Long-term follow-up of the randomized trial of mesorectal excision with or without lateral lymph node dissection in rectal cancer (JCOG0212).

BACKGROUND: Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non-inferiority phase III trial of patients with clinical stage II-III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence-free survival (RFS). The planned primary analysis at 5 years failed to confirm the non-inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long-term follow-up data from JCOG0212. METHODS: Patients with clinical stage II-III rectal cancer below the peritoneal reflection and no lateral pelvic lymph node enlargement were included in this study. After surgeons confirmed R0 resection by ME, patients were randomized to receive ME alone or ME with LLND. The primary endpoint was RFS. RESULTS: A total of 701 patients from 33 institutions were assigned to ME with LLND (351) or ME alone (350) between June 2003 and August 2010. The 7-year RFS rate was 71.1 per cent for ME with LLND and 70·7 per cent for ME alone (hazard ratio (HR) 1·09, 95 per cent c.i. 0·84 to 1·42; non-inferiority P = 0·064). Subgroup analysis showed improved RFS among patients with clinical stage III disease who underwent ME with LLND compared with ME alone (HR 1·49, 1·02 to 2·17). CONCLUSION: Long-term follow-up data did not support the non-inferiority of ME alone compared with ME and LLND. ME with LLND is recommended for patients with clinical stage III disease, whereas LLND could be omitted in those with clinical stage II tumours.

ANTECEDENTES: El JCOG0212 (ClinicalTrials.gov: NCT00190541) fue un ensayo fase III de no inferioridad en pacientes con cáncer de recto en estadio clínico II/III sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. El ensayo comparó la escisión del mesorrecto (mesorectal excision, ME) con la ME con disección de los ganglios linfáticos laterales (lateral lymph node dissection, LLND), siendo el criterio de valoración principal la supervivencia libre de recidiva (recurrence free survival, RFS). El análisis primario planificado a los 5 años de seguimiento no pudo confirmar la no inferioridad de la ME frente a la ME con LLND. Este estudio tuvo como objetivo comparar la ME como procedimiento único y la ME con LLND utilizando datos de seguimiento a largo plazo del ensayo JCOG0212. MÉTODOS: En este estudio se incluyeron pacientes con cáncer de recto en estadio clínico II/III por debajo de la reflexión peritoneal sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. Después de que los cirujanos confirmaran la resección R0 mediante la ME, los pacientes fueron asignados al azar al brazo de ME sola o al brazo de ME con LLND. El criterio de valoración principal fue la supervivencia libre de recidiva (RFS). RESULTADOS: Un total de 701 pacientes de 33 instituciones fueron asignados al azar para ser tratados mediante una ME con LLND (n = 351) o EM sola (n = 350) entre junio de 2003 y agosto de 2010. Las tasas de RFS a 7 años fueron del 71,1% para ME con LLND y 70,7 % para ME sola (cociente de riesgos instantáneos, hazard ratio, HR: 1,09 (i.c. del 95% 0,84-1,42), no inferioridad P = 0,064)). El análisis de subgrupos mostró una mejor RFS entre los pacientes en estadio clínico III que se sometieron a ME con LLND en comparación con ME sola (HR: 1,49 (i.c. del 95%: 1,02-2,17)). CONCLUSIÓN: Los datos de seguimiento a largo plazo no justificaron la no inferioridad de la ME en comparación con la ME con LLND. Se recomienda la ME con LLND para pacientes en estadio clínico III, mientras que LLND podría omitirse para pacientes en estadio clínico II.

Faecal lactoferrin is a useful biomarker for mucosal healing in patients with ulcerative colitis during granulocyte and monocyte adsorptive apheresis therapy.

AIM: The study investigated the value of faecal lactoferrin as a follow-up biomarker for mucosal healing of ulcerative colitis during granulocyte and monocyte adsorptive apheresis (GMA) therapy. METHOD: Patients with ulcerative colitis exhibiting a moderate or severe disease activity with a partial Mayo Score (pMS) of over 4 were enrolled in this study. The patients received 10 courses of GMA therapy. The pMS value and faecal lactoferrin level were monitored and compared with the findings of endoscopy until 12 months after the last dose of GMA therapy. RESULTS: Twenty patients (male:female 11:9) were enrolled in this study. Twelve had total colitis, while six had left-sided involvement and two had distal proctitis. Thirteen (65.0%) responded to GMA therapy. The faecal lactoferrin levels were significantly decreased in patients who responded to GMA therapy (P < 0.05), whereas the levels did not change in non-responders. Moreover, the faecal lactoferrin levels correlated with the endoscopic findings (r = 0.792, P < 0.01) and pMS scores (r = 0.529, P < 0.01). The correlation coefficients between the faecal lactoferrin levels and mucosal findings were higher than those observed between the pMS score and mucosal findings. CONCLUSION: The faecal lactoferrin level is a useful biomarker of the mucosal findings in ulcerative colitis. Although endoscopy is the gold standard, the faecal lactoferrin level can be used as a biomarker during GMA therapy in patients with ulcerative colitis.

