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This study aimed to assess pharyngeal function between no bolus and bolus propofol induced sedation during gastric endoscopic submucosal dissection. A retrospective study was conducted involving consecutive gastric cancer patients. Patients in the no bolus group received a 3 mg/kg/h maintenance dose of propofol after the initiation of sedation without bolus injection. All patients in the bolus group received the same maintenance dose of propofol with bolus 0.5 mg/kg propofol injection. Pharyngeal functions were evaluated endoscopically for the first 5 min following the initial administration of propofol. Fourteen patients received no bolus propofol induction and 13 received bolus propofol induction. Motionless vocal cords were observed in 2 patients (14%) in the no bolus group and 3 (23%) in the bolus group. Trachea cartilage was not observed in the no bolus group but was apparent in 6 patients (46%) in the bolus group (P < 0.01). Scope stimulated pharyngeal reflex was observed in 11 patients (79%) in the no bolus group and in 3 (23%) in the bolus group (P < 0.01). Propofol induced sedation without bolus administration preserves pharyngeal function and may constitute a safer sedation method than with bolus.

Neutrophil is a major player in the pathophysiology of severe sepsis. Recent studies have revealed that the cell death mechanism of neutrophils directly relates to the development of organ dysfunction during sepsis. Here we discuss about the different types of neutrophil cell death such as necrosis, apoptosis, autophagy, and the unique cell death style dubbed NETosis. NETosis cells release neutrophil extracellular traps (NETs), which are composed of chromatin bound to granular and nucleic proteins. The primary purpose of NET release is thought to be the control of microbial infections; however, it acts as a danger signal for the host as well. The harmful substances such as DNA, histones, and high-mobility group box 1 (HMGB1) and many other danger-associated molecular patterns (DAMPs) released along with NETosis or from necrotic neutrophils also contribute to the pathogenesis of sepsis. At the same time, the coagulation system, which is closely tied to these neutrophil cell death mechanisms, is often over-activated. It is well known that individual bacterial pathogens express virulence factors that modulate cell death pathways and influence the coagulation disorder during sepsis. Moreover, extensive cross talk exists between these two phenomena, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. A greater knowledge of cell death pathways in sepsis informs the potential for future therapies designed to ameliorate excessive immune responses during sepsis.

Unlabelled: Both phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling and antiapoptotic Bcl-2 family members are critical for survival of acute myeloid leukemia (AML) cells. Here, we demonstrate the antileukemic effects of simultaneous inhibition of PI3K by the selective class I PI3K inhibitor GDC-0941 and of Bcl-2 family members by the BH3 mimetic ABT-737 in the context of the bone marrow microenvironment, where hypoxia and interactions with bone marrow stromal cells promote AML cell survival and chemoresistance. The combination of GDC-0941 and ABT-737 profoundly downregulated antiapoptotic Mcl-1 expression levels, activated BAX, and induced mitochondrial apoptosis in AML cells co-cultured with bone marrow stromal cells under hypoxic conditions. Hypoxia caused degradation of Mcl-1 and rendered Mcl-1-overexpressing OCI-AML3 cells sensitive to ABT-737. Our findings suggest that pharmacologic PI3K inhibition by GDC-0941 enhances ABT-737-induced leukemia cell death even under the protective conditions afforded by the bone marrow microenvironment., Key Message: Combined blockade of PI3K and Bcl-2 pathways down-regulates anti-apoptotic Mcl-1 expression PI3K and Bcl-2 induced Mcl-1 down-regulation activates BAX PI3K and Bcl-2 blockage induces apoptosis in AML under hypoxic BM microenvironment.

In addition to pathogen-associated molecular patterns from invasive microorganisms, alarmins, which are major components of host defense mechanisms, are involved in the pathophysiology of sepsis. In fact, the magnitude of the insult is defined according to the damage-associated molecular pattern (DAMP), which is composed of alarmins as well as pathogen-associated molecular patterns, such as those involving nucleosomes, histones, and DNA. Regarding the antimicrobial mechanism of neutrophils, an alternative non-phagocytic mechanism was first recognized as "NETosis" in 2004. In this mechanism, microorganisms are trapped and eliminated by neutrophil extracellular traps (NETs). These NETs are composed of histones and DNA that have been expelled from the nucleus as well as antimicrobial proteases, including elastase and myeloperoxidase. NETosis, a cell death pathway reported to be distinct from apoptosis, is an active area of research. As NETs are composed of deleterious substances, they are extremely harmful to the host cells once they are released into the circulating blood. Therefore, the meanings and putative roles of these components in sepsis have attracted much attention.

Background/aims: We previously demonstrated that elevated serum C-reactive protein (CRP) level is associated with depth of tumor invasion in operable colorectal cancer. There is also increasing evidence to show that raised CRP concentration is associated with poor survival in patients with colorectal cancer. The purpose of this study was to investigate the correlation between preoperative CRP concentrations and short-term disease recurrence in cases with stage II and III colorectal cancer., Methodology: Of the 224 cases with resected colorectal cancer, 55 patients with TNM stage II and 50 with stage III were analyzed in this study. The clinical features were reviewed according to the CRP level, and statistical analysis was performed. In cases with stage II and III, 11 and 6 of which had elevated serum CRP (>=10mg/L), respectively. Recurrence-free interval was defined as the interval from surgery to the time disease recurrence was diagnosed. Among the cases with stage II and III colorectal cancer, 4 and 10 had recurrent disease., Results: Among various clinicopathological characteristics, depth of tumor invasion was independently associated with preoperative elevation of CRP in stage II and III colorectal cancer in multivariate subgroup analysis. However, recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with preoperative CRP concentrations., Conclusions: Our results suggest that elevated serum CRP level is associated with depth of tumor, but not with recurrent disease in stage II and III colorectal cancer.

