Rapid Turnover Proteins Research Articles

Postoperative Nutritional Assessment of Laparoscopic Versus Open Partial Hepatectomy.

No studies have investigated the advantage of laparoscopic hepatectomy (LH) compared with open hepatectomy (OH) from a nutritional perspective. This study aimed to compare the postoperative nutritional status between LH and OH. A total of 186 patients who underwent partial hepatic resection for liver tumors were analyzed retrospectively. We compared perioperative variables between LH and OH. The nutritional status was assessed using serum albumin (Alb) and rapid turnover protein concentrations. We investigated risk factors for postoperative malnutrition using univariate and multivariate analyses. The LH group, compared with the OH group, had a significantly shorter operative time (239 vs. 344 min, p<0.03), less intraoperative blood loss (100 vs. 343 g, p<0.01), and a shorter length of postoperative stay (8 vs. 11 days, p<0.01). Postoperative serum Alb and prealbumin concentrations in the LH group were significantly higher than those in the OH group (3.4 vs. 3.2 g/dl, p<0.01; 15.0 vs. 12.0 mg/dl, p=0.02, respectively). The multivariate analysis showed that OH (p=0.02) and hepatocellular carcinoma (p<0.01) were significant and independent risk factors for postoperative malnutrition. LH may be superior to OH in terms of the postoperative nutritional status, intraoperative blood loss, and length of postoperative stay.

Preoperative level of serum transthyretin as a novel biomarker predicting survival in resected pancreatic ductal adenocarcinoma with neoadjuvant therapy

BackgroundSystemic inflammation and altered metabolism are essential hallmarks of cancer. We hypothesized that the rapid turnover protein transthyretin (TTR) (half-life: 2–3 days), compared with the conventional marker albumin (21 days), better reflects the inflammatory/metabolic dynamics of pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and is a useful prognostic marker. MethodsSerum TTR and albumin levels were measured in 104 consecutive post-NAT PDAC patients before curative resection. The associations of preoperative TTR and albumin levels with overall survival (OS) after pancreatectomy were retrospectively analyzed. ResultsThe mean (SD) TTR and albumin levels were 21.6 (6.4) mg/dL (normal range: ≥22.0 mg/dL) and 3.9 (0.55) g/dL. A low (<22.0 mg/dL) post-NAT TTR level was associated with an advanced tumor stage and higher CEA and CRP levels. Patients with low TTR levels showed significantly worse OS compared with normal levels (3-year OS 39 % vs. 54 %, P = 0.037), although albumin levels did not. We modified prognostic biomarkers of systemic inflammation/metabolism, such as GPS, PNI, and CONUT scores, using the serum TTR instead of albumin level and successfully showed that modified scores were better associated with OS compared with original scores using serum albumin level. ConclusionsOur data suggest that the TTR level is a promising prognostic biomarker for PDAC patients after NAT.

Clinical Significance of Prealbumin Level Measurement Before Neoadjuvant Chemotherapy in Elderly Patients With Locally Advanced Esophageal Cancer.

Radical esophagectomy after preoperative neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, careful treatment selection is required when considering organ function in elderly patients. Prealbumin, a rapid turnover protein, is a short-term dynamic nutritional index, and its relationship with long-term postoperative survival in various cancers has been previously reported. However, the association between serum prealbumin level before NAC and survival in elderly patients remains unclear. This study investigated the clinical significance of prealbumin level measurement before NAC in elderly patients with locally advanced ESCC who underwent surgery after NAC. Eighty patients aged ≥65 years diagnosed with cStage II/III ESCC and undergoing radical esophagectomy after cisplatin and 5-fluorouracil therapy as NAC, were included. The cutoff value of the serum prealbumin level before NAC was set at 18.2 mg/dl using receiver operating characteristic curve analysis, and postoperative complications, recurrence, and overall survival were compared between the low and high prealbumin groups. There were no differences in patient background, clinicopathological characteristics, postoperative complications, or recurrence-free survival between the two groups. Overall survival (OS) was significantly worse in the low prealbumin group than in the high prealbumin group (5-year survival, 33.3% vs. 67.0%; p=0.0341). Furthermore, on univariate and multivariate analysis, low prealbumin level was an independent poor OS factor (p=0.036). In elderly patients with locally advanced ESCC, serum prealbumin level before NAC may be a useful prognostic factor and may be important in selecting a treatment strategy that considers individual organ function.

