Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study.

BACKGROUND: Grade 3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) origin with Ki-67 indices <55% do not respond well to platinum-based chemotherapy. The combination of capecitabine and temozolomide (CAPTEM) has shown favorable responses in grade 1-2 NENs, but has rarely been studied in patients with grade 3 NENs. PATIENTS AND METHODS: This open-label, single-arm phase II trial included patients with unresectable or metastatic grade 3 NENs of GEP origin with Ki-67 indices <55% enrolled between June 2017 and July 2020. Patients received oral capecitabine 750 mg/m2 twice daily on days 1 to 14 and oral temozolomide 200 mg/m2 once daily on days 10 to 14 every 4 weeks. Histologic findings were centrally reviewed after the completion of enrollment. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Of the 30 patients included in the full analysis set, 1 (3.3%) achieved complete response, 8 (26.7%) had partial responses, and 14 (46.7%) had stable disease, making the overall response rate 30.0%. At a median follow-up of 19.2 months, the median PFS was 5.9 months and the median OS was not reached. Patients with well-differentiated NENs showed significantly better median PFS (9.3 months versus 3.5 months, P = 0.005) and median OS (not reached versus 6.2 months, P = 0.004) than patients with poorly differentiated tumors. Expression of O6-methyl-guanine methyltransferase protein did not correlate with clinical outcomes. The most common grade 3-4 adverse events were thrombocytopenia (10%), anemia (6.7%), and nausea (6.7%). CONCLUSIONS: CAPTEM was effective and well tolerated in patients with grade 3 GEP-NENs with Ki-67 indices <55%, with superior efficacy outcomes compared with the historical controls receiving platinum-based chemotherapy.

Management of isolated recurrence after surgery for pancreatic adenocarcinoma.

BACKGROUND: Recurrence of pancreatic cancer after primary pancreatectomy occurs in the vast majority of patients. The role of surgical treatment for recurrent pancreatic cancer is not well established. METHODS: Patients who underwent primary pancreatectomy with curative intent from 2000 to 2014 at a single large-volume centre were evaluated retrospectively. CT or PET was used to select patients with an isolated recurrence. The clinicopathological features and survival outcomes were compared according to treatment modalities. RESULTS: Of the 1610 patients with pancreatic cancer who underwent resection, 1346 (83·6 per cent) were diagnosed with recurrent pancreatic cancer. Recurrence was locoregional in 366 patients (27·2 per cent), distant multifocal in 251 (18·6 per cent), distant isolated in 188 (14·0 per cent), locoregional plus distant in 153 (11·4 per cent) and peritoneal seeding in 388 (28·8 per cent). Of the 1346 patients with recurrence, 197 (14·6 per cent) had isolated recurrence; of these, 48 (24·4 per cent of all isolated recurrences; 3·6 per cent of all recurrences) underwent resection. Median survival of the 197 patients after diagnosis of isolated recurrence was 14·7 months; it was longer in patients who underwent surgical resection than among those treated non-surgically (23·5 versus 12·0 months; P = 0·014). Multivariable analysis showed that chemotherapy and resection for recurrence were associated with better prognosis. Median survival after recurrence was longest in the 23 patients with isolated pulmonary recurrence (33·3 months). Survival after recurrence was better in patients who underwent resection of isolated recurrence in the remnant pancreas (median 28·0 versus 12·0 months, P = 0·010) and lung (median 36·5 versus 9·5 months; P = 0·010) than in those who did not undergo resection. CONCLUSION: Surgical resection may be considered an option for treatment of patients with isolated recurrent pancreatic cancer.