Hypoxia and interactions with bone marrow (BM) stromal cells have emerged as essential components of the leukemic BM microenvironment in promoting leukemia cell survival and chemoresistance. High levels of transforming growth factor beta 1 (TGFβ1) produced by BM stromal cells in the BM niche regulate cell proliferation, survival, and apoptosis, depending on the cellular context. Exogenous TGFβ1 induced accumulation of acute myeloid leukemia (AML) cells in a quiescent G0 state, which was further facilitated by the co-culture with BM-derived mesenchymal stem cells (MSCs). In turn, TGFβ-neutralizing antibody 1D11 abrogated rhTGFβ1 induced cell cycle arrest. Blocking TGFβ with 1D11 further enhanced cytarabine (Ara-C)-induced apoptosis of AML cells in hypoxic and in normoxic conditions. Additional constituents of BM niche, the stroma-secreted chemokine CXCL12 and its receptor CXCR4 play crucial roles in cell migration and stroma/leukemia cell interactions. Treatment with 1D11 combined with CXCR4 antagonist plerixafor and Ara-C decreased leukemia burden and prolonged survival in an in vivo leukemia model. These results indicate that blockade of TGFβ by 1D11 and abrogation of CXCL12/CXCR4 signaling may enhance the efficacy of chemotherapy against AML cells in the hypoxic BM microenvironment.

Background: Traditional Japanese medicine, known as Kampo medicine, consists of mixtures of several medicinal herbs widely used to treat upper gastrointestinal disorders in Japan. Rikkunshito, one of these medicines, has not been evaluated with respect to its influence on gastrointestinal motor activity. We investigated the effect of rikkunshito on upper gastrointestinal motility and plasma ghrelin concentrations in conscious dogs., Methods: Contractile response to intragastric administration of rikkunshito was studied via surgically implanted force transducers. A powdered extract of rikkunshito (1.3, 2.7, and 4.0 g) dissolved in water was administered into the stomachs of normal and vagotomized dogs before feeding and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and ondansetron) were injected intravenously before intragastric administration of rikkunshito. Plasma acylated ghrelin levels after intragastric administration of rikkunshito were measured., Results: In a fasting state, intragastric administration of rikkunshito induced phasic contractions in the duodenum and jejunum in normal dogs. Rikkunshito-induced contractions were inhibited by atropine, hexamethonium and ondansetron. In vagotomized dogs, rikkunshito induced phasic contractions, similar to normal dogs. Gastric emptying was accelerated by intragastric administration of rikkunshito in a dose-dependent manner. The plasma acylated ghrelin level 150 min after intragastric administration of 4.0 g of rikkunshito was significantly higher than the control value., Conclusions: Intragastric administration of rikkunshito stimulates gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors. Moreover, rikkunshito increases plasma acylated ghrelin levels. Rikkunshito may alleviate gastrointestinal disorders through its prokinetic effects.

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: One of the typical modifications on the surface of cancer cells is sialylation of terminal carbohydrates. The expression of several types of sialylation of glycoconjugates was investigated in colorectal cancer., Methods: The cancer tissue specimens obtained from 65 colorectal cancer patients were stained with sialic acid-binding lectins from Maackia amurensis (MAM), Sambucus sieboldiana (SSA), Maackia amurensis agglutinin (MAA) and monoclonal antibodies, and compared with their clinicopathological features., Results: Cancer tissue specimens from 44.6% of patients had positive staining with MAM, which recognized α2,3sialylated type 2 chain (NeuAcα2,3Galβ1,4GlcNAcβR) structures, but normal colorectal mucosa showed only weak staining with MAM was observed. More lymph node metastases and lymphatic invasion were seen in patients with positive staining with MAM (P < 0.01), while not with other lectins or antibodies that recognized sialylated glycoconjugates or sialyl Lewis-related antigens. The five-year survival rate of patients with MAM-positive staining was significantly lower than that with MAM-negative staining when including T0-1 cases, but there was no difference in cases with T2-4. There was no difference in the patients' survival rates when the tissues were stained with MAA, SSA or PNA lectins., Conclusion: α2,3Sialylated type 2 chain structures were predominantly expressed in colorectal tissues associated with the malignant transformation, in particular, with lymphatic spread of distal colorectal adenocarcinomas.

Background: Automated digital morphology systems are utilized for blood cell morphological examination. The aim of this study is to evaluate the accuracy and efficacy of RBC morphological anomaly screening using the CellaVision DM96 (DM96) automated image analysis system., Methods: The automated analysis of RBC shape, size, and chromasia abnormalities was conducted on the DM96 using 478 blood samples. A manual microscopic review was independently performed., Results: The DM96 preclassified samples as poikilocytosis-positive for 98% of cases with schistocytosis or echinocytosis, 97% of elliptocytosis, and 92% or 65% of cases that were positive for teardrop cells or for target cells, respectively. The accuracy of the DM96 in the detection of RBC size and chromasia abnormalities of iron deficiency anemia cases was higher than direct microscopic observation., Conclusions: Automated morphological analysis with the DM96 has potential utility in the morphological screening of RBC anomalies that are associated with disease.

Background/aims: The advantages of combined pharmacological and physical methods for venous thromboembolism (VTE) prophylaxis after colorectal surgery have not been clearly determined. The aim of this study is to compare the efficacy and safety of fondaparinux combined with intermittent pneumatic compression (IPC) with IPC alone for VTE prophylaxis after resection for colorectal cancer., Methodology: Between June 2008 and March 2010, 137 consecutive patients with colorectal cancer (CRC) who underwent colorectal resection in our surgical unit were enrolled in the study. Patients were divided into 2 groups. The IPC group was treated with IPC alone as controls. The fondaparinux group was treated with IPC and received subcutaneous injections of fondaparinux once daily. The aim of this study was to compare the efficacy and safety of fondaparinux combined with IPC with IPC alone for VTE prophylaxis., Results: The demographic variables and risk factors, operating time, blood loss and length of the postoperative hospital stay were similar in the two groups. No clinically evident VTE, critical bleeding, and postoperative death occurred during the study period. No adverse reactions due to fondaparinux were observed., Conclusions: In patients undergoing resection of colorectal cancer, receiving fondaparinux and IPC thromboprophylaxis was highly effective, well tolerated and safe. The use of combined modalities for VTE prophylaxis is justified in patients at high risk of VTE.