High-symmetry polarization domains in low-symmetry ferroelectrics.

We present experimental evidence for polygonal domain faceting in the ferroelectric polymer poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE) films with the lower orthorhombic crystallographic symmetry. It is proposed that this effect can arise from purely electrostatic depolarizing forces. We show that, in contrast to magnetic bubble shape domains, where such type of deformation instability has a predominantly elliptical character, the emergence of more symmetrical circular harmonics is favored in ferroelectrics with high dielectric constants.

Immunological inflammatory biomarkers as prognostic predictors for advanced hepatocellular carcinoma.

BACKGROUND: The immunological inflammatory biomarkers for advanced hepatocellular carcinoma are unclear. We aimed to investigate the association of immunity and inflammatory status with treatment outcomes in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. PATIENTS AND METHODS: We enrolled 728 consecutive patients with advanced hepatocellular carcinoma who received sorafenib (n = 554) or lenvatinib (n = 174) as primary treatment in Japan between May 2009 and June 2020. Changes in the neutrophil-to-lymphocyte ratio before and 1 month after treatment and their impact on survival were evaluated. The cut-off values of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting overall and progression-free survival were calculated using receiver operating characteristic curves. RESULTS: The neutrophil-to-lymphocyte ratio, but not the platelet-to-lymphocyte ratio, was an independent prognostic factor. Patients with decreased neutrophil-to-lymphocyte ratio survived significantly longer than patients with increased neutrophil-to-lymphocyte ratio (median overall survival: 14.7 versus 10.4 months, P = 0.0110). Among patients with a low pre-treatment neutrophil-to-lymphocyte ratio, the overall survival did not differ significantly between those with decreased and those with increased neutrophil-to-lymphocyte ratio after 1 month (median: 19.0 versus 14.8 months, P = 0.1498). However, among patients with high pre-treatment neutrophil-to-lymphocyte ratio, those whose neutrophil-to-lymphocyte ratio decreased after 1 month showed significantly longer survival than those whose neutrophil-to-lymphocyte ratio increased (median: 12.7 versus 5.5 months, P < 0.0001). The therapeutic effect was not correlated with pre-treatment neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio. CONCLUSIONS: The neutrophil-to-lymphocyte ratio is a prognostic factor, along with liver function and tumor markers, in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Thus, the neutrophil-to-lymphocyte ratio could be a prognostic biomarker for advanced hepatocellular carcinoma primarily treated with immunotherapy.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

[Experience with surgical resections of metachronous liver and bilateral pulmonary metastases from gastric cancer].

A 75-year-old female patient underwent distal gastrectomy with lymph node dissection for gastric cancer. Six months later, computed tomography (CT) and magnetic resonance imaging (MRI) revealed liver metastasis and radio frequency ablation (RFA) was performed. Ten months later, she underwent a partial hepatectomy for recurrent hepatic metastasis. Then, pulmonary nodules were revealed 1 year later, and segmentectomy (S4 + S5) for left pulmonary metastasis and wedge resection for right middle lobe pulmonary metastasis were sequentially performed after 9 months and 10 months observation by CT, respectively. Two years have passed since the last surgery, and the patient has survived more than 5 years since initial gastrectomy.

