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).

First Direct Mass Measurements of Nuclides around Z=100 with a Multireflection Time-of-Flight Mass Spectrograph.

The masses of ^{246}Es, ^{251}Fm, and the transfermium nuclei ^{249-252}Md and ^{254}No, produced by hot- and cold-fusion reactions, in the vicinity of the deformed N=152 neutron shell closure, have been directly measured using a multireflection time-of-flight mass spectrograph. The masses of ^{246}Es and ^{249,250,252}Md were measured for the first time. Using the masses of ^{249,250}Md as anchor points for α decay chains, the masses of heavier nuclei, up to ^{261}Bh and ^{266}Mt, were determined. These new masses were compared with theoretical global mass models and demonstrated to be in good agreement with macroscopic-microscopic models in this region. The empirical shell gap parameter δ_{2n} derived from three isotopic masses was updated with the new masses and corroborates the existence of the deformed N=152 neutron shell closure for Md and Lr.

Effectiveness of Bortezomib in a Patient With Acute Rejection Associated With an Elevation of Donor-Specific HLA Antibodies After Small-Bowel Transplantation: Case Report.

BACKGROUND: A significant association between donor-specific antibody (DSA) and graft rejection has recently been documented. However, confirmed strategy has not been established for DSA-associated rejection after intestinal transplantation (ITx). CASE REPORT: A 20-year-old male patient with chronic intestinal obstruction caused by hypoganglionosis of the entire intestine underwent cadaveric donor ITx with grafting performed on 232 cm of the small intestine, cecum, and a part of the ascending colon. On post-operative day (POD) 14, a histological evaluation showed an acute rejection of indeterminate grade. The patient had severe acute rejection on POD 16, which prompted us to administer bolus steroids and polyclonal anti-thymocyte antibody, along with baseline maintenance immunosuppression. The histopathological findings of the graft indicated typical acute cellular rejection, although C4d was positive. We then detected donor-specific HLA antibody. The patient initially responded well to the therapy and showed decreased histological rejection signs. However, the refractory low-grade rejection persisted in the graft. During this period, the patient showed increased levels of DSA, and we speculated that the persistent rejection was associated with DSA; thus, bortezomib was administered at this stage as a salvage therapy. This rejection was thereafter successfully controlled without severe adverse effect. Twenty-three months after ITx, the patient is currently alive with complete enteral autonomy. CONCLUSIONS: A case of acute graft rejection followed by a marked elevation of DSA is presented. In this particular case, a modified treatment protocol using bortezomib in addition to the typical immunosuppressive agents was effective.

Characterization of a novel bacteriophage, Phda1, infecting the histamine-producing Photobacterium damselae subsp. damselae.

AIMS: Photobacterium damselae subsp. damselae is a potent histamine-producing micro-organism. The aim of this study was to isolate and characterize a bacteriophage Phda1 that infected P. damselae subsp. damselae to inhibit its growth and histamine accumulation. METHODS AND RESULTS: Phda1 was isolated from a raw oyster, and the host range, morphology and the bacteriophage genome size were analysed. Phda1 formed a clear plaque only against P. damselae subsp. damselae JCM8969 among five Gram-positive and 32 Gram-negative bacterial strains tested. Phda1 belongs to the family Myoviridae, and its genome size was estimated as 35·2-39·5 kb. According to the one-step growth curve analysis, the latent period, rise period and burst size of Phda1 were 60 min, 50 min and 19 plaque-forming units per infected cell, respectively. Divalent cations, especially Ca(2+) and Mg(2+) , strongly improved Phda1 adsorption to the host cells and its propagation. Phda1 treatment delayed the growth and histamine production of P. damselae subsp. damselae in an in vitro challenge test. CONCLUSIONS: The bacteriophage Phda1 might serve as a potential antimicrobial agent to inhibit the histamine poisoning caused by P. damselae subsp. damselae. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first description of a bacteriophage specifically infecting P. damselae subsp. damselae and its potential applications. Bacteriophage therapy could prove useful in the prevention of histamine poisoning.

Nuclear chemistry. Synthesis and detection of a seaborgium carbonyl complex.