We report on a patient with 11 metachronous multiple early gastric cancers treated by gastrectomy after endoscopic resection. An 87-year-old Japanese woman was admitted to our hospital for treatment of four synchronous multiple early gastric cancers detected by endoscopic examination. The patient had a history of two endoscopic treatments for four metachronous early gastric cancers. The pathological findings of four lesions resected by endoscopic resection and four biopsy specimens showed well-differentiated carcinoma. In March 2012, we performed a distal gastrectomy for four lesions. The surgical specimen revealed 3 minute lesions after surgery in addition to these four lesions. Histologically, all seven lesions were intramucosal well-differentiated adenocarcinomas without vascular invasion. Although the incidence of synchronous and metachronous early gastric cancer is reportedly 11-14.5 % and 8.5-14 %, respectively, only two or three lesions are generally present. Moreover, multiple early gastric cancers usually originate as differentiated adenocarcinoma in male elderly patients with intestinal metaplasia. In the present case, there were multiple early gastric cancers, whose origin may be correlated with the background of intestinal metaplasia, in excess of the number generally expected.

We report a case of neuronal hypertrophy associated with acute appendicitis in which significant neuronal fibers and the number of ganglion cells increased in the absence of inflammatory cells. Differential diagnosis from diffuse ganglioneuromatosis by the pathologic findings of resected specimen was difficult. A 33-year-old Japanese female visited our hospital complaining of acute abdominal pain. The patient underwent appendectomy upon the diagnosis of acute appendicitis on the day of admission. Postoperative examinations found no neoplastic lesions in other organs or inherited disorders such as multiple endocrine neoplasia (MEN) type 2b and von Recklinghausen's disease (VRD). The pathologic diagnosis was neuronal hypertrophy of the appendix. Because the clinical outcomes of diffuse ganglioneuromatosis and neuronal hypertrophy of the gastrointestinal tract are quite different, clinical and pathologic examination should be carefully carried out for lesions in which significant proliferation of neuronal components is seen.

Background/aims: The current standard chemotherapy for metastatic colorectal cancer is the FOLFOX or the FOLFIRI regimen. Although these regimens include the continuous infusion of an anticancer agent, chemotherapy is possible by using implantable central venous port systems with a portable disposable pump in an outpatient setting. This study is an evaluation of the usefulness of implantable central venous port systems for colorectal cancer chemotherapy., Methodology: An implantable central venous port system was placed in 93 consecutive patients with metastatic colorectal cancer. All patients received modified FOLFOX6 ± bevacizumab or FOLFIRI ± bevacizumab regimens via the port system. Follow-up continued for each patient until removal of the port system, death or unavailability of further information. The incidence and details of the complications were investigated retrospectively., Results: Out of 1,246 treatments, a total of 16 incidents of port system-related complications were identified (1.28%). Incidents involved infections (n=12), catheter pinch off (n=2), fibrin sheath (n=1) and drug leakage (n=1). A port system removal was required in 14 cases., Conclusions: Implantable central venous port systems are safe and have a low long-term complication rate. We consider port systems, such as modified FOLFOX6 ± bevacizumab or FOLFIRI ± bevacizumab regimens, useful for colorectal cancer patients receiving chemotherapy.

Background/aims: The prognostic significance of extranodal metastasis (ENM) in colorectal cancer (CRC) is disregarded by the TNM classification system. The influence of ENM on survival among locally advanced CRC patients was examined., Methodology: We reviewed retrospectively the clinical course of 263 patients who underwent surgical resection of locally advanced CRC at our Department between 2005 and 2009. We analyzed the prognostic factors with special reference to the clinicopathological factors of primary tumors., Results: Thirty-eight cases of ENM were detected among patients with CRC. Compared with ENM negative cancers, ENM-positive cancers were associated with poorer tumor differentiation grade (p=0.026) and higher prevalence of TNM-stage (p<0.0001), T-status (p=0.024), N-status (p<0.0001) and postoperative recurrence (p<0.0001). In univariate analysis, TNM-stage (p<0.0035), T-status (p=0.002), N-status (p<0.0024) and positive ENM (p<0.0001) were significant predictors of poor survival. Multivariate analyses showed a positive ENM to be a highly significant independent predictor of mortality (HR=1.98, 95% CI=1.23- 3.23, p=0.0053). Survival analyses using Kaplan-Meier curves demonstrated that patients with ENM-positive cancers had significantly poorer survival than patients with ENM-negative cancers. Patients with ENM-negative cancers did not show significantly different survival from patients with node-negative cancers (p=0.272, data not shown)., Conclusions: ENM appears to be a strong independent negative prognostic factor of poor survival in locally advanced CRC.

The objective of this study was to determine the relationship between clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and antimicrobial consumption in hospitalized patients over a 14-year period. The study was retrospectively conducted between January 1995 and December 2008 at Juntendo University Hospital, Tokyo, Japan, a 1,020-bed tertiary-care teaching hospital. The incidence of MRSA isolates was examined using clinical specimens presented to the microbiology laboratory in the hospital. Antimicrobial consumption through intravenous injection was calculated in terms of the number of defined daily doses per 100 bed-days. The correlation between the incidence of MRSA isolates and antimicrobial consumption was determined employing a multiple stepwise regression analysis. A total of 109,946 bacterial isolates were consecutively collected over the 14-year period, and, of these, 13,872 (64% of S. aureus strains excluding coagulase-negative staphylococci) were MRSA strains. The longitudinal observation showed that the number and rate of MRSA isolates marginally decreased. The rate of MRSA isolates among S. aureus strains in 1995 was 68.5%, whereas that in 2008 was 53.8%. Consumption of cephalosporins decreased. Among carbapenems, the rate of imipenem (IPM) consumption decreased, whereas that of meropenem increased. A multiple stepwise regression analysis revealed that the antimicrobial consumption of cefmetazole, cefotiam, and IPM was positively correlated with the incidence of MRSA isolates. The use of β-lactam antimicrobials may contribute to the development of MRSA strains.

We evaluated antifungal activity as assessed by the contact time in topical use of gentian violet (GV) and povidone-iodine (PI) against Candida strains. A total of 102 yeast isolates were used in this study. A markedly lower minimal inhibitory concentration (MIC)(90) of GV than of PI was detected for all yeast isolates. No remarkable difference in the MICs was observed among the identical strains isolated from different clinical sites for both GV and PI. Although the minimal fungicidal activities (MFCs) of PI were identical for all tested time points, the fungicidal activity of GV decreased during the time course of incubation. These results indicate that, whereas GV is more effective than PI, the topical disinfectant efficacy of GV should be estimated using the MFC(5 min) and not the MIC or the MFC(24 h) for overall prevention of catheter-related bloodstream infections and oral infections.