Strategies and tactics to perform safe pancreaticoduodenectomy for 94-year-old patient: report of a case

BackgroundDespite improvement of postoperative management, pancreatoduodenectomy still has a high rate of major complications. Therefore, careful assessment is critically important when we consider high risk surgery for extremely elderly patients.Case presentationA 94-year-old man, who suffered dark urine, epigastric pain, and loss of appetite, was diagnosed as bile duct cancer and underwent endoscopic retrograde biliary drainage. He has past history of hypertension and paroxysmal atrial fibrillation. Computed tomography (CT) showed a nodule in the lower bile duct, which was slowly enhanced by dynamic CT. The patient was evaluated whether he overcomes pancreatoduodenectomy by cardiac ultrasonography, brain magnetic resonance angiography, nutritional evaluation (rapid turnover proteins), and CT-based general assessment, including sarcopenia and osteopenia. The patient was independent in activities of daily living and has enough ejection fraction of 65%, and examinations revealed no impairment of cognitive function, sarcopenia, and osteopenia. With a diagnosis of bile duct cancer with no distant metastasis, the patient underwent subtotal stomach-preserving pancreatoduodenectomy with lymph node dissection. Operation time was 299 min and estimated blood loss was 100 ml. Pathological examination revealed papillary adenocarcinoma of the bile duct (pT3N1M0 Stage IIIB). Enteral nutrition was given through jejunostomy and then the patient started oral intake after an evaluation of swallowing function. Postoperative course was uneventful and all drains including pancreatic duct stent, biliary stent, and jejunostomy were removed by 3 weeks after operation. The levels of rapid turnover proteins dropped at postoperative day 7, but recovered at 1 month after operation via appropriate nutrition and rehabilitation. He remains well with no evidence of tumor recurrence as of 1 year after resection.ConclusionsWe herein report successfully treated cases of bile duct cancer in 94-year-old patient by pancreatoduodenectomy with careful evaluation of osteopenia, sarcopenia and nutrition.

Preoperative Pre-albumin Concentration as a Predictor of Short-term Outcomes in Elderly Patients With Colorectal Cancer.

Population aging results in increasing numbers of elderly persons undergoing surgery for colorectal cancer. We sought to identify objective preoperative indicators of outcomes, with a view toward development of safe, effective treatments for such patients. The study included 99 patients aged 80 years or more, who were treated surgically for stage I- III colorectal cancer. Preoperative nutritional status was compared retrospectively between those who suffered postoperative complications (n=40) and those who did not (n=59). Univariate analysis revealed low prealbumin (PreAlb) concentration (p=0.032) and low platelet-to-lymphocyte ratio (p=0.116) as risk factors for postoperative complications. Multivariate analysis showed preoperative PreAlb concentration to be an independent risk factor (OR=0.884; 95% confidence interval=0.791-0.989; p=0.024) associated with postoperative length of hospital stay (coef.=-0.336, p=0.002). PreAlb, a rapid turnover protein, shows promise as a simple predictor of postoperative complications in elderly patients treated for colorectal surgery.

Preoperative transferrin level is a novel indicator of short- and long-term outcomes after esophageal cancer surgery

This study aimed to examine whether preoperative serum transferrin, a rapid-turnover protein, correlates with short- and long-term outcomes after esophagectomy. Preoperative transferrin levels, calculated by summing serum iron and unsaturated iron-binding capacity, were evaluated in 224 patients who underwent esophagectomy for stage I-III esophageal cancer without preoperative treatment. Transferrin levels are directly proportional to total iron-binding capacity (TIBC), and we defined TIBC < 250μg/dL as low transferrin. We evaluated the relationship between preoperative transferrin levels and short- and long-term outcomes after esophagectomy using univariate and multivariate Cox proportional hazards analyses. Of all patients, 25 (11.2%) had low preoperative transferrin levels. Low preoperative transferrin levels were strongly correlated with worse preoperative performance status, advanced pathological T stage, and more open esophagectomy (p = 0.0078, 0.0001, and 0.013, respectively). Patients with low preoperative transferrin levels experienced significantly more frequent postoperative pneumonia in univariate and multivariate analysis [hazard ratio (HR) 3.30, 95% confidence interval (CI) 1.032-10.033, p = 0.0443]. Additionally, these patients were significantly correlated with worse overall survival (OS) in univariate and multivariate analyses (HR 2.75, 95% CI 1.018-7.426, p = 0.0460). Furthermore, we investigated the relationship between OS and postoperative pneumonia to elucidate why low preoperative transferrin, which is an independent risk factor for postoperative pneumonia, leads to poor prognosis. Patients with postoperative pneumonia were strongly associated with a shorter OS (p = 0.0099). Preoperative serum transferrin levels may be a novel indicator of postoperative pneumonia and OS after esophagectomy.

