Totally laparoscopic resection of right-sided colon cancer using transvaginal specimen extraction with a 10-mm-long abdominal incision.

BACKGROUND: Natural orifice specimen extraction (NOSE) has been developed as a means of decreasing the incidence of surgical wound complications. We refined the procedure for totally laparoscopic colectomy with transvaginal specimen extraction using the reduced port surgery technique with the ultimate goal of attenuating damage to the abdominal wall. We herein report this innovative technique and its short- and long-term outcomes. METHODS: We prospectively collected data on seven patients who underwent totally laparoscopic colectomy using transvaginal specimen extraction with a 10-mm-long abdominal incision for right-sided colon cancer from January 2014 to December 2021. Two 5-mm ports were used in the procedure without laparotomy. Transverse transabdominal posterior colpotomy was then performed. We introduced a GelPOINT Mini advanced access platform (Applied Medical, Rancho Santa Margarita, CA, USA) into the transvaginal route for the insertion of a laparoscope, forceps, and stapling device. Lymph node dissection and transection of the ileum and distal colon were performed with transvaginal assistance. A specimen was then extracted transvaginally. Intracorporeal functional end-to-end anastomosis was conducted using a linear stapler through the vagina. After the removal of GelPOINT Mini, the vaginal incision was closed transvaginally. RESULTS: Seven patients successfully underwent this procedure. Median operative time was 219 min (range 174-255 min), median blood loss was 23 ml (range 10-37 ml), median number of harvested lymph nodes was 21 (range 17-35 lymph nodes) and median margins were 17.0 cm (range 9.0-25.0 cm) for the proximal margin and 9.5 cm (range 5.0-13.0 cm) for the distal margin. There were no complications more severe than Clavien-Dindo Grade II and there was no mortality. The median frequency of use intravenous analgesics from postoperative day 1 to discharge was once. Two patients did not require analgesics. A node-positive patient developed recurrence at the lung and paraaortic lymph nodes. CONCLUSIONS: This procedure appears to be feasible, safe, and oncologically acceptable for selected cases.

Short communication: Menaquinone-4 (vitamin K2) induces proliferation responses in bovine peripheral blood mononuclear cells.

The effects of vitamin K (VK) on immune cells in ruminants are yet to be fully investigated. The objective of this study was to examine the effects of VK on peripheral blood mononuclear cells (PBMC) in Holstein dairy cows. A cell proliferation assay was performed to evaluate the effect of menaquinone-4 (MK-4, the biologically active form of VK) on immune response of PBMC. The proliferation of PBMC stimulated by MK-4 was significantly higher than that of nonstimulated controls. The expression of T cell-related genes in PBMC, stimulated with MK-4, was assessed by quantitative PCR. No significant changes were observed in the mRNA expression levels of both CD4 and CD8 as helper T cell and cytotoxic T cell markers, respectively. The present study demonstrated that MK-4 positively influenced cow PBMC proliferation and suggested the possibility of bovine-specific immune cell activation. The present study lays a foundation for understanding the physiological role of VK in cattle.

Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease.

Cathelicidin peptide LL-37 plays an important role in the early host response against invading pathogens via its broad-spectrum anti-microbial activity. In this study, we investigated LL-37 expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, the regulatory mechanism of LL-37 induction was investigated in human colonic subepithelial myofibroblasts (SEMFs). LL-37 mRNA expression and protein secretion were analysed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Intracellular signalling pathways were analysed using immunoblotting and specific small interference RNA (siRNA). The expression of LL-37 mRNA was increased significantly in the inflamed mucosa of ulcerative colitis and Crohn's disease. The Toll-like receptor (TLR)-3 ligand, polyinosinic-polycytidylic acid (poly(I:C), induced LL-37 mRNA expression and stimulated LL-37 secretion in colonic SEMFs. The transfection of siRNAs specific for intracellular signalling proteins [Toll/IL-1R domain-containing adaptor-inducing interferon (IFN) (TRIF), tumour necrosis factor receptor-associated factor (TRAF)6, transforming growth factor ß-activated kinase (TAK)1] suppressed the poly(I:C)-induced LL-37 mRNA expression significantly. Poly(I:C)-induced phosphorylation of mitogen-activated protein kinases (MAPKs) and activated nuclear factor kappa B (NF-κB) and activating factor protein (AP)-1. siRNAs specific for NF-κB and c-Jun inhibited poly(I:C)-induced LL-37 mRNA expression. LL-37 suppressed lipopolysaccharide (LPS)-induced interleukin (IL)-6 and IL-8 expression significantly in colonic SEMFs. The expression of LL-37 was up-regulated in the inflamed mucosa of IBD patients. LL-37 was induced by TLR-3 stimulation and exhibited an anti-microbial effect via interaction with lipopolysaccharide (LPS).