Experimental investigations of transactinoide elements provide benchmark results for chemical theory and probe the predictive power of trends in the periodic table. So far, in gas-phase chemical reactions, simple inorganic compounds with the transactinoide in its highest oxidation state have been synthesized. Single-atom production rates, short half-lives, and harsh experimental conditions limited the number of experimentally accessible compounds. We applied a gas-phase carbonylation technique previously tested on short-lived molybdenum (Mo) and tungsten (W) isotopes to the preparation of a carbonyl complex of seaborgium, the 106th element. The volatile seaborgium complex showed the same volatility and reactivity with a silicon dioxide surface as those of the hexacarbonyl complexes of the lighter homologs Mo and W. Comparison of the product's adsorption enthalpy with theoretical predictions and data for the lighter congeners supported a Sg(CO)6 formulation.

Gypsy embryo specifies ovule curvature by regulating ovule/integument development in rice.

The embryo position in a seed is stable in most plant species, indicating the existence of a strict regulatory mechanism that specifies the embryo position in the seed. To elucidate this mechanism, we analyzed the gypsy embryo (gym) mutant of rice, in which the position of the mature embryo in the seed is altered at a low frequency. Analyses of early embryogenesis and ovule development showed that the ectopic embryo was derived from an ill-positioned egg cell, which resulted from the incomplete curvature of the ovule. Although the development of both the inner and outer integuments was impaired, the ovule curvature was associated closely with the extent of inner integument growth. Therefore, inner integument development controls ovule curvature in rice. The expression patterns of OSH1 and OsMADS13 indicated that, in gym, a small number of indeterminate cells are maintained on the style side of the ovule and then in the integument primordium at a low frequency. The prolonged survival of these indeterminate cells disturbs normal integument development. The gym fon2 double mutant suggests that GYM and FON2 are involved redundantly in floral meristem determinacy. Possible functions of the GYM gene and the ovule developmental mechanism are discussed.

Advantages of oxygen inhalation therapy for postoperative pulmonary hypertension.

Total correction was performed in a case of complete transposition of the great arteries (TGA) with severe pulmonary vascular obstructive disease (PVOD). Although severe pulmonary hypertension remained after surgery, oxygenation was continued for 15 months, which included a shift to at-home oxygen inhalation therapy (HOT). Cardiac catheterization 15 months after surgery demonstrated that pulmonary hypertension was greatly improved. For patients in whom the palliative Mustard operation is considered due to severe PVOD on the basis of lung biopsy diagnosis, total correction of TGA is possible by employing HOT after surgery.

Pulmonary vascular changes induced by unilateral pulmonary venous obstruction.

The relation of pulmonary hemodynamics to pathological change in the pulmonary vasculature was examined in a model of unilateral pulmonary venous (PV) obstruction. The left upper pulmonary vein (A group, n=6) or both the left upper and left lower pulmonary veins (B group, n=6) of two-week-old piglets were banded; the control group (n=6) was sham operated. At eight weeks after PV banding, mean pulmonary arterial pressure was highest in the B group, intermediate in the A group and lowest in the control group. In all groups, the media of the pulmonary artery was equally thickened in both lungs, whereas the media of the pulmonary vein was thickened only in those lung lobes having stenotic pulmonary veins. For all animals from three groups, left pulmonary arterial wedge pressure (PAWP) correlated with medial thickness of the pulmonary arteries of the right lung (r=0.76, p=0.003), the left upper lobe (r=0.54, p<0.03), the left lower lobe (r=0.49, p=0.04). This finding suggests that the pathogenesis of PAWP-related medial thickening of the bilateral lung pulmonary artery begins with the sensing by the bilateral lung of PV pressure buildup in the unilateral lung.

Selective attachment of pyrenyl groups to ethylene-co-vinyl acetate copolymers: dynamic and static fluorescence studies.

Micromorphology is an important factor in determining polymer properties and uses. Here, steady-state and dynamic fluorescence from covalently attached 1-alkylpyrenyl groups are used to investigate the micromorphology of several random ethylene-co-vinyl acetate (EVA) copolymers with defined compositions of vinyl acetate monomer. The results are compared with those from homopolymers of high- and low-density polyethylenes and poly(vinyl acetate). Selective attachment of pyren-1-yl groups to polymer chains was accomplished by irradiation of pyren-1-yldiazomethane sorbed into polymer films. Steady-state fluorescence spectra and fluorescence decay rates of attached pyrenyl groups in films of the polymers have been compared with those from films with sorbed pyrene. I1/I3 intensity ratios from vibrational bands in the fluorescence spectra and the fluorescence decay rates of attached 1-alkylpyrenyl groups are much less sensitive to changes in the copolymer composition than are those of pyrene. These observations suggest that attachment occurs selectively to the olefinic segments (rather than to the acetate-rich regions) of polymer chains of EVA copolymers. This conclusion is consistent with the known preferences for reaction by pyren-1-ylcarbene in solution.