Background/aims: To demonstrate the feasibility of solo laparoscopic colorectal resection (SLCR) is performed by the laparoscopist only. This study is an evaluation of the feasibility of SLCR for patients with colorectal cancer., Methodology: Fifty-one consecutive patients received SLCR from 2008 to 2009. The procedure was performed with four trocars and one laparoscopist. The short-term outcomes and complications were investigated retrospectively., Results: The median age of the patients was 67 years (range 42-81). The median operating time for SLCR was 168 minutes (range 90-268). For one patient (1.96%) conversion to open surgery was required. Anastomotic leakage developed in 1 (1.96%) patient and ileus developed in 2 (3.9%). The median postoperative hospital stay was 8 (range 6-60) days without in-hospital deaths., Conclusions: In our experience, SLCR for patients with colorectal cancer is feasible and compares favorably with the standard technique. The diminished need for human operative assistance provides significant economic and organizational benefits.

Peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RARs), members of the nuclear receptor superfamily, are transcription factors that regulate a variety of important cellular functions. PPARs form heterodimers retinoid X receptor (RXR), an obligate heterodimeric partner for other nuclear receptors. Several novel links between retinoid metabolism and PPAR responses have been identified, and activation of PPAR/RXR expression has been shown to increase response to retinoids. PPARγ has emerged as a key regulator of cell growth and survival, whose activity is modulated by a number of synthetic and natural ligands. While clinical trials in cancer patients with thiazolidinediones (TZD) have been disappointing, novel structurally different PPARγ ligands, including triterpenoids, have entered clinical arena as therapeutic agents for epithelial and hematopoietic malignancies. Here we shall review the antitumor advances of PPARγ, alone and in combination with RARα ligands in control of cell proliferation, differentiation, and apoptosis and their potential therapeutic applications in hematological malignancies.

Background/aims: Tumor cells at high density are considered to be resistant to hyperthermia. Our objective in this study was to investigate hyperthermia sensitivity of clusters, cancer cell aggregation, compared with that of monolayer cells., Methodology: Colon carcinoma cells HT29 were cultured on poly 2-hydroxyethyl methacrylate-coated dishes for 7 days and the clusters were selected by a 40µm pore filter. To detect the cell reproductive potential, a colony formation assay was performed in HT29 cells from a monolayer and from clusters after exposure to cis-diamino-dichloroplatinum, fluorouracil and/or hyperthermia. Western blotting was used to analyze the induction of heat shock protein expression by hyperthermia., Results: Histological findings of the clusters less than 400µm in diameter showed dividing cells and no secondary central necrosis. Cluster cells were more sensitive to hyperthermia than monolayer cells (p<0.0001). However, cluster formation induced cis-diamino-dichloroplatinum resistance (p<0.0001). The enhancement of hyperthermia sensitivity in clusters was not observed when the cells were heated after dispersion to single cells (p<0.0001). No difference of heat-induced HSP70/72 and HSP27 expression between cluster cells and monolayer cells was found., Conclusions: Cluster formation induced hyperthermia sensitivity, and cell-to-cell interaction in the clusters might enhance hyperthermia sensitivity.

Background/aims: Oxaliplatin, which is effective for colorectal cancer (CRC) in combination with 5-fluorouracil (5-FU) and leucovorin (LV), is widely used for metastatic CRC. With the increasing use of oxaliplatin, however, serious adverse events have been experienced, including hematologic and neurologic toxicities. The aim of this study was to evaluate whether tri-weekly modified FOLFOX6 (mFOLFOX6) maintenance chemotherapy is associated with a low incidence of severe hematologic and neurologic toxicities in the treatment of patients with metastatic CRC., Methodology: We developed a new treatment regimen with mFOLFOX6 biweekly for 8-10 consecutive cycles (induction phase) followed by a 3-week rest period, after which treatment was resumed with cycles of tri-weekly mFOLFOX6 at standard doses (maintenance phase). Validity and complications were investigated retrospectively., Results: Twenty-nine patients were enrolled in this study. The median progression-free survival (PFS) and overall survival (OS) times were 9.4 months and 23 months, respectively. All patients had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 2 patients (6.9%)., Conclusions: mFOLFOX6 maintenance chemotherapy was associated with a very low incidence of grade 3 hematologic and neurologic toxicities. The toxicities associated with PFS and OS were comparable to those reported in the treatment of patients with metastatic CRC. A tri-weekly mFOLFOX maintenance strategy of alternative treatment with a less-toxic regimen may reduce toxicity and maintain efficacy.

Background: The safety of regional hyperthermia has been tested in locally advanced rectal cancer. The aim of this study was to assess the effects of shorter distal margins on local control and survival in rectal cancer patients who were treated with preoperative hyperthermochemoradiation therapy (HCRT) and underwent rectal resection by using the total mesorectal excision (TME) method., Patients and Methods: Ninety-three patients with rectal adenocarcinoma who received neoadjuvant HCRT (total radiation: 50 Gy) were included in this study. Surgery was performed 8 weeks after HCRT, and each resected specimen was evaluated histologically. Length of distal surgical margins, status of circumferential margins, pathological response, and tumor node metastasis stage were examined for their effects on recurrence and survival., Results: Fifty-eight (62.4%) patients had tumor regression, and 20 (21.5%) had a pathological complete response. Distal margin length ranged from 1 to 55 mm (median, 21 mm) and did not correlate with local recurrence (p=0.57) or survival (p=0.75) by univariate analysis. Kaplan-Meier estimates of recurrence-free survival and local recurrence for the <10 mm versus ≥10 mm groups were not significantly different. Positive circumferential margins and failure of tumors to respond were unfavorable factors in survival., Conclusion: Distal resection margins that are shorter than 10 mm but are not positive appear to be equivalent to longer margins in patients who undergo HCRT followed by rectal resection with TME. To improve the down-staging rate, additional studies are needed.