Endoscopic submucosal dissection for colorectal tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a state-of-the-art method that enables resection of larger tumors than those resectable by conventional endoscopic mucosal resection (EMR). However, the individual role of each method in the treatment of colorectal tumors remains undetermined. OBJECTIVE AND METHODS: To consider the respective indications of ESD and EMR for colorectal tumors, we analyzed the results of the two treatments retrospectively. RESULTS: Tumors treated by ESD (44 tumors) were significantly larger, more often located in the rectum and more often coexistent with cancer than those treated by EMR (512 tumors). EMR was used in the majority of adenomas, and showed high rates of both one-piece resection (OPR) and complete resection (CR) for adenomas less than 20 mm. However, for adenomas and cancers greater or equal to 20 mm, the CR rate for EMR was significantly lower than that for ESD because of the incidence of OPR with a positive lateral margin (16% vs 0% with ESD vs EMR). Histopathology (cancer), size (> or =20 mm) and macroscopic type (laterally spreading tumors) were shown to be significant risk factors for that incidence. For tumors with these factors, ESD showed a higher CR rate than did EMR. However, ESD required longer operating times and tended to have a higher rate of perforation compared with EMR. ESD was aborted halfway in seven cases due to technical difficulties and perforation. CONCLUSION: ESD and EMR have different characteristics as treatment for colorectal tumors. Careful evaluation of the lesion and of the balance between benefits and risks are mandatory before selecting either of these treatments for colorectal tumors.

Thymidine kinase-1/CD31 double immunostaining for identifying activated tumor vessels.

Although angiogenesis plays a crucial role in cancer growth and progression, no reliable method for assessing angiogenesis in tumor tissue sections currently is available. Using biomarkers with high specificity for proliferating endothelial cells could help quantify angiogenic activity. Thymidine kinase-1 (TK1) is an enzyme involved in the salvage pathway of DNA synthesis and its activity is correlated with cell proliferation. We investigated the use of double immunostaining for TK1 and CD31 for identifying activated tumor vessels. Differences in TK1/CD31 positive vessel rates (PVRs) between tumor and adjacent normal tissues were evaluated in 39 colorectal carcinoma (CRC) samples and compared with those of Ki67/CD31 double stained tissues. Mean TK1/CD31 PVR (23.6%) in CRCs was 13.9 fold greater than in adjacent normal tissues (1.7%)). By comparison, mean Ki67/CD31 PVR in CRCs was 20.0%, i.e. only 4.8 fold greater than in normal tissues (4.2%). Also, mean TK1/CD31 PVR in normal tissues was significantly less than mean Ki67/CD31 PVR. Our findings indicate that double immunostaining for TK1/CD31 can detect activated tumor vessels more accurately than staining for Ki67/CD31 and potentially could identify tumors that will respond to anti-angiogenic therapy.

Dependence of ferroelectric and magnetic properties on measuring temperatures for polycrystalline BiFeO(3) films.

A multiferroic BiFeO(3) film was fabricated on a Pt/Ti/SiO(3)/Si(100) substrate by a chemical solution deposition (CSD) method, and this was followed by postdeposition annealing at 923 K for 10 min in air. X-ray diffraction analysis indicated the formation of the polycrystalline single phase of the BiFeO(3) film. A high remanent polarization of 89 microC/cm(2) was observed at 90 K together with a relatively low electric coercive field of 0.32 MV/cm, although the ferroelectric hysteresis loops could not be observed at room temperature due to a high leakage current density. The temperature dependence of the ferroelectric hysteresis loops indicated that these hysteresis loops lose their shape above 165 K, and the nominal remanent polarization drastically increased due to the leakage current. Magnetic measurements indicated that the saturation magnetization was less than 1 emu/cm(3) at room temperature and increased to approximately 2 emu/cm(3) at 100 K, although the spontaneous magnetization could not appear. The magnetization curves of polycrystalline BiFeO3 film were nonlinear at both temperatures, which is different with BiFeO3 single crystal.

Ferroelectric and magnetic properties of multiferroic BiFeO(3)-based composite films.

BiFeO(3)-based composite films were fabricated onto the Pt/Ti/SiO(2)/Si(100) substrates by a chemical solution deposition (CSD) method using the precursor solutions with various excess iron composition followed by annealing at 923 K for 30 minutes under oxygen gas flow. Coexistence of spontaneous magnetization and remanent polarization could be obtained in the BiFeO(3)-based composite films with high excess iron composition. The remanent magnetization of almost 20 emu/cm(3) and the magnetic coercive field of 1.5 kOe were obtained at the iron composition ratio of Fe/Bi = 1.25. In this specimen, the remanent polarization at 90 K was approximately 10 microC/cm(2) at the electric field of 1500 kV/cm. Structural analysis suggested that the remanent polarization has a possibility to increase by suppressing the formation of the secondary phases of Bi(2)Fe(4)O(9) and alpha-Fe(2)O(3), these are the nonferroelectric material as well as antiferromagnetic phase.