Reduction in recalcitrant pulmonary hypertension after operation for atrial septal defect.

We present the case of a patient with atrial septal defect and severe pulmonary hypertension with pulmonary artery peak pressure greater than 110 mm Hg. Open lung biopsy was done prior to the corrective operation, and pathological findings in the small pulmonary arteries included "musculoelastosis" and complete occlusion of 70% of these small arteries and arterioles. The atrial septal defect was closed, and long-term oral prostacyclin therapy was initiated. Pulmonary artery peak pressure decreased to 65 mm Hg 2 years after the operation. This case demonstrates that in a patient with 70% complete occlusion of small pulmonary arteries and arterioles resulting from "musculoelastosis," not only is surgical intervention possible but also pulmonary artery pressure decreases in the long term after operation.

Hypoxia and cold stress on pulmonary venous obstruction.

Hemodynamic changes induced by hypoxia and cold stress were examined on the model of pulmonary venous obstruction (PVO) to investigate the mechanism of pulmonary hypertensive crisis. Bilateral pulmonary venous stenosis was surgically created in 7 newborn piglets of the PVO group. Sham operations were performed on 6 piglets of the control group. Following the baseline hemodynamic measurement (FiO2 = 0.3) at 8 weeks after the operation, the piglets were exposed to hypoxia (FiO2 = 0.14) for 10 minutes, and were also exposed to cold stress for 20 minutes. Hypoxia significantly increased mean pulmonary arterial pressure in the PVO group. Hypoxia increased not only pulmonary arterial resistance, but also pulmonary venous resistance in the PVO group. Cold stress did not change pulmonary arterial resistance or pulmonary venous resistance in each group. In the lungs of the PVO group, the medial muscular layer of the pulmonary arteries and pulmonary veins were thickened. This probably accelerates hypoxia-induced vasoconstriction, which in turn increases pulmonary arterial and venous resistances.

[Indication for lung biopsy and usefulness of lung biopsy].

The criteria of open lung biopsy for operative indication were determined on the basis of hemodynamics in each congenital cardiac anomalies with pulmonary hypertension. More than 10.6, 8 and 8 units. m2 of pulmonary vascular resistance (PVR) were considered as indication for open lung biopsy in the patients with complete transposition of the great arteries, complete atrioventricular canal defect and atrial septal defect respectively. Lung biopsy should be done in patients with ventricular septal defect when PVR is more than 8 units. m2 and if it is greater than 4 with the oxygen inhalation test or 6 with the Tolazoline test. The usefulness of lung biopsy was also emphasized on the basis of the postoperative result in which lung biopsy diagnosis has been done.

Molecular cloning of beta-galactosidase from Japanese pear (Pyrus pyrifolia) and its gene expression with fruit ripening.

We have cloned a cDNA fragment encoding a beta-galactosidase from Japanese pear (Pyrus pyrifolia) fruit (JP-GAL). It contained an untranslated sequence of 182 nucleotides at the 5' end, a presumptive coding sequence of 2,193 nucleotides and an untranslated sequence of 268 nucleotides including a polyadenylation signal and a poly (A) tail at the 3' end. It encoded a protein with a calculated molecular weight of 80.9 kDa which consists of 731 amino acids. Both the nucleotide and the deduced amino acid sequences showed a 98% sequence identity with that obtained from the apple beta-galactosidase cDNA. The peptide sequence obtained from the purified Japanese pear beta-galactosidase III matched the deduced amino acid sequence of SVSYDHKAIIINGQKRILISG (amino acid 25-45). Northern blot analysis showed that the probe derived from JP-GAL hybridized to a single 2.6 kb RNA. The mRNA was detected solely in the fruit; none was detected in the buds, leaves, roots or shoots of the Japanese pear. The steady-state level of the beta-galactosidase mRNA was measured during fruit ripening in three cultivars, Housui, Kousui (early ripening) and Niitaka (late ripening). The results showed that regardless of the cultivar, no JP-GAL mRNA was detected in the immature fruit. Increment of the mRNA level with fruit ripening coincided with the increase in the beta-galactosidase III activity. Our results showed that the expression of JP-GAL correlated with fruit softening and JP-GAL may be beta-galactosidase III.

