A negative pressure-based visualization technique for abdominal Veress needle insertion.

PURPOSE: Abdominal Veress needle insertion is commonly performed to generate a pneumoperitoneum during laparoscopy. Various safety tests are conducted to confirm accurate needle tip positioning into the abdominal cavity. However, these occasionally yield unclear results and do not help directly visualize the peritoneum puncture. We validated a negative pressure-based technique that helps instantly visualize the moment of the Veress needle entry into the abdominal cavity. METHODS: This study included 761 patients who underwent laparoscopic hernioplasty between 2003 and 2021 that entailed pneumoperitoneum creation using a Veress needle. They were divided into conventional technique (CON) and negative pressure visualization technique (NPV) groups. The patients were propensity score-matched (1:1) to minimize selection bias. To determine whether the technique gave a clear result to the surgeon and precisely informed the moment of entry, failed entry and emphysematous complications were compared between the groups. RESULTS: The propensity score-matching yielded 105 pairs in the matched CON and NPV groups. Failed entry did not occur in the NPV group, whereas it occurred in 8 patients (7.6%) in the CON group (p = 0.004). No patient experienced extraperitoneal emphysema in the matched NPV group, whereas 7 patients (6.7%) in the CON group did (p = 0.007). The groups did not differ in the incidence of omental or mesenteric emphysema. CONCLUSION: The NPV eliminated the incidence of failed entry and decreased the incidence of extraperitoneal emphysema, indicating that it could simply and adequately inform the moment of needle entry into the abdominal cavity.

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study.

PURPOSE: In this follow-up of the R-NAC-01 study, we assessed the long-term oncological benefit of four courses of modified leucovorin, 5-fluorouracil (FU), and oxaliplatin (mFOLFOX6) chemotherapy before rectal surgery. METHODS: In this prospective, multicenter study (UMIN 000012559) involving 11 hospitals in Japan, patients with lower rectal cancer underwent four cycles of mFOLFOX6 chemotherapy and subsequent surgery within four to six weeks. The 3-year recurrence-free survival and local recurrence rates were then reported. RESULTS: Of 41 patients (36 males, 5 females; mean age: 60.8 years old) who received 4 courses of chemotherapy, 40 underwent total mesorectal excision, and 1 underwent total pelvic exenteration. R0 resection was achieved in 40 patients, but none showed a pathological complete response. Twenty-nine patients received adjuvant chemotherapy for an average of 4 months. The 3 year recurrence-free survival and local recurrence rates in patients undergoing curable resection were 72.8% and 8.5%, respectively. cStage III patients with adjuvant chemotherapy had a significantly higher 3 year recurrence-free survival than those without adjuvant chemotherapy (76.6 vs. 40.0%, log-rank p = 0.03). CONCLUSION: Four courses of mFOLFOX6 chemotherapy before surgery may be a promising treatment strategy for locally advanced rectal cancer. Adjuvant chemotherapy might be needed for cStage III patients, even after four courses of neoadjuvant mFOLFOX6.

Discovery of benzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivatives as orally available bromodomain and extra-terminal domain (BET) inhibitors with efficacy in an in vivo psoriatic animal model.

Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.

International Survey on Determinants of Antibiotic Duration and Discontinuation in Pediatric Critically Ill Patients.

OBJECTIVES: We hypothesized that antibiotic use in PICUs is based on criteria not always supported by evidence. We aimed to describe determinants of empiric antibiotic use in PICUs in eight different countries. DESIGN: Cross-sectional survey. SETTING: PICUs in Canada, the United States, France, Italy, Saudi Arabia, Japan, Thailand, and Brazil. SUBJECTS: Pediatric intensivists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used literature review and focus groups to develop the survey and its clinical scenarios (pneumonia, septic shock, meningitis, and intra-abdominal infections) in which cultures were unreliable due to antibiotic pretreatment. Data analyses included descriptive statistics and linear regression with bootstrapped SEs. Overall response rate was 39% (482/1,251), with individual country response rates ranging from 25% to 76%. Respondents in all countries prolonged antibiotic duration based on patient characteristics, disease severity, pathogens, and radiologic findings (from a median increase of 1.8 d [95% CI, 0.5-4.0 d] to 9.5 d [95% CI, 8.5-10.5 d]). Younger age, severe disease, and ventilator-associated pneumonia prolonged antibiotic treatment duration despite a lack of evidence for such practices. No variables were reported to shorten treatment duration for all countries. Importantly, more than 39% of respondents would use greater than or equal to 7 days of antibiotics for patients with a positive viral polymerase chain reaction test in all scenarios, except in France for pneumonia (29%), septic shock (13%), and meningitis (6%). The use of elevated levels of inflammatory markers to prolong antibiotic treatment duration varied among different countries. CONCLUSIONS: Antibiotic-related decisions are complex and may be influenced by cultural and contextual factors. Evidence-based criteria are necessary to guide antibiotic duration and ensure the rational use of antibiotics in PICUs.

