Epidemiology of Physeal Fractures and Clinically Significant Growth Disturbances Affecting the Distal Tibia, Proximal Tibia, and Distal Femur: A Retrospective Cohort Study.

INTRODUCTION: Childhood fractures involving the physis potentially result in premature physeal closure that can lead to growth disturbances. Growth disturbances are challenging to treat with associated complications. Current literature focusing on physeal injuries to lower extremity long bones and risk factors for growth disturbance development is limited. The purpose of this study was to provide a review of growth disturbances among proximal tibial, distal tibial, and distal femoral physeal fractures. METHODS: Data were retrospectively collected from patients undergoing fracture treatment at a level I pediatric trauma center between 2008 and 2018. The study was limited to patients 0.5 to 18.9 years with a tibial or distal femoral physeal fracture, injury radiograph, and appropriate follow-up for determination of fracture healing. The cumulative incidence of clinically significant growth disturbance (CSGD) (a growth disturbance requiring subsequent physeal bar resection, osteotomy, and/or epiphysiodesis) was estimated, and descriptive statistics were used to summarize demographics and clinical characteristics among patients with and without CSGD. RESULTS: A total of 1,585 patients met the inclusion criteria. The incidence of CSGD was 5.0% (95% confidence interval, 3.8% to 6.6%). All cases of growth disturbance occurred within 2 years of initial injury. The risk of CSGD peaked at 10.2 years for males and 9.1 years for females. Complex fractures that required surgical treatment, distal femoral and proximal tibial fractures, age, and initial treatment at an outside hospital were significantly associated with an increased risk of a CSGD. DISCUSSION: All CSGDs occurred within 2 years of injury, indicating that these injuries should be followed for a period of at least 2 years. Patients with distal femoral or proximal tibial physeal fractures that undergo surgical treatment are at highest risk for developing a CSGD. LEVEL OF EVIDENCE: Level III Retrospective Cohort Study.

Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Correction to: Development of micro mechanical device having two-dimensional array of micro chambers for cell stretching.

The original article has been corrected. Instances of the character "µ" should be replaced by the term "micro".

Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

BACKGROUND: Hydrogen (H2) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I-R renal injury (composition of dual gas; N2: 77.8%; O2: 20.9%; H2: 1.30%; CO: 250 parts per million). METHODS: Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H2 gas alone inhalation (H2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. RESULTS: Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. CONCLUSIONS: Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury.

Development of micro mechanical device having two-dimensional array of micro chambers for cell stretching.

This paper presents a novel cell stretching micro device having two-dimensional array of micro chambers. It enables an in situ time-lapse observation of stretched cell by using an optical microscope with high measurement efficiency. The presented device consists of a cell culture dish and the array of micro chambers made of silicone elastomer and extension structures made of photocurable resin, and is fabricated with MEMS technology. The fabrication process of the thin micro chamber array combines photoresist mold and lift-off process based on conventional photolithography. The fabricated device has 134micro chambers in 5µm or less thickness. It was demonstrated that the fabricated micro device could be used to make in-situ time-lapse observation of cell responses to stretching under optical microscopy. In addition, the influence of the chamber thickness to the quality of the microscope image observed was evaluated. It is confirmed that the proposed device having two-dimensional array of the thin micro chambers makes it possible to observe cell response for stretch stimuli with high quality and efficiency.

Effects of duloxetine on pain and walking distance in neuropathic pain models via modulation of the spinal monoamine system.

