Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.

BACKGROUND: Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS: The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS: The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION: Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.

ANTECEDENTES: La quimioterapia intraperitoneal con paclitaxel se considera una terapia experimental para el tratamiento de la carcinomatosis peritoneal. Este estudio tuvo como objetivo determinar la dosis recomendada y evaluar la eficacia clínica y la seguridad de la combinación de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal en pacientes con cáncer de páncreas y metástasis peritoneales. MÉTODOS: Se evaluaron las frecuencias de las toxicidades limitantes de la dosis, y la dosis recomendada se determinó en la fase I. El objetivo principal de la fase II fue la tasa de supervivencia global a 1 año. Los objetivos secundarios fueron los efectos antitumorales, los efectos de alivio de los síntomas, la seguridad y la supervivencia global. RESULTADOS: Las dosis recomendadas de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal fueron de 800, 75 y 20 mg/m2 , respectivamente. De los 46 pacientes incluidos en la fase II del estudio, la mediana de tiempo hasta el fracaso del tratamiento fue de 6,0 meses (rango, 0-22,6). Las tasas de respuesta y de control de la enfermedad fueron del 45% y 95%, respectivamente. La ascitis desapareció en el 40% de los pacientes, y la citología se negativizó en el 39% de los pacientes. La mediana del tiempo de supervivencia fue de 14,5 meses y la tasa de supervivencia global a 1 año del 60,9%. La cirugía de rescate se realizó en ocho (17%) pacientes, y los que se sometieron a cirugía sobrevivieron significativamente más tiempo que los que no fueron tratados quirúrgicamente (mediana de supervivencia no alcanzada versus 12,4 meses). Las toxicidades hematológicas de grado 3/4 ocurrieron en el 76% de los pacientes, mientras que los eventos adversos no hematológicos se presentaron en el 15% de los pacientes. CONCLUSIÓN: Agregar paclitaxel intraperitoneal tuvo eficacia clínica con una tolerabilidad aceptable. (UMIN000018878).

Endocytoscopy for in situ real-time histology of oral mucosal lesions.

This study investigated the utility of endocytoscopy, a novel emerging endoscopic system, for in situ real-time histology of oral mucosal lesions. Endocytoscopy involves the use of a contact light microscopy system with 380-fold magnification. With the development of endoscopic instruments, it has become possible to observe the abnormal microvascular and capillary patterns of tumour cells. The resolution of the endoscopic image is improved in situ, and a more detailed diagnosis is possible. In this study, endocytoscopy along with other diagnostic modalities was used in nine patients. Normal mucous membranes and oral malignant lesions were observed. Endocytoscopy enabled the pathological diagnosis of oral malignancies in situ and the observation of both structural and cytological atypia. In the future, it is expected that pathological diagnoses will be made in situ by direct viewing of living cells. This technique has the potential to allow an 'optical biopsy'.

Alterations in 18F-FDG accumulation into neck-related muscles after neck dissection for patients with oral cancers.

BACKGROUND: 18F-fluoro-2-deoxy-D-glucose (18F-FDG) accumulations are commonly seen in the neck-related muscles of the surgical and non-surgical sides after surgery with neck dissection (ND) for oral cancers, which leads to radiologists having difficulty in diagnosing the lesions. To examine the alterations in 18F-FDG accumulation in neck-related muscles of patients after ND for oral cancer. MATERIAL AND METHODS: 18F-FDG accumulations on positron emission tomography (PET)-computed tomography (CT) in neck-related muscles were retrospectively analyzed after surgical dissection of cervical lymph nodes in oral cancers. RESULTS: According to the extent of ND of cervical lymph nodes, the rate of patients with 18F-FDG-PET-positive areas increased in the trapezius, sternocleidomastoid, and posterior neck muscles of the surgical and/or non-surgical sides. In addition, SUVmax of 18F-FDG-PET-positive areas in the trapezius and sternocleidomastoid muscles were increased according to the extent of the ND. CONCLUSIONS: In evaluating 18F-FDG accumulations after ND for oral cancers, we should pay attention to the 18F-FDG distributions in neck-related muscles including the non-surgical side as false-positive findings.

Maxillary single-jaw surgery combining Le Fort I and modified horseshoe osteotomies for the correction of maxillary excess.

