Influence of Sorafenib on Host Immunity in Patients with Liver Cirrhosis With Advanced Hepatocellular Carcinoma Stratified by Etiology.

AIM: We previously reported that sorafenib induces Th1 [interferon-γ (IFNγ)-positive interleukin 4 (IL4)-negative] dominance which prevents tumor cells from escaping the host immune system in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC). However, in that study we did not assess the influence of sorafenib on host immunity according to the etiology of LC. Therefore, this study was retrospectively performed to evaluate the impact of sorafenib therapy for aHCC on host immunity in patients stratified according to the etiology of LC: Patients and Methods: A total of 116 adult Japanese patients with LC and aHCC received sorafenib therapy at our hospital. Blood samples were collected before and after treatment for 4 weeks. RESULTS: Twenty-two patients had hepatitis B virus (HBV)-related LC, 62 patients had hepatitis C virus (HCV)-related LC, 22 patients had alcoholic LC, and 10 patients had LC without these causative factors. In patients receiving sorafenib at a dose of 400 mg/day, patients in Child-Pugh class A, and patients with stage IVA aHCC, Th2 (IFNγ-negative/IL4-positive) cells decreased significantly after treatment, although there was no significant impact on the tumor response. In addition, Th2 cells decreased significantly in patients with HCV-related LC after treatment, while there were no significant changes in the other groups. CONCLUSION: Sorafenib might prevent tumor cells from escaping the host immune system in patients with aHCC and HCV-related LC, although it does not seem to do so in those with LC of other etiologies.

Topography Influences Adherent Cell Regulation of Osteoclastogenesis.

The importance of osteoclast-mediated bone resorption in the process of osseointegration has not been widely considered. In this study, cell culture was used to investigate the hypothesis that the function of implant-adherent bone marrow stromal cells (BMSCs) in osteoclastogenesis is influenced by surface topography. BMSCs isolated from femur and tibia of Sprague-Dawley rats were seeded onto 3 types of titanium surfaces (smooth, micro, and nano) and a control surface (tissue culture plastic) with or without osteogenic supplements. After 3 to 14 d, conditioned medium (CM) was collected. Subsequently, rat bone marrow-derived macrophages (BMMs) were cultured in media supplemented with soluble receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) as well as BMSC CM from each of the 4 surfaces. Gene expression levels of soluble RANKL, osteoprotegerin, tumor necrosis factor α, and M-CSF in cultured BMSCs at different time points were measured by real-time polymerase chain reaction. The number of differentiated osteoclastic cells was determined after tartrate-resistant acid phosphatase staining. Analysis of variance and t test were used for statistical analysis. The expression of prominent osteoclast-promoting factors tumor necrosis factor α and M-CSF was increased by BMSCs cultured on both micro- and nanoscale titanium topographies (P < 0.01). BMSC CM contained a heat-labile factor that increased BMMs osteoclastogenesis. CM from both micro- and nanoscale surface-adherent BMSCs increased the osteoclast number (P < 0.01). Difference in surface topography altered BMSC phenotype and influenced BMM osteoclastogenesis. Local signaling by implant-adherent cells at the implant-bone interface may indirectly control osteoclastogenesis and bone accrual around endosseous implants.

VEGF in patients with advanced hepatocellular carcinoma receiving intra-arterial chemotherapy.

AIM: Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis and over-expression of VEGF has been detected in hepatocellular carcinoma (HCC). The aim of the present study was to clarify the usefulness of VEGF for monitoring the response to intra-arterial chemotherapy in patients with HCC. PATIENTS AND METHODS: Seventy-three patients with liver cirrhosis (LC) and advanced HCC (aHCC) received hepatic arterial infusion chemotherapy (HAIC: leucovorin (LV) at 12 mg/h, cisplatin (CDDP) at 10 mg/h and 5-fluorouracil (5-FU) at 250 mg/22 h) via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneous drug delivery system. RESULTS: i) Serum VEGF levels were higher in patients with progressive disease than those in patients with a partial response or stable disease. ii) VEGF levels were higher in patients with alcoholic LC than those in patients with hepatitis C-related or hepatitis B-related LC. iii) VEGF levels were higher in stage IVB patients than those in patients with stage III or IVA disease. iv) VEGF levels were significantly higher in patients with giant or confluent multinodular tumors than those in patients with multiple discrete nodules. v) Serum VEGF levels were higher in patients with vascular invasion than in patients without vascular invasion. CONCLUSION: Monitoring the serum VEGF level is useful for predicting the response of aHCC to HAIC, as well as for predicting metastasis, tumor type and vascular invasion.

Sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) and portal vein tumor thrombus (PVTT) still have a very poor prognosis, even though the oral multikinase inhibitor sorafenib has revolutionized treatment of aHCC in patients with liver cirrhosis (LC). Standardization of multimodal therapy for aHCC with PVTT has not yet been achieved. AIM: This retrospective study was performed to clarify the usefulness of combined treatment with sorafenib and hepatic arterial infusion chemotherapy (HAIC) for patients with LC, aHCC and PVTT. PATIENTS AND METHODS: Twenty adult Japanese patients with LC underwent HAIC (HAIC group) between 2002 and 2009, while 18 patients received HAIC after treatment with sorafenib between 2009 and 2014 (SF-HAIC group). RESULTS: Among patients with Child-Pugh class A disease, the median survival time of the SF-HAIC group (315 days) was significantly longer than that of the HAIC group (197 days), while there was no significant difference between the two groups (234 and 228 days) among patients with Child-Pugh class B disease. HAIC led to a partial response (PR) in 16.7% of patients with class A disease and 21.4% of patients with class B disease. With SF-HAIC, PR was obtained in 63.8% and 42.9% of patients respectively, although the PR rate was only 9.1% and 0.0%, respectively, after treatment with sorafenib alone for four weeks. CONCLUSION: When multimodal therapy is employed for patients with LC in Child-Pugh class A disease with aHCC and PVTT, performing HAIC after four weeks of sorafenib treatment might improve both the tumor response and patient survival.

Diagnostic laparoscopy identifies a peritoneal adenomatoid-like mesothelioma masquerading as ovarian cancer: a case report.

The authors report a rare case of peritoneal adenomatoid mesothelioma in a woman with no history of asbestos exposure. A 61-year-old woman was originally suspected of having a bilateral ovarian tumor based on chest radiography and magnetic resonance imaging (MRI). Upon referral to our hospital, the presence of two solid masses was confirmed by enhanced MRI and 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG-PET/CT). Physical examination was normal, as were serum concentrations of the tumor markers CA 19-9, CA 125, and CEA. Laparoscopic surgery showed a right ovarian tumor and laparoscopic right salpingo-oophorectomy and adhesiotomy were performed. Two months later, the patient underwent laparoscopic segmental resection of the sigmoid colon, with histological analysis identifying an adenomatoid-like tumor. The final diagnosis was peritoneal adenomatoid-like mesothelioma with invasion of the right ovary. This case report demonstrates that imaging techniques must be coupled with laparoscopic surgery for an accurate diagnosis of peritoneal mesothelioma.

Two receptors are involved in the central functions of kynurenic acid under an acute stress in neonatal chicks.

Intracerebroventricular (i.c.v.) injection of kynurenic acid (KYNA) had sedative and hypnotic effects during stress in neonatal chicks. However, its mechanism has not been clarified. KYNA is an endogenous antagonist of the α7 nicotinic acetylcholine (α7nACh) receptor and N-methyl-d-aspartate (NMDA) receptor. Therefore, this study clarified the mechanism of sedative and hypnotic effects of KYNA in the brain during an acute stress. In Experiment 1, to investigate the relationship between KYNA and the α7nACh receptor, KYNA was injected i.c.v. with galantamine, an agonist of the allosteric potentiating site of the α7nACh receptor. Galantamine did not attenuate the effect of KYNA, but higher levels of galantamine caused harmful effects. In Experiment 2, the role of the NMDA receptor was investigated using the NMDA receptor antagonist (+)-MK-801, d-serine which has high affinity to a co-agonist glycine site at the NMDA receptors, NMDA as the NMDA receptor agonist, and 2,3-pyridinedicarboxylic acid (QUIN), an agonist of the NMDA receptor subgroup containing the subunits NR2A and NR2B. The behavioral changes following KYNA were partially attenuated by QUIN alone. In conclusion, we suggest that KYNA functioned via the simultaneous inhibition of the α7nACh receptor and NMDA receptor subgroup containing the subunits NR2A and NR2B.

ß-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation.

The Wnt/ß-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated ß-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/ß-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of ß-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that ß-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that ß-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that ß-catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of ß-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia.