Pulmonary vascular disease in Down's syndrome with complete atrioventricular septal defect.

We sought to determine the predisposing factors of pulmonary vascular disease (PVD) in complete atrioventricular septal defect. Down's syndrome is considered a risk factor for PVD, but the progression of PVD differs in each case. Morphometric analysis in autopsied hearts showed that Rastelli type A morphology had a narrower left ventricular outlet and a wider right ventricular outlet than did type C. In 81 consecutive patients with Down's syndrome who underwent cardiac catheterization, we estimated the following variables: Rastelli subtypes, pulmonary vascular resistance, pulmonary-to-systemic flow ratio, patients' age, and operative outcome. The hemodynamic variables in those <1 year old did not differ between the groups with type A and type C. However, all 5 patients with fatal pulmonary hypertension in early infancy had type A morphology. The lung histology revealed that 3 of these patients already had irreversible PVD. At >/=1 year old, those with type A showed a significantly higher pulmonary vascular resistance (p <0.001) and a lower pulmonary to systemic flow ratio (p <0.05) than did those <1 year old. In contrast, neither of these variables in the type C group differed between those >/=1 and <1 year old. Moreover, those with type A had a greater risk of being contraindicated for surgical repair (p <0.05). We suspect, therefore, that type A morphology is an independent risk factor for PVD in those with Down's syndrome associated with this anomaly. This hemodynamic influence could become obvious once patients are >/=1 year old. It may also sometimes result in irreversible PVD even in early infancy.

Purification and characterization of a NAD+-dependent sorbitol dehydrogenase from Japanese pear fruit.

NAD+-dependent sorbitol dehydrogenase NAD-SDH, EC 1.1.1.14) from Japanese pear fruit was purified to apparent homogeneity (single band by SDS-PAGE with silver staining), and had a specific activity of 916.7 nKatal/mg protein. The molecular of the native enzyme was calculated to be 160 kDa by gel filtration, whereas SDS-PAGE gave a subunit size of 40 kDa, indicating that the native enzyme is a homotetramer. The protein immunologically reacted with an antibody raised in rabbit against the fusion protein expressed in E. coli harboring an apple NAD-SDH cDNA. The Km, values for sorbitol and fructose were 96.4+/-8.60 and 4239+/-33.5 mM, respectively, and optimum pH for sorbitol oxidation was 9.0 and 7.0 for fructose reduction. Pear NAD-SDH had a very narrow substrate specificity, that is, sorbitol, L-iditol, xylitol and L-threitol were oxidized but not any of the other alcohols tested. These data suggest the structural importance of an S configuration at C-2 and an R configuration at C-4 in the substrate(s). Its enzymatic activity was strongly inhibited both by heavy metal ions such as mercury, and by thiol compounds, such as L-cysteine. However, the addition of zinc ion reversed the enzyme inactivation caused by addition of L-cysteine.

Purification and characterization of two sucrose synthase isoforms from Japanese pear fruit.

Two isoforms (SS I and SS II) of sucrose synthase (SS; EC 2.54.1.13) were purified from Japanese pear fruit and their properties were compared. SS I mainly appeared in young fruit and SS II mainly in mature fruit. SS I and SS II were purified to the specific activity of 3.37 and 4.26 (units (mg protein)(-1)), respectively. The MW of native and subunit proteins of SS I and SS II were almost the same and both SSs seemed to be a tetramer composed of an 83 kDa polypeptide. However, the ionic charges of the native proteins and the kinetic parameters of SSs were different. Specifically, the Km value for UDP-glucose in SS I was the same as that for UDP, while the Km value for UDP-glucose in SS II was less than that for UDP. SS II easily reacted for sucrose synthesis than sucrose cleavage compared with SS I. Therefore, it is considered that SS I and SS II play different roles in the utilization of carbohydrate in young and mature fruit, respectively.