A modified technique of horseshoe osteotomy combined with Le Fort I osteotomy for superior and posterior repositioning of the maxilla is presented. Eight patients with maxillary excess associated with retrogenia or microgenia were treated with this technique in combination with genioplasty. The maxillary segment was repositioned a maximum of 5.0mm posteriorly and 7.0mm superiorly at point A. The mandible autorotated anterosuperiorly to achieve sound occlusion. Point B moved 2.0-10.0mm anteriorly and 5.0-10.0mm superiorly. The pogonion moved 7.0-17.0mm anteriorly in combination with genioplasty. All patients obtained sound occlusion and a good profile after the operation. Almost no skeletal relapse was observed during 1 year of postoperative follow-up. Patients with long faces with maxillary excess and retrogenia often have small, unstable condyles. In these cases, because surgical intervention to the ramus can result in postoperative progressive condylar resorption, maxillary single-jaw surgery with a horseshoe osteotomy, thereby avoiding ramus intervention, is a less invasive option.

An osteonecrosis model induced by oral bisphosphonate in ovariectomised rats.

OBJECTIVE: To develop a model of osteonecrosis using oral bisphosphonate in ovariectomy-induced osteoporotic rats. MATERIALS AND METHODS: Thirty-six rats were subjected to ovariectomy or sham surgery. After 8 weeks, rats received oral alendronate (1.0 mg kg(-1) ) or saline once weekly for 4 weeks; then, serum C-telopeptide cross-linked collagen type I levels were measured to evaluate bone metabolism. Twelve rats from each group were injected with either lipopolysaccharide or saline into the bone marrow of the mandibles and femurs, and the areas of osteonecrosis were evaluated by histomorphometry. RESULTS: Serum C-telopeptide cross-linked collagen type I levels were significantly increased in the ovariectomy group (105.1 ± 2.1 ng ml(-1) ) compared with the sham group (78.9 ± 12.5 ng ml(-1) ); they were significantly reduced following oral alendronate administration in the ovariectomy group (91.0 ± 4.4 ng ml(-1) ). Following alendronate and lipopolysaccharide administration, extensive osteonecrosis was observed in the mandibles and femurs of ovariectomy (0.45 ± 0.08 mm(2) , 1.69 ± 0.72 mm(2) , respectively) and sham (1.12 ± 0.45 mm(2) , 1.84 ± 0.66 mm(2) , respectively) groups. Significantly wider osteonecrosis occurred in the mandibles of sham-operated rats than ovariectomy rats following alendronate or lipopolysaccharide treatment. CONCLUSIONS: We successfully developed a model of osteonecrosis in ovariectomised rats following oral bisphosphonate administration.

Role of aquaporin-5 in gallbladder carcinoma.

BACKGROUND/PURPOSE: Aquaporins (AQPs) are important in controlling bile formation. However, the exact role in human gallbladder carcinogenesis has not yet been defined. METHODS: AQP-5-expressing gallbladder carcinoma (GBC) cell lines (NOZ) were transfected with anti-AQP-5 small interfering RNA (siRNA). Growth, migration, invasion assay, and drug susceptibility tests were performed. Next, microRNA (miRNA) expression was analyzed by miRNA oligo chip (3D-Gene®). AQP-5 and AQP-5-related miRNA target gene expressions were also analyzed using tissue microarray (TMA) in 44 GBC samples. RESULTS: Treatment with AQP-5 siRNA decreased cell proliferation, migration, and invasion. On the other hand, those cells increased IC50 of gemcitabine. By performing miRNA assays, miR-29b, -200a, and -21 were shown to be highly overexpressed in cells treated with AQP-5 siRNA NOZ. When focusing on miR-21, phosphatase and tensin homolog (PTEN) was found to be a target of miR-21. In the TMA, AQP-5/PTEN coexpression was significantly associated with the depth of invasion and MIB-1 index (p = 0.003, 0.010). Survival of patients with a high AQP-5/PTEN coexpression was longer than that of patients with a low coexpression (p = 0.003). CONCLUSIONS: Our result suggested that miR-21 and PTEN may contribute to the role of AQP-5 in GBC. AQP-5 and PTEN cascades are favorable biomarkers of GBC.

Variety and complexity of fluorine-18-labelled fluoro-2-deoxy-D-glucose accumulations in the oral cavity of patients with oral cancers.

OBJECTIVES: To elucidate the points that require attention when interpreting fluorine-18-labelled fluoro-2-deoxy-d-glucose ((18)F-FDG)/positron emission tomography (PET) images by demonstration of (18)F-FDG accumulation in various areas of the oral cavity other than primary lesions in patients with oral cancers. METHODS: (18)F-FDG accumulations with a maximal standardized uptake value of over 2.5 in various areas of the oral cavity other than primary lesions were identified in 82 patients with oral cancers. RESULTS: (18)F-FDG/PET-positive areas, excluding primary tumours, included the front intrinsic muscles of the tongue (89.0%), upper and lower marginal parts of the orbicularis oris muscle (64.6%), sublingual glands, palatine tonsil, pharyngeal tonsil, and lingual tonsil. In addition, some areas in the jaws also showed accumulation. CONCLUSIONS: In patients with oral cancers, areas of (18)F-FDG accumulation in the oral cavity should be precisely identified and appropriately diagnosed, because accumulations can be seen in areas other than the primary tumour.