Prognostic Value of the Metabolic and Volumetric Parameters of 11C-Methionine Positron-Emission Tomography for Gliomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have demonstrated that 11C-methionine positron-emission tomography provides information on prognosis. PURPOSE: We performed a systematic review and meta-analysis of the prognostic value of the metabolic and volumetric parameters of 11C-methionine-PET for gliomas. DATA SOURCES: A systematic search was performed using the following combination of keywords: "methionine," "PET," "glioma," and "prognosis." STUDY SELECTION: The inclusion criteria were the use of 11C-methionine-PET as an imaging tool, studies limited to gliomas, studies including metabolic parameters (tumor-to-normal ratio) and/or volumetric parameters (metabolic tumor volume), and studies reporting survival data. The electronic search first identified 181 records, and 14 studies were selected. DATA ANALYSIS: Event-free survival and overall survival were the outcome measures of interest. The effect of the tumor-to-normal ratio and metabolic tumor volume on survival was determined by the effect size of the hazard ratio. Hazard ratios were extracted directly from each study when provided or determined by analyzing the Kaplan-Meier curves. DATA SYNTHESIS: The combined hazard ratios of the tumor-to-normal ratio for event-free survival was 1.74 with no significance and that of the tumor-to-normal ratio for overall survival was 2.02 with significance. The combined hazard ratio of the metabolic tumor volume for event-free survival was 2.72 with significance and that of the metabolic tumor volume for overall survival was 3.50 with significance. LIMITATIONS: The studies selected were all retrospective, and there were only 4 studies involving the metabolic tumor volume. CONCLUSIONS: The present meta-analysis of 11C-methionine-PET suggests that the tumor-to-normal ratio for overall survival and the metabolic tumor volume for event-free survival and overall survival are significant prognostic factors for patients with gliomas.

Remote Preconditioning on Rat Hepatic Ischemia-Reperfusion Injury Downregulated Bax and Cleaved Caspase-3 Expression.

OBJECTIVE: Hepatic ischemia-reperfusion injury (IRI) is considered a major cause of hepatic damage in liver surgery. The aim of this study was to investigate the effect of the remote ischemic perconditioning method on hepatic IRI in a rat model. METHODS: Seventeen rats underwent hepatic IRI for 30 minutes followed by reperfusion, and were divided into 3 groups: group I, only hepatic IRI (n = 5); group II, hepatic IRI with remote perconditioning (n = 7); and group III, hepatic IRI with remote postconditioning (n = 5). RESULTS: For Bax/ß-actin, mean values of the 3 groups (±standard deviation) were 1.29 ± 0.26 (group I), 0.89 ± 0.15 (group II), and 1.02 ± 0.23 (group III). The level of Bax/ß-actin in group II was significantly lower than in group I (P < .01). The cleaved Caspase-3/ß-actin ratio for groups I, II, and III was 0.93 ± 0.22, 0.46 ± 0.16, and 0.63 ± 0.22, respectively. The level of cleaved Caspase-3/ß-actin in groups II and III were significantly lower than in group I (P < .01 and P < .05, respectively). The Bcl-2/ß-actin ratio for groups I, II, and III was 1.01 ± 0.09, 1.19 ± 0.39, and 1.20 ± 0.12, respectively. However, there were no significant difference between groups II and III and group I. CONCLUSIONS: The remote perconditioning on rat hepatic IRI downregulated the Bax and cleaved Caspase-3 expression.

Closed intramedullary nailing with percutaneous cement augmentation for long bone metastases.

AIMS: The purpose of the study was to investigate whether closed intramedullary (IM) nailing with percutaneous cement augmentation is better than conventional closed nailing at relieving pain and suppressing tumours in patients with metastases of the femur and humerus. PATIENTS AND METHODS: A total of 43 patients (27 men, 16 women, mean age 63.7 years, standard deviation (sd) 12.2; 21 to 84) underwent closed IM nailing with cement augmentation for long bone metastases. A further 27 patients, who underwent conventional closed IM nailing, served as controls. Pain was assessed using a visual analogue scale (VAS) score pre-operatively (pre-operative VAS), one week post-operatively (immediate post-operative VAS), and at six weeks post-operatively (follow-up post-operative VAS). Progression of the tumour was evaluated in subgroups of patients using F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET)/computed tomography (CT) and/or bone scintigraphy (BS), at a mean of 8.8 and 7.2 months post-operatively, respectively. RESULTS: The mean pain scores of patients who underwent closed nailing with cement augmentation were significantly lower than those of the control patients post-operatively (immediate post-operative VAS: 3.8, sd 0.9 versus 6.0, sd 0.9; follow-up post-operative VAS: 3.3, sd 2.5 versus 6.6, sd 2.2; all p < 0.001). The progression of the metastasis was suppressed in 50% (10/20) of patients who underwent closed nailing with augmentation, but in only 8% (1/13) of those in the control group. CONCLUSION: Percutaneous cement augmentation of closed IM nailing improves the relief of pain and limits the progression of the tumour in patients with metastases to the long bones. TAKE HOME MESSAGE: Percutaneous cement augmentation while performing closed IM nailing has some advantages for long bone metastases. Cite this article: Bone Joint J 2016;98-B:703-9.

cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis.

Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMPResponse Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro decidualization, we showed that CREB3L1 is required for the decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.

