Multicentre study of perioperative versus adjuvant chemotherapy for resectable colorectal liver metastases.

Background: It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM. Methods: Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS. Results: Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16; P = 0·318). For the subgroup of 165 patients who received adjuvant FOLFOX successfully (for at least 3 months), the adjusted effect of neoadjuvant chemotherapy was not significant (HR 1·19, 0·74 to 1·90; P = 0·476). No significant effect of neoadjuvant chemotherapy was observed in multivariable regression analysis. Conclusion: Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully.

Antecedentes: Se desconoce si la quimioterapia perioperatoria en comparación con la quimioterapia adyuvante sola mejora la supervivencia libre de enfermedad (disease­free survival, DFS) en pacientes con metástasis hepáticas de origen colorrectal (colorectal liver metastases, CLM) resecables de inicio. El objetivo de este estudio fue estimar el impacto de la neoadyuvancia con 5­fluorouracilo, leucovorina y oxaliplatino (FOLFOX) sobre la DFS en pacientes con CLM resecables desde el principio. Métodos: Se incluyeron pacientes consecutivos que presentaban hasta cinco CLM resecables en dos centros japoneses y dos centros franceses entre 2008 a 2015. Ambas instituciones francesas favorecían FOLFOX perioperatorio, mientras que los dos grupos japoneses utilizaban sistemáticamente la cirugía de entrada y quimioterapia adyuvante. Se utilizaron la probabilidad inversa del tratamiento ponderado (Inverse Probability of Treatment Weighting, IPTW) y el modelo multivariable de regresión de Cox para ajustar por factores de confusión. El resultado primario fue la DFS. Resultados: Se incluyeron 300 pacientes (grupo de quimioterapia perioperatoria n = 151 y grupo de cirugía de entrada más quimioterapia adyuvante n = 149). La DFS a los 3 años ponderada fue del 33% después de quimioterapia perioperatoria versus 27% tras cirugía de entrada (cociente de riesgos instantáneos, hazard ratio HR: 0,85; i.c. del 95% (0,62­1,16); P = 0,32). Cuando se consideró el subgrupo de pacientes que (n = 165) de manera efectiva (al menos 3 meses) recibieron FOLFOX adyuvante, el efecto ajustado de la quimioterapia neoadyuvante no fue significativo (HR: 1,19 (0,74­1,90); P = 0,48). No se observó un efecto significativo de la quimioterapia neoadyuvante en el análisis de regresión multivariable. Conclusión: En comparación con la quimioterapia adyuvante, el FOLFOX perioperatorio no mejora la DFS en CLM resecables siempre y cuando la quimioterapia adyuvante se administre de forma efectiva.

Effects of mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, on N-type calcium channel currents of rat dorsal root ganglion culture neurons.

Mirogabalin, which is a novel ligand for the α2δ subunit of voltage-gated calcium channels, is being developed for treating neuropathic pain including diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique α2δ subunit binding characteristics and has potent and long-lasting analgesic effects in neuropathic pain models. In the present study, we investigated the effects of mirogabalin on N-type calcium channel currents of the rat dorsal root ganglion (DRG) culture neurons using the whole-cell patch clamp technique. Small or medium DRG neurons were isolated from Sprague-Dawley rats and were incubated for 20 to 24 h with mirogabalin or pregabalin. The DRG neurons were depolarised from a holding potential of -40 mV to +40 mV in steps of 10 mV for 220 ms, and elicited N-type calcium channel currents were recorded. The N-type calcium channel currents were verified by sensitivity to ω-conotoxin GVIA, a selective N-type calcium channel blocker. Mirogabalin inhibited the calcium channel currents of rat DRG neurons at 50 µM, and pregabalin inhibited them at 200 µM. Mirogabalin and pregabalin showed significant differences in the peak current densities at depolarisation to -20 and -10 mV when compared with that shown by the vehicle control. In conclusion, mirogabalin inhibits N-type calcium channel currents in rat DRG culture neurons. The potent and long-lasting analgesic effects of mirogabalin are thought to be associated with its potent and selective binding to α2δ-1 subunits and following functional inhibition of calcium channel currents.

Analgesic effects of the novel α2δ ligand mirogabalin in a rat model of spinal cord injury.

