Lymphangiogenesis:A new player in cancer progression

Lymph node metastasis is the hallmark of colon cancer progression,and is considered one of the most important prognostic factors.Recently,there has been growing evidence that tumor lymphangiogenesis(formation of new lymphatic vessels) plays an important role in this process.Here,we review the latest f indings of the role of lymphangiogenesis in colorectal cancer progression,and discuss its clinical application as a biomarker and target for new therapy.Understanding the molecular pathways that regulate lymphangiogenesis is mandatory to pave the way for the development of new therapies for cancer.In the future,tailored treatments consisting of combinations of chemotherapy,other targeted therapies,and anti-lymphangiogenesis agents will hopefully improve patient outcomes.This progression to the clinic must be guided by new avenues of research,such as the identif ication of biomarkers that predict response to treatment.

Inverted Meckel's diverticulum as a cause of occult lower gastrointestinal hemorrhage

Meckel's diverticulum is a common asymptomatic congenital gastrointestinal anomaly,but rarely it can present with hemorrhage.Over the last few years inverted Meckel's diverticulum has been reported in the literature with increasing frequency as an occult source of lower gastrointestinal hemorrhage.Here,we report a case of a 54-year-old male,who was referred for surgical evaluation with persistent anemia and occult blood per rectum after a work up which failed to localize the source over 12 mo,including upper and capsule endoscopy,colonoscopy,enteroclysis,Meckel scan,and tagged nuclear red blood cell scan.An abdominal computed tomography scan showed a possible mid-ileal intussusception and intraluminal mass.During the abdominal exploration,inverted Meckel's diverticulum was diagnosed and resected.We review the literature,discuss the forms in which the disease presents,the diagnostic modalities utilized,pathological findings,and treatment.Although less than 40 cases have been reported in the English literature from 1978 to 2005,19 cases have been reported in the last 6 years alone(2006-2012) due to improved diagnostic modalities.Successful diagnosis and treatment of this disease requires a high index of clinical suspicion,which is becoming increasingly relevant to general gastroenterologists.

Genetic changes of p53,K-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary

AIM: To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary.METHODS: We examined 42 cases of gallbladder carcinoma: 22 Japanese and 20 Hungarian cases. p53 mutations at exons 5 to 8 and K-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of five-microsatellite markers (BAT-25, BAT-26, D2S123, D5S346, and D17S250).RESULTS: Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases (11/22 vs 6/18, P = 0.348). Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant (0/11 vs 2/6, P = 0.110). K-ras mutations were detected in only one of the Hungarian cases. Eight of 19 (42.1%) Japanese cases were MSI-high (presence of novel peaks in more than one of the five loci analyzed), whereas only 1 of 15 (6.7%) Hungarian cases was MSI-high (P = 0.047).CONCLUSION: It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis.

Prophylactic lateral pelvic lymph node dissection in stage Ⅳ low rectal cancer

AIM To assess the clinical significance of prophylactic lateral pelvic lymph node dissection (LPLND) in stage Ⅳ low rectal cancer.METHODS We selected 71 consecutive stage Ⅳ low rectal cancer patients who underwent primary tumor resection,and enrolled 50 of these 71 patients without clinical LPLN metastasis.The patients had distant metastasis such as liver,lung,peritoneum,and paraaortic LN.Clinical LPLN metastasis was defined as LN with a maximum diameter of 10 mm or more on preoperative pelvic computed tomography scan.All patients underwent primary tumor resection,27 patients underwent total mesorectal excision(TME) with LPLND(LPLND group),and 23 patients underwent only TME(TME group).Bilateral LPLND was performed simultaneously with primary tumor resection in LPLND group.R0 resection of both primary and metastatic sites was achieved in 20 of 50 patients.We evaluated possible prognostic factors for 5-year overall survival (OS),and compared 5-year cumulative local recurrence between the LPLND and TME groups.RESULTS For OS,univariate analyses revealed no significant benefit in the LPLND compared with the TME group (28.7% vs 17.0%,P = 0.523); multivariate analysis revealed that R0 resection was an independent prognostic factor.Regarding cumulative local recurrence,the LPLND group showed no significant benefit compared with TME group (21.4% vs 14.8%,P = 0.833).CONCLUSION Prophylactic LPLND shows no oncological benefits in patients with Stage Ⅳ low rectal cancer without clinical LPLN metastasis.

Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer

Inflammation is a central process in several disorders and contributes to cancer progression. Inflammation involves a complex cascade of pro-inflammatory and anti-inflammatory signaling events with protein and lipid mediators. Recent advances in lipid detection have revealed the importance of lipid mediators in inflammation. Omega three polyunsaturated fatty acids(ω-3 PUFA) are found naturally in fish oil and have been extensively studied in multiple inflammatory diseases with improved outcomes. Resolvins are thought to be the active metabolites of ω-3 PUFA, and are responsible for facilitating the resolving phase of acute inflammation. Clinically, resolvins have been associated with resolution of acute kidney injury and acute lung injury, micro and macro vascular response to injury, and inhibition of microglia-activated inflammation in neurodegenerative disorders. In addition to inflammatory diseases, ω-3 PUFA and resolvins appear to modulate cancer progression. ω-3 PUFA intake has been associated with reduced inflammation in colorectal cancer, and favorable phenotype in breast cancer. Resolvins offer promising therapeutic potential as they may modulate inflammation with minimal side-effects, in contrast to currently available anti-inflammatory medications. This review describes the roles of ω-3 PUFA and resolvins in the inflammatory cascade, various inflammatory diseases, and specific cancers. Additionally, it will discuss the clinical therapeutic potential of resolvins astargets in inflammatory diseases and cancers.

Perimuscular connective tissue contains more and larger lymphatic vessels than the shallower layers in human gallbladders

AIM: To clarify whether perimuscular connective tissuecontains more lymphatic vessels than the shallowerlayers in human gallbladders.METHODS: Lymphatic vessels were stainedimmunohistochemically with monoclonal antibody D2-40,which is a specific marker of lymphatic endothelium, inrepresentative sections of 12 normal human gallbladdersobtained at the time of resection for colorectal carcinomaliver metastases. In individual gallbladder specimens,nine high-power (× 200) fields with the highestlymphatic vessel density (LVD), termed "hot spots", wereidentified for each layer (mucosa, muscle layer, andperimuscular connective tissue). In individual hot spots,the LVD and relative lymphatic vessel area (LVA) weremeasured microscopically using a computer-aided imageanalysis system. The mean LVD and LVA values for thenine hot spots in each layer were used for statisticalanalyses.RESULTS: In the mucosa, muscle layer, andperimuscular connective tissue, the LVD was 16.1 ± 9.2,35.4 ± 15.7, and 65.5 ± 12.2, respectively, and the LVAwas 0.4 ± 0.4, 2.1 ± 1.1, and 9.4 ± 2.6, respectively.Thus, both the LVD and LVA differed significantly (P <0.001 and P < 0.001, respectively; Kruskal-Wallis test)among the individual layers of the wall of the gallbladder,with the highest LVD and LVA values in the perimuscularconnective tissue. Most (98 of 108) of the hot spotswithin the perimuscular connective tissue were locatedwithin 500 μm of the lower border of the muscle layer.CONCLUSION: The perimuscular connective tissuecontains more and larger lymphatic vessels than the shallower layers in the human gallbladder. This observation partly explains why the incidence of lymph node metastasis is high in T2 (tumor invading the perimuscular connective tissue) or more advanced gallbladder carcinoma.

Cost-Effectiveness Analysis of Neoadjuvant Chemotherapy with Zoledronic Acid for HER2-Negative Breast Cancer in Japan: The JONIE1 Study

Objective: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption. Adding ZOL to neoadjuvant chemotherapy has been shown to have potential anticancer benefits in women with HER2-negative breast cancer. The objective of the present study was to investigate ZOL’s cost-effectiveness from the perspective of health care payers in Japan. Methods: A Markov model was developed to evaluate the costs and effectiveness associated with ZOL + chemotherapy (CTZ) and chemotherapy (CT) alone over a 10-year time horizon. Monthly transition probabilities were estimated according to JONIE1 (Japan Organization of Neoadjuvant Innovative Expert) Study data and an extrapolated Weibull model. Health outcomes were measured in quality-adjusted life years (QALYs). Costs were calculated using year-2018 Japanese yen (JPY) (1.00 US dollars (USD) = 110.4 JPY). Model robustness was addressed through one-way and probabilistic sensitivity analysis. The costs and QALYs were discounted at a rate of 2% per year. Results: In the base case, the use of CTZ was associated with a gain of 3.94 QALYs. The incremental cost per QALY of the CTZ gain was 681,056.1 JPY (6168.99 USD) per QALY. Conclusion: It is convincing that neoadjuvant CTZ for patients with breast cancer would be expected to have statistically significant clinical efficacy. Addition of ZOL to CT might be a cost-effective option compared with CT alone.

Bile acids as global regulators of hepatic nutrient metabolism

Bile acids(BA)are synthesized from cholesterol in the liver.They are essential for promotion of the absorption of lipids,cholesterol,and lipid-soluble vitamins from the intestines.BAs are hormones that regulate nutrient metabolism by activating nuclear receptors(farnesoid X receptor(FXR),pregnane X receptor,vitamin D)and G protein-coupled receptors(e.g.,TGR5,sphingosine-1-phosphate receptor 2(S1PR2))in the liver and intestines.In the liver,S1PR2 activation by conjugated BAs activates the extracellular signal-regulated kinase 1/2 and AKT signaling pathways,and nuclear sphingosine kinase 2.The latter produces sphingosine-1-phosphate(S1P),an inhibitor of histone deacetylases 1/2,which allows for the differential up-regulation of expression of genes involved in the metabolism of sterols and lipids.We discuss here the emerging concepts of the interactions of BAs,FXR,insulin,S1P signaling and nutrient metabolism.