Promoter Methylation of Specific Genes is Associated with the Phenotype and Progression of Colorectal Adenocarcinomas

Background

Promoter methylation of colorectal cancer-related genes were examined with respect to phenotype and tumor progression.

Materials and Methods

We assayed promoter methylation of 11 genes including established CpG island methylator phenotype (CIMP) markers (MLH1, MINT1, MINT2, MINT31, p16 ^INK4a , p14 ^ARF , and CACNA1G) and four genes (COX2, DAPK, MGMT, and APC) frequently methylated in colorectal cancer in 285 patients with sporadic colorectal cancer.

Results

CIMP+ tumors were more than two times more frequent among high-frequency microsatellite instability tumors (MSI-H) than in tumors without MSI (P ≤ .0001–.002). COX2 and DAPK methylation were significantly associated with CIMP+ and MSI. KRAS showed tendency toward more frequent codon 12-13 mutations identified in tumors with APC and p16 ^INK4a methylation than in those with unmethylation (P = .033 and .05, respectively). Additionally, tumors with synchronous adenoma were associated with p16 ^INK4a methylation (P = .004). The p16 ^INK4a methylation was significantly associated with poor overall and disease-free survival in 131 rectal cancer patients who underwent curative operation, according to multivariate analyses (relative risk [RR] = 0.317 and 0.349; P = .033 and .024, respectively). Specifically, in 175 stage II and III patients receiving adjuvant-based fluoropyrimidine chemotherapy, p16 ^INK4a methylation and MINT31 unmethylation showed a significant or tendency toward an association with recurrence and DFS (P = .007–.032).

Conclusions

The study suggests that specific CIMP markers, such as p16 ^INK4a and MINT31, should be further verified as potential epigenetic targets for the design of efficient chemotherapy regimens. We also identified a subset of colorectal cancer, possibly comprising APC methylation-KRAS mutation-p16 ^INK4a methylation.     

Effects of Pulsed Electromagnetic Fields on Human Osteoblastlike Cells (MG-63): A Pilot Study

Background

Although pulsed electromagnetic fields (PEMFs) are used to treat delayed unions and nonunions, their mechanisms of action are not completely clear. However, PEMFs are known to affect the expression of certain genes.

Questions/purposes

We asked (1) whether PEMFs affect gene expression in human osteoblastlike cells (MG63) in vitro, and (2) whether and to what extent stimulation by PEMFs induce cell proliferation and differentiation in MG-63 cultures.

Methods

We cultured two groups of MG63 cells. One group was treated with PEMFs for 18 hours whereas the second was maintained in the same culture condition without PEMFs (control). Gene expression was evaluated throughout cDNA microarray analysis containing 19,000 genes spanning a substantial fraction of the human genome.

Results

PEMFs induced the upregulation of important genes related to bone formation (HOXA10, AKT1), genes at the transductional level (CALM1, P2RX7), genes for cytoskeletal components (FN1, VCL), and collagenous (COL1A2) and noncollagenous (SPARC) matrix components. However, PEMF induced downregulation of genes related to the degradation of extracellular matrix (MMP-11, DUSP4).

Conclusions and Clinical Relevance

PEMFs appear to induce cell proliferation and differentiation. Furthermore, PEMFs promote extracellular matrix production and mineralization while decreasing matrix degradation and absorption. Our data suggest specific mechanisms of the observed clinical effect of PEMFs, and thus specific approaches for use in regenerative medicine.     

Age at trauma exposure and PTSD risk in young adult women

The aim of the current study was to test the independent and joint contributions of 8 different types of trauma to posttraumatic stress disorder (PTSD) risk using data from a young adult female cohort. Associations of traumatic events with PTSD onset were examined using Cox proportional hazards models. Differences in risk as a function of age at trauma were tested. Childhood sexual assault, physical abuse, and neglect were stronger predictors of PTSD onset than adolescent and early adult occurrence of these events in individual models. In a model including all traumatic events, differential risk by age remained for sexual assault and physical abuse. Early sexual assault was the strongest predictor of risk, but additional traumatic events increased risk even in its presence.     

Not an equal opportunity disease – a sex and gender-based review of colorectal cancer in men and women: Part II

This paper reviews the literature on colorectal cancer from a sex and gender-based perspective. Colorectal cancer is a major cause of death in the developed world, with rates increasing in developing countries. Although described by some writers as an ‘equal opportunity’ disease, it presents more risk to men than women. Both biological, or sex-linked factors, and gender-linked factors play a part in the aetiology of the disease, while gender differences in the use of screening and treatment also help shape the mortality gap between women and men for this condition. Without an appreciation of the part played by sex and gender in the risk of colorectal cancer, and without a gender-sensitive approach to screening in particular, it is possible that the mortality gap between men and women for this condition will widen in the future.     