Parechovirus-A3 encephalitis presenting with focal seizure mimicking herpes simplex virus infection.

BACKGROUND: Febrile neonates and young infants presenting with seizure require immediate evaluation and treatment. Herein we experienced two young infants with parechovirus-A3 (PeV-A3) encephalitis, initially presented with focal seizure suspecting herpes simplex virus (HSV) encephalitis. CASES: We have experienced 2 infantile cases, initially presented with focal seizure. At presentation, HSV encephalitis was strongly suspected and empiric acyclovir therapy was started; however, serum and/or cerebrospinal fluid (CSF) PCR for HSV were negative. Instead, serum and/or CSF PCR for parechovirus-A was positive. PeV-A3 infection was confirmed by genetic sequence analyses. Both cases required multiple anticonvulsant therapy and intensive care for intractable seizure. Diffusion-weighted imaging of brain magnetic resonance imaging (MRI) showed distinct findings; high-intensity lesions in the gray matter of parietal and occipital lobes in Case 1, and bilateral decreased diffusion of the deep white matter and corpus callosum in Case 2. We have followed two cases more than four years; Case 1 developed epilepsy, has been on an anticonvulsant to control her seizure. Case 2 has significant neurodevelopmental delay, unable to stand or communicate with language. CONCLUSIONS: PeV-A3 encephalitis needs to be in differential diagnosis when neonates and young infants present with focal seizure, mimicking HSV encephalitis. Special attention may be necessary in patients with PeV-A3 encephalitis given it could present with intractable seizure with high morbidity in a long-term.

Insufficiency of prosthetic posterolateral overlap related to recurrence after laparoscopic transabdominal preperitoneal inguinal hernioplasty, as assessed by video review.

BACKGROUND: Technical factors leading to hernia recurrence after transabdominal preperitoneal repair include insufficient dissection, inadequate prosthetic overlap and prosthetic size, improper fixation and folding, or crinkling of the prosthesis. However, determining intraoperatively if a case will develop recurrent hernias due to these factors remains unclear. METHODS: Five surgeons blind-reviewed operation videos of primary laparoscopic hernioplasty in 13 lesions that went on to develop recurrent hernias (i.e., future recurrence), as well as 28 control lesions, to assess twelve items of surgical techniques. Since we changed a surgical policy of covering myopectineal orifice (MPO) in April 2003, we analyzed the data for the earlier and later periods. The data was analyzed with hierarchical clustering to obtain a gross grouping. The differences of the ratings between the future recurrent and control lesions were then analyzed and the association of the techniques with the hernia recurrence rate, the size of the prosthesis, and the hernia type across hernia recurrence were explored. RESULTS: The lesions were grouped based on the time series, and its boundary was approximated when we changed our surgical policy. This policy change caused ratings to progress from 34% satisfactory, to 79% satisfactory. The recurrence rate decreased to 0.7% (5/678), compared with 6.2% (10/161) before the policy was implemented (p < 0.001). With univariate analysis, the ratings of posterior prosthesis overlap to the MPO in the recurrent lesions were significantly lower than controls in the later period (p = 0.019). Although various types of recurrences were noted in the earlier period, only primary indirect and recurrent indirect hernias were observed in the later period (p = 0.006). CONCLUSIONS: Fully covering the MPO with mesh is essential for preventing direct recurrence hernias. Additional hernia recurrence prevention can be obtained by giving appropriate attention to prosthesis overlap posterior to the MPO in a large indirect hernia.

