Transrectal ultrasound and magnetic resonance imaging measurement of extramural tumor spread in rectal cancer

AIM:To evaluate the agreement between transrectal ultrasound(TRUS) and magnetic resonance imaging(MRI) in classification of ≥ T3 rectal tumors.METHODS:From January 2010 to January 2012,86 consecutive patients with ≥ T3 tumors were included in this study.The mean age of the patients was 66.4 years(range:26-91 years).The tumors were all ≥ T3 on TRUS.The sub-classification was defined by the penetration of the rectal wall:a:0 to 1 mm;b:1-5 mm;c:6-15;d:> 15 mm.Early tumors as ab(≤ 5 mm) and advanced tumors as cd(> 5 mm).All patients underwent TRUS using a 6.5 MHz transrectal transducer.The MRI was performed with a 1.5 T Philips unit.The TRUS findings were blinded to the radiologist performing the interpretation of the MRI images and measuring the depth of extramural tumor spread.RESULTS:TRUS found 51 patients to have an early ≥ T3 tumors and 35 to have an advanced tumor,whereas MRI categorized 48 as early ≥ T3 tumors and 38 as advanced tumors.No patients with tumors classified as advanced by TRUS were found to be early on MRI.The kappa value in classifying early versus advanced T3 rectal tumors was 0.93(95% CI:0.85-1.00).We found a kappa value of 0.74(95% CI:0.63-0.86) for the total sub-classification between the two methods.The mean maximal tumor outgrowth measured by TRUS,5.5 mm ± 5.63 mm and on MRI,6.3 mm ± 6.18 mm,P = 0.004.In 19 of the 86 patients the following CT scan or surgery revealed distant metastases;of the 51 patients in the ultrasound ab group three(5.9%) had metastases,whereas 16(45.7%) of 35 in the cd group harbored distant metastases,P = 0.00002.The odds ratio of having distant metastases in the ultrasound cd group compared to the ab group was 13.5(95% CI:3.5-51.6),P = 0.00002.The mean maximal ultrasound measured outgrowth was 4.3 mm(95% CI:3.2-5.5 mm) in patients without distant metastases,while the mean maximal outgrowth was 9.5 mm(95% CI:6.2-12.8 mm) in the patients with metastases,P = 0.00004.Using the MRI classification three(6.3%) of 48 in the MRI ab group had distant metastases,while 16(42.1%) of the 38 in the MRI cd group,P = 0.00004.The MRI odds ratio was 10.9(95% CI:2.9-41.4),P = 0.00008.The mean maximal MRI measured outgrowth was 4.9 mm(95% CI:3.7-6.1 mm) in patients without distant metastases,while the mean maximal outgrowth was 11.5 mm(95% CI:7.8-15.2 mm) in the patients with metastases,P = 0.000006.CONCLUSION:There is good agreement between TRUS and MRI in the pretreatment sub-classification of ≥ T3 tumors.Distant metastases are more frequent in the advanced group.

Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity

AIM: To describe the establishment of a Danish inflammatory bowel diseases(IBD) twin cohort with focus on concordance of treatment and inflammatory markers.METHODS: We identified MZ twins, likely to be discordant or concordant for IBD, by merging information from the Danish Twin Register and the National Patient Register. The twins were asked to provide biological samples, questionnaires, and data access to patient files and public registries. Biological samples were collected via a mobile laboratory, which allowed for immediate centrifugation, fractionation, and storage of samples. The mean time from collection of samples to storage in the-80 ℃ mobile freezer was less than one hour. The diagnoses where validated using the Copenhagen diagnostic criteria.RESULTS: We identified 159 MZ IBD twin pairs, in a total of 62(39%) pairs both twins agreed to participate. Of the supposed 62 IBD pairs, the IBD diagnosis could be confirmed in 54 pairs. The cohort included 10 concordant pairs, whereof some were discordant for either treatment or surgery. The 10 concordant pairs, where both pairs suffered from IBD, included eight CD/CD pairs, one UC/UC pair and one UC/IBDU pair. The discordant pairs comprised 31 UC, 5 IBDU(IBD unclassified), and 8 CD discordant pairs. In the co-twins not affected by IBD, calprotectin was above 100 μg/g in 2 participants, and above 50 μg/g in a further 5 participants.CONCLUSION: The presented IBD twin cohorts are an excellent resource for bioinformatics studies with proper adjustment for disease-associated exposures including medication and inflammatory activity in the co-twins.