Introduction: We have previously demonstrated that the risk of incisional surgical site infection (SSI) increases with obesity and that the most useful predictor of incisional SSI is the thickness of subcutaneous fat. Based on this finding, we have recently attempted a closure technique in surgery for the obese in which a subcutaneous drain is inserted for the prevention of incisional SSI. The aim of this study was to assess the utility of a subcutaneous drain for preventing incisional SSI in patients undergoing colorectal surgery who are at high risk for incisional SSI., Materials and Methods: Seventy-nine patients who underwent colorectal resection with high risk for incisional SSI, including patients with obesity (thick subcutaneous fat tissue, >20 mm) and those undergoing emergency operations, were enrolled in this study. The clinical features of these cases with or without a subcutaneous drain were reviewed, and statistical analysis was performed., Results: In these high-risk cases, the overall incidence of incisional SSI was 27.8%. The incidences of incisional SSI in these cases with or without a subcutaneous drain were 14.3% and 38.6%, respectively. Our results suggest that subcutaneous drains are effective for preventing incisional SSI in patients with thick subcutaneous fat in colorectal surgery., Conclusion: Therefore, incisional SSI surveillance for obese patients should be performed separately, which should lead to a further reduction in incisional SSIs.

Background/aims: There is increasing evidence to show that the presence of raised concentrations of serum C-reactive protein (CRP) is associated with poor survival in patients with colorectal carcinoma. The CRP response with respect to tumor characteristics in colorectal carcinoma was examined to identify factors that might reflect a raised CRP level., Methodology: One hundred and eighty-one patients who underwent elective colorectal resection were identified for inclusion in this study. Eighteen patients with high CRP levels were compared to a control group of 163 patients without high CRP levels, and the correlation between preoperative CRP level and clinicopathological features in operable colorectal carcinoma was investigated., Results: The analysis of factors with seeming potential to be associated with CRP levels following colorectal surgery, disclosed that only the depth of tumor invasion, serum albumin and lymphovascular invasion were of statistical significance. Multivariate subgroup analysis of the association between these factors and CRP showed that depth of invasion and albumin were independently associated with CRP., Conclusions: Our results suggest that depth of tumor invasion is associated with an increase in CRP levels. CRP is considered an important indicator of advanced local invasion in operable colorectal surgery, if other inflammatory conditions are excluded.

Free-standing films composed of several layers of chiral smectic liquid crystals (SmC*) exhibited unidirectional director precession under various vapor transfers across the films. When the transferred vapors were general organic solvents, the precession speed linearly depended on the momentum of the transmembrane vapors, where the proportional constant was independent of the kind of vapor. In contrast, the same SmC* films under water transfer exhibited precession in the opposite direction. As a possible reason for the rotational inversion, we suggest the competition of two origins for the torques, one of which is microscopic and the other macroscopic. Next, we tried to move an external object by making use of the liquid crystal (LC) motion. When a solid or a liquid particle was set on a film under vapor transfer, the particle was rotated in the same direction as the LC molecules. Using home-made laser tweezers, we measured the force transmitted from the film to the particle, which we found to be several pN.

Introduction: The objective of this study was to explore whether an automated coagulation analyzer could be applied to normal plasma mixing studies for the assessment of blood samples showing a prolonged activated partial thromboplastin time (APTT)., Materials and Methods: Ten laboratory staff members performed normal plasma mixing studies and evaluated plasma samples using 3 different methods: (1) manual dilution and analysis, (2) manual dilution and automatic analysis with STA-R®, and (3) automatic dilution and analysis with the Coapresta® 2000 (CP2000). The time from the start of the analysis to the generation of the result plots and the plasma volumes required were determined. We analyzed patient plasma samples showing a prolonged APTT using the CP2000, and the result plots were categorized into 3 curve patterns based on the area ratio values: the inhibitor type (convex pattern), deficiency type (concave pattern), and suspicious inhibitor type (approximately straight pattern)., Results: When pooled patient plasma was used, the same patterns were obtained from normal plasma mixing studies using the 3 different methods. The time required to complete the mixing studies and the plasma volumes required were 28.2 ± 2.4 min and 350 μL for manual analysis, 23.2 ± 2.1 min and 875 μL for STA-R(®), and 8.5 +/- 0.1 min and 175 μL for CP2000, respectively. Of 31 patient samples, 9 were categorized into the inhibitor type, 15 were categorized into the deficiency type, and 7 were categorized into the suspicious inhibitor type., Conclusions: The CP2000 analyzer is applicable to the laboratory diagnosis of a prolonged APTT using pattern recognition, as it requires a shorter time to complete mixing studies and a smaller plasma volume in comparison with manual analysis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background/aims: For rectal carcinoid tumors smaller than 10mm in diameter, local excision is thought to be an appropriate treatment. On the other hand, the biological behavior of tumors measuring 10 to 20mm is unpredictable. In this study our goal was to assess the validity of transanal excision in the treatment of rectal carcinoid tumors., Methodology: We identified 18 rectal carcinoid cases that underwent transanal excision. These patients' clinical data were reviewed retrospectively for details of age, gender, tumor location, lesion size, recurrence at follow-up assessment and histopathological findings., Results: Patients were divided based on tumor size (<10, 10-15mm) and then analyzed for clinical and pathological factors. Of the 18 tumors, 9 were smaller than 10mm. Of patients with tumors <10mm, 1 patient had invasion into the muscularis propria. Of patients with tumors 10-15mm, 3 tumors had invaded the muscularis propria and lymphovascular invasion was seen in 2 tumors. No patient showed recurrence or tumor-related mortality., Conclusions: Our results suggest that transanal local excision against smaller rectal carcinoids (<15mm) is effective in the treatment of rectal carcinoid tumors. To achieve disease clearance, local excision should be performed even in the case of small rectal carcinoid tumors. Our strategy for treating rectal carcinoid tumors with lesions smaller than 15mm with initial local resection to assess histopathological findings is thought to be an appropriate treatment.

Background: We previously demonstrated that extracapsular invasion (ECI) at a metastatic sentinel node was significantly associated with the presence of positive non-sentinel nodes in patients with breast cancer. However, the mechanism of metastatic spreading of tumor cells to distant lymph nodes in patients with colorectal carcinoma is not fully understood. In this study, we investigated the factors that may determine the likelihood of additional regional lymph node metastasis when metastasis is found in nodes at the N1 site in colorectal cancer, especially focusing on the presence of ECI., Methods: Two hundred and twenty-eight consecutive patients who underwent colorectal resection were identified for inclusion in this study, of which 37 (16.2%) had positive lymph nodes at the N1 site. Six of these 37 cases had additional metastasis in N2 site lymph nodes. We reviewed the clinicopathological features of these cases and performed statistical analysis of the data., Results: In the univariate analysis ECI at the N1 site was the only factor significantly associated with the presence of cancer cells in the N2 site. Other factors, including number of positive lymph nodes, lymphovascular invasion of the primary tumor, tumor size and tumor depth of invasion, were not associated with metastatic involvement at the N2 site., Conclusions: Our results suggest that the presence of ECI at metastatic lymph nodes at the N1 site is correlated with further metastasis at the N2 site. These findings imply the possibility that ECI might indicate the ability of colorectal tumor cells to disseminate to distant lymph nodes.