Mirogabalin, which is a novel ligand for the α2δ subunit of voltage-gated calcium channels, is under development for the treatment of pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique binding characteristics to α2δ subunits and potent and long-lasting analgesic effects in peripheral neuropathic pain models. In the present study, we investigated the analgesic effects of mirogabalin in a rat model of spinal cord injury as an experimental animal model for central neuropathic pain. The spinal cord injury model was established by acute compression of the spinal cord at the T6/7 level with a microvascular clip in male rats. Twenty-eight days after spinal cord injury, the animals received the test compound orally, and the paw withdrawal threshold to mechanical stimulation was determined using the von Frey test at 0 (before administration), 2, 4, 6, 8, and 24 h after administration. The area under the curve of the paw withdrawal threshold (paw withdrawal threshold AUC) was also calculated. In rats subjected to spinal cord injury, mechanical allodynia was demonstrated by a decreased paw withdrawal threshold. A single oral administration of mirogabalin (2.5, 5, or 10 mg/kg) significantly increased the paw withdrawal threshold. The effects of mirogabalin were still significant 6 or 8 h after administration. The paw withdrawal threshold AUC was significantly higher in the treated animals than in the control group. In conclusion, mirogabalin showed potent and long-lasting analgesic effects in a rat model of spinal cord injury and may therefore provide effective pain relief for patients with central neuropathic pain.

Re-evaluation of stomach position as a simple prognostic factor in fetal left congenital diaphragmatic hernia: a multicenter survey in Japan.

OBJECTIVES: To document outcome and to explore prognostic factors in fetal left congenital diaphragmatic hernia (CDH). METHODS: This was a multicenter retrospective study of 109 patients with prenatally diagnosed isolated left CDH born between 2002 and 2007. The primary outcome was intact discharge, defined as discharge from hospital without major morbidities, such as a need for respiratory support including oxygen supplementation, tube feeding, parenteral nutrition or vasodilators. All patients were managed at perinatal centers with immediate resuscitation, gentle ventilation (mostly with high-frequency oscillatory ventilation) and surgery after stabilization. Prenatal data collected included liver and stomach position, lung-to-head ratio, gestational age at diagnosis and presence or absence of polyhydramnios. Stomach position was classified into four grades: Grade 0, abdominal; Grade 1, left thoracic; Grade 2, less than half of the stomach herniated into the right chest; and Grade 3, more than half of the stomach herniated into the right chest. RESULTS: Overall intact discharge and 90-day survival rates were 65.1% and 79.8%, respectively. Stomach herniation was classified as Grade 0 in 19.3% of cases, Grade 1 in 45.9%, Grade 2 in 13.8% and Grade 3 in 21.1%. Multivariate analysis revealed that liver position was the strongest prognostic variable for intact discharge, followed by stomach position. Based on our results, we divided patients into three groups according to liver (up vs. down) and stomach (Grade 0-2 vs. Grade 3) position. Intact discharge rates declined significantly from liver-down (Group I), to liver-up with stomach Grade 0-2 (Group II), to liver-up with stomach Grade 3 (Group III) (87.0%, 47.4% and 9.5% of cases, respectively). CONCLUSION: Current status and outcomes of prenatally diagnosed left CDH in Japan were surveyed. Stomach herniation into the right chest was not uncommon and its grade correlated with outcome. The combination of liver and stomach positions was useful to stratify patients into three groups (Group I-III) with different prognoses.

Fetal pleuroamniotic shunting for bronchopulmonary sequestration with hydrops.

Bronchopulmonary sequestration (BPS), a non-functional pulmonary tissue mass, when complicated by fetal hydrops, carries a high risk of perinatal mortality. However, a limited number of cases of BPS complicated by fetal hydrops with an informative clinical course have been reported. We report here on three cases of BPS complicated by fetal hydrothorax and hydrops that were successfully treated by pleuroamniotic shunting, which should be considered as a treatment option for fetal hydrothorax and hydrops associated with BPS.

Isocyano compounds as non-toxic antifoulants.

The marine sponge Acanthella cavernosa and nudibranchs of the family Phyllidiidae contain isocyanoterpenoids and their related compounds that show potent antifouling activity against cypris larvae of the barnacle Balanus amphitrite, while their toxicity to cyprids is weak. To develop non-toxic antifoulants based on isocyanoterpenoids, especially 3-isocyanotheonellin, a total of 36 isocyano compounds have been synthesized. They were evaluated by both antifouling activity and toxicity toward B. amphitrite cyprids, which led some insight into the structure-activity relationships. Since linear alkyl isocyanides showed antifouling activity at nontoxic concentrations, a large amount of 1,1-dimethyl-10-undecyl isocyanide was synthesized, incorporated into paints, and tested for antifouling activity in the field with promising results. Therefore, isocyano compounds were considered as candidate non-toxic antifouling agents.

Prenatal diagnosis of fetal hydrometrocolpos secondary to a cloacal anomaly by magnetic resonance imaging.