The Significance of the Rapid Turnover Protein Score as a Predictor of the Long-Term Outcomes in Hepatocellular Carcinoma After Hepatic Resection.

Nutritional status assessment is essential in cancer patients because a poor nutritional status has been associated with poor outcomes; however, the impact of rapid turnover proteins (RTPs), such as prealbumin, transferrin, and retinol-binding protein, on the outcomes of hepatocellular carcinoma (HCC) has not been well-investigated. We therefore examined the prognostic significance of RTPs in patients with HCC after curative resection. This study included 150 patients who underwent elective hepatic resection for HCC between January 2011 and December 2018. The prealbumin, transferrin, and retinol-binding protein levels were classified into two groups (high vs. low); the RTP score (0-3) was calculated as the sum of each RTP measurement (high=0; low=1). We retrospectively investigated the relationship between the RTP score and disease-free and overall survival. Multivariate analysis showed that a high RTP score (P=0.022), presence of sarcopenia (P=0.001), and stage III or higher (P=0.005) were independent predictors of disease-free survival, while a high RTP score (P<0.001), presence of sarcopenia (P=0.017), and stage III or higher (P=0.012) were independent predictors of overall survival. In patients with high RTP scores, positive hepatitis B and C viral infection, high indocyanine green (ICG) at 15 min (ICGR15), Child-Pugh grade B, poorly differentiated carcinoma, and postoperative ascites were more common than in patients with low RTP scores. The preoperative RTP score may be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection, suggesting an important role of RTP in the assessment of nutritional status in cancer patients.

ASO Visual Abstract: The Significance of the Rapid Turnover Protein Score as a Predictor of the Long-Term Outcomes in Hepatocellular Carcinoma After Hepatic Resection

ASO Visual Abstract: The Significance of the Rapid Turnover Protein Score as a Predictor of the Long-Term Outcomes in Hepatocellular Carcinoma After Hepatic Resection

ASO Author Reflections: Perspectives in the Measurement of Rapid Turnover Proteins in Patients with Hepatocellular Carcinoma.

ASO Author Reflections: Perspectives in the Measurement of Rapid Turnover Proteins in Patients with Hepatocellular Carcinoma.

Significance of serum branched-chain amino acid to tyrosine ratio measurement in athletes with high skeletal muscle mass

BackgroundFew nutritional markers reflect the hypermetabolic state of athletes with high levels of skeletal muscle. Although branched-chain amino acids (BCAA) play crucial roles in protein metabolism in skeletal muscle, the relationship between skeletal muscle mass and amino acid imbalances caused by the metabolism of BCAA and aromatic amino acids remains unclear. The aim of this study is to test the hypothesis that athletes with high levels of skeletal muscle mass have plasma amino acid imbalances, assessed by serum BCAA to tyrosine ratio (BTR) which can be measured conveniently.MethodsThe study enrolled 111 young Japanese men: 70 wrestling athletes and 41 controls. None of them were under any medications, extreme dietary restrictions or intense exercise regimens. Each participant’s body composition, serum concentrations of albumin and rapid turnover proteins including transthyretin and transferrin, BTR, and thyroid function were assessed.ResultsCompared to the controls, the athletes had significantly higher skeletal muscle index (SMI) (p < 0.001), and lower serum albumin concentration (p < 0.001) and BTR (p < 0.001). Kruskal–Wallis tests showed that serum albumin concentration and BTR were significantly lower in the participants with higher SMI. Serum albumin concentration and BTR were inversely correlated with SMI by multiple regression analysis (logarithmic albumin, β = − 0.358, p < 0.001; BTR, β = − 0.299, p = 0.001). SMI was inversely and transthyretin was positively correlated with serum albumin (SMI, β = − 0.554, p < 0.001; transthyretin, β = 0.379, p < 0.001). Serum concentration of free 3,5,3′-triiodothyronine (FT3) was inversely correlated with BTR, and, along with SMI and albumin, was independent predictor of BTR (SMI, β = − 0.321, p < 0.001; FT3, β = − 0.253, p = 0.001; logarithmic albumin, β = 0.261, p = 0.003). However, FT3 was not correlated with SMI or serum albumin. Serum concentrations of rapid turnover proteins were not correlated with BTR.ConclusionsIncreased skeletal muscle mass enhances the circulating amino acid imbalances, and is independently facilitated by thyroid hormones. Serum BTR may be a useful biomarker to assess the hypermetabolic state of wrestling athletes with high levels of skeletal muscle.