Background: The determination of polymerase chain reaction (PCR) amplification product sizes of the Bcl-2/IgH fusion gene from follicular lymphoma (FL) provides evidence of clonal identity., Methods: The present study describes detection of Bcl-2/IgH fusion gene clonality utilizing a small, simple microcapillary electrophoretic chip combined with a real-time PCR method., Results: The microcapillary electrophoretic chip system effectively detects size differences among the Bcl-2/IgH fusion gene amplification products of FL from patient samples; something that is not possible using traditional gel electrophoresis. We also describe the potential of this system to utilize formalin-fixed, paraffin-embedded tissue samples sectioned on charged slides., Conclusions: The simple detection of Bcl-2/IgH fusion gene clonality using a microcapillary electrophoretic chip provides reliable information for monitoring minimal residual disease of FL, and can be an effective tool for use in clinical laboratories.

Background/aims: Serum C-reactive protein (CRP) is an acknowledged marker of infections. For early detection of postoperative infections, CRP levels may be a useful marker. In this study, the CRP response with respect to wound infections (incisional surgical site infection (SSI)) in elective colorectal surgery was examined to define the role of serum CRP as a predictor of incisional SSI., Methodology: One hundred forty-eight patients who underwent elective colorectal resection were identified for inclusion in this study. The outcome of interest was incisional SSI. Twenty-eight patients with incisional SSI were compared to a subgroup of 118 patients with an uneventful postoperative course, and the correlation between postoperative serum CRP levels and incisional SSI in colorectal surgery was investigated., Results: For uneventful cases, the CRP rose postoperatively to a maximum on the third day, and the concentrations then returned to near normal levels on postoperative day (POD) 7. In incisional SSI cases, persistent elevation or a second rise in CRP concentrations was seen. Although no statistically significant differences in CRP concentrations were seen on POD 1 or 3, the initial rise in CRP of cases with incisional SSI was relatively higher compared to uneventful cases. A deviation became obvious at POD 7. A cut-off level of 36 mg/L on POD 7 was recorded (sensitivity of 71.4% and a specificity of 83.1%) for incisional SSI., Conclusion: Our results suggest that elevated serum CRP levels are correlated with incisional SSI. Persistent CRP elevation is predictive of incisional SSI in colorectal surgery if pneumonia or anastomotic leakage are unlikely or excluded.

Aim: To evaluate the presence of extracapsular invasion (ECI) in positive nodes as a predictor of disease recurrence disease in colorectal cancer., Methods: Two hundred and twenty-eight consecutive patients who underwent colorectal resection were identified for inclusion in this study, of which 46 had positive lymph nodes. Among 46 cases with stage IIIcolorectal cancer, 16 had ECI at positive nodes and 8 had disease recurrence. The clinical and pathological features of these cases were reviewed., Results: In the univariate analysis, the number of positive lymph nodes and depth of tumor invasion were significantly associated with the presence of ECI at positive nodes. Multivariate analysis demonstrated that only ECI was a predictor of recurrence. The recurrence-free interval differed significantly among patients with ECI at positive nodes., Conclusion: Our results suggest that ECI at metastatic nodes can identify which cases are at high risk of short-term disease recurrence in colorectal cancer.

Orientational correlations in Langmuir monolayers of nematic and smectic-C liquid crystal (LC) phases are investigated by molecular dynamics simulation. In both phases, the orientational correlation functions decay algebraically yet with the different exponents of 1.9 and 0.2 for the nematic and the smectic-C monolayers, respectively. The power law decay, i.e., the absence of long-range orientational order, means the both monolayers should be the ideal 2D system with a continuous symmetry, whereas the large difference in the exponents of power law gives rise to the crucial difference in their optical properties; the nematic monolayer is optically isotropic while the smectic-C monolayer exhibits an anisotropy on the length scale of visible light. Since the exponent is inversely proportional to the molecular exchange energy, the averaged molecular interaction in the nematic monolayer should be an order of magnitude smaller than that in the smectic-C monolayer, which is ascribed to the low molecular density and the weak molecular dipole due to the water molecule. The relation between the molecular interaction and the orientational correlation calculated for the 2D LC system offers much information not only about the 2D LCs but also on the bulk system.

This study demonstrated a pronounced synergistic growth-inhibitory effect of an MDM2 inhibitor Nutlin-3 and a proteasome inhibitor bortezomib in mantle cell lymphoma (MCL) cells regardless of TP53 mutant status and innate bortezomib sensitivity. In the mutant TP53 MCL cells which are intrinsically resistant to bortezomib, the combination of Nutlin-3/bortezomib synergistically induced cytotoxicity through the mitochondrial apoptotic pathway mediated by transcription-independent upregulation of NOXA, sequestration of MCL-1, activation of BAX, BAK, caspase-9 and -3. In the bortezomib sensitive wild-type TP53 MCL cells, the Nutlin-3/bortezomib combination caused G0/G1 cell cycle arrest followed by the increase in apoptosis induction. These findings indicate potential therapeutic efficacy of Nutlin-3/bortezomib combination for the treatment of chemorefractory MCL., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Chronic lymphocytic leukemia (CLL) is relatively rare in Japan. Among 46 cases of mature B-cell leukemia, we identified 28 Japanese patients with CLL, including prolymphocytoid and lymphoplasmacytoid morphological variants. Compared with Western patients with CLL, only 52.0% of cases showed the typical immunophenotypic profile. IgG-bearing (15.4%) and clearly CD20-expressing (71.4%) cases were frequently observed. Most cases harbored a mutated immunoglobulin heavy-chain (VH) gene (88.5%) and commonly used a VH3 family member (61.5%) other than VH3-21. During the median follow-up period of 64 months, 20 cases (71.4%) showed an indolent clinical course without any treatment, and six cases (21.4%) were accompanied by other malignancies. Binet A stage (p = 0.003), low-risk category according to the modified Rai classification (p = 0.016), and ≤ 15 U/mL level of serum thymidine kinase activity (p = 0.016) were associated with prolongation of treatment-free status. Although Japanese cases of CLL showed heterogeneity in morphology and immunophenotype, most cases arose from post-antigen-selected B cells and presented with indolent clinical behavior.