Postoperative treatment of carvedilol following low dose landiolol has preventive effect for atrial fibrillation after coronary artery bypass grafting.

BACKGROUND: Postoperative atrial fibrillation (AF) is the most common complication after coronary artery bypass grafting (CABG). We have reported that the intra- and perioperative administration of landiolol has a preventive effect on postoperative AF in the early postoperative period after CABG surgery. The purpose of this study was to investigate the prophylactic effect of postoperative treatment with carvedilol following landiolol against postoperative AF. METHODS: We reviewed all patients who underwent CABG from December 2005 and February 2009. Fifty-three patients underwent scheduled isolated CABG and were divided two groups; carvedilol group (n = 31), and control group (n = 22). Incidences of postoperative AF were noted. RESULTS: There was no statistical difference between the two groups with regard to the occurrence of AF after CABG. The maximum ventricular rate of AF was significantly lower in the carvedilol group than in the control group. All patients with AF in the control group needed treatment for tachycardia, but this was not necessary in the carvedilol group. CONCLUSIONS: Postoperative treatment with carvedilol following landiolol has the effect of preventing tachycardia during AF after coronary artery bypass grafting.

Postoperative skeletal stability and accuracy of a new combined Le Fort I and horseshoe osteotomy for superior repositioning of the maxilla.

Postoperative skeletal stability and accuracy were evaluated in a combination of Le Fort I and horseshoe osteotomies for superior repositioning of maxilla in bi-maxillary surgeries in 19 consecutive patients. 9 underwent Le Fort I osteotomy alone (preoperative planned superior movement <3.5 mm). 10 underwent Le Fort I and horseshoe osteotomy (combination group) (preoperative planned superior movement >3.5 mm). The maxilla was osteotomized and fixed with 4 titanium Le Fort plates followed by bilateral sagittal split ramus osteotomy of the mandible, fixed with 2 semi-rigid titanium miniplates. Maxillomandibular fixation was performed for 1 week. Lateral cephalograms were obtained preoperatively, 1 week postoperatively, 3, 6, 12 months later. The changes in point A, point of maxillary tuberosity, and upper molar mesial cusp tip were examined. Discrepancy between the planned and measured superior movement of the maxilla in the Le Fort I and combination groups was 0.30 and 0.23 mm, respectively. The maxillae in both groups were repositioned close to their planned positions during surgery. 1 year later, both groups showed skeletal stability with no significant postoperative changes. When high superior repositioning of the maxilla is indicated, horseshoe osteotomy combined with Le Fort I is reliable and useful for accuracy and postoperative stability.

Maxillary reconstruction using a bipedicled osteocutaneous scapula flap.

When managing extensive maxillary defects it is difficult to provide a stable biomechanical frame for prostheses, and obturators are difficult to use. This study reviews cases involving angular branch artery pedicled scapular bone flaps (SBF) combined with or without latissimus dorsi musculocutaneous flap (LDMF). Between 2004 and 2007, four wide maxillary defects were repaired using the angular vascularized branch of the scapular bone. Tumor resection with immediate reconstruction using combined LDMF and angular artery pedicled SBF was used in 3 cases and angular artery pedicled SBF alone in 1 case. Follow up was 6 months to 2 years. Satisfactory results were obtained for facial contour, appearance, speech, deglutition and breathing. No donor site complications or restricted shoulder movements were detected. The only complication was a minor infection of one flap. This procedure is useful, functionally and aesthetically, for reconstruction of wide extensive maxillary defects as bone supplied by the angular branch has a wider arc of rotation in relation to skin flaps and has a longer pedicle length from the axillary artery, long enough to reach the maxilla. This procedure also benefits from the flexibility of the soft tissue pedicle, such as the latissimus dorsi, serratus anterior and fasciocutaneous flaps.

A novel modification of a bone repositioning device and a new technique for reestablishing facial contours after mandibular resection surgery.