Plasma half-life and tissue distribution of leukocyte cell-derived chemotaxin 2 in mice

Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that causes skeletal muscle insulin resistance. The circulating levels of LECT2 are a possible biomarker that can predict weight cycling because they reflect liver fat and precede the onset of weight loss or gain. Herein, to clarify the dynamics of this rapid change in serum LECT2 levels, we investigated the in vivo kinetics of LECT2, including its plasma half-life and tissue distribution, by injecting 125I-labelled LECT2 into ICR mice and radioactivity tracing. The injected LECT2 was eliminated from the bloodstream within 10 min (approximate half-life, 5 min). In the kidneys, the radioactivity accumulated within 10 min after injection and declined thereafter. Conversely, the radioactivity in urine increased after 30 min of injection, indicating that LECT2 is mainly excreted by the kidneys into the urine. Finally, LECT2 accumulated in the skeletal muscle and liver until 30 min and 2 min after injection, respectively. LECT2 accumulation was not observed in the adipose tissue. These findings are in agreement with LECT2 action on the skeletal muscle. The present study indicates that LECT2 is a rapid-turnover protein, which renders the circulating level of LECT2 a useful rapid-response biomarker to predict body weight alterations.

MON-PO530: In Fasting, BMI, Activity of Daily Living and Immunity are not Deteriorated Even when Rapid Turnover Proteins Decrease, However, Thereafter, Deteriorated with a Reduction of Serum Albumin

MON-PO530: In Fasting, BMI, Activity of Daily Living and Immunity are not Deteriorated Even when Rapid Turnover Proteins Decrease, However, Thereafter, Deteriorated with a Reduction of Serum Albumin

Abstract TP481: Rapid Improvement of Malnutrition Following Treatment by Leucine- Enhanced Branched Chain Amino Acid in Severe Acute Stroke Patients Fed With Enteral Nutrition

Background and Issues: Malnutrition such as hypo-proteinemia or sarcopenia often occurs in severe acute stroke patients fed with enteral nutrition. However, it has not been established how to Improve the malnutrition. Leucine, one of essential branched chain amino acids (BCAA), has been shown to trigger muscle growth or stimulate muscle protein synthesis. Purpose: Leucine-enhanced BCAA (LE-BCAA) supplementations can stimulate protein synthesis and improve hypo-proteinemia in severe acute stroke patients. Methods: We included acute stroke patients 1) who were admitted from October 2016 to July 2018, 2) who received enteral nutrition due to severe stroke while their hospitalization 3) whose serum Pre-albumin (Pre-Alb) levels dropped below 20 mg/dl during hospitalization 4) who received LE-BCAA supplementation including leucine more than 1.2 g of leucine per 200 kcal. We measured Biochemical indices for nutrition assessment (Albumin (Alb), Pre-Alb, and Total Cholesterol (T-CHO)) just before and 3 days after starting LE-BCAA. Results: Fifty-six patients met our inclusive criteria and female gender was 35. Their average age was 85 years. Their average body mass index (BMI) on admission was 19.9 kg/m2. When LE-BCAA was started median on the 4 th day after admission, patients’ median Pre-Alb was 12.4 mg/dl, indication severe malnutrition. Then, patients started to tale more than 2.8 g per day of Leucine by LE-BCAA and 3 days later their median Pre-Alb increased up to 13.8 mg/dl, although median Alb level decreased from 2.9 to 2.6 g/dl and median T-CHO level decreased from 164 to 156 mg/dl just before and 3 days after LE-BCAA. Among 56 patients, 41 (73%) had decrease of serum albumin level, 32 (58%) had decrease of serum T-CHO level, whereas 37 (66%) experienced rapid increase of serum Pre-Alb level, this was probably because Pre-Alb was one of rapid turnover proteins. Conclusions: Leucine-enhanced BCAA supplementation can stimulate protein synthesis and achieve rapid improvement of hypoproteinemia in severe stroke patients fed with enteral nutrition.