Posterior Vertebral Column Resection for VATER/VACTERL Associated Spinal Deformity: A Case Report

The VATER/VACTERL association is a syndrome notable for congenital vertebral malformations, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, and renal or limb malformations. Vertebral malformations may include the entire spectrum of congenital spinal deformities, including kyphosis, as was seen in this case. A 14-year-old girl presented to our institution with severe rigid sagittal deformity in the thoracolumbar spine that had recurred following three prior spinal fusion surgeries: the first posterior only, the second anterior and posterior, and the third a posterior only proximal extension. These surgeries were performed to control progressive kyphosis from a complex failure of segmentation that resulted in a 66° kyphosis from T11 to L3 by the time she was 9 years old. Our evaluation revealed solid arthrodesis from the most recent procedures with resultant sagittal imbalance, and surgical options to restore balance included anterior and posterior revision spinal fusion with osteotomies, multiple posterior extension osteotomies with circumferential spine fusion, and posterior vertebral column resection with circumferential spine fusion. She was advised that multiple posterior extension osteotomies would likely be insufficient to restore sagittal balance in the setting of solid arthrodesis from anterior and posterior surgery, and that the posterior-only vertebral column resection would provide results equivalent to revision anterior and posterior surgery, without the morbidity of the anterior approach. She successfully underwent posterior vertebrectomy and circumferential spinal fusion with instrumentation and is doing well 2 years postoperatively. Severe rigid sagittal deformity can be effectively managed with a posterior-only surgical approach, vertebrectomy, and circumferential spinal fusion with instrumentation. An erratum to this article can be found at     

Sentinel Node Biopsy and Concomitant Probe-Guided Tumor Excision of Nonpalpable Breast Cancer

Background Preliminary data have shown encouraging results of a single intratumoral radiopharmaceutical injection that enables both sentinel node biopsy and probe-guided excision of the primary tumor in patients with nonpalpable breast cancer. The aim of the study was to evaluate this approach in a large group of patients. Methods Lymphoscintigraphy was performed in 368 patients with nonpalpable breast cancer after intratumoral injection of ^99mTc-nanocolloid (.2 mL, 123 MBq, 3.3 mCi) guided by ultrasound or stereotaxis. The sentinel node was pursued with the aid of vital blue dye (1.0 mL, intratumoral) and a gamma ray detection probe. In case of breast-conserving surgery, the probe was used to guide the excision. Results At least one sentinel node could be identified intraoperatively in 357 patients (97%), of whom 69 had involved nodes (19%). Age over 60 years was associated with less frequent nonaxillary lymphatic drainage and absence of internal mammary chain dissemination. Tumor-free margins were obtained in 262 (89%) of the 293 patients who underwent segmental excision. Re-excision of the primary tumor bed was performed in six patients (2%). During a median follow-up of 22 months, one breast recurrence and one axillary recurrence were observed. Conclusions Lymphatic mapping and probe-guided tumor excision of nonpalpable breast cancer by intralesional administration of a single dose of ^99mTc-nanocolloid and blue dye resulted in 97% identification of the sentinel node and in tumor-free margins in 89% of the patients who underwent breast-conserving surgery. Longer follow-up is needed to substantiate the accuracy and safety of this technique.     

Prognosis Scores of Tokuhashi and Tomita for Patients With Spinal Metastases of Renal Cancer

Background Retrospective evaluation of the prognosis scores of Tokuhashi and Tomita for life expectancy in 37 consecutive patients with spinal metastases secondary to renal cancer who underwent surgery. The score of Tokuhashi, composed of six parameters, each rated from zero to two, has been proposed in 1990 for the prognostic assessment of patients with spinal metastases. In 2001, Tomita et al. created another prognostic score, composed of three parameters, growth behaviour of the primary tumor (slow, moderate and rapid) and the evidence of visceral and bony metastases. Methods Thirty-seven patients, surgically treated for vertebral metastases secondary to renal cancer were studied. The scores according to Tokuhashi and Tomita were calculated for each patient. Results Applying the Tokuhashi Score for the estimation of life expectancy of renal cancer patients with vertebral metastases was found to provide very reliable results with a statistically high significance. The analysis according to Tomita showed no correlation between predicted and real survival. The statistical analysis did not show any significance. Conclusion For surgical decisions in renal cancer patients with spinal metastases, the prognostic score of Tokuhashi appears to be much more valuable than the Tomita score.     

Lymphatic Drainage of the Peritoneal Space: A Pattern Dependent on Bowel Lymphatics

Background Understanding lymph drainage patterns of the peritoneum could assist in staging and treatment of gastrointestinal and ovarian malignancies. Sentinel lymph nodes (SLNs) have been identified for solid organs and the pleural space. Our purpose was to determine whether the peritoneal space has a predictable lymph node drainage pattern. Methods Rats received intraperitoneal injections of near-infrared (NIR) fluorescent tracers: namely, quantum dots (designed for retention in SLNs) or human serum albumin conjugated with IRDye800 (HSA800; designed for lymphatic flow beyond the SLN). A custom imaging system detected NIR fluorescence at 10 and 20 minutes and 1, 4, and 24 hours after injection. To determine the contribution of viscera to peritoneal lymphatic flow, additional cohorts received bowel resection before NIR tracer injection. Associations with appropriate controls were assessed with the χ² test. Results Quantum dots drained to the celiac, superior mesenteric, and periportal lymph node groups. HSA800 drained to these same groups at early time points but continued flowing to the mediastinal lymph nodes via the thoracic duct. After bowel resection, both tracers were found in the thoracic, not abdominal, lymph node groups. Additionally, HSA800 was no longer found in the thoracic duct but in the anterior chest wall and diaphragmatic lymphatics. Conclusions The peritoneal space drains to the celiac, superior mesenteric, and periportal lymph node groups first. Lymph continues via the thoracic duct to the mediastinal lymph nodes. Bowel lymphatics are a key determinant of peritoneal lymph flow, because bowel resection shifts lymph flow directly to the intrathoracic lymph nodes via chest wall lymphatics. Dr. Parungo was the recipient of an award at the SSO meeting.