A Meta-Analysis to Determine the Effect of Primary Tumor Resection for Stage IV Colorectal Cancer with Unresectable Metastases on Patient Survival

Background

Approximately 20 % of patients diagnosed with colorectal cancer will have distant metastases at first presentation (stage IV disease). The effect of removing the primary tumor on survival for patients with stage IV disease with unresectable metastases remains unclear. To address this a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in cases of stage IV colorectal cancer with unresectable metastases was performed.

Methods

A comprehensive search for published studies examining the effect of primary tumor resection in the setting of colorectal cancer with unresectable metastases was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data.

Results

There were 21 studies including a total of 44,226 patients that met the inclusion criteria. Resection of the primary tumor in patients with unresectable metastases compared with chemotherapy alone was associated with a lower mortality risk (OR 0.28; 95 % CI 0.165–0.474; P < 0.001), translating into a difference in mean survival of 6.4 months in favor of resection (95 % CI 5.025–7.858, P < 0.001). Patients who underwent resection of the primary tumor were more likely to have liver metastasis only (OR 1.551; 95 % CI 1.247–1.929; P < 0.001), were less likely to have ≥2 metastasis (OR 0.653; 95 % CI 0.508–0.839; P = 0.001), and were less likely to have rectal cancer (OR 0.495; 95 % CI 0.390–0.629; P < 0.001). There was significant cross-study heterogeneity.

Conclusions

Resection of the primary tumor may confer a survival advantage in stage IV colorectal cancer with unresectable metastases but significant selection bias exists in current studies. Randomized controlled trials are essential to validate these findings.     

Electroporation enhances transfection efficiency in murine cutaneous wounds

Transfection of wounds with DNA-encoding growth factors has the potential to improve healing, but current means of nonviral gene delivery are inefficient. Repeated high doses of DNA, necessary to achieve reliable gene expression, are detrimental to healing. We assessed the ability of in vivo electroporation to enhance gene expression. Full-thickness cutaneous excisional wounds were created on the dorsum of female mice. A luciferase- encoding plasmid driven by a CMV promoter was injected at the wound border. Following plasmid administration, electroporative pulses were applied to injection sites. Pulse parameters were varied over a range of voltage, duration, and number. Animals were euthanized at intervals after transfection and the luciferase activity measured. Application of electric pulses consistently increased luciferase expression. The electroporative effect was most marked at a plasmid dose of 50 micro g, where an approximate tenfold increase was seen. Six 100- micro s-duration pulses of 1750 V/cm were found to be the most effective in increasing luciferase activity. High numbers of pulses tended to be less effective than smaller numbers. This optimal electroporation regimen had no detrimental effect on wound healing. We conclude that electroporation increases the efficiency of transgene expression and may have a role in gene therapy to enhance wound healing.     

Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy

Gastric emptying was studied with a double radioisotopic method in 12 patients with insulin-dependent diabetes mellitus complicated by autonomic neuropathy and in 22 control subjects. In the diabetics, the acute and chronic effects of oral domperidone on gastric emptying, symptoms of gastroparesis, and glycemic control were assessed. Gastric emptying of solid and liquid was slower in diabetics than controls (P<0.001). Acute administration of domperidone increased the rate of both solid and liquid emptying (P<0.005). Domperidone was most effective in those patients with the greatest delay in gastric emptying. After chronic administration (35–51 days), domperidone had no significant effect on solid emptying (P>0.05), but was still effective in increasing liquid emptying (P<0.025). Symptoms of gastroparesis were less after domperidone (P<0.001).Dr. M. Horowitz was supported by a grant from the National Health and Medical Research Council of Australia.     

A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine

What's known on the subject? and What does the study add? Multiple studies report on the detection of methylation in voided urine samples as a possible approach for the follow‐up of non‐muscle invasive bladder cancer patients. Previous studies analyze methylation gene panels in a mixture of primary and recurrent tumours. As primary tumours are larger than recurrent tumours and thus easier to detect in urine, validation of methylation markers in urine samples from patients with primary tumours will result in a test sensitivity that does not reflect the true sensitivity of the assay. This study is the first to select a subset of genes specifically methylated in non‐muscle invasive bladder cancer recurrences and validates the gene panel in two independent sets of urine samples from recurrent patients, thus simulating the disease course according to the clinical presentation.

OBJECTIVE

• ? To develop a methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) assay for the detection of non‐muscle invasive bladder cancer (NMIBC) recurrences in voided urine.

PATIENTS AND METHODS

• ? Genes frequently methylated in NMIBC tumours (n= 37) were selected to develop a BC‐specific MS‐MLPA assay.
• ? Genes methylated in blood from patientswith BC (n= 29) and genes methylated in urine from patients with no history of BC (n= 46) were excluded.
• ? A four‐gene panel with the highest predictive value was selected from the initial assay. This four‐gene panel was tested and validated on urine from patients with a histologically confirmed recurrence (n= 68 test set; n= 49 validation set) and urine samples from patients without BC (n= 91, test set) and urine from recurrence‐free BC (rec‐free BC) patients (n= 60, validation set).
• ? A model was developed to predict the probability of having a recurrence based on methylation of the four‐gene panel and a threshold probability with the highest sensitivity and specificity was determined.
• ? The outcome of the model was validated on BC urine samples (n= 65) and on urine samples from rec‐free BC patients (n= 29).

RESULTS

• ? The BC MS‐MLPA assay consisted of 23 methylation probes. The selected four‐gene panel included: APC_a, TERT_a, TERT_b, and EDNRB. This panel reached an area under the receiver operating characteristic curve (AUC) of 0.82 (test set) and AUC 0.69 (validation set). Sensitivity and specificity for the detection of a concomitant tumour were 63.3% and 58.3% respectively (test set) and 72.3% and 55.2%, respectively (validation set).

CONCLUSIONS

• ? We have developed a methylation detection assay specifically for the detection of recurrences in patients with NMIBC in voided urine.
• ? The findings are promising and improvement of this test could eventually contribute to a more individualized patient friendly surveillance.

     

Development of a reconstructed human skin model for angiogenesis

We have previously shown that reconstructed human skin engineered from autologous keratinocytes, fibroblasts, and sterilized donor allodermis stimulates angiogenesis within 5-7 days when placed on well-vascularized wound beds in nude mice. When this reconstructed skin was used clinically in more demanding wound beds, some grafts were lost, possibly due to delayed vascularization. As this reconstructed skin lacks any endothelial cells, our aim in this study was to develop an angiogenic reconstructed skin model in which to explore strategies to improve angiogenesis both in vitro and in vivo. We report that culture of small-vessel human dermal microvascular endothelial cells (HuDMECs) was achieved using magnetic beads coated with an antibody to platelet cell adhesion molecule as a means of purifying the culture. Keratinocytes, fibroblasts