Decreased Bcl-6 and increased Blimp-1 in the peritoneal cavity of patients with endometriosis.

PURPOSE OF INVESTIGATION: The authors investigated the expression patterns of interleukin (IL)-lß and tumor necrosis factor (TNF)-α, cytokines associated with peritoneal inflammatory reactions, and of B cell leukemia lymphoma (Bcl)-6 and B lymphocyte inducer of maturation program (Blimp)-1, transcriptional factors associated with immunoglobulin (Ig) production; the concentrations of Igs, and their correlation, in patients with and without endometriosis. MATERIALS AND METHODS: The authors analyzed the peritoneal fluid of 98 patients, 46 with endometriosis, and 52 with benign tumors. RESULTS: IL-1 and TNF-α mRNAs and IgG and IgA concentrations were higher in the endometriosis group, but the differences were not statistically significant. However, Bcl-6 mRNA level was significantly lower and Blimp-1 mRNA level was significantly higher in the endometriosis group with significant correlations among transcriptional factors, Igs, and cytokines (p < 0.05). CONCLUSION: Peritoneal immune responses in patients with endometriosis may be due to increased IgG and IgA concentrations, as well as to changes in expression of proinflammatory cytokines and transcriptional factors.

Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study.

BACKGROUND: Metformin use has been associated with a decreased incidence and mortality of various cancers. AIM: To evaluate the association between metformin use and gastric cancer. METHODS: We randomly selected 100 000 type 2 diabetic patients from the 2004 Korean National Health Insurance claim database, and assessed gastric cancer incidence among 39 989 patients (aged 30-97 years) who were regularly treated with anti-diabetic drugs and followed-up from 2004 to 2010. In total, 26 690 patients had used metformin out of 32 978 diabetics who had not regularly used insulin (insulin non-users), and 5855 patients had used metformin out of 7011 regular insulin users. RESULTS: Patients who used metformin showed a lower incidence of gastric cancer than those who did not use metformin, in insulin non-users (P = 0.047, log-rank test). However, in patients on regular insulin, there was no difference of gastric cancer incidence according to metformin use. In insulin non-users, the adjusted hazard ratio (AHR) for metformin use was 0.73 (95% confidential interval [CI], 0.53-1.01) with borderline statistical significance (P = 0.059). Duration of metformin use was associated with the reduction in gastric cancer risk (AHR, 0.88; 95% CI 0.81-0.96, P = 0.003), especially in patients who used metformin for more than 3 years (AHR, 0.57; 95% CI, 0.37-0.87; P = 0.009). CONCLUSION: Metformin use >3 years in type 2 diabetics who do not use insulin is associated with a significantly reduced gastric cancer risk.

Levels of 4-1BB transcripts and soluble 4-1BB protein are elevated in the adipose tissue of human obese subjects and are associated with inflammatory and metabolic parameters.

BACKGROUND: 4-1BB, a member of the TNF receptor superfamily, has a role in various inflammatory pathologies through its interaction with 4-1BB ligand. We previously demonstrated that it participates in initiating and promoting obesity-induced adipose inflammation in a rodent model. OBJECTIVE: In this study, we examined whether 4-1BB is related to obesity-induced adipose inflammation and metabolic parameters in humans. METHODS: A total of 50 subjects, 25 obese (body mass index (BMI)≥25 kg m(-2)) and 25 lean (BMI<23 kg m(-2)) participated in the study. The levels of 4-1BB transcripts and soluble 4-1BB protein (s4-1BB) in subcutaneous adipose tissue were measured by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Inflammatory and metabolic parameters were measured by enzymatic analysis and immunoassay. RESULTS: Obese subjects had higher levels of both 4-1BB transcripts and s4-1BB protein in subcutaneous adipose tissue than lean controls, and the levels were correlated with BMI and the expression of inflammatory markers, as well as with serum metabolic parameters. Moreover, s4-1BB was released from human adipocytes, and elicited chemotactic responses from human monocytes/T cells as well as enhancing their inflammatory activity, indicating that it may promote human adipose inflammation. DISCUSSION: Our data demonstrate that elevated levels of 4-1BB transcripts and s4-1BB in adipose tissue are closely associated with obesity-induced inflammation and metabolic dysregulation. They suggest that both 4-1BB transcripts and s4-1BB could serve as novel biomarkers and/or therapeutic targets for obesity-induced inflammation and metabolic syndrome in humans.

γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate.