Intracerebroventricular injection of kynurenic acid attenuates corticotrophin-releasing hormone-augmented stress responses in neonatal chicks.

In the brain of neonatal chicks, tryptophan has a sedative effect, and a part of this effect might be dependent upon its metabolite, serotonin. However, the functional mechanisms have not been fully clarified, since l-tryptophan produces kynurenic acid (KYNA) through the kynurenine pathway. The present study aimed to clarify the effect of KYNA on the stress response upon social isolation. Intracerebroventricular injection of KYNA induced a strong sedative effect under stress compared with the effect of l-tryptophan, with or without intracerebroventricular injection of corticotrophin-releasing hormone (CRH). KYNA dose-dependently induced sedative and hypnotic effects under CRH-augmented social isolation stress. Taken together, these results indicate that KYNA is a likely candidate for the sedative and hypnotic effects of tryptophan under acutely stressful conditions.

Simvastatin enhances bone formation around titanium implants in rat tibiae.

Statins are cholesterol-lowering drugs that have been reported to promote bone formation. The purpose of this study was to investigate the effect of simvastatin on the enhancement of bone formation around titanium implants. Thirty-week-old female rats received pure titanium implants in both tibiae. The animals were intra-peritoneally administered 0, 0.125, 1, 5 or 10 mg kg(-1) of simvastatin daily. After 30 days, the animals were sacrificed, and specimens were prepared. The bone contact ratio of the implant, bone density in the medullary canal and percentage of cortical bone were obtained. Markers for bone turnover were also measured using sera collected at the time of euthanasia. In the medullary canal, a scanty amount of bone was observed in the 0, 0.125 and 1 mg kg(-1) groups. In contrast, in both the 5 and 10 mg kg(-1) groups, thicker bone trabeculae were abundant. Histometric observations showed that the bone contact ratio and the bone density of both groups were significantly greater than those of the other groups (anova, P < 0.01). However, no significant difference in the percentage of cortical bone was found between groups. Serum chemistry showed that statin increased bone formation markers and decreased bone resorption markers. In conclusion, although the dose equivalent to that used in human patients with hypercholesterolemia was not effective, a simvastatin dose of 5 mg kg(-1) or higher increased medullary bone formation around the titanium. In contrast, no effect of simvastatin on pre-existing cortical bone was indicated.

Platelet-rich plasma suppresses osteoclastogenesis by promoting the secretion of osteoprotegerin.

BACKGROUND AND OBJECTIVE: Platelet-rich plasma is characterized by containing fundamental protein growth factors. Although many in vitro studies have documented the capability of platelet-rich plasma to induce the growth of osteoblasts or osteoblast-like cells, the effect of platelet-rich plasma on osteoclastogenesis has not yet been studied. The aim of the present study was to evaluate the effects of platelet-rich plasma and platelet-poor plasma on osteoclastogenesis with rat bone marrow cell culture. MATERIAL AND METHODS: Platelet-rich plasma and platelet-poor plasma were produced from the whole blood of rat. For cell culture, rat bone marrow cells were isolated from rat tibiae and then treated with 1,25alpha dihydroxy vitamin D(3) and with different concentrations of platelet-rich plasma or platelet-poor plasma. After 4 d of culture, rat bone marrow cells were stained with tartrate-resistant acid phosphatase (TRAP), and TRAP-positive cells that had more than three nuclei (TRAP-positive multinucleated cells) were counted as osteoclast-like cells. Osteoprotegerin, known as an osteoclastogenesis-related factor, cells was quantified using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Although platelet-poor plasma had no effect on the formation of TRAP-positive multinucleated cells, platelet-rich plasma decreased the number of TRAP-positive multinucleated cells in a dose-dependent manner. The amount of osteoprotegerin produced from rat bone marrow cells and from MC3T3-E1 cells was enhanced in platelet-rich plasma-treated groups. CONCLUSION: Under our experimental conditions, platelet-rich plasma decreased the formation of TRAP-positive multinucleated cells and increased the secretion of osteoprotegerin. This study suggests that platelet-rich plasma suppresses osteoclastogenesis, therefore inhibiting bone resorption. In addition we also demonstrated that platelet-rich plasma increased the secretion of osteoprotegerin, an inhibitor for osteoclast formation, thus suggesting that the enhancement of osteoprotegerin secretion induces this inhibitory effect.