Preoperative FOLFOX in resectable locally advanced rectal cancer can be a safe and promising strategy: the R-NAC-01 study.

PURPOSE: The aim of this study was to assess the safety of rectal surgery after 5-fluorouracil-leucovorin-oxaliplatin chemotherapy (FOLFOX6). METHODS: This was a prospective, multicenter study in 11 Japanese hospitals. We included patients with rectal cancer who received 4 courses of modified FOLFOX6 (mFOLFOX6) before rectal surgery and examined the postoperative complication rate, the clinicopathological response, and the rate of chemotherapy-related adverse events (UMIN 000012559). RESULTS: The study population included 36 men and 5 women. The average age of the patients was 60.8 years and the average body mass index was 23.1 kg/m2. After 4 courses of chemotherapy, grade 2 peripheral nerve disorder and other grade 3 adverse events were seen in 3 patients each (7.3%). Twenty-eight (73.7%) and 8 (21.1%) patients underwent low anterior resection and abdominoperineal resection, respectively. The pelvic nerves were preserved in 35 patients. Surgical morbidity (grade ≥ 3) occurred in 4 patients (10.5%). Anastomotic leakage occurred after surgery in 2 patients (7.1%). No patients achieved pathologically complete remission. However, downstaging of the clinical stage and N stage was seen in 17 (41.5%) and 22 (53.7%) patients, respectively. CONCLUSIONS: Surgery after four courses of mFOLFOX6 chemotherapy can be a safe and promising strategy for patients with locally advanced rectal cancer.

Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer: A phase II study.

Cisplatin plus 5-fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib-III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2 ) and nedaplatin (50 mg/m2 ) on days 1 and 8, and a continuous infusion of 5-fluorouracil (400 mg/m2 /day) on days 1-5 and 8-12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end-point was the completion rate of the protocol treatment. Twenty-eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty-five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment-related deaths and major surgical complications did not occur. Estimated 2-year progression-free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).

Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity.

We previously isolated an IL-11-mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R-expressing tumors in vivo. This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high IL-11R expression levels in a large cohort of patients (n = 368). In matching surgical specimens (i.e., paired tumors and nonmalignant tissues), the cytoplasmic levels of IL-11R in tumor areas were significantly higher than in nonmalignant tissues (n = 36; P = 0.003). Notably, marked overexpression of IL-11R was observed in both tumor epithelial and vascular endothelial cell membranes (n = 301; P < 0.0001). BMTP-11 induced in vitro cell death in a representative panel of human lung cancer cell lines. BMTP-11 treatment attenuated the growth of subcutaneous xenografts and reduced the number of pulmonary tumors after tail vein injection of human lung cancer cells in mice. Our findings validate BMTP-11 as a pharmacologic candidate drug in preclinical models of lung cancer and patient-derived tumors. Moreover, the high expression level in patients with non-small cell lung cancer is a promising feature for potential translational applications.

Accuracy analysis of intrahepatic fat density measurements using dual-energy computed tomography: Validation using a test phantom.

BACKGROUND: Currently, no standardized method for measuring intrahepatic fat density via conventional computed tomography (CT) exists. OBJECTIVE: We aim to quantify intrahepatic fat density via material decomposition analysis using rapid kilovolt peak-switching dual-energy (RSDE) CT. METHODS: Homogenized porcine liver and fat (lard) were mixed in various ratios to produce phantoms for fat density verification. The actual fat density was measured on the basis of the phantom volume and weight, and these measurements were used as reference densities. The fat and liver mass attenuation coefficients, which were used as the material basis pairs, were employed in the material decomposition analysis. Then, the measured fat density of each phantom was compared with the reference densities. RESULTS: For fat content differences exceeding 2%, the measured fat density for the phantoms became statistically significant (p < 0.01). The correlation between the reference densities and RSDE-measured fat densities was reasonably high (R > 0.9997); this indicates the validity of this analysis method. CONCLUSIONS: Intrahepatic fat density can be measured using the mass attenuation coefficients of fat and liver in a material decomposition analysis. Given the knowledge of the accuracy and the limitations found in this study, our method can quantitatively evaluate fat density.

Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis.