BACKGROUND: Approximately 40% of patients with chronic low back pain have a neuropathic component. In this study, we assessed the effects of analgesics on tactile hypersensitivity and walking distance in the rat cauda equina compression (CEC) model of neuropathic low back pain. METHODS: The effects of analgesics on tactile hypersensitivity were examined using the von Frey test in CEC and partial sciatic nerve ligation (pSNL) models. Effects on walking distance were assessed using a treadmill test. Levels of α2δ1 subunit and ATF-3 mRNA in dorsal-root ganglion (DRG) neurons and those of α2δ1 subunit protein in the spinal cord were determined using quantitative RT-PCR and western blotting, respectively. Histological features were assessed using immunohistological methods. RESULTS: Histological changes indicating nerve damage (increase in ATF-3 mRNA, decrease in NF-200 and an increase in CD68 immunoreactivity) were observed in the CEC model. Duloxetine had analgesic effects in both models and improved walking distance in the CEC model. Pregabalin had analgesic effects in both models; however, the effect was weaker in the CEC model than in the pSNL model. α2δ1 subunit expression in DRG neurons and in the spinal cord was unchanged in the CEC model, but significantly increased in the pSNL model. Indomethacin had no analgesic effect in either model. Intrathecal yohimbine inhibited the effects of duloxetine with significant effects on depression. CONCLUSIONS: These findings suggest that the analgesic effects of duloxetine are mainly mediated by the spinal monoamine system, independent of the antidepressant effects of this agent. SIGNIFICANCE: The findings of this study suggest that duloxetine may be an effective treatment of broad neuropathic pain states, including neuropathic low back pain. The analgesic effects of duloxetine might be mediated by alterations of the descending pain modulatory pathways in the spinal cord, independent of the antidepressant effects.

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling.

Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.

A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

Survey of patient exposure from general radiography and mammography in Japan in 2014.

With the objective of reducing patient exposure to radiation, we conducted a questionnaire survey regarding radiographic conditions in 2014. Here we report estimates of dose exposure in general radiography and mammography through an investigation and comparison of present patient exposure conditions. Questionnaires were sent to 3000 facilities nationwide in Japan. Surveys asked questions on a total of 16 items related to general radiography, including the chest, abdomen, and breast. Output data from x-ray tubes measured in the Chubu area of Japan were used as the mean in these estimates. The index of patient exposure was adopted as the entrance skin dose (ESD) for general radiography and as the mean glandular dose (MGD) for mammography. The response rate for this survey was 21.9%. Our results showed that doses received through the use of flat-panel detector (FPD) devices were lower than those received through computed radiography devices, except for the ankle joint (e.g. in chest examination, the dose from FPD and CR was 0.24 mGy, 0.31 mGy on the average, respectively). These results suggest that more widespread use of FPD devices could lead to decreases in the ESD and MGD, thereby reducing patient exposure.

Survey of volume CT dose index in Japan in 2014.

OBJECTIVE: The aims of this study are to propose a new set of Japanese diagnostic reference levels (DRLs) for 2014 and to study the impact of tube voltage and the type of reconstruction algorithm on patient doses. The volume CT dose index (CTDI(vol)) for adult and paediatric patients is assessed and compared with the results of a 2011 national survey and data from other countries. METHODS: Scanning procedures for the head (non-helical and helical), chest and upper abdomen were examined for adults and 5-year-old children. A questionnaire concerning the following items was sent to 3000 facilities: tube voltage, use of reconstruction algorithms and displayed CTDI(vol). RESULTS: The mean CTDI(vol) values for paediatric examinations using voltages ranging from 80 to 100 kV were significantly lower than those for paediatric examinations using 120 kV. For adult examinations, the use of iterative reconstruction algorithms significantly reduced the mean CTDI(vol) values compared with the use of filtered back projection. Paediatric chest and abdominal scans showed slightly higher mean CTDI(vol) values in 2014 than in 2011. The proposed DRLs for adult head and abdominal scans were higher than those reported in other countries. CONCLUSION: The results imply that further optimization of CT examination protocols is required for adult head and abdominal scans as well as paediatric chest and abdominal scans. ADVANCES IN KNOWLEDGE: Low-tube-voltage CT may be useful for reducing radiation doses in paediatric patients. The mean CTDI(vol) values for paediatric scans showed little difference that could be attributed to the choice of reconstruction algorithm.

Development of a cell culture surface conversion technique using alginate thin film for evaluating effect upon cellular differentiation.

Here, we sought to develop a cell culture surface conversion technique that would not damage living cells. An alginate thin film, formed on a glass plate by spin coating of sodium alginate solution and dipping into calcium chloride solution, was used to inhibit adhesion of cells. The film could be removed by ethylenediaminetetraacetate (EDTA) at any time during cell culture, permitting observation of cellular responses to conversion of the culture surface in real time. Additionally, we demonstrated the validity of the alginate thin film coating method and the performance of the film. The thickness of the alginate thin film was controlled by varying the rotation speed during spin coating. Moreover, the alginate thin film completely inhibited the adhesion of cultured cells to the culture surface, irrespective of the thickness of the film. When the alginate thin film was removed from the culture surface by EDTA, the cultured cells adhered to the culture surface, and their morphology changed. Finally, we achieved effective differentiation of C2C12 myoblasts into myotube cells by cell culture on the convertible culture surface, demonstrating the utility of our novel technique.