Pramipexole safely replaces ergot dopamine agonists with either rapid or slow switching.

This prospective, open-label, multicentre study examined the efficacy and safety of rapidly (overnight) or slowly (after 2 weeks of concomitant usage) switching patients with Parkinson's disease (PD) from conventional ergot dopamine agonists (DAs) to the non-ergot DA, pramipexole. Fifty-nine early-to-advanced PD patients with motor symptoms that were inadequately controlled by ergot DAs were enrolled. Patients were switched from ergot derivatives to pramipexole and evaluated every 2 weeks for 12 weeks by Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale (UPDRS) and a modified Epworth Sleepiness Scale (mESS). The UPDRS III subscores and total UPDRS scores significantly improved, independent of switching method. Adverse events, all of which were mild, occurred in 29.2% of patients. No sudden onset of excessive daytime sleepiness or significant worsening in mESS was seen. Switching patients with PD from ergot DA to pramipexole, using either a slow or rapid switching method, appeared to be well tolerated and effective, although further dose adjustment may be necessary in some patients after the switch.

Occlusal and TMJ loads in subjects with experimentally shortened dental arches.

To determine whether shortened dental arches (SDAs) cause functional overloading of the teeth and the temporomandibular joints, which has been implicated in periodontal diseases and temporomandibular disorders, we investigated the influences of SDA on occlusal and joint loads. Bite force and masticatory muscle electromyograms were recorded in five dentate subjects who clenched maximally on intra-oral appliances, creating symmetrical SDAs experimentally. Muscular forces estimated from the recorded electromyograms were fed into a finite element jaw model for calculating bite forces and joint loads. Comparison between the measured and the calculated bite forces ensured that the joint loads were representative. The bite force on each tooth increased with missing molar occlusions, while joint loads decreased. The bite force per root surface area was always greatest on the most posterior tooth, and these values were most constant. The findings provide no evidence that SDA causes overloading of the joints and the teeth, which suggests that neuromuscular regulatory systems are controlling maximum clenching strength under various occlusal conditions.

[Successful management of a patient who developed intra-operative pulmonary tumor embolism].

A 68-year-old female with retroperitoneal tumor extending into the inferior vena cava (IVC) developed massive pulmonary tumor embolism during removal of the tumor. Because of her unstable hemodynamics, emergency pulmonary embolectomy under cardiopulmonary bypass was performed. Successful management of her intra- and post-operative persistent right heart failure led to a satisfactory postoperative course without serious neurological complications. In peri-operative management of a patient with an extended tumor into IVC, prevention of the embolism, detection of the pulmonary embolism and treatment of intra- and post-operative right heart failure are important.

Orthotopic intestinal transplantation using the cuff method in rats: a histopathological evaluation of the anastomosis.

Segmental small intestine transplantation (SIT) in rats, using a cuff technique, has achieved a high success rate. However, there have been few reports on the influence of the foreign body reaction to polyethylene cuff on vessel anastomoses and graft after SIT. This study involves the histopathological examination of the site of cuff anastomosis and grafts in the short- and long-term survival of segmental SIT. The data obtained from the suture anastomosis model also served as a control. One week after heterotopic segmental SIT using the cuff technique, orthotopic continuations were carried out in syngeneic combination. Twenty-five of 30 rats surviving >200 days (83.3%) were examined for vessel anastomosis. All arterial anastomoses were patent, but the portovenous anastomoses in 10 grafts (33%) were totally occluded and were associated with the formation of collateral vessels. Histopathological examination demonstrated good patency of the artery and vein anastomotic site in the short term, but granulation, fibrosis, and neovascularization at the anastomosis site surrounding the cuffs in the long-surviving group. However, the grafts appeared to be intact, with normal features of the villi. On the contrary, the site of the sutured anastomosis in the long-survival rats showed no inflammatory reaction. Although a polyethylene cuff caused foreign body reaction, the graft blood supplies were maintained by collateral vessels. Considering the low mortality and high success rate, polyethylene cuff is good for short-term study and an alternative method for long-term SIT experiments.

[Notes about two paintings in the Francis A. Countway Library of Medicine].