UNLABELLED: Increased hepatic iron accumulation is thought to be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic iron accumulation, as well as oxidative DNA damage, is significantly increased in NASH livers. However, the precise mechanism of iron accumulation in the NASH liver remains unclear. In this study, 40 cases with a diagnosis of NASH (n = 25) or simple steatosis (SS; n = 15) by liver biopsy were enrolled. An oral iron absorption test (OIAT) was used, in which 100 mg of sodium ferrous citrate was administered to each individual. The OIAT showed that absorption of iron from the gastrointestinal (GI) tract was increased significantly in NASH patients, compared to SS and control subjects. Iron reduction therapy was effective in patients with NASH, who exhibited iron deposition in the liver and no alanine aminotransferase improvement after other therapies (n = 9). Serum hepcidin concentration and messenger RNA (mRNA) levels of divalent metal transporter 1 (DMT1) also were significantly elevated in patients with NASH. OIAT results were correlated with grade of liver iron accumulation and DMT1 mRNA levels. Then, we demonstrated that DMT1 mRNA levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with serum from NASH patients. An electrophoresis mobility shift assay showed activation of iron regulatory protein (IRP) in those cells, and IRP1 small interfering RNA clearly inhibited the increase of DMT1 mRNA levels. CONCLUSION: In spite of elevation of serum hepcidin, iron absorption from the GI tract increased through up-regulation of DMT1 by IRP1 activation by humoral factor(s) in sera of patients with NASH.

Novel anti-inflammatory agent 3-[(dodecylthiocarbonyl)-methyl]-glutarimide ameliorates murine models of inflammatory bowel disease.

OBJECTIVE AND DESIGN: To examine the effect of 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel anti-inflammatory agent that inhibits lipopolysaccharide (LPS) activation of RAW264.7 macrophages, on murine models of colitis and RAW264.7 cells. MATERIALS AND METHODS: Colitis was induced by rectally infusing trinitrobenzenesulfonic acid (TNBS) (1.5 mg in 50% ethanol) in BALB/c mice or orally administering 3% dextran sulfate sodium (DSS) for 5 days in C57BL/6 mice. The severity of colitis was assessed after intraperitoneally injecting DTCM-G (40 mg/kg). The anti-inflammatory properties of DTCM-G and its mechanisms were investigated in LPS-stimulated RAW264.7 cells. RESULTS: DTCM-G significantly ameliorated TNBS-induced colitis, according to the body weight loss, disease activity index, colonic obstruction, macroscopic colonic inflammation score, mucosal myeloperoxidase activity, and histopathology. Immunohistochemistry and isolated lamina propria mononuclear cells showed significantly reduced colonic F4/80(+) and CD11b(+) macrophage infiltration. DTCM-G significantly suppressed tumor necrosis factor (TNF)-α and interleukin (IL)-6 messenger RNA expression in the colon and attenuated DSS-induced colitis, according to the disease activity index and histopathology. In RAW264.7 cells, DTCM-G suppressed LPS-induced TNF-α/IL-6 production and enhanced glycogen synthase kinase-3ß phosphorylation. CONCLUSIONS: DTCM-G attenuated murine experimental colitis by inhibiting macrophage infiltration and inflammatory cytokine expression. Thus, DTCM-G may be a promising treatment for inflammatory bowel disease.

A Model for the Active-Site Formation Process in DMSO Reductase Family Molybdenum Enzymes Involving Oxido-Alcoholato and Oxido-Thiolato Molybdenum(VI) Core Structures.