Results of a 2011 national questionnaire for investigation of mean glandular dose from mammography in Japan.

Diagnostic reference levels (DRLs) for mammography have yet to be created in Japan. A national questionnaire investigation into radiographic conditions in Japan was carried out for the purpose of creating DRLs. Items investigated included the following: tube voltage; tube current; current-time product; source-image distance; craniocaudal view; automatic exposure control (AEC) settings; name of mammography unit; image receptor system (computed radiography (CR), flat panel detector (FPD), or film/screen (F/S)); and supported or unsupported monitor diagnosis (including monitor resolution). Estimation of the mean glandular dose (MGD) for mammography was performed and compared with previous investigations. The MGD was 1.58(0.48) mGy, which did not significantly differ from a 2007 investigation. In relation to image receptors, although no difference in average MGD values was observed between CR and FPD systems, F/S systems had a significantly decreased value compared to both CR and FPDs. Concerning digital systems (FPDs), the MGD value of the direct conversion system was significantly higher than the indirect conversion system. No significant difference in MGD value was evident concerning type of monitor diagnosis for either the CR or the FPD digital systems; however, hard copies were used more often in CR. No significant difference in the MGD value was found in relation to monitor resolution. This report suggests ways to lower the doses patients undergoing mammography receive in Japan, and serves as reference data for 4.2 cm compressed breast tissue of 50% composition DRLs. Furthermore, our findings suggest that further optimisation of FPD settings can promote a reduction in the MGD value.

Recipientes e substratos na produção de mudas e no cultivo hidropônico de tomilho (Thymus vulgaris L. ) / Containers and substrates on seedling production and hydroponic cultivation of thyme (Thymus vulgaris L. )

Bandejas com diferente número de células (128, 200 e 288) e dois substratos (fibra de casca de coco e casca de pinus) foram avaliados para a produção de mudas de tomilho e sobre o desempenho das plantas em sistema hidropônico. Para ambos os experimentos, o delineamento foi em blocos ao acaso. As mudas provenientes de estaquia foram avaliadas aos 30 dias quanto ao comprimento e massa seca de raízes. Aos 40 dias após o transplante das mudas, as plantas cultivadas em sistema hidropônico foram avaliadas quanto à massa fresca da parte aérea, massa seca da parte aérea e massa seca das raízes. A maior massa seca de raízes foi obtida para as mudas cultivadas em substrato à base de casca de fibra de coco. As mudas com maior comprimento de raízes foram obtidas nas bandejas com 128 e 200 células. As plantas de tomilho provenientes de mudas produzidas em bandejas de 128 células apresentaram maior massa fresca da parte aérea, massa seca da parte aérea e massa seca das raízes.

Trays with different number of cells (128, 200 and 288) and two substrates (coir and pine bark-based) were studied for thyme seedling production and plant development in hydroponic system. In both experiments, experimental design was in randomized blocks. Seedlings from cuttings were evaluated at 30 days as to root length and dry matter. At 40 days after transplanting, plants grown in hydroponic system were evaluated for shoot fresh matter, shoot dry matter and root dry matter. The highest root dry matter was detected in seedlings grown in coir-based substrate. Seedlings that presented the greatest root length were obtained by using trays with 128 and 200 cells. Thyme plants from seedlings produced in trays with 128 cells had higher shoot fresh matter, shoot dry matter and root dry matter.

Comparison of sensitivity of lung nodule detection between radiologists and technologists on low-dose CT lung cancer screening images.