Density profile measurement with a heavy ion beam probe in a toroidal plasma of the compact helical system.

A possibility of electron density measurements with heavy ion beam probes (HIBPs) has been demonstrated, along with their capability to measure the potential and magnetic field. A method has been proposed to reconstruct the electron density profile [A. Fujisawa et al., Rev. Sci. Instrum. 74, 3335 (2003)]. In the method, the profile of secondary beam currents is converted into a local density profile by taking into account local brightness and so-called path integral effects which mean the effect of beam attenuation along the beam orbit. Here the article presents the HIBP measurement of the electron density profile after the proposed method was first applied on the real experimental data of compact helical system plasmas. In the real application, the hollow density and the peaked profiles are successfully obtained with sufficiently high temporal resolution (a few ms), in accordance with the electron density profile measured with Thomson scattering for electron cyclotron resonance heating and neutral beam injection plasmas.

Identification of a functional receptor for granulocyte colony-stimulating factor on platelets.

Since granulocyte colony-stimulating factor (G-CSF) is thought to be a granulocyte lineage-specific cytokine, G-CSF receptors on blood cells other than those of granulocyte or monocyte lineage have not been well investigated. We now report that G-CSF receptors are present on platelets. The expression of G-CSF receptors on platelets was demonstrated by flow cytometry and radioreceptor assay. The mean number of G-CSF-binding sites per cell was 41 and the binding affinity was high (Kd 300 pM), similar to the affinity observed on granulocytes. Cross-linking assay revealed that G-CSF receptors were present on a single subunit protein of approximately 150 kD on the platelets. To clarify whether or not G-CSF might produce some direct functional influence on platelet response, the effects on platelet aggregation were studied. Although G-CSF itself did not affect platelet aggregation in vitro, preincubation with G-CSF augmented a secondary aggregation of platelets induced by low concentrations of adenosine diphosphate (ADP). There was a dose-response relationship for this G-CSF activity at concentrations of up to 10 ng/ml. Furthermore, the augmented ADP-induced secondary aggregation of platelets on G-CSF receptors was completely abrogated in the presence of anti-G-CSF polyclonal antibodies. These results indicate that platelets possess functional G-CSF receptors.

Endoscopic submucosal dissection for rectal tumors.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) has recently been developed for one-piece resection of gastric tumors. In order to improve patients' quality of life, it may be desirable to use the same technique for rectal tumors. METHODS: 35 consecutive patients with rectal tumors were enrolled. ESD was carried out using the same technique as for the stomach. The efficacy, technical feasibility, operation time, complications, and follow-up results were assessed. RESULTS: The mean size of the epithelial tumors was 26.2 +/- 14.0 mm, and the rates of one-piece resection and one-piece resection with tumor-free margins were 73.3% (22 of 30) and 70.0% (21 of 30), respectively. The median operation time was 70 min (range 8-360 min). All five carcinoid tumors were completely resected. No patient needed blood transfusion or had the complication of problematic bleeding. Perforation during ESD occurred in one patient (2.9%), who was managed with conservative medical treatment after endoscopic closure of the perforation. Excluding seven patients, who either underwent additional surgery or whose follow-up period was less than 1 year, all 23 patients with epithelial tumors were free of recurrence during a mean follow-up period of 25.7 months (range 12-53 months). CONCLUSIONS: ESD was thus found to be feasible for the treatment of rectal tumors, with promising results although the follow-up periods were short. ESD may therefore be indicated for rectal tumors which are not resectable en bloc by conventional procedures, in order to improve the patients' quality of life.

Genetic exploration of interactive domains in RNA polymerase II subunits.

The two large subunits of RNA polymerase II, RPB1 and RPB2, contain regions of extensive homology to the two large subunits of Escherichia coli RNA polymerase. These homologous regions may represent separate protein domains with unique functions. We investigated whether suppressor genetics could provide evidence for interactions between specific segments of RPB1 and RPB2 in Saccharomyces cerevisiae. A plasmid shuffle method was used to screen thoroughly for mutations in RPB2 that suppress a temperature-sensitive mutation, rpb1-1, which is located in region H of RPB1. All six RPB2 mutations that suppress rpb1-1 were clustered in region I of RPB2. The location of these mutations and the observation that they were allele specific for suppression of rpb1-1 suggests an interaction between region H of RPB1 and region I of RPB2. A similar experiment was done to isolate and map mutations in RPB1 that suppress a temperature-sensitive mutation, rpb2-2, which occurs in region I of RPB2. These suppressor mutations were not clustered in a particular region. Thus, fine structure suppressor genetics can provide evidence for interactions between specific segments of two proteins, but the results of this type of analysis can depend on the conditional mutation to be suppressed.