BACKGROUND: γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect. METHODS: We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo. RESULTS: Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased. CONCLUSION: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

Arthroscopic shoulder surgery under general anesthesia with brachial plexus block: postoperative respiratory dysfunction of combined obstructive and restrictive pathology.

OBJECTIVE: Changes in respiratory parameters and pulmonary function tests were evaluated after shoulder arthroscopic surgery with brachial plexus block (BPB). The purpose of this study was to identify the mechanism of respiratory dysfunction after this type of surgery. METHODS: Patients undergoing arthroscopic rotator cuff repair under general anesthesia (GA) with BPB were enrolled in the arthroscopy group (n = 30) while those undergoing open reduction of a clavicle or humerus fracture under GA were enrolled in the control group (n = 30). Forced vital capacity (FVC) and forced expiratory volume 1 s (FEV(1)) were measured at the outpatient clinic stage (#1) before (#2) and 20 min after BPB (#3) and 1 h after extubation (#4). Respiratory variable measurements along with the cuff leak test were performed 5 min after surgical positioning (T1) and at the start of skin closure (T2). Respiratory discomfort was evaluated after extubation. The upper airway diameters and soft tissue depth of chest wall were also measured by ultrasonography at stages #3 and #4. RESULTS: Static compliance decreased significantly at T2 in the arthroscopy group (50 ± 11 at T1 vs. 44 ± 9 ml/cm H(2)O at T2, p =0.035) but not in the control group. The incidence of positive cuff leak tests at T2 was significantly higher in the arthroscopy group than in the control group (47% in the arthroscopy group vs. 17% in controls, p =0.010). While FEV(1) and FVC remained stable at stages #1 and #2, FVC and FEV(1) decreased at stages #3 and #4 only in the arthroscopy group (FVC in arthroscopy group, #2: 3.26 ± 0.77 l; #3: 2.55 ± 0.63 l, p =0.015 vs. #2; #4: 2.66 ± 0.41 l, p =0.040 vs. #2). The subglottic diameter decreased at #4 in the arthroscopy group, while no changes occurred in the control group (0.70 ± 0.21 cm vs. 0.85 ± 0.23 cm in the arthroscopy and control groups, respectively, p =0.011). Depth of skin to pleura increased at both intercostal spaces 1-2 and 3-4 in the arthroscopy group. There were three cases of hypoxia (S(p)O(2) < 95%) with room air in the arthroscopy group while none occurred in the controls. CONCLUSION: Shoulder arthroscopic surgery under GA with BPB induced both restrictive and obstructive pathologies. It is important to maintain a high level of awareness for the potential negative respiratory effects of this surgery especially for subjects with pre-existing cardiopulmonary disease. The measurements in this study would be useful to monitor the risk of respiratory dysfunction in these patients.

Effect of setback Le Fort I osteotomy on midfacial soft-tissue changes as evaluated by cone-beam computed tomography superimposition for cases of skeletal Class III malocclusion.

This study employed the cone-beam computed tomography (CBCT) superimposition method to evaluate postoperative midfacial soft-tissue changes in cases of skeletal Class III malocclusion after double-jaw surgery with setback and vertical reduction Le Fort I osteotomy. A retrospective study was carried out on 15 patients who had undergone maxillary setback Le Fort I osteotomy and mandibular setback sagittal split ramus osteotomy with alar cinch suturing and V-Y soft-tissue closure. Three dimensional CBCT volume scans were recorded preoperatively (T0) and 6 months postoperatively (T1) to measure soft-tissue changes of the upper lip and midface. Post-surgery, soft-tissue landmarks in the cheek and paranasal areas had moved forward; the soft-tissue thickness at the A-point had markedly increased (P<0.05); there was no significant change in the subnasale, and the midline of the soft-tissue of the upper-lip area had moved backward. The extent of the mean soft-tissue change at the labrale superius was greater than that at the other soft-tissue landmarks of the upper lip. The results suggest that maxillary setback movement of the maxilla by alar cinch suturing has a beneficial effect on paranasal soft-tissue and lip contours for patients with protrusive lip and acute nasolabial angle.

Radiofrequency ablation combined with transcatheter arterial embolisation in rabbit liver: investigation of the ablation zone according to the time interval between the two therapies.