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 µg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Cathepsin B activity has a crucial role in the developmental competence of bovine cumulus-oocyte complexes exposed to heat shock during in vitro maturation.

Cathepsin B was found to be correlated inversely with the quality of bovine oocytes and embryos. The aims of this study were to evaluate i) the relationship between heat shock during in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs) and cathepsin B activity in relation to apoptosis and ii) the effect of supplementation of cathepsin B inhibitor (E-64) during IVM of heat-shocked COCs on embryonic development. After IVM at 38.5 °C for 22 h (control group) or at 38.5 °C for 5 h followed by 41 °C for 17 h (heat shock group) either with or without 1 µM E-64, activities and protein expression of cathepsin B and caspase 3 were evaluated as well as TUNEL staining. After IVF, developmental rate, total cell number, and the percentage of apoptotic cells in blastocysts were evaluated on day 8 (day 0, IVF day). Heat-shocked IVM COCs showed significantly high activities and expressions of both cathepsin B, and caspase 3 accompanied by a significant increase in number of TUNEL-positive cells. Addition of E-64 significantly decreased the activities of cathepsin B and caspase 3, and TUNEL-positive cells in heat-shocked IVM COCs. Moreover, addition of 1 µM E-64 during IVM under heat shock conditions significantly improved both developmental competence and quality of the produced embryos. These results indicate that heat shock induction of cathepsin B is associated with apoptosis of COCs, and inhibition of cathepsin B activity can improve the developmental competence of heat-shocked COCs during IVM.

Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03.

BACKGROUND: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. RESULTS: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). CONCLUSION: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

Efficacy, toxicity and cost analysis for non-platinum triplet (gemcitabine and vinorelbine, followed by docetaxel) vs. platinum-based chemotherapy in IIIB/IV non-small-cell lung cancer: single-institution experience.

A new non-platinum sequential triplet combination chemotherapy regimen, comprising gemcitabine (1000 mg/m(2)) and vinorelbine (25 mg/m(2)), followed by docetaxel (60 mg/m(2)), was compared in terms of efficacy, toxicity and cost with platinum-based chemotherapy regimens (comprising cisplatin plus one or more other anti-tumour drugs) for the treatment of advanced non-small-cell lung cancer in a matched, small-sample size, case-control study. Patients were selected from a single institution. Patients in the platinum and non-platinum groups were matched for clinical stage (IIIB/IV), performance status (0/1), age and sex. For the non-platinum and platinum groups, the overall response rates were 40% and 47%, and the median survival times were 14 and 14.5 months respectively. The most common grade 3-4 toxicity was neutropenia (27%) in the non-platinum group and nausea/vomiting (67%) in the platinum group. The total treatment cost did not differ significantly between the two groups. The non-platinum sequential triplet combination chemotherapy regimen studied was shown to be as effective as the traditional cisplatin-based combination chemotherapy regimen, and was associated with less toxicity.

Cross talk between neurometals and amyloidogenic proteins at the synapse and the pathogenesis of neurodegenerative diseases.

Increasing evidence suggests that disruption of metal homeostasis contributes to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, prion diseases, Lewy body diseases, and vascular dementia. Conformational changes of disease-related proteins (amyloidogenic proteins), such as ß-amyloid protein, prion proteins, and α-synuclein, are well-established contributors to neurotoxicity and to the pathogenesis of these diseases. Recent studies have demonstrated that these amyloidogenic proteins are metalloproteins that bind trace elements, including zinc, iron, copper, and manganese, and play significant roles in the maintenance of metal homeostasis. We present a current review of the role of trace elements in the functions and toxicity of amyloidogenic proteins, and propose a hypothesis integrating metal homeostasis and the pathogenesis of neurodegenerative diseases that is focused on the interactions among metals and between metals and amyloidogenic proteins at the synapse, considering that these amyloidogenic proteins and metals are co-localized at the synapse.

A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.

Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.

Stings of edible jellyfish (Rhopilema hispidum, Rhopilema esculentum and Nemopilema nomurai) in Japanese waters.

Three edible jellyfish Rhopilema hispidum, R. esculentum and Nemopilema nomurai are virulent to humans. We monitored one patient that was stung sequentially by these three species of jellyfish. The first species caused a persistent eruption, the second produced significant pruritus and the last induced only cutaneous symptoms rather than severe systemic disorders reported for its Chinese counterpart. The lesions of these jellyfish species are characteristic and common in workers harvesting medusae. There is no significant incidence of symptoms by ingesting these animals.