New bis(ene-1,2-dithiolato)-oxido-alcoholato molybdenum(VI) and -oxido-thiolato molybdenum(VI) anionic complexes, denoted as [Mo(VI)O(ER)L2](-) (E = O, S; L = dimethoxycarboxylate-1,2-ethylenedithiolate), were obtained from the reaction of the corresponding dioxido-molybdenum(VI) precursor complex with either an alcohol or a thiol in the presence of an organic acid (e.g., 10-camphorsulfonic acid) at low temperature. The [Mo(VI)O(ER)L2](-) complexes were isolated and characterized, and the structure of [Mo(VI)O(OEt)L2](-) was determined by X-ray crystallography. The Mo(VI) center in [Mo(VI)O(OEt)L2](-) exhibits a distorted octahedral geometry with the two ene-1,2-dithiolate ligands being symmetry inequivalent. The computed structure of [Mo(VI)O(SR)L2](-) is essentially identical to that of [Mo(VI)O(OR)L2](-). The electronic structures of the resulting molybdenum(VI) complexes were evaluated using electronic absorption spectroscopy and bonding calculations. The nature of the distorted O(h) geometry in these [Mo(VI)O(EEt)L2](-) complexes results in a lowest unoccupied molecular orbital wave function that possesses strong π* interactions between the Mo(d(xy)) orbital and the cis S(p(z)) orbital localized on one sulfur donor from a single ene-1,2-dithiolate ligand. The presence of a covalent Mo-S(dithiolene) bonding interaction in these monooxido Mo(VI) compounds contributes to their low-energy ligand-to-metal charge transfer transitions. A second important d-p π bonding interaction derives from the ∼180° O(oxo)-Mo-E-C dihedral angle involving the alcoholate and thiolate donors, and this contributes to ancillary ligand contributions to the electronic structure of these species. The formation of [Mo(VI)O(OEt)L2](-) and [Mo(VI)O(SEt)L2](-) from the dioxidomolybdenum(VI) precursor may be regarded as a model for the active-site formation process that occurs in the dimethyl sulfoxide reductase family of pyranopterin molybdenum enzymes.

Tidal-Flat Macrobenthos as Diets of the Japanese Eel Anguilla japonica in Western Japan, with a Note on the Occurrence of a Parasitic Nematode Heliconema anguillae in Eel Stomachs.

Dietary items of the Japanese eel Anguilla japonica inhabiting estuaries were examined by analyses of the gut (stomach and intestine) contents in two areas in Kyushu, western Japan. In a small estuary in Kagoshima Bay, where seven eel guts were examined, almost all of the dietary organisms consisted of Hemigrapsus crabs and Hediste polychaetes, both of which commonly occurred on tidal flats of this site during our survey on the macrobenthic fauna. In another large estuary in the innermost part of the Ariake Sea, where 14 eel guts were examined, 11 macrobenthic species (nine crustaceans, a polychaete, and a gastropod) were found in the gut contents, mostly consisting of mudflat-specific species. The dietary items are almost completely different not only between the two estuaries, but also among three neighboring sites within the large estuary in the Ariake Sea. These results show that Japanese eels feed on various macrobenthic invertebrates inhabiting estuarine tidal flats at each site. The variety of the prey species occupying different habitats indicates that their foraging areas extend to a wide range of estuarine tidal flats from the upper to lower littoral zones. The physalopterid nematode Heliconema anguillae was found parasitic in eel stomachs in both estuaries. The prevalence of the nematode was higher in the estuary in Kagoshima Bay (100%) than that in the Ariake Sea (43%), although the intensity in the former (4-94 nematodes per infected stomach) was comparable to that of the latter (2-96). The relationship between the nematode infection and the dietary items of Japanese eels is discussed.

Frequency, clinical manifestations, and outcomes of Staphylococcus lugdunensis Bacteremia in children.

BACKGROUND: Staphylococcus lugdunensis (S. lugdunensis) is known as a common cause of clinically significant infections in adults although the clinical importance of S. lugdunensis isolates from pediatric samples is less known. The aim of this study is to assess the incidence, characteristics, and outcomes of S. lugdunensis bacteremia (SLB) in children. METHODS: From January 2009 to March 2014, all blood culture isolates were retrospectively screened for S. lugdunensis. We analyzed the isolates for antimicrobial susceptibility and patients who had developed SLB by reviewing the electronic medical records. Additionally, we identified mecA and blaZ for available isolates by polymerase chain reaction (PCR). RESULTS: Of the 647 positive blood cultures during the period, 277 (42.8%) yielded coagulase negative Staphylococcus (CoNS), and 10 of 277 CoNS were S. lugdunensis (3.6% of all CoNS isolates). Of eight SLB episodes identified, seven (87.5%) were considered to have clinically significant bacteremia. All patients had underlying diseases, and all SLB were either healthcare-associated or hospital acquired. There was no infectious endocarditis (IE) development. All patients were treated with antibiotics and recovered without sequelae. We found that the isolates in our study showed higher antibiotic resistance to penicillin (8/8: 100%) and oxacillin (6/8: 75.0%) than previously reported. Among isolates available, we detected mecA in all four isolates resistant to oxacillin and blaZ in 5 of 6 isolates resistant to penicillin. CONCLUSIONS: S. lugdunensis is a rare but an important cause of bacteremia in children.