Elderly Disabled Patients in Oral Anticoagulation Treatment: An Evaluation of a Bioanalyst-Led Management Program Reaching an Average of 72% of Time in Therapeutic Range

Introduction: The need for anticoagulation therapy increases with age, mainly due to the increased prevalence of atrial fibrillation. Time in therapeutic range (TTR) is a marker of the quality of the therapy as TTR is inversely correlated with adverse reactions. We developed a bioanalyst-led management program for control of warfarin treatment in elderly disabled patients in their own home and maintain a high TTR. Material and Methods: Residents in nursing home settings were included. Visiting nurses measured INR with a point of care testing device. If INR was within Therapeutic Range (TR), the nurse dosed warfarin unaltered. If INR was out of TR, the visiting nurse contacted a specially trained bioanalyst by phone. An explanation was sought, and a new dosage plan was made. Results: A total of 579 patients were included;356 females (61%). Mean age was 79.6 years. Approximately 10% were residents in nursing home settings and the rest in domiciliary care. TTR was 72%. The subtherapeutic values were 15% and supratherapeutic values 13%. In total, 139 patients died during the study period. Ten deaths could be related to possible side effects of warfarin treatment. Conclusions: Our results indicate that a bioanalyst-led program is able to simplify anticoagulation monitoring, while maintaining INR control similar to a specialized clinic. Furthermore, we avoided hospitalizations when INR was unacceptably high by treating the patient with oral vitamin-K at home. Our findings could be helpful when planning warfarin treatment in elderly, fragile patients.

Biomarkers in inflammatory bowel diseases:Current status and proteomics identification strategies

Unambiguous diagnosis of the two main forms of inflammatory bowel diseases(IBD):Ulcerative colitis(UC)and Crohn’s disease(CD),represents a challenge in the early stages of the diseases.The diagnosis may be established several years after the debut of symptoms.Hence,protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients.Moreover,the biomarkers could aid physicians to predict disease courses and in this way,identify patients in need of intensive treatment.Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events.In addition,identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment.Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies.Thus,the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value.The technological development in recent years within proteomic research(determination and quantification of the complete protein content)has made the discovery of novel biomarkers feasible.Several IBD-associated protein biomarkers are known,but none have been successfully implemented in daily use to distinguish CD and UC patients.The intestinal tissue remains an obvious place to search for novel biomarkers,which blood,urine or stool later can be screened for.When considering the protein complexity encountered in intestinal biopsysamples and the recent development within the field of mass spectrometry driven quantitative proteomics,a more thorough and accurate biomarker discovery endeavor could today be performed than ever before.In this review,we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers,as well as suggesting future targets for analysis.

【特刊综述】性腺功能低下在克氏综合征中的角色

Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.

Colorectal cancer in patients with inflammatory bowel disease:Can we predict risk?

The inflammatory bowel diseases(IBD),Crohn's disease(CD) and ulcerative colitis(UC),may be complicated by colorectal cancer(CRC).In a recent populationbased cohort study of 47 347 Danish patients with IBD by Tine Jess and colleagues 268 patients with UC and 70 patients with CD developed CRC during 30 years of observation.The overall risk of CRC among patients with UC and CD was comparable with that of the general population.However,patients diagnosed with UC during childhood or as adolescents,patients with long duration of disease and those with concomitant primary sclerosing cholangitis were at increased risk.In this commentary,we discuss the mechanisms underlying carcinogenesis in IBD and current investigations of genetic susceptibility in IBD patients.Further advances will depend on the cooperative work by epidemiologist and molecular geneticists in order to identify genetic polymorphisms involved in IBD-associated CRC.The ultimate goal is to incorporate genotypes and clinical parameters into a predictive model that will refine the prediction of risk for CRC in colonic IBD.The challenge will be to translate these new findings into clinical practice and to determine appropriate preventive strategies in order to avoid CRC in IBD patients.The achieved knowledge may also be relevant for other inflammation-associated cancers.