Paternal dual barrier by Ifg2-H19 and Dlk1-Gtl2 to parthenogenesis in mice.

The functional difference between the maternal and paternal genome, which is characterized by epigenetic modifications during gametogenesis, that is genomic imprinting, prevents mammalian embryos from parthenogenesis. Genomic imprinting leads to nonequivalent expression of imprinted genes from the maternal and paternal alleles. However, our research showed that alteration of maternal imprinting by oocyte reconstruction using nongrowing oocytes together with deletion of the H19 gene, provides appropriate expression of maternally imprinted genes. Here we discuss that further alteration of paternally imprinted gene expressions at chromosomes 7 and 12 allows the ng/fg parthenogenetic embryos to develop to term, suggesting that the paternal contribution is obligatory for the descendant.

Detection of tumor-associated antigens in the sera of lung cancer patients by three monoclonal antibodies.

One hundred sixty-one sera from lung cancer patients, including 46 samples from patients who had not yet received treatment were screened for tumor-associated antigens with 3 monoclonal antibodies, CSLEX1, CSLEA1, and CLEX5, by a new cell binding inhibition assay. We had previously determined that the antigens recognized by CSLEX1 and CSLEA1 are sialosylated Lewisx and sialosylated Lewisa, respectively. Either of these two antibodies alone reacted with about 65% of the 46 untreated patients' sera. Eighty-seven % of the 46 showed positive results with at least one of the two antibodies. The CLEX5 monoclonal antibody is presented here as recognizing a potential tumor-associated antigen. CLEX5 reacted with 54% of the 46 sera from nontreated lung cancer patients. When the results for all three antibodies were combined, the percentage of positive sera was 89% (of 46). Some interesting patterns in the serum levels of the antigens detected by these antibodies were observed. Levels of sialosylated Lewisx were significantly higher in sera from nontreated advanced stage (III and IV) patients (P less than 0.0003). In addition, levels of the antigens detected by CSLEX1 and CSLEA1 were dependent on whether or not the patient had been receiving treatment. These observations suggest potential applications of monoclonal antibodies to diagnosis and monitoring of therapies.

Randomized controlled study of adjuvant immunotherapy with Nocardia rubra cell wall skeleton for inoperable lung cancer.

In order to evaluate the clinical benefit of Nocardia rubra cell wall skeleton (N-CWS), a randomized controlled study was performed with inoperable lung cancer patients entered in 5 institutions from October 1978 to June 1981. Patients without pleural effusions were treated initially with conventional therapies such as chemotherapy and/or radiotherapy, according to common protocol, and then patients in performance statuses 0 to 3 were randomized into control and N-CWS groups with stratification into 16 categories according to 4 histological types and 4 clinical stages In the N-CWS group, 400 micrograms N-CWS were initially injected once or twice into the bronchial tumor using a fiberoptic bronchoscope, and subsequently 200 micrograms of N-CWS were injected at monthly intervals into the skin from the shoulders to upper arms. Of 309 patients, 118 patients in the N-CWS group and 108 patients in the control group were eligible for statistical analysis. There was statistically no significant difference in survival rate between the control and the N-CWS groups. According to histological type, significant prolongation of the survival period was observed in patients with small-cell carcinoma. The 97 patients with pleural effusions were initially randomized into control and N-CWS groups. In the control group, local chemotherapy with Adriamycin was performed and, in the N-CWS group, local administrations and monthly intracutaneous injections of N-CWS were given. Tube thoracostomy was performed in both groups. The local response rate was statistically greater in the N-CWS group than in the control group, and survival period was also prolonged significantly in the N-CWS group. The main adverse reactions to N-CWS were skin lesions in the injected sites and fever, but these were temporary and not serious.

Sialosylated Lewisx in the sera of cancer patients detected by a cell-binding inhibition assay.

A new cell-binding inhibition assay to detect tumor-associated antigens in sera was developed. This assay determined that sialosylated Lewisx, as detected by the CSLEX1 monoclonal antibody, is present in the sera of 95% of patients with advanced lung adenocarcinomas. Sera with inhibition titers of 1:16 or higher were presumed to contain sialosylated Lewisx. Tests of over 900 sera samples from both malignant and benign disease patients yielded the following percentages of positive inhibition: lung cancers, 43.8%; stomach cancer, 26.0%; colon cancer, 44.4%; gall bladder and bile duct cancers, 47.8%; pancreas cancer, 37.5%; breast cancer, 26.7%; cancers of the hematopoietic system, 2.9%; benign diseases, 0.9% (332 sera); and normal healthy donors, 0.7% (280 sera). Within the lung cancer group, 95% of the sera from 21 advanced (Stages III and IV) nontreated adenocarcinoma patients gave positive results with high inhibition titers, whereas only 27% of sera from treated advanced adenocarcinoma patients yielded positive results. The sensitivity of the cell-binding inhibition assay is similar to those of the solid-phase radioimmunosandwich and reverse passive-hemagglutination assays. Reproducibility tests yielded an r value of 0.90. These results suggest that this simple cell-binding inhibition assay could be applied with monoclonal antibodies, such as CSLEX1, to monitor cancer.

Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells.

Iron (Fe) and aluminum (Al) have been implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we examined neuronal and glial cells to clarify which contributes most to metal accumulation after internalization through the transferrin-independent iron uptake (Tf-IU) systems in primary neuronal and glial predominant (NP and GP) cells from rat cerebral cortex, which affect the accumulation of transition metals in a variety of cultured cells. Al more significantly upregulated the Tf-IU activity in GP cells than in NP cells. GP cells were more resistant to Fe and Al exposure than NP cells. However, a chemiluminescence analysis specific for reactive oxygen species (ROS) showed that ROS levels in Fe- or Al-loaded NP cells were twice as high as in Fe- or Al-loaded GP cells. Northern blot analysis and gel retardation assay showed that the Al and Fe exposure taken up by the cells suppress Tf receptor mRNA expression to a greater extent in GP than NP cells, indicating that Al and Fe more markedly accumulate in glial than in neuronal cells. These results suggest that glial cells rather than neuronal cells contribute to the metal accumulation and are more resistant to oxidative stress caused by metals than neuronal cells. The present study may help to explain the pathogenesis of neurodegeneration in AD disorders caused by metal-generated oxidative stress.

Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer.

PURPOSE: A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improves survival in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29, and 36), and mitomycin (8 mg/m(2) on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions). RESULTS: Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher (84. 0%) than that of the sequential arm (66%) (P =.0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P =.03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P =.0001). CONCLUSION: In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.

Phase I/II study of vinorelbine, mitomycin, and cisplatin for stage IIIB or IV non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated doses (MTDs) of vinorelbine (VRB), mitomycin (MMC), and cisplatin (P), given in two courses every 28 days to previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: At least three or four patients were entered at each dose level. The starting dose was 20 mg/m(2) for VRB on days 1 and 8 and 4 mg/m(2) for MMC on day 1, with a fixed dose of P 80 mg/m(2) on day 1 every 4 weeks. MMC was increased to 6 mg/m(2) at dose level 2 and subsequently to 8 mg/m(2) at dose level 4. At dose level 3, VRB was increased to 25 mg/m(2). Twenty-five patients were entered onto the phase I study and 19 patients were entered onto phase II study. RESULTS: Nadir leukocyte and platelet counts decreased at each dose level. At dose levels 1 and 2, the dose-limiting toxicity (DLT) was not seen, but at dose levels 3 and 4, DLT was encountered in two patients. Nearly half the patients at dose level 4 had dose reduction due to grade 4 leukopenia. A mathematic model of all toxicity suggested that dose level 4 (VRB 25 mg/m(2) on days 1 and 8 and MMC 8 mg/m(2) and P 80 mg/m(2) on day 1, every 4 weeks) would be the recommended dose for phase II study at which grade 4 toxicity is expected in

A randomized trial in inoperable non-small-cell lung cancer: vindesine and cisplatin versus mitomycin, vindesine, and cisplatin versus etoposide and cisplatin alternating with vindesine and mitomycin.

Patients with inoperable non-small-cell lung cancer (NSCLC) were randomly assigned to receive one of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine, and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). In 199 assessable patients, the response rates were VP, 33%; MVP, 43%; and EP/VM, 19%. The addition of mitomycin to the VP regimen did not significantly improve the response rate. The response rate was significantly lower with the EP/VM regimen than with the MVP regimen (P less than .01). The median survival times were VP, 50 weeks; MVP, 42 weeks; and EP/VM, 40 weeks. These differences were not significant. Grade III or IV thrombocytopenia was significantly greater (P less than .01) in MVP patients (22%) than in the VP (5%). Other toxicities were similar in the three groups. Analyses of prognostic factors showed that treatment with MVP, sex, and histologic classification (squamous cell carcinoma) were predictive of improved response. Important factors for improved survival, according to the Cox regression analysis, were the stage of disease, performance status, sex, weight loss before diagnosis, and hemoglobin concentration.