Strong cytoplasmic expression of NF-κB/p65 correlates with a good prognosis in patients with triple-negative breast cancer.

PURPOSE: Recent studies have indicated that constitutive NF-κB activity could be involved in the proliferation of triple-negative breast cancer. METHODS: The NF-κB/p65 expression and the effects of a NF-κB inhibitor, (-)-DHMEQ, were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed for their expression of NF-κB/p65, Bcl2 and Ki67 by immunohistochemistry in pre- and post-treatment specimens. The factors predicting the response to neoadjuvant chemotherapy and the prognosis were analyzed. RESULTS: NF-κB/p65 was predominantly expressed in the cytoplasm of MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-κB/p65 expression was detected in the nuclei of a few cells in seven tumors before neoadjuvant chemotherapy, while the expression of NF-κB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. The expression levels of NF-κB/p65 were not associated with the response to neoadjuvant chemotherapy, although the cytoplasmic NF-κB/p65 staining intensity was significantly decreased in the post-treatment tumor samples compared with the pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-κB/p65 expression before neoadjuvant chemotherapy are currently disease free. CONCLUSION: Our results suggest that strong cytoplasmic NF-κB/p65 expression could be a prognostic marker for patients with triple-negative breast cancer.

[Successful Hematopoietic Cell Transplantation Following Azacitidine Treatment in an Acute Myeloid Leukemia Patient with t(3;3)(q21;q26.2) Translocation and Marked Thrombocythemia].

A 39-year-old man visited our department complaining of general malaise and appetite loss. He presented with anemia and marked thrombocythemia; his plasma transforming growth factor (TGF)-b concentration was markedly increased and his thrombopoietin (TPO)concentration was decreased. Since the patient's disease had progressed to acute myeloid leukemia (AML) with an increase in the peripheral blast count, he was diagnosed with AML along with t(3;3) (q21;q26.2) through a bone marrow aspiration sample. Remission induction therapy was performed using idarubicin/cytarabine. The patient achieved complete remission. His platelet count returned to the normal range, plasma TGF-b concentration decreased, and serum TPO concentration increased. The patient was treated with azacitidine as post-remission therapy for bone marrow transplantation, following which he underwent allogeneic hematopoietic cell transplantation.

Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRAS mutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were various and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experienced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clinical course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML.

Effects of the continuous intake of a milk drink containing Lactobacillus casei strain Shirota on abdominal symptoms, fecal microbiota, and metabolites in gastrectomized subjects.

OBJECTIVE: This article is based on our previously reported results of irregular bowel movement and disturbances of the intestinal microbiota/environment in gastrectomized patients. A placebo-controlled, double-blind comparative study was carried out to evaluate the effects of a fermented milk beverage containing Lactobacillus casei strain Shirota (LcS) in such patients. The major evaluated factors of this article were "bowel movement" and "quality of life." The secondary evaluated factors were "fecal microbiota" and "enteric environment." METHODS: Of the 190 gastrectomized subjects who participated in our previously reported defecation survey, 134 subjects judged as having abnormal defecation gave consent to participate in this study. These subjects continuously ingested the test beverage containing 40 billion LcS or placebo (one bottle per day, 4 weeks). RESULTS: In the LcS-ingested group, among the 118 subjects who completed the tests, the assessments of the subjects were based on their division into groups based on their symptoms with our scoring system for constipation/diarrhea; although there was no significant ingestion effect in total, in the constipation group, LcS reduced the degree of constipation compared with that in the placebo group. In the diarrhea group, LcS ingestion improved diarrhea compared with that in the preingestion state. Fecal Staphylococcus level was decreased. CONCLUSIONS: The results suggest the possibility that the continuous consumption of LcS-fermented milk relieves irregular bowel movement in gastrectomized patients.