PS02.170: EFFICACY OF PERIOPERATIVE IMMUNONUTRITION OF ESOPHAGECTOMY FOR ESOPHAGEAL CANCER

Abstract Background Malnutrition is frequent in esophageal cancer patients and aggravated by operation, increasing postoperative complications and mortality. Although a preoperative immunonutrition pharmaceutics diet significantly reduced the incidence of postoperative infectious complications, the effect of perioperative immunonutrition of esophagectomy for esophageal cancer still remains unclear. Methods This study design was a prospective randomized study. 40 patients with thoracic esophageal carcinoma who underwent esophagectomy were divided into two groups. Continiously 7 days before and after surgery, they enrolled and received either immunomodulating enteral nutrition (IMPACT® Group: IG) or standard enteral nutrition (Ensure® Group: EG). The nutrition statement, postoperative ICU stay, postoperative hospital stay, morbidity and mortality were investigated prospectively. Results There was no difference of patient demographics between two groups. Retinol-binding protein as rapid turnover protein was significantly higher on postoperative day (POD) -1, POD 7 and POD 14 in the IG than in the EG (P = 0.009, P = 0.004 and P = 0.024, respectively). The incidence of postoperative infectious complications and changes to therapeutic antibiotics was significantly lower in the IG than in the EG (P = 0.048 and P = 0.012, respectively). No difference was observed in postoperative ICU stay and postoperative hospital stay between two groups. The 5-year PFS in the IG and EG groups were 75% and 64% (P = 0.188), respectively, and OS were 68% and 55% (P = 0.187), respectively. Conclusion This study showed that immunonutrition would be effective to improve the early nutritional status and reduce postoperative infectious complications. Disclosure All authors have declared no conflicts of interest.

Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy.

Malnutrition is common in patients with esophageal cancer, resulting in increased postoperative complications and mortality. Although preoperative immunonutrition can significantly reduce the incidence of postoperative infectious complications, its effect in patietns with esophageal cancer undergoing esophagectomy remains unclear. The aim of this study was to investigate the effects of perioperative immunonutritional support on the postoperative course and long-term survival of this group of patients. This prospective, randomized study enrolled 40 patients with thoracic esophageal carcinoma undergoing esophagectomy. The patients were divided into two groups and received either immunomodulating enteral nutrition (IMPACT group; IG) or standard enteral nutrition (Ensure group; EG) continuously for 7 d before and 7 d after surgery. Nutritional status, such as rapid turnover protein, postoperative intensive care unit (ICU) length of stay (LOS), postoperative hospital LOS, morbidity, and mortality were investigated prospectively. There were no significant differences in patient demographic characteristics between the two groups. Levels of retinol-binding protein, as a rapid-turnover protein, were significantly higher on postoperative day (POD) -1, 7, and 14 in the IG compared with the EG group (P = 0.009, P = 0.004, and P = 0.024, respectively). The incidence of postoperative infectious complications and changes to therapeutic antibiotics were significantly lower in the IG group than in the EG group (P = 0.048 and P = 0.012, respectively). There was no significant difference in postoperative ICU or postoperative hospital LOS between the two groups. The 5-y progression-free survival rates in the IG and EG groups were 75% and 64%, respectively (P = 0.188), and the overall survival rates were 68% and 55%, respectively (P = 0.187). Perioperative immunonutrition may improve early postoperative nutritional status and reduce postoperative infectious complications in patients with esophageal cancer undergoing esophagectomy.

Clinical Impact of Neoadjuvant Therapy on Nutritional Status in Pancreatic Cancer.