A divergent testis-specific alpha-tubulin isotype that does not contain a coded C-terminal tyrosine.

On the basis of analysis of cDNA clones of alpha-tubulin RNAs expressed during spermiogenesis in chickens, we report the identification of a novel alpha-tubulin which is expressed exclusively in chicken testes. Comparison of its sequence with those previously determined not only demonstrates that the encoded polypeptide is significantly divergent from other alpha-tubulins but also supports the hypothesis that alpha-tubulin isotypes are distinguished by a carboxy-terminal variable region sequence and, to a lesser extent, by a domain near the amino terminus. Since essentially all previously known alpha-tubulins undergo a unique cycle of removal and posttranslational readdition of a tyrosine residue at the extreme carboxy terminus, the presence in this testes alpha-tubulin of a very divergent carboxy terminus that does not contain an encoded tyrosine raises the possibility that this polypeptide does not participate in the usual cycle of tyrosination/detyrosination.

Conditional mutations occur predominantly in highly conserved residues of RNA polymerase II subunits.

Conditional mutations in the Saccharomyces cerevisiae RNA polymerase II large subunit, RPB1, were obtained by introducing a mutagenized RPB1 plasmid into yeast cells, selecting for loss of the wild-type RPB1 gene, and screening the cells for heat or cold sensitivity. Sequence analysis of 10 conditional RPB1 mutations and 10 conditional RPB2 mutations revealed that the amino acid residues altered by these distinct mutations are nearly always invariant among eucaryotic RPB1 and RPB2 homologs. These results suggest that RNA polymerase mutants might be obtained in other eucaryotic organisms by alteration of these invariant residues.

Production of interleukin 6 from human liver cell lines: production of interleukin 6 is not concurrent with the production of alpha-fetoprotein.

The production of interleukin (IL) 6 from six human liver cell lines, including Chang liver, HLF, HLE, HepG2, PLC/PRF/5, and HuH-7, was investigated using enzyme-linked immunosorbent assay and Northern blot analysis. When cells were cultured in the presence of 12-O-tetradecanoylphorbol-13-acetate, significant amounts of IL6 were detected in the culture supernatants of Chang liver cells, HLF cells, and HLE cells. However, IL6 was not detected in the culture supernatants from HepG2 cells, PLC/PRF/5 cells, or HuH-7 cells which had been treated similarly. To further investigate the production of IL6, expression of the IL6 gene was studied. Results of Northern blot analysis using IL6 complementary DNA as a probe showed that the induction was initiated at the mRNA level. Moreover, IL6 mRNA was also induced by IL1 beta and tumor necrosis factor but not by a calcium ionophore (A23187) or IL6 itself in Chang liver cells. This is the first study to demonstrate the production of human IL6 in liver cells. Furthermore, when the production of alpha-fetoprotein (AFP) from the liver cell lines was examined, the three that were able to produce IL6 failed to produce AFP, whereas the other three cell lines succeeded in producing AFP. These observations may indicate the heterogeneous origin of the liver cell lines.

Effect of human recombinant granulocyte/macrophage colony-stimulating factor and native granulocyte colony-stimulating factor on clonogenic leukemic blast cells.

The effects of human recombinant granulocyte/macrophage colony-stimulating factor (GM-CSF) and human native purified granulocyte colony-stimulating factor (G-CSF) on the growth of clonogenic leukemic blast cells from eight Japanese patients with acute myeloblastic leukemia were studied, using an in vitro leukemic blast colony assay. The results showed that GM-CSF stimulated leukemic blast colony formation in all cases examined, whereas G-CSF stimulated colony formation in four of the eight cases. The maximum stimulating activity of GM-CSF on the growth of clonogenic leukemic blast cells was higher than that of G-CSF in the majority of cases, while sometimes GM-CSF and G-CSF worked synergistically. Thus, the clonogenic leukemic blast cell populations seemed to be heterogeneous with respect to their in vitro response to growth regulators.