OBJECTIVES: The objective of this study was to compare the sensitivity of detection of lung nodules on low-dose screening CT images between radiologists and technologists. METHODS: 11 radiologists and 10 technologists read the low-dose screening CT images of 78 subjects. On images with a slice thickness of 5 mm, there were 60 lung nodules that were ≥5 mm in diameter: 26 nodules with pure ground-glass opacity (GGO), 7 nodules with mixed ground-glass opacity (GGO with a solid component) and 27 solid nodules. On images with a slice thickness of 2 mm, 69 lung nodules were ≥5 mm in diameter: 35 pure GGOs, 7 mixed GGOs and 27 solid nodules. The 21 observers read screening CT images of 5-mm slice thickness at first; then, 6 months later, they read screening CT images of 2-mm slice thickness from the 78 subjects. RESULTS: The differences in the mean sensitivities of detection of the pure GGOs, mixed GGOs and solid nodules between radiologists and technologists were not statistically significant, except for the case of solid nodules; the p-values of the differences for pure GGOs, mixed GGOs and solid nodules on the CT images with 5-mm slice thickness were 0.095, 0.461 and 0.005, respectively, and the corresponding p-values on CT images of 2-mm slice thickness were 0.971, 0.722 and 0.0037, respectively. CONCLUSION: Well-trained technologists may contribute to the detection of pure and mixed GGOs ≥5 mm in diameter on low-dose screening CT images.

Development of a micro cell compression stimulator for evaluating real-time cellular responses.

This paper presents a micro cell compression stimulator for evaluating real-time cellular responses to compression stimuli. The device was produced by a micro three-dimensional structure fabrication process using multiple exposures to the photoresist. The device consists of a pressure inlet port, cell inlet ports, a gasket, microchannels, cell culture chambers, and a diaphragm on the culture chamber for applying compressive pressure to cells. Compression stimuli applied to the cells can be controlled by regulating the expansion of the diaphragm via a pressure control. The device permits the observation of cellular responses to compressive pressure in real time because it is made of transparent materials and stimulates the cells without deforming the cell culture surface, when observed by optical microscopy. We demonstrated the validity of the fabrication process, evaluated the performance of the fabricated device, and compared the experimental results with the FEM structural analysis results. We found through operational testing that the diaphragm was deformed quickly by applying negative/positive pressure and that the diaphragm displacement became larger with increasing applied pressure. These results indicate that this device can be used to control the intensity and the cell stimulus profile by regulating the applied pressure. In all cases, the cellular deformation during compression stimulus was successfully observed in real time using an optical microscope. The device is expected to facilitate the control of stem cell differentiation and the clarification of cellular mechanoreceptor mechanisms and signal transduction pathways.

Feasibility of delta-shaped anastomoses in totally laparoscopic distal gastrectomy.

BACKGROUND: Delta-shaped (DS) anastomosis is a new reconstruction method for totally laparoscopic distal gastrectomy (TLDG) using a linear stapler. We evaluated the feasibility of using this method for TLDG. METHODS: A retrospective analysis was performed in 114 patients who underwent TLDG with DS anastomosis. Twenty-four patients reconstructed with a Roux-en-Y (RY) anastomosis during the same period were analyzed as control subjects. RESULTS: The patient characteristics of DS and RY anastomoses were slightly different in terms of tumor location and extent of lymph node dissection, since this was not a prospective comparative study. Blood loss, postoperative complication rate and postoperative hospital stay were not different between the two groups. There was only 1 case of anastomotic leakage, and no case of anastomotic stricture after DS anastomosis. The length of the operation using DS anastomosis was significantly shorter than for RY anastomosis. The rates of body weight loss were not significantly different at 1 year after the operation. CONCLUSIONS: Although this was a small retrospective analysis, DS anastomosis was feasible, required a shorter operation time, and had no associated complications. This method can therefore be recommended as a standard procedure for TLDG.

Calculation of personal dose equivalent for positron-emitting radionuclides using Monte Carlo code EGS5.

The conversion coefficients, H'(d,α)/Φ, for monoenergetic positrons and positron-emitting radionuclides were calculated by using the user code UCICRPM of the Monte Carlo code EGS5 to estimate the radiation dose for medical staff involved in positron emission tomography examinations. From these coefficients, the dose equivalent rates per unit activity at 0.07 and 10 mm depths in a soft tissue for a straight-line source of 2-deoxy-2-[(18)F]fluoro-d-glucose ((18)F-FDG) were calculated by using the developed user code UCF18DOSE. The dose equivalent rates per unit activity at 0.07 and 10 mm depths were measured by using a personal dosemeter (DOSE(3)) under the same conditions as those considered in the calculation. The calculated dose equivalent rates per unit activity at 0.07 and 10 mm depths were 0.116 and 0.0352 pSv min(-1) Bq(-1), respectively, at 20 cm from the (18)F-FDG injection tube.

Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.

Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.