Two interesting mural-sized oil paintings hang in the Francis A. Countway Library of Medicine in Boston. One is "The First Operation Under Ether" painted by Robert C. Hinckley in the nineteenth century, and the other is "The First Successful Kidney Transplantation" painted by Joel Babb in 1996. The theme of the former is the first operation with ether performed publicly on October 16, 1846, at the Massachusetts General Hospital. That of the latter is the first successful renal transplantation between identical twins performed at the Peter Bent Brigham Hospital on December 23, 1954. "The First Operation Under Ether" was recreated by the painter, Robert Hinckley, who gathered information by himself about the event, which had occurred over three decades previously in his hometown. He seemed to have exercised some degree of artistic license in recreating the scene. On the other hand, "The First Successful Kidney Transplantation" was planned by the three doctors who were themselves involved in the memorable operation. The painter, Joel Babb, began to recreate the scene after he had been handed some sketches and photos of the event and several photos of the participants. In this case, it seems that authenticity was the main consideration.

Identification of a silent pituitary somatotropic adenoma based on a paradoxic response of growth hormone on a thyrotropin-releasing hormone or gonadotropin-releasing hormone provocation test.

Preoperative endocrinologic identification and surgical removal of a silent somatotropic adenoma among patients with either amenorrhea or galactorrhea, or both, are beneficial for the restoration of menstruation and ovulation. Paradoxic rises of serum growth hormone in either a thyrotropin-releasing hormone or a gonadotropin-releasing hormone provocation test and high serum growth hormone levels were noted in the 3 patients with a silent somatotropic adenoma.

[Pulmonary embolism during laparoscopic cholecystectomy detected by sudden decrease in end-tidal carbon dioxide pressure].

We report a case of intraoperative pulmonary embolism, detected by a sudden decrease in end-tidal carbon dioxide pressure (PETCO2). The patient was a 56-year-old female without any history of pulmonary disease. The patient was intubated and ventilated manually during the operation under anesthesia with sevoflurane, nitrous oxide, and vecuronium. The percutaneous oxygen saturation (SpO2) and PETCO2 were monitored continuously. Twenty minutes after starting the laparoscopic procedure, PETCO2 decreased suddenly from values between 34 and 38 mmHg to 24 mmHg, and SpO2 decreased from 99% to 95%. Nitrous oxide was discontinued. Removal of the drape revealed profound subcutaneous emphysema. Postoperative pulmonary scanning revealed areas with reduced pulmonary perfusion (Fig. 2). An intravenous bolus of heparin (3000 IU) was given immediately, followed by 10,000 IU heparin over the next 24 hours. The patient was discharged on the fifteenth postoperative day without any sequelae. Although monitoring pulmonary arterial pressure is generally considered a more reliable method for the early detection of pulmonary embolism, an invasive monitoring procedure, such as the insertion of a Swan-Ganz catheter, is usually not indicated in laparoscopic surgery. For the early detection of pulmonary embolism, we therefore recommend the continuous monitoring of PETCO2 during laparoscopic surgery.

Treatment of steroid-resistant idiopathic thrombocytopenic purpura in pregnancy with repeated high-dose intravenous immunoglobulin.

High-dose intravenous immunoglobulin (HD-IVIG) has temporary but reliable efficacy in idiopathic thrombocytopenic purpura (ITP). HD-IVIG has been described as the representative management in pregnant cases of refractory to corticosteroid or immunosuppressants. There have been few cases treated with repeated HD-IVIG to sustain pregnancy from the early phase of pregnancy. This case report describes a pregnant case of steroid-refractory ITP, treated with six times repeated HD-IVIG, resulting in the successful delivery of a healthy newborn with a normal platelet count. No adverse effects were observed.

External genitalia formation: role of fibroblast growth factor, retinoic acid signaling, and distal urethral epithelium.

The process of fetal external genitalia development might be divided into two processes. The first process accomplishes the initial outgrowth of the anlage, genital tubercle (GT). Previous analysis suggests that the distal urethral epithelium (DUE) of the GT, the Fgf8-expressing region, regulates the outgrowth of the GT. The second process eventually generates the sexually dimorphic development of the external genitalia, which is dependent on the action of steroid hormones. Several key genes, for example, RARs, RXRs, RALDH2, and CYP26, were dynamically expressed during GT development. The teratogenic dose of RA at 9.0 d.p.c. induced a drastic malformation of the urethral plate during GT formation, but did not show gross abnormalities in its outgrowth. In RA-treated embryos, Fgf8 expression was still detected in the distal GT regions. Possible regulatory roles of the FGF and RA signaling systems in external genitalia formation are discussed.