Pulmonary vascular changes induced by congenital obstruction of pulmonary venous return.

BACKGROUND: Pulmonary venous obstruction (PVO) induces pulmonary arterial hypertension, as well as pulmonary venous hypertension, and jeopardizes the repair of cardiac lesions. METHODS: Four cases of congenital mitral stenosis and 4 cases of cor triatriatum (Lucas type A), ages ranging from 2 months to 16 years, were histologically examined on pulmonary vasculature. Histometrical analysis was performed on medial thickness and intimal changes of both pulmonary arteries and veins. For comparison, the examination of pulmonary vasculature in ventricular septal defect (VSD) cases was also performed. RESULTS: Medial thickening and intimal fibrosis, in both pulmonary arteries and veins with widespread lymphangiectasia, were characteristic vascular changes of PVO cases. Medial thickness of pulmonary arteries was correlated with preoperative pulmonary arterial pressure (PAP) (r = 0.77, p = 0.03 for systolic PAP), and greater than that of VSD cases. Medial thickness of pulmonary veins was also greater in PVO cases. Intimal fibrosis of pulmonary arteries and veins was seen extensively at the advanced ages, whereas no plexiform lesions or more advanced stages of pulmonary vascular disease were present. CONCLUSIONS: Congenital PVO induced progressive medial thickening and intimal fibrosis in pulmonary arteries and veins accompanied by lymphangiectasia. However, no plexiform lesions or more advanced stages of pulmonary vascular disease were present, which may explain the reversibility of pulmonary hypertension due to congenital PVO.

Extremely thickened media of small pulmonary arteries in fatal pulmonary hypertension with congenital heart disease--a morphometric and clinicopathological study.

There are patients with congenital heart disease and fatal pulmonary hypertension in whom the medial hypertrophy of the small pulmonary arteries is quite beyond the extent of ordinary cases of hypertension, a condition described as pulmonary hypertension with extremely thickened media of small pulmonary arteries (PH/ETM). Lungs from 6 infants, all younger than 2 years of age, who had congenital heart disease and fatal pulmonary hypertension, were analyzed by accurately measuring the media using Suwa's method. In PH/ETM, the media of the small pulmonary arteries was shown to be not only unusually thick, but extending toward the periphery, whereas the intimal changes were unexpectedly mild. In the PH/ETM group, the % wall thickness at a diameter of 50 microm (%Tw(50)), determined from regression analysis, was 23.2+/-1.3%, which was significantly higher than in either the control (10.3+/-1.2%) or ventricular septal defect group (18.9+/-1.6%). In persistent pulmonary hypertension of the newborn (PPHN), it was 22.3+/-1.8%, not significantly different from PH/ETM. The striking medial hypertrophy in PH/ETM and PPHN was apparently confined to small pulmonary arteries and in both conditions is likely to be the result of maldevelopment of these arteries. Surgical intervention may trigger a critical elevation of the pulmonary arterial resistance.

Structural relationship of kappa-type light chains with AL amyloidosis: multiple deletions found in a VkappaIV protein.

Two amyloidogenic Bence Jones proteins (Am37 VkappaIV and NIG1 VkappaI) and one non-amyloidogenic protein (NIG26 VkappaIII) were characterized. The protein Am37 had four deletions when compared with the translated germ-line gene sequence: two Ser residues following position 27 (27e, 27f) in CDR1 and two amino acids Pro-44, and Tyr-49 in FR2 were deleted. A strictly conserved salt-bridge-forming amino acid, Asp-82, was replaced by the hydrophobic residue Leu. In a comparative study of amyloidogenic and non-amyloidogenic proteins, five amino acids (Ser-10, Ala-13, Ser-65, Gln-90, and Ile-106) were found to be unique to NIG1 and several other amyloidogenic proteins. Additional substitutions also occur within these proteins. These substitutions might be significant in altering protein folding as well as in contributing to their aggregation as amyloid fibrils.

Molecular cloning of vacuolar H(+)-pyrophosphatase and its expression during the development of pear fruit.

The cDNA of vacuolar proton-translocating inorganic pyrophosphatase was cloned from pear fruit. It contained an open reading frame of 2,301 nucleotides, coding for a polypeptide of 767 amino acids. The level of mRNA was very low in young fruit and increased with maturation, differing from the changes in the level of polypeptide.