A novel modification of a bone repositioning device previously published by the same authors is introduced. A flexible tube to define the intersegmental bony relationship is filled with light-cured resin. It solidifies following exposure to strong visible light for about 1 min. This technique can be used for bone positioning after mandibular resection surgery and during positioning of the proximal segment after sagittal split ramus osteotomy. The authors also propose a simple method for determining the contour of the reconstructed mandible to regain the original shape and form. The advantage of this technique is its simplicity and flexibility compared with other methods of bone positioning during mandibular segmental surgery.

Mandibular reconstruction with bone transport in a patient with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) was originally considered a connective tissue disorder, primarily involving type 1 collagen. It is characterized by numerous skeletal and extraskeletal defects, including bone fragility, multiple fractures, blue sclerae, hearing deficits, skin and ligament laxity, and dentinogenesis imperfecta (DI). The authors describe a 24-year-old Japanese man with OI and DI who had an ossifying fibroma of the mandible. Segmental resection was performed, and the mandible was reconstructed by distraction osteogenesis with the transport segment technique. This is the first report to describe a patient with OI undergoing mandibular reconstruction with bone transport, to the authors' knowledge.

Hepatocyte growth factor and interleukin-6 in combination with prostate volume are possible prostate cancer tumor markers in patients with gray-zone PSA levels.

The aim was to assess whether hepatocyte growth factor (HGF) and interleukin (IL)-6 in combination with prostate volume are able to accurately detect prostate cancer in patients with gray-zone prostate-specific antigen (PSA) levels. A total of 159 patients with PSA levels of <10 ng ml(-1) were enrolled. Forty-two (35.3%) were diagnosed with prostate cancer, whereas 117 (64.7%) had no cancer and were used as benign group. HGF and IL-6 density (HGFD and IL-6D, respectively) values were calculated by dividing serum HGF and IL-6 levels with prostate volume. Median IL-6 (2.3 pg ml(-1)) levels for the prostate cancer group were significantly higher than those for the benign group before adjustment for age (1.7 pg ml(-1)) (P=0.0098). After age adjustments, median IL-6 (2.17 pg ml(-1)), HGFD (0.00972 ng ml(-1) cm(-3)), and IL-6D (0.0848 pg ml(-1) cm(-3)) values for the prostate cancer group were significantly higher than those for the benign group (IL-6, 1.78 pg ml(-1); HGFD, 0.00732 ng/ml/cc; and IL-6D, 0.049 pg/ml/cc; P=0.0416, 0.007 and 0.0005, respectively). In receiver operating characteristic analyses, the areas under the curves for HGFD (0.64) and IL-6D (0.68) were significantly greater than those for HGF (0.52) and IL-6 (0.61) (P=0.0006 and 0.019, respectively). With an HGFD cutoff value of 0.00392 ng ml(-1) cm(-3) (sensitivity=100%, specificity=11%), 11.1% of the benign group were able to avoid unnecessary biopsies without missing prostate cancer. HGF and IL-6 levels in combination with prostate volume were shown to be useful parameters for prostate cancer screening in patients with gray-zone PSA levels.

Morphological features of cartilage observed during mandibular distraction in rabbits.

Ossification during distraction osteogenesis can be classified as intramembranous or endochondral. It is not known whether cartilage in the distraction gap is transformed into new bone. The aim of this study was to investigate the morphological features of ossification in the transition of cartilage to bone during mandibular distraction osteogenesis in a rabbit model. A cortical osteotomy was performed and custom-made devices were applied. Immediately after surgery, the devices were lengthened by 0.25 mm every 12h for up 10 days, during which time four rabbits were killed at 0, 5 and 10 days and examined using histological staining and immunohistochemical methods. Apoptotic cells were identified by an in-situ detection assay for nuclear DNA fragmentation using a modified TUNEL procedure, with several sections analyzed using software for histomorphometric analysis. The results showed that the amount of cartilage in the distraction gap was significantly decreased. The cartilage had ossified in two ways, termed endochondral ossification and transchondroid bone formation.

A simple method for bone positioning of mandibular segments.

A simple bone-positioning technique is reported, using a combination of bone plates and a flexible tube filled with acrylic polymer. The flexible tube is solidified by injection of acrylic monomer. This technique is applicable for bone positioning after mandibular resection as well as positioning of the proximal segment after sagittal split ramus osteotomy. This technique has the advantages of greater simplicity and flexibility compared to previously reported methods of bone positioning.

Instability of background fat intensity suppression using fat-saturated (FS) MR imaging techniques according to region and reconstruction procedure in patients with oral cancer.