The association between neoadjuvant therapy (NAT) and nutritional status in pancreatic cancer (PC) is unknown. The aim of this study was to assess the impact of NAT on nutritional status. Overall, 161 patients who underwent pancreatoduodenectomy for PC between August 2010 and March 2017 were enrolled and were divided into two groups: the neoadjuvant group (NAG; n = 67) and the control group (CG; n = 94). Based on relative dose intensity (RDI), patients in the NAG group were further divided into RDI ≥ 80% (n = 39) and RDI < 80% (n = 19). Changes in nutritional index, inflammatory index, and inflammation-based prognostic scores during NAT and the perioperative period were assessed. Retinol-binding protein, prealbumin, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutrition index significantly worsened in the NAG after NAT (p = 0.007, p = 0.03, p = 0.04, p = 0.007, and p = 0.004, respectively). The recovery of rapid turnover proteins after postoperative day 5 was significantly worse in the NAG compared with the CG (p < 0.05), but tended to be more prompt in the RDI ≥ 80% group among the NAG. There was no significant difference in the incidence of postoperative complications, length of hospital stay, and time to postoperative adjuvant therapy between the NAG and the CG. NAT for PC could aggravate nutritional status and hamper its postoperative recovery. Furthermore, malnutrition might decrease tolerance of NAT. These findings suggest the importance of nutritional support for patients with NAT in PC.

Clinical implication of nutrition for neoadjuvant therapy and impact of nutritional support in pancreatic cancer.

416 Background: Several studies have shown that nutritional support is important to reduce chemotherapy-related toxicities and improve tolerance to chemotherapy, but little is known about the nutritional influence of neoadjuvant therapy (NAT) for pancreatic cancer. The aim of this study was to assess the influence of NAT on nutritional status and the effectiveness of postoperative nutritional support in patients with NAT for pancreatic cancer. Methods: Between 2010 and 2017, 169 consecutive patients who underwent pancreatoduodenectomy of pancreatic cancer were enrolled, and divided into the neoadjuvant group (NAG, n = 70) and the control group (CG, n = 99). We assessed the change of nutritional index (body weight, albumin and rapid turnover proteins; retinol binding protein, prealbumin and transferrin), inflammatory index, and inflammation-based prognostic scores during NAT. Perioperative change of rapid turnover proteins at the point of pre-operation, postoperative day (POD) 5, POD12 and POD21, and perioperative and oncological outcomes between NAG and CG were evaluated. Finally, we divided NAG into nutrition group (n = 27) who received postoperative enteral immunonutrition from POD 1 to POD 21 and without nutrition group (n = 41), and compared perioperative change of rapid turnover proteins between two groups. Results: After NAT, the retinol binding protein, prealbumin, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio and prognostic nutrition index significantly got worse in NAG (P &lt; 0.05). The recovery of rapid turnover proteins after POD5 was significantly worse in NAG compared to CG (P &lt; 0.05). There was no significant difference in the incidence of postoperative complications and time to adjuvant therapy between two groups. The recovery of retinol binding protein and prealbumin after POD12 was significantly better in nutrition group compared to without nutrition group (P &lt; 0.05). Conclusions: NAT for pancreatic cancer could decrease nutritional status and its postoperative recovery. Postoperative enteral nutrition could be effective in patients with NAT for pancreatic cancer. Based on these results, we plan to perform the nutritional support at earlier stage of therapy.

Abstract 3679: VEGF-A is increased and correlates with MDSC-driven immune suppression, systemic inflammation, nutritional impairment and poor prognosis in patients with cancer