OBJECTIVES: This study was designed to evaluate the extent of the radiofrequency ablation zone in relation to the time interval between transcatheter arterial embolisation (TAE) and radiofrequency ablation (RFA) and, ultimately, to determine the optimal strategy of combining these two therapies for hepatocellular carcinoma. METHODS: 15 rabbits were evenly divided into three groups: Group A was treated with RFA alone; Group B was treated with TAE immediately followed by RFA; and Group C was treated with TAE followed by RFA 5 days later. All animals underwent perfusion CT (PCT) scans immediately after RFA. Serum liver transaminases were measured to evaluate acute liver damage. Animals were euthanised for pathological analysis of ablated tissues 10 days after RFA. Non-parametric analyses were conducted to compare PCT indices, the RFA zone and liver transaminase levels among the three experimental groups. RESULTS: Group B showed a significantly larger ablation zone than the other two groups. Arterial liver perfusion and hepatic perfusion index represented well the perfusion decrease after TAE on PCT. Although Group B showed the most elevated liver transaminase levels at 1 day post RFA, the enzymes decreased to levels that were not different from the other groups at 10 days post-RFA. CONCLUSIONS: When combined TAE and RFA therapy is considered, TAE should be followed by RFA as quickly as possible, as it can be performed safely without serious hepatic deterioration, despite the short interval between the two procedures.

Mucosal protective effect of PGI2 on canine small bowel auto-transplantation.

PURPOSE: We designed this experimental study to assess the mucosal protective effects of continuous prostaglandin I2 (PGI2) infusion after canine small bowel autotransplantation. MATERIALS AND METHODS: Six Mongrel dogs were randomly divided two groups: PGI2 (n = 3) and control (n = 3). The small bowel from jejunum to ileum was obtained, including the mesenteric vascular pedicle. After cold flushing ex vivo, the harvested segment was preserved in an icebox for 3 hours. Thereafter we reimplanted the harvested intestinal segment. While completing the anastomosis, PGI2 (50 µg) was slowly infused through the mesenteric artery in the PGI2 group versus the same volume of saline in the control group. At 1, 3 and 6 days after autotransplantation, we obtained blood samples, and at 6 days, small bowel segments. Endotoxin and interleukin 6 (IL-6) levels were measured and all histologic specimens stained with hematoxylin-eosin H-E were reviewed by a pathologist to grade mucosal damage as: mild (1 point), moderate (2 points), or severe (3 points) change. RESULTS: Mean basal serum endotoxin levels were similar in both groups the PGI2 groups versus control group were 0.216 ± 0.018 versus 0.223 ± 0.040 EU/mL, respectively. However, on day 3 after the operation, the PGI2 group showed much decreased levels of serum endotoxin compared to control levels: 0.349 ± 0.196 versus 0.842 ± 0.446 EU/mL. The mean concentration of serum IL-6 on day 1 after operation among the PGI2 versus control group were 32.13 ± 7.13 pg/mL versus 36.96 ± 3.65 pg/mL. The histologic scores at 6 days after the operation were PGI2 group versus control group: 1.33 versus 1.66 (P = NS). CONCLUSION: Continuous infusions of PGI2 through the mesenteric artery after the canine small bowel autotransplantation may protect the small bowel mucosal barrier.

Cone-beam computed tomography evaluation of short- and long-term airway change and stability after orthognathic surgery in patients with Class III skeletal deformities: bimaxillary surgery and mandibular setback surgery.

The purpose of this study was to evaluate the volumetric change of the upper airway space in 36 Class III patients who had undergone bimaxillary surgery or isolated mandibular setback, and, further, to analyse the relation between post-surgical stability and airway change using cone-beam computed tomography (CBCT). A three-dimensional (3D) CBCT examination was performed at three stages: T0 (before surgery), T1 (an average of 4.6 months after surgery), and T2 (an average of 1.4 years after surgery). The results showed that the volumes of the oropharyngeal and hypopharyngeal airways decreased significantly 4.6 months post-surgery in the mandibular setback group (p<0.05), and these diminished airways had not recovered 1.4 years post-surgery. In the bimaxillary surgery group, the volume of the oropharyngeal airway also decreased. A Spearman correlation analysis showed that the anteroposterior length of the hypopharyngeal area had a correlation with post-surgical stability in the isolated mandibular surgery group, and that the cross-sectional area of the nasopharynx was correlated with maxillary relapse only in the bimaxillary surgery group (p<0.05).

Alteration of ictal and interictal perfusion in patients with paroxysmal kinesigenic dyskinesia.