Fetal female urogenital anomalies are often difficult to evaluate by ultrasonography, especially in late gestation. We report a case of fetal hydrometrocolpos detected at 35 weeks of gestation. Ultrasonography revealed a large retrovesical septate hypoechogenic mass in the fetal abdomen, however the sonographic findings were inconclusive. Magnetic resonance imaging (MRI) confirmed that the abdominal mass was fluid-filled with a mid-plane septum in the midline posterior to the bladder, and showed a connection to the dilated uterus that was duplicated. These findings were consistent with a diagnosis of hydrometrocolpos with septate vagina and uterus didelphys. The neonate showed abdominal distension, ambiguous genitalia and anal atresia with a single perineal opening. Hydrometrocolpos was secondary to a urethral type of cloacal anomaly. Aspiration of the mass and a colostomy were performed on the first postnatal day, followed by anorectoplasty at 19 months of age. MRI is a useful complementary tool for assessing fetal urogenital anomalies when ultrasonography is inconclusive.

Combined fibrolamellar carcinoma and cholangiocarcinoma exhibiting biphenotypic antigen expression: a case report.

Fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC), very rarely occurs in association with cholangiocarcinoma (CC). This report describes the first case of FLC coexisting with CC (FLC-CC) from Japan. Although the major part of the tumour located in the right lobe of the liver showed the typical features of FLC, CC was admixed with the FLC, not only in the primary hepatic tumour, but also in the lymph node metastases. Immunohistochemical analysis revealed that, although carcinoembryonic antigen (CEA), which can be detected with monoclonal antibodies in the cytoplasm and the cell surface of CC cells but not HCC cells, was expressed in only the CC cells in the primary tumour, it was expressed extensively in the cytoplasm of both CC and FLC cells in the metastatic and recurrent tumours. Furthermore, Hep Par 1, a hepatocyte specific antigen, was also expressed in both the FLC and CC cells. These findings suggest that, in this case, both FLC and CC were possibly derived from the same cancer stem cell with the capacity to differentiate into both hepatocytes and bile duct epithelium, and that both the cellular components, therefore, exhibited biphenotypic antigen expression.

The mechanism of epidermal hyperpigmentation in café-au-lait macules of neurofibromatosis type 1 (von Recklinghausen's disease) may be associated with dermal fibroblast-derived stem cell factor and hepatocyte growth factor.

BACKGROUND: The mechanism of the accentuated melanization in café-au-lait macules (CALMs) in patients with neurofibromatosis type 1 (NF1; von Recklinghausen's disease) has not been elucidated. OBJECTIVES: To clarify the mechanism involved in the hyperpigmentation of CALMs in NF1. METHODS: Using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of cultured cells, we measured the levels of cytokines produced and secreted by keratinocytes and fibroblasts derived from CALMs (group RC: Recklinghausen CALM) skin, compared with cells derived from the skin of normal individuals (group NN: Normal skin of Normal individuals) and cells derived from non-CALM skin of NF1 patients (group RN: Recklinghausen Non-CALM). RESULTS: ELISA revealed that the secretion of hepatocyte growth factor (HGF) and stem cell factor (SCF) by cultured fibroblasts was significantly elevated in group RC compared with groups RN and NN. In parallel, semiquantitative real-time RT-PCR of HGF and SCF mRNAs demonstrated increased expression of both types of transcripts by cultured fibroblasts in group RC compared with group NN. In contrast, the secretion of endothelin-1 and granulocyte/macrophage colony-stimulating factor by cultured keratinocytes occurred at a similar level among all three groups, RC, RN and NN. CONCLUSIONS: These findings suggest that increased secretion of HGF and SCF by dermal fibroblasts may be associated with the accentuated epidermal melanization observed in CALMs in the skin of NF1 patients.

Pulmonary epithelial cell maturation in hyperplastic lungs associated with fetal tracheal agenesis.

BACKGROUND/PURPOSE: Cellular differentiation of pulmonary hyperplasia has not been reported in human cases. The authors studied surfactant protein expression and ultrastructure of pulmonary epithelial cells in fetal hyperplastic lungs associated with congenital tracheal agenesis. METHODS: The maturation of pulmonary epithelial cells was assessed by immunohistochemical examination for surfactant proteins (SP-A, mature SP-B, proSP-B, proSP-C, and SP-D) and transmission electron microscopy. As controls normal lung portions of 8 fetuses born at 21 weeks gestation were used. RESULTS: Mature SP-B and SP-D was detected in terminal airways in this case, but not in controls. In electron microscopy, lamellar bodies were recognized, and glycogen granules were less abundant in terminal airway cells. CONCLUSION: The differentiation of pulmonary epithelial cells appeared to be more advanced for the gestational age in pulmonary hyperplasia with congenital tracheal agenesis. J Pediatr Surg 36:1845-1848.

