination and blood sampling for thyroid function tests were performed on 2004 subjects. The subjects were reassessed and classified into disease-free subjects (Group 1), subjects with cysts only (Group 2), subjects with nodules (Group 3), and subjects with malignancy or suspected malignancy (Group 4). Serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4), thyrotropin (TSH), thyroglobulin, and the fT3/fT4 ratio were classified according to the diagnoses. RESULTS: Inverse relationships between age and log TSH values (Spearman's correlation r = -0.311, p = 0.015), serum fT3 concentration (r = -0.688, p < 0.001), and the fT3/fT4 ratio (r = -0.520, p < 0.001) were observed in Group 1. When analysis of covariance with Bonferroni post hoc comparisons was used in the four groups, the log TSH values were significantly lower in both Group 3 and Group 4 compared with Group 1 and Group 2 after correcting for age (p < 0.001; Group 1 vs. Group 3, p = 0.016; Group 1 vs. Group 4, p = 0.022; Group 2 vs. Group 3, p = 0.001; Group 2 vs. Group 4, p = 0.008). However, no significant differences were observed between the four groups regarding levels of fT3, fT4, fT3/fT4 ratio, and thyroglobulin (p = 0.304, 0.340, 0.208, and 0.583, respectively). CONCLUSION: TSH suppression can be present in response to illness, including thyroid nodules, in young subjects. Low TSH levels may be associated with the finding of papillary thyroid cancer as well as with thyroid nodules in children and adolescents.

[Surgical Treatment of Thyroid Cancer].

The strategy for surgical treatment of thyroid cancer differs depending on the histopathological type. In papillary thyroid cancer, which accounts for most cases of thyroid cancer, total thyroidectomy is recommended in high-risk cases with tumors of more than 5 cm or with N1, EX2, or M1 tumors in Japan. On the other hand, ipsilateral lobectomy is performed for low-risk cases with T1N0M0. Our department has also added a treatment policy for the prognostic factor, age. Prophylactic lymph node dissection is performed in the central neck region but is not recommended in the lateral neck region. In follicular thyroid cancer, total thyroidectomy is recommended for widely invasive cancer, and hemithyroidectomy or ipsilateral lobectomy is performed for minimally invasive cancer. When widely invasive cancer is diagnosed after lobectomy, completion thyroidectomy is recommended. Whether minimally invasive follicular cancer with vascular invasion requires completion thyroidectomy is controversial. I also handle medullary thyroid cancer, poorly differentiated thyroid cancer, undifferentiated thyroid cancer, and thyroid malignant lymphoma with a different policy. It is important to balance a surgical treatment strategy with a molecular targeted therapy and radioactive iodine treatment.

Tactile sensor is useful for estimating liver hardness and liver fibrosis compared with ultrasonography and computed tomography.

BACKGROUND/AIMS: We examined whether conventional ultrasonography (US) and computed tomography (CT) were useful to evaluate liver hardness and hepatic fibrosis by comparing the results with those obtained by a tactile sensor using rats with liver fibrosis. METHODOLOGY: We used 44 Wistar rats in which liver fibrosis was induced by intraperitoneal administration of thioacetamide. The CT and US values of each liver were measured before laparotomy. After laparotomy, a tactile sensor was used to measure liver hardness. We prepared Azan stained sections of each excised liver specimen and calculated the degree of liver fibrosis (HFI: hepatic fibrosis index) by computed color image analysis. RESULTS: The stiffness values and HFI showed a positive correlation (r=0.690, p<0.001), as did the tactile values and HFI (r=0.709, p<0.001).In addition, the stiffness and tactile values correlated positively with each other (r=0.814, p<0.001). There was no correlation between the CT values and HFI, as well as no correlation between the US values and HFI. CONCLUSION: We confirmed that it was difficult to evaluate liver hardness and HFI by CT or US examination, and considered that, at present, a tactile sensor is useful method for evaluating HFI.

[Significance of preoperative radiotherapy and lateral lymph node dissection for locally advanced rectal cancer - a comparative study involving different hospitals].

The aim of this study was to compare the results between lateral lymph node dissection (LLND) alone, and preoperative radiotherapy (preRT) followed by LLND, for the treatment of locally advanced rectal cancer. This study assessed 44 consecutive patients with lower rectal cancer (clinical Stages II and III) without lateral lymph node metastasis by preoperative imaging at two hospitals. Twenty-five patients at one hospital received preoperative short-course radiation therapy (total 25 Gy) followed by a curative LLND operation (preRT group), and 19 patients at another hospital underwent a curative operation by LLND alone (non-preRT group). The 5-year locoregional relapse-free survival, disease-free survival, and overall survival rates were not different between the preRT and non-preRT groups. Although three patients in each group had lateral lymph node metastases, none developed pelvic sidewall recurrence. This study suggests that preRT followed by curative surgery with LLND for lower rectal cancers without lateral lymph node metastasis before surgery would not improve survival and local control rates.

[Two cases of rectal NET excised by laparoscopic surgery].

Even if grade 1 neuroendocrine tumors (NET) have low malignant potential, they may still be associated with lymph node metastasis. While the World Health Organization (WHO) classification requires determination of the grade of malignancy and presence of metastasis, it is also useful to evaluate tumor diameter, extent of invasion, and histological characteristics(cell variant, nuclear atypia, and ductal invasion). The authors present 2 cases of rectal NET excised by laparoscopic surgery. Considerations for surgical indications in rectal NET are made based on these case reports.