Though differential counting of peripheral blood cells is an important diagnostic tool, this technique requires highly trained staff. Automation of differentials is desirable for economic and time-saving reasons. Recently, the CellaVision DM96 (DM96, CellaVision AB, Lund, Sweden) has been introduced as an automated cell analysis system capable of morphological classification of WBCs and RBCs in pheripheral blood smears. In this study, we routinely analyzed the blood samples from 216 patients by the DM96. The overall preclassification of WBC analysis accuracy value for the DM96 was 90.3%. Good correlation coefficients between final results of the DM96 and manual differentiation were observed. The DM96 system performed high sensitivity and specificity for blasts and immature granulocytes. Although the DM96 system operates more effectively in the normal blood samples than pathological ones, its ability of review slides on the computer screen with a cell-by-cell basis provides real-time collaboration between colleagues when they face the abnormal cells.

Background and Aims: The objective of this study is to compare the postoperative motility between hand-sewn end-to-end anastomosis and functional end-to-end anastomosis., Methods: Fifteen conscious dogs were divided into three groups: normal intact dog group, end-to-end anastomosis group (EE), and functional end-to-end anastomosis group (FEE). In the EE and FEE groups, the dogs underwent a transection of the jejunum 30 cm distal to the Treitz ligament and anastomosis in each method. To compare the gastrointestinal motility, the time to the appearance and the rate of propagation of interdigestive migrating motor contractions (IMC) across the anastomosis, as well as the motility index (MI) at the oral and anal sides of the anastomosis, were measured using strain gauge force transducers. Furthermore, the histological examination of intrinsic nerve fibers was evaluated., Results: The time to the appearance of propagation of IMC in the EE and FEE was not significantly different. The propagation rates of IMC in the EE and FEE completely recovered within 4 weeks of the surgery. The MI in the EE and FEE was not significantly different. In addition, no continuity of intrinsic nerve fibers across the anastomosis could be identified in either group., Conclusions: In the present study, there are no significant differences between the EE and FEE with regard to the time of the appearance and the rate of propagation of IMC. These results suggest that the effect of functional end-to-end anastomosis on postoperative motility is not different from that of hand-sewn end-to-end anastomosis.

Sysmex XE-5000 offers the body fluid modus which provides the opportunity to count and differentiate leukocytes in body fluids and cerebrospinal fluid (CFS). In this study, we evaluated the basic performance of this application using routinely obtained samples in comparison with manual counting. Reproducibility study yielded good results in samples with a high white blood cell (WBC) count, whereas relatively high imprecision was observed at low WBC counts. Linearity was established up to 1,500 cells/microL in CFS and 5,600 cells/microL in body fluid. The cell count by XE-5000 was highly correlated with that of the microscopic reference method. Highly fluorescent body fluid cells percent (HF-BF%) was observed in samples with tumor cells or activated macrophages, which provides information about the possible presence of tumor cells. In conclusion, total and differential WBC counts in body fluid and CFS can be reliably determined by XE-5000 in samples with increased cell counts. XE-5000 also provides screening information about the presence of tumor cells for further manual examination.

Monosodium l-glutamate (MSG) is a substance known to produce the umami taste. Recent studies indicate that MSG also stimulates a variety of activities in the gastrointestinal tract through its receptor in the gut, but no study has reported the activity in conscious large experimental animals. The aim of our study was to investigate whether direct intragastric MSG stimulates gut motility and to identify the mechanism in conscious dogs. Contractile response to intraluminal injection of MSG was studied in the fed and fasted states by means of chronically implanted force transducers. MSG (5, 15, 45, and 90 mM/kg) dissolved in water was injected into the stomach and duodenum in normal and vagotomized dogs. MSG solution was administered into the stomach before feeding, and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and granisetron) were injected intravenously before MSG administration to the stomach. The effect of MSG was investigated in Pavlov (vagally innervated corpus pouch), Heidenhain (vagally denervated corpus pouch), and antral pouch (vagally innervated) dogs. Upper gut motility was significantly increased by intragastric MSG but not significantly stimulated by intraduodenal MSG. Intragastric MSG (45 mM/kg) stimulated postprandial motility and accelerated gastric emptying. MSG-induced contractions were inhibited by truncal vagotomy, atropine, hexamethonium, and granisetron. Gut motility was increased by intrapouch injection of MSG in the Pavlov pouch, but it was not affected in the Heidenhain or antral pouch dogs. We conclude that intragastric MSG stimulates upper gut motility and accelerates gastric emptying. The sensory structure of MSG is present in the gastric corpus, and the signal is mediated by the vagus nerve.

Zinc (Zn) is an essential trace element for humans and its deficiency can lead to several clinical problems. This study examined the relationship between the serum zinc concentration and anemia in middle-aged and elderly people. Samples were obtained from 150 men and 303 women who received health checkups over the course of 40 years. The serum concentration of Zn was measured as well as the complete blood count (CBC), alanine aminotransferase (AST), aspartate aminotransferase (ALT), gamma-glutamyl transferase (gamma GT), total cholesterol (TC), high density lipoprotein (HDL-C), triglyceride (TG), creatinine (Cr), uric acid (UA) and fasting plasma glucose (FPG). The serum Zn concentration was 77.4 +/- 9.7 microg/dL in men and 79.1 +/- 10.4 microg/dL in women (p= 0.09). The serum Zn concentration correlated inversely with age (r=-0.11, p=0.018). Anemia diagnosed by the World Health Organization criteria, was present in 17.3% of men and in 13.5% of women. However, more than 80% of the anemia was normocytic (men 86%, women 81%). The serum Zn concentration was significantly lower in those with anemia than in those without anemia. The Hb level correlated with the serum Zn concentration (men r=0.25, p=0.002, women r=0.23, p<0.001). A multiple regression analysis confirmed a low serum Zn concentration to be associated with a low Hb level. In conclusion, this study indicates that the serum Zn concentration decreases with age and that a low Zn concentration is associated with normocytic anemia, thus suggesting that a Zn deficiency may therefore be one of the causes of anemia in elderly people.