Effects of all-trans retinoic acid on melanogenesis in pigmented skin equivalents and monolayer culture of melanocytes.

The effects of all-trans retinoic acid (RA) on melanogenesis and the mechanism of its action in topical treatment have not been elucidated. The purpose of this study was to determine the effects of RA on melanogenesis in the pigmented skin equivalent as well as in monolayer culture of melanocytes, and to determine whether RA, hydroquinone (HQ), and hydrocortisone (HC) show synergistic depigmenting effects in combined treatments of each other. The suppressing effect of RA on melanogenesis was not observed in pigmented skin equivalents and monolayer culture of murine and human melanocytes, although HQ showed strong inhibition of melanogenesis. The synergistic effects between RA, HQ, and HC were not particularly seen. The results suggested that RA neither has direct inhibitory effects on melanogenesis of melanocytes, nor influences the cell-cell interactions between melanocytes, keratinocytes and fibroblasts, such as paracrine actions with regard to melanin production. The role of RA in bleaching treatments appears to be in other specific actions, such as promotion of keratinocytes proliferation and acceleration of epidermal turnover.

Effect of procainamide on the postrepolarization refractoriness in cardiac muscle: evaluation using the block coupling interval in the artificial isthmus model in the canine right atrium.

The post-repolarization refractoriness (PRR) is an important factor to determine the conduction block in cardiac muscle. Recently, we proposed the block coupling interval (BCI) as an useful electrophysiological index for evaluating the PRR. In the present study, the effect of procainamide on PRR was evaluated using the BCI and the effective refractory period (ERP). In five beagle dogs, radiofrequency linear ablation was performed on the right atrial surface parallel to the AV groove, forming an artificial isthmus (8-10 mm width and 15-20 mm length). Bipolar recordings were performed in the isthmus at a resolution of 1.2 mm and single extrastimuli with eight basic drive trains were delivered to cause conduction blocks in the isthmus. When a conduction block occurred, the recorded coupling interval at the recording site just proximal to the site of block was defined as BCI. At the site of the block, the ERP and duration of the monophasic action potential (MAP) at each drive cycle length was measured. The PRR was calculated using two different formulas: (1) [ERP-MAP] and (2) [BCI-MAP]. Procainamide was administrated intravenously at a dose of 15 mg/kg after the control study and the whole study protocol was repeated. The site of the block in an individual dog was always the same. BCI, ERP, and MAP were all shortened in accordance with the shortening of the basic drive cycle length, and the BCI was always the longest, ERP the middle, and the MAP was the shortest. The administration of procainamide prolonged each parameter, but the order of BCI > ERP > MAP remained unchanged. The PRR calculated as [BCI-MAP] was prolonged from 15 +/- 10 ms to 29 +/- 8 ms by the administration of procainamide (P = 0.048), but [ERP-MAP] was unchanged (8 +/- 10 ms vs 8 +/- 4 ms). In the conduction block model in the canine right atrium, procainamide prolonged the [BCI-MAP], but did not change the [ERP-MAP]. The procainamide effect of prolonging the PRR might be expressed better by the change in the BCI than the ERP.

Single vaginal ectopic ureter and renal hypoplasia associated with urogenital sinus and abdominal muscular hypoplasia-a novel subtype of prune-belly syndrome in a female child?

We report a rare case that can be classified as prune-belly syndrome in a female. This patient came to our attention during the 19th week of gestation when massive ascites was found by ultrasound and the mother was transferred to our hospital. After birth, it was demonstrated that the infant had complicated anomalies, including abdominal muscular hypoplasia, urogenital sinus, a single, right-sided vaginal ectopic ureter, and hypoplasia of the right kidney. A sibling had a right hypoplastic kidney and right vesicoureteral reflux. Considering the combination of anomalies and the family history of urinary tract disease, her anomalies could be attributed to a genetic mutation.

Benzylic intermolecular carbon-carbon bond formation by selective anodic oxidation of dithioacetals.

[reaction: see text]. Novel anodic intermolecular carbon-carbon bond formation has been accomplished by the oxidative carbon-sulfur bond fission of benzylic dithioacetals to give a wide variety of aromatic compounds. The substitution reaction successfully took place by the selective anodic oxidation of a sulfur atom of a dithioacetal. Stepwise double-substitution reactions were also achieved by the regulation of oxidation potential.