Abstract Vascular Endothelial Growth Factor (VEGF) is a key factor for tumor progression through induction of angiogenesis and other actions including immune alteration. Myeloid-derived suppressor cells (MDSC) are a major type of immune-suppressing cell that appear in cancer or inflammation and that have been reported to express the VEGF-receptor and to be activated by VEGF. To study the clinical importance of VEGF and MDSC for cancer, peripheral blood was collected from patients with gastrointestinal, ovarian, breast, thyroid and pulmonary cancers. Peripheral blood mononuclear cells (PBMC) were separated using a Ficoll-density gradient and were used for the detection of MDSC (CD11b+CD14-CD33+) using flow cytometry and for cytokine-production assays. For these assays, PBMC were stimulated with PHA and the production of cytokines including IL-12 (Th1 inducer), IL-10, (anti-inflammatory cytokine) and IL-17, (pro-inflammatory cytokine), were measured over 24 h using ELISAs. Serum concentrations of IL-10 and VEGF were also measured using ELISAs. The serum levels of both VEGF and MDSC were significantly increased in almost all types of cancer tested and significantly correlated with each other. Their levels also significantly correlated with neutrophil/lymphocyte ratios (NLR) (inflammation marker) and CRP levels, and were inversely correlated with the PHA-stimulation index (SI) (cell mediated immune responses marker) and serum concentrations of rapid-turnover protein (RTP) (nutrition marker). VEGF levels also correlated with serum concentrations of IL-10 and VEGF, and production of IL-17, and inversely correlated with production of IL-12. The prognosis of stage IV colorectal cancer with high VEGF was significantly worse than that with low VEGF. In thyroid cancer, the number of MDSC was significantly higher, NLR and CRP levels were higher, and RTP levels were lower in patients with undifferentiated carcinoma than in those with differentiated carcinoma including papillary and follicular carcinomas. Thus VEGF was increased in cancer and correlated with immune suppression driven by MDSC, inflammation and malnutrition. Although cancer immunotherapy is currently in use for a number of cancers, MDSC have been reported to be a major inhibitor of cancer immunotherapy even in cases in which an immune checkpoint inhibitor was used. An anti-VEGF treatment strategy has now been established in combination with chemotherapy for many types of cancer. Among various types of anti-MDSC trials, anti-VEGF treatment seems to be an effective adjuvant therapy of cancer immunotherapy. Citation Format: Masahiko Shibata, Kenji Gonda, Takahiro Nakajima, Koji Kono, Hiroyuki Suzuki, Seiichi Takenoshita. VEGF-A is increased and correlates with MDSC-driven immune suppression, systemic inflammation, nutritional impairment and poor prognosis in patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3679. doi:10.1158/1538-7445.AM2017-3679

Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer

Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and experimental mice with tumors by their suppression of T cell activation. MDSCs have also been reported to be associated with chronic inflammation. In advanced cancer, the T helper (Th) cell balance tends to shift from Th1 to Th2 predominance, and immune function, including cell-mediated immunity, is impaired by cytokines produced by Th2 cells. The present study examined the correlations between MDSC levels and inflammation, immune suppression, malnutrition, and poor prognosis in 155 patients with breast cancer. The levels of MDSCs in preoperative patients and in patients with recurrent breast cancer were significantly higher compared with postoperative patients, patients with recurrent breast cancer who received chemotherapy and healthy volunteers. The MDSC levels of preoperative patients were significantly positively correlated with interleukin (IL)-6 production by peripheral blood mononuclear cells (PBMCs), the neutrophil/lymphocyte ratio and C-reactive protein, and were negatively correlated with the production of interferon-γ and IL-12, serum concentration of rapid turnover protein, and the stimulation index. These patients were divided into two groups based on the levels of MDSCs. In preoperative patients with MDSC levels >1.0% of total PBMCs, the overall survival of patients with stage IV disease was significantly shorter compared with other disease stages, and was also significantly shorter compared with patients with MDSC levels <1.0% of total PBMCs. Thus, the MDSC levels of preoperative patients may function as a good prognostic indicator, particularly in patients with advanced breast cancer.

Deubiquitylation of hepatitis B virus X protein (HBx) by ubiquitin-specific peptidase 15 (USP15) increases HBx stability and its transactivation activity

Hepatitis B virus X protein (HBx) plays important roles in viral replication and the development of hepatocellular carcinoma. HBx is a rapid turnover protein and ubiquitin-proteasome pathway has been suggested to influence HBx stability as treatment with proteasome inhibitors increases the levels of HBx protein and causes accumulation of the polyubiquitinated forms of HBx. Deubiquitinases (DUBs) are known to act by removing ubiquitin moieties from proteins and thereby reverse their stability and/or activity. However, no information is available regarding the involvement of DUBs in regulation of ubiquitylation-dependent proteasomal degradation of HBx protein. This study identified the deubiquitylating enzyme USP15 as a critical regulator of HBx protein level. USP15 was found to directly interact with HBx via binding to the HBx region between amino acid residues 51 and 80. USP15 increased HBx protein levels in a dose-dependent manner and siRNA-mediated knockdown of endogenous USP15 reduced HBx protein levels. Increased HBx stability and steady-state level by USP15 were attributable to reduced HBx ubiquitination and proteasomal degradation. Importantly, the transcriptional transactivation function of HBx is enhanced by overexpression of USP15. These results suggest that USP15 plays an essential role in stabilizing HBx and subsequently affects the biological function of HBx.