Although previous cerebral blood flow studies have suggested that the basal ganglia or thalamus are involved in the pathogenesis of paroxysmal kinesigenic dyskinesia (PKD), the precise anatomic substrate or pathophysiological networks associated with PKD remain unclear. Here, ictal and interictal single photon emission computed tomography (SPECT) in 2 patients with idiopathic PKD compared to 6 age-matched normal controls and the perfusion findings of subtraction ictal SPECT co-registered to MRI (SISCOM) in 1 patient are reported. The interictal and ictal perfusion changes were different in each of the patients and there were no consistent anatomic substrates observed. 2 patients had significant perfusion changes in the left frontal/temporal cortices compared to controls, whereas the others showed an increased uptake of 99mTc-ethyl cysteinate dimer (ECD) in the left occipital area on subtraction SPECT imaging. The results of this study suggest that the pathophysiology of PKD cannot be simply explained by lesions of the basal ganglia or thalamus, and that other associated areas of the cortex are likely involved in these movement disorders.

Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector.

Ideal cancer gene therapies should have high tumor specificity and efficacy, and allow systemic administration to target metastases. We recently developed a bi-directional, two-step transcriptional amplification (TSTA) system driven by the tumor-specific Survivin promoter (pSurv) to amplify the correlated expression of both the reporter gene firefly luciferase (FL) and therapeutic gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we compare the specificity and potency of an adenovirus carrying this system (Ad-pSurv-TSTA-TRAIL-FL) to a nonspecific vector (Ad-pCMV-FL) in an orthotopic hepatocellular carcinoma (HCC) rat model after systemic administration. At 24 h after injection of Ad-pCMV-FL, bioluminescence imaging revealed a trend (P=0.30) towards greater FL expression in liver versus tumor. In striking contrast, Ad-pSurv-TSTA-TRAIL-FL showed increased FL activity within the tumor compared with the liver (P<0.01), a strong trend towards reduced liver expression compared with Ad-pCMV-FL (P=0.07), and importantly, similar FL levels within tumor compared with Ad-pCMV-FL (P=0.32). Hence, this vector shows potent, tumor-specific transgene expression even after extensive liver transduction and may be of significant value in avoiding hepatotoxicity in HCC patients. Future studies will explore the benefits of tumor-specific TRAIL expression in this model, the potential to target metastases and the extension of this vector for the treatment of other Survivin-positive tumors is warranted.

The assessment of the short- and long-term changes in the condylar position following sagittal split ramus osteotomy (SSRO) with rigid fixation.

The purpose of this study was to compare the short- and long-term changes in condylar position related to the glenoid fossa, and skeletal and occlusal stability after orthognathic surgery. All of the study patients were assessed by cone-beam computed tomography images for condylar rotational changes and anteroposterior position in the pre-surgery, post-surgery and post-retention period. The condylar positions were evaluated on three planes: axial, coronal and sagittal. In the skeletal and occlusal measurements, there was no significant difference between the post-surgery group and the post-retention group. After sagittal split ramus osteotomy (SSRO), the condyle on the axial plane rotated inward (P < 0.05) and maintained during the post-retention period. In the anteroposterior condylar position related to the glenoid fossa, the condyles had changed from the anterior position in the pre-surgery group to a concentric position in the post-surgery group and then returned to the anterior position in the post-retention groups. These results suggested that the changed anteroposterior condylar position in the glenoid fossa after SSRO with rigid fixation had moved from a concentric to anterior position for post-retention period.

New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53.

Most of the p53 target genes, all except MDM2, COP1 and PIRH2, perform functions in apoptosis, differentiation and cell cycle arrest. The aforementioned oncogenes downregulate p53 through a negative feedback mechanism, and thus contribute to tumor development. In this study, we report a new p53 target, PRL-1, which is believed to be a significant regulator in the development and metastasis of a variety of cancer types. Phosphatase of regenerating liver 1 (PRL-1) overexpression reduced the levels of endogenous and exogenous p53 proteins, and inhibited p53-mediated apoptosis. On the other hand, the ablation of PRL-1 by small interfering RNA (siRNA) increased p53 protein levels. The p53 downregulation was mediated by p53 ubiquitination and subsequent proteasomal degradation. Furthermore, p53 ubiquitination by PRL-1 was achieved through two independent pathways, by inducing PIRH2 transcription and by inducing MDM2 phosphorylation through Akt signaling. In addition, we showed that the PRL-1 gene harbors a p53 response element in the first intron, and its transcription is regulated by the p53 protein. These findings imply that the new oncogenic p53 target, PRL-1, may contribute to tumor development by the downregulation of p53 by a negative feedback mechanism.