Fetal tracheal occlusion in the rat model of nitrofen-induced congenital diaphragmatic hernia: tracheal occlusion reverses the arterial structural abnormality.

BACKGROUND/PURPOSE: The high mortality rate of congenital diaphragmatic hernia (CDH) is ascribed generally to pulmonary hypoplasia and persistent pulmonary hypertension characterized by associated pulmonary arterial structural changes. Prenatal tracheal occlusion (TO) accelerates lung growth, but the effect of TO on pulmonary arterial structure in CDH has not been well defined. The authors hypothesized that TO could reverse the pulmonary arterial structural changes observed in CDH. To address this hypothesis, we utilized the nitrofen-induced rat model of CDH to examine the effect of TO on pulmonary arterial morphology of CDH lungs. METHODS: Left-sided CDH was induced by administering 100 mg of nitrofen to pregnant Sprague-Dawley rats on day 9 of gestation. TO was performed on day 19, and the fetuses were harvested on day 21.5 of gestation. After the ductus arteriosus was ligated, the pulmonary arteries were injected with a barium-gelatin mixture, and the lungs were inflation fixed. Coronal sections of the lungs were stained with elastin van Gieson. External diameter (ED), internal diameter (ID), and medial and adventitial wall thickness of the pulmonary arteries were measured using a computer image analyzer, and the percent medial thickness (%MT) and adventitial thickness (%AT) were calculated. The lungs from nitrofen-exposed fetuses with left-sided CDH (CDH group), trachea-occluded left-sided CDH (CDH+TO group), non-CDH (non-CDH group), and normal fetuses (normal group) were compared. RESULTS: The %MT was significantly increased in all sizes of arteries in CDH compared with non-CDH and normal groups (P < .01). Compared with the CDH group, the CDH+TO group had significantly reduced %MT in all sizes of arteries (P < .01), to values comparable or less than the non-CDH and normal groups. The %AT of the CDH group was significantly increased in larger arteries compared with non-CDH and normal control groups (P < .01). CDH+TO had significantly decreased %AT compared with CDH in both larger (P < .01), and smaller arteries (P < .05) and that was comparable with the non-CDH and normal control groups. CONCLUSIONS: TO in hypoplastic CDH lung can reverse the pulmonary arterial structural changes that are seen in the nitrofen-induced fetal rat model of CDH. These data suggest that TO may reduce pulmonary vascular reactivity, and the risk of postnatal persistent pulmonary hypertension observed in human neonates with severe CDH. J Pediatr Surg 36:839-845.

Inhomogeneity in the appearance of electrical remodeling during chronic rapid atrial pacing: evaluation of the dispersion of atrial effective refractoriness.

In the present study, the long-term process of progression of electrical remodeling at various atrial sites, which is not well understood, was compared while monitoring continuously the electrophysiologic parameters at multirecording sites in canine atria during continuous atrial burst pacing. A rapid pacing device was implanted in 5 dogs, and continuous atrial burst pacing (400 beats/min) was delivered at the right atrial appendage (RAA). Four pairs of epicardial wire electrodes were sutured on (1) the RAA, (2) Bachmann's bundle (BB), (3) the right atrium close to the inferior vena cava (IVC), and (4) the left atrium (LA). The distal ends of those wires were exteriorized posteriorly and used for pacing and recording. The atrial effective refractory period (AERP), AERP dispersion (AERPd), atrial conduction time (CT) and inducibility of atrial fibrillation (AF) were evaluated during burst pacing for 14 days and during the subsequent 7 days' recovery. The AERP at the LA pacing site was shorter than that at the other sites on day 0. The AERP shortening was greater in the RAA and LA sites than in the BB and IVC sites. The AERPd increased during pacing and reached the maximum level on day 3, and then decreased during the recovery phase. Prolongation of CT tended to be longer between the RAAand IVC sites than that between the other sites. The incidence of AF induction became higher in accordance with the time course of the rapid pacing phase. There was another peak of AF induction on days 7-10. In a canine chronic rapid atrial stimulation model, the progression of electrical remodeling (ie, the shortening of the AERP and the prolongation of the CT) was not homogeneous in both atria, the AERPd showed a temporal increase between days 3 and 7 and matched the increase in AF inducibility at the LA pacing site, the increase in the AERPd was mainly caused by more rapid AERP shortening at the RAA or LA sites, and the LA site always showed a shorter AERP than the other atrial sites in the control state and during the rapid pacing phase, whereas AF inducibility was higher at the LA site than the other sites.