[A case of a giant rectal gastrointestinal stromal tumor radically resectable after treatment with neoadjuvant imatinib mesylate].

A 64-year-old male patient was diagnosed with rectal gastrointestinal stromal tumor(GIST)by prostate biopsy, because of high PSA. We considered that a radical operation was impossible because the tumor occupied the pelvis, and we suspected prostate invasion. After neoadjuvant chemotherapy(imatinib mesylate 400 mg/day), the tumor size was reduced(90×85 mm→60×50mm), and we could thus perform radical resection. The patient is currently receiving adjuvant chemotherapy (imatinib mesylate 400 mg/day), without recurrence.

Serum levels of vascular endothelial growth factor are increased and correlate with malnutrition, immunosuppression involving MDSCs and systemic inflammation in patients with cancer of the digestive system.

Vascular endothelial growth factor (VEGF) reportedly has an important role in the progression of malignant neoplasms and has been reported to induce myeloid-derived suppressor cells (MDSCs) that appear in cancer and inflammation. In the present study, serum concentrations of VEGF were measured in patients with digestive system cancer and the correlations with nutritional damage, immune suppression and systemic inflammation were analyzed. A significant increase in VEGF serum levels was observed in patients with esophageal, gastric and colorectal cancers compared with healthy volunteers. Levels of VEGF were inversely correlated with the serum concentrations of albumin, prealbumin and retinol-binding protein. The serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)-12 and correlated with MDSC counts. VEGF levels were also correlated with neutrophil and neutrophil/lymphocyte counts and inversely correlated with lymphocyte count. Serum VEGF levels were divided at a cutoff of 500 pg/ml, with levels of prealbumin and retinol-binding protein significantly decreased in patients with higher VEGF levels. The stimulation index and IL-12 production were significantly decreased in the group with higher VEGF levels and MDSC counts tended to be higher in this group. These results demonstrated that increased production of VEGF was correlated with systemic inflammation, nutritional impairment and the inhibition of cell-mediated immunity involving MDSCs.

Tumor delivery of Photofrin® by PLL-g-PEG for photodynamic therapy.

Photofrin® (porfimer sodium) is a photosensitive reagent used for photodynamic therapy (PDT) of tumors and dysplasias. Because only photo-irradiated sites are damaged, PDT is less invasive than systemic treatments. However, a photosensitive reaction is a major side effect of systemically delivered Photofrin. To enhance localization of Photofrin to tumors, we have formulated Photofrin with the tumor-localizing graft copolymer poly(ethylene glycol)-grafted poly(l-lysine), PLL-g-PEG. We demonstrate that Photofrin preferentially interacts with PLL-g-PEG through both ionic and hydrophobic interactions. The serum competitive study showed that the highly PEG-grafted PLL is better for preventing serum binding to the Photofrin/PLL-g-PEG complex. In tumor-bearing mice, formulation of Photofrin with PLL-g-PEG enhanced tumor localization of Photofrin as twice as Photofrin alone and concomitantly suppressed the photosensitivity reaction drastically.

Increased IL-17 production correlates with immunosuppression involving myeloid-derived suppressor cells and nutritional impairment in patients with various gastrointestinal cancers.

Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cell mechanisms mediating this relationship have not been elucidated. Th17 cells, which produce the proinflammatory cytokine interleukin 17 (IL-17), have been recognized as one of the key factors in the regulation of inflammatory bowel disease and rheumatoid arthritis. This study demonstrated that, in patients with various types of gastrointestinal cancer, IL-17 production was correlated with myeloid-derived suppressor cell (MDSC) levels and with markers for nutritional impairment, immune suppression and chronic inflammation. IL-17 was significantly higher in patients with various types of gastrointestinal cancer compared to normal volunteers. In addition, IL-17 levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio (NLR) and significantly inversely correlated with cell-mediated immune response indicators [lymphocyte phytohemagglutinin (PHA)-blastogenesis and IL-12 induction] and patient nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism contributing to disease progression through enhancement of immune suppression or cachexia. Controlling the activation of Th17 cells may prove to be a valuable strategy for the treatment of gastrointestinal cancer patients.

[Myeloid-derived suppressor cells in cancer patients].

Myeloid-derived suppressor cells (MDSCs) are one of the major cell populations responsible for regulating immune responses. MDSCs have been reported to accumulate in the blood, lymph nodes, and at tumor sites in most patients during tumor progression and chronic infection, where they potentially suppress T cell functions. We analyzed MDSCs (CD11b+ CD14- CD33+) in peripheral blood mononuclear cells by flow cytometry in 222 patients with esophageal, gastric, colorectal, hepatocellular, cholangiocellular, pancreatic, breast, ovarian, thyroid, and lung cancer, and 18 healthy volunteers. MDSCs were significantly higher in patients with esophageal, gastric, colorectal, hepatocellular, pancreatic, and breast cancer than in healthy volunteers, and the differences were not significant in patients with cholangiocellular, ovarian, thyroid, and lung cancer. Production of the cytokines IFN-γ and IL-6 in response to phytohemagglutinin was assayed using enzyme-linked immunosorbent assay (ELISA) test kits. Serum concentrations of sIL-2R were measured by ELISA. The percentages of MDSCs in patients with colorectal cancer positively correlated with neutrophil counts and the concentration of sIL-2R(both p<0.05), and inversely correlated with the production of IFN-γ( p<0.0001), serum albumin concentration(p<0.005), and lymphocyte counts (p<0.05). These data suggested that MDSCs are strongly related to chronic inflammation and nutritional impairment.