Background/aims: In this study, we have attempted to identify and assess factors that would be most predictive of postoperative incisional surgical site infection (SSI) in colorectal surgery, including representative markers for nutrition or obesity., Methods: 152 patients who underwent elective colorectal resection were identified for inclusion in this study. The outcome of interest was incisional SSI. Variables thought to be predictive of incisional SSI, including body mass index (BMI) and the thickness of subcutaneous fat (TSF), were assessed by univariate and multivariate analysis. TSF was evaluated preoperatively using computed tomography (CT)., Results: The study's overall incidence of incisional SSI following a colorectal operation was 29 (19.1%). TSF was independently associated with incisional SSI. While BMI was significantly associated with incisional SSI on univariate analysis, this variable lost its significance on multivariate analysis that included TSF. Other nutritional markers were not significantly associated with the risk of incisional SSI., Conclusions: Our results suggest that the risk of incisional SSI increases with obesity, and that the most useful predictor of incisional SSI is TSF, as evaluated by preoperative CT. These findings indicate that CT is useful for the evaluation of TSF and the prediction of the risk of incisional SSI., (Copyright 2010 S. Karger AG, Basel.)

Purpose: The mechanism for the initiation of giant migrating contractions (GMCs) associated with defecation is not well known. The aim of this study was to describe the characteristics of special propulsive contractions (SPCs), such as GMCs, during evacuation in four experimental dog models, with emphasis on denervation., Materials and Methods: Twenty healthy dogs were used in this study, and they were divided into four groups, i.e., control (underwent force transducer implantation alone), denervation (underwent transection of the descending nerve fibers along the caudal mesenteric artery (CMA)), transection (underwent transection of the rectum, which corresponds to transection of the enteric nerve fibers), and denervation-plus-transection (underwent transection of the descending nerve fibers along the CMA and transection of the rectum). Colonic contractile activities were continuously recorded on a computer. Five force transducers were implanted at the serosal surfaces of the colon (C1-R). The consistency of dog feces was checked daily. The parameters of rectal relaxation (RR), defecation characteristics, and SPCs, such as motility index (MI), duration, and frequency, were measured., Results: In the control and denervation groups, GMCs were observed with evacuation, and RR occurred synchronously with the initiation of GMCs. On the other hand, in the transection and denervation-plus-transection groups, strong force contractions without RR occurred only during evacuation. The MI and duration of the transection and denervation-plus-transection groups were higher than those of other groups (p < 0.05). The frequency of SPCs was the highest in the denervation-plus-transection group., Conclusions: In conclusion, the continuity of enteric nerves is necessary for the occurrence of GMCs and rectal relaxation (RR).

Objectives: The quantification of 24 hrs urinary protein excretion is valuable for diagnosing and monitoring renal disease. However, because of its practical difficulties, the spot urinary protein/creatinine (P/C) ratio has been utilized. We aimed to evaluate the analytical performance of P/C ratio by comparing with the qualitative urinary protein values and the microscopic urine sediment analysis., Methods: We obtained 5,538 urinary samples from the outpatients of Juntendo University Hospital. Testing for urinary P/C ratio was performed by Atlas Pro12 (cut-off 150 mg/g x Cr), urinary protein (proteinuria) was detected quantitatively by full-automated system ATLAS XL (cut-off 30 mg/dL). Microscopic exams were conducted following to the JCCLS reference method., Results: The P/C ratio demonstrated higher sensitivity but lower specificity for urinary abnormal casts detected by microscopic exams compared to proteinuria (sensitivity; P/C 87%, proteinuria 77%. specificity; P/C 74%, proteinuria 93%). From the comparative study with microscopic exams, both P/C and proteinuria performed high positive rate (> 80%) for the granular cast type and mixture cast type. For the cellular cast type, however, the positive rate of P/C was 56% and that of proteinuria was only 36%. The overall abnormal casts by microscopic exams showed better correlation with the positive P/C ratio than proteinuria., Conclusion: This study emphasizes that a spot urine P/C ratio is useful in screening for the further microscopic exams. P/C ratio can be a convincing index of urinary protein excretion when attenuation urine is doubted.

Background: Long-term physiological variations, such as seasonal variations, affect the screening efficiency at medical checkups. This study examined the seasonal variation in liver function tests using recently described data-mining methods., Methods: The 'latent reference values' of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (gammaGT), cholinesterase (ChE) and total bilirubin (T-Bil) were extracted from a seven-year database of outpatients (aged 20-79 yr; comprising approximately 1,270,000 test results). After calculating the monthly means for each variable, the time-series data were separated into trend and seasonal components using a local regression model (Loess method). Then, a cosine function model (cosinor method) was applied to the seasonal component to determine the periodicity and fluctuation range. A two-year outpatient database (215,000 results) from another hospital was also analysed to confirm the reproducibility of these methods., Results: The serum levels of test results tended to increase in the winter. The increase in AST and ALT was about 6% in men and women, and was greater than that in ChE, ALP (in men and women) and gammaGT (in men). In contrast, T-Bil increased by 3.6% (men) and 5.0% (women) in the summer. The total protein and albumin concentrations did not change significantly. AST and ALT showed similar seasonal variation in both institutions in the comparative analysis., Conclusions: The liver function tests were observed to show seasonal variations. These seasonal variations should therefore be taken into consideration when establishing either reference intervals or cut-off values, which are especially important regarding aminotransferases.

In hematological malignancies, there are dynamic interactions between leukemic cells and cells of the bone marrow microenvironment. Specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. This review focuses on molecular and cellular biology of the normal hematopoietic stem cell and the leukemia stem cell niche, and of the molecular pathways critical for microenvironment/leukemia interactions. The key emerging therapeutic targets include chemokine receptors (CXCR4), adhesion molecules (VLA4 and CD44), and hypoxia-related proteins HIF-1alpha and VEGF. Finally, the genetic and epigenetic abnormalities of leukemia-associated stroma will be discussed. This complex interplay provides a rationale for appropriately tailored molecular therapies targeting not only leukemic cells but also their microenvironment to ensure improved outcomes in leukemia.