The purpose of the present study is to evaluate the background fat intensity suppression instability of each area in the head and neck region, and in the post-reconstruction with metal plate and myocutaneous flap, of patients with oral cancer using fat-saturated (FS) images. STIR and FS T2-weighted images at pre- and post-surgery in 59 patients with oral cancer were scored for uniformity of fat suppression and tissue conspicuity in each region of the head and neck. The scores of FS on uniformity of fat suppression pre-operatively were worse than those of STIR in the mandibular level, but not lesion and tissue conspicuity. However, the deterioration both of scores between pre- and post-surgery using FS was worse than that using STIR using metal plate and/or myocutaneous flap. At diagnosis, we should recognize on MR images using FS that instability of the status of fat suppression might be brought about by respective area and reconstruction with metal plate and myocutaneous flap of patients with oral cancer.

Effects of latency period in a rabbit mandibular distraction osteogenesis.

Recently, distraction osteogenesis has been widely used in the craniomaxillofacial skeleton. There are varying views, however, about the need for a latency period for mandibular distraction, which has been reported from 0 to 14 days. We used a rabbit model to determine the ideal latency period for mandibular distraction osteogenesis. We performed a subperiosteal corticotomy of the bilateral mandible and then applied an external device. We used 0-, 2-, 5-, and 10-day latency periods. Distraction was done at a rate of 0.5 mm per day (0.25 mm every 12 h) to elongate by 5 mm after each latency period. Hematoxylin-eosin stain was used for histologic observation, and bone labelling was observed with a fluorescence microscope. In the 0-day latency, the lengthened region was filled with fibrous tissue. Cartilage formed like isles along the lengthened edge. In the 10-day latency, the lengthened region was almost completely filled with woven bone. In the 2- and 5-day latency, there were mineralization zones at the periphery of this fibrous interzone. The primary osteon remodelling zones were located at both ends of the zones of mineralization zones. In the 5-day latency, new bone formation was observed around the periosteum.

Increasing the thermostability of Flavobacterium meningosepticum glycerol kinase by changing Ser329 to Asp in the subunit interface region.

The thermostability enhancement of Flavobacterium meningosepticum glycerol kinase (FGK) by random mutagenesis in the subunit interface region was investigated. A single Escherichia coli transformant, which produced a more thermostable glycerol kinase than the parent enzyme, was obtained. The nucleotide sequence of the gene of the mutant enzyme (FGK2615) was determined, and the four amino acid replacements were identified as Glu327 to Asp, Ser329 to Asp, Thr330 to Ala and Ser334 to Lys. Although the properties of FGK2615 were fundamentally similar to those of the parent enzyme, the thermostability and Km for ATP had changed. The thermostability of FGK2615 was apparently increased; the temperature at which the enzyme activity is inactivated by 50% for a 30-min incubation of FGK2615 was determined to be 72.1 degrees C which was 3.1 degrees C higher than that of the parent FGK. Four additional mutants each having a single amino acid replacement (Glu327 to Asp, Ser329 to Asp, Thr330 to Ala and Ser334 to Lys) were prepared and their thermostability and Km for substrates were evaluated. The effect of the substitution of Ser329 to Asp is discussed.

Structural basis for the ADP-specificity of a novel glucokinase from a hyperthermophilic archaeon.

BACKGROUND: ATP is the most common phosphoryl group donor for kinases. However, certain hyperthermophilic archaea such as Thermococcus litoralis and Pyrococcus furiosus utilize unusual ADP-dependent glucokinases and phosphofructokinases in their glycolytic pathways. These ADP-dependent kinases are homologous to each other but show no sequence similarity to any of the hitherto known ATP-dependent enzymes. RESULTS: We solved the crystal structure at 2.3 A resolution of an ADP-dependent glucokinase from T. litoralis (tlGK) complexed with ADP. The overall structure can be divided into large and small alpha/beta domains, and the ADP molecule is buried in a shallow pocket in the large domain. Unexpectedly, the structure was similar to those of two ATP-dependent kinases, ribokinase and adenosine kinase. Comparison based on three-dimensional structure revealed that several motifs important both in structure and function are conserved, and the recognition of the alpha- and beta-phosphate of the ADP in the tlGK was almost identical with the recognition of the beta- and gamma-phosphate of ATP in these ATP-dependent kinases. CONCLUSIONS: Noticeable points of our study are the first structure of ADP-dependent kinase, the structural similarity to members of the ATP-dependent ribokinase family, its rare nucleotide specificity caused by a shift in nucleotide binding position by one phosphate unit, and identification of the residues that discriminate ADP- and ATP-dependence. The strict conservation of the binding site for the terminal and adjacent phosphate moieties suggests a common ancestral origin of both the ATP- and ADP-dependent kinases.