Pit-and trench-forming osteoclasts:a distinction that matters

Osteoclasts（OCs）seeded on bone slices either drill round pits or dig long trenches.Whereas pits correspond to intermittent resorption,trenches correspond to continuous and faster resorption and require a distinct assembly of the resorption apparatus.It is unknown whether the distinction between pits and trenches has any biological relevance.Using OCs prepared from different blood donors,we found that female OCs achieved increased resorption mainly through pit formation,whereas male OCs did so through trench formation.Trench formation went along with high collagenolytic activity and high cathepsin K（CatK）expression,thereby allowing deeper demineralization.A specific CatK inhibitor abrogated the generation of trenches,while still allowing the generation of pits.OCs obtained from bone marrow were more prone to generate trenches than those obtained from blood.Scanning electron microscopy of bone surfaces eroded in vivo showed trenches and pits of similar size as those made by OCs in culture.We conclude that the distinction between trench-and pit-forming OCs is relevant to the differences among OCs from different skeletal sites,different individuals,including gender,and results from differences in colIagenolytic power.This indicates a biological relevance and highlights the importance of discriminating between pits and trenches when assessing resorption.

DNA-repair ERCC1 Gene Polymorphisms in Epithelial Ovarian Cancer and Relation to Platinum Resistance and Survival

Objectives: Excision repair cross-complementation group 1 (ERCC1) is a key DNA repair gene in the nucleotide excision repair pathway which is activated in the repair of intra- and interstrand DNA crosslink caused by platinum-based treatment. Two single nucleotide polymorphisms (SNPs) of the ERCC1 gene, codon 118 C/T and C8092A, have been reported to be functional, but the influence on platinum resistance and survival is not yet clear. The primary aim of the present study was to investigate whether the two SNPs were associated with resistance to standard combination carboplatin and paclitaxel chemotherapy and the potential prognostic impact in newly diagnosed ovarian cancer patients. Methods: Serum samples from 202 patients with newly diagnosed ovarian cancer were assessed for ERCC1 SNP genotyping using real time PCR. All patients were treated with first line carboplatin/paclitaxel chemotherapy. Results: There were no correlation between the ERCC1 118 C/T and C8092A genotypes and platinum resistance (P = 0.79 and P = 0.36, respectively). Furthermore, the results showed no association to progression free survival (P = 0.18 and P = 0.16, respectively) or overall survival (P = 0.89 and P = 0.78, respectively) for the two SNPs. Conclusions: The ERCC1 118 C/T and C8092A polymorphisms did not have significant influence on clinical outcome defined as platinum resistance, PFS and OS.

MicroRNA-126 and epidermal growth factor-like domain 7 predict recurrence in patients with colon cancer treated with neoadjuvant chemotherapy

Aim:Neoadjuvant chemotherapy may represent a shift in the treatment of locally advanced colon cancer.The angiogenic couple has-microRNA-126(miRNA-126)and epidermal growth factor-like domain 7(EGFL7)are transcribed from the same gene and regulates all aspects of angiogenesis and may influence the ability of tumor cells to disseminate.The aim was to analyze the relationship between miRNA-126 and EGFL7 and disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy.Methods:This study included 71 patients from a phase II study all planned for three cycles of capecitabine and oxaliplatin before surgery.Blood was sampled at baseline and right before and after the operation.Circulating miRNA-126 was analysed by RT-qPCR and a quantitative immunoassay was used for the analyses of EGFL7.Results:The rates of 5-year disease-free survival(DFS)and overall survival(OS)were 80%and 85%,respectively.The level of circulating miRNA-126 before the operation predicts recurrence,P=0.035.In patients with values below and above the median the recurrence rate was 31%and 4%,respectively.Similar results applied to EGFL7.A combined estimate identified a subgroup of patients(25 of 71)with no recurrence and a 5-year DFS and OS rate of 100%,respectively.Conclusion:MicroRNA-126 and EGFL7 are predictors for disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy and may assist in selection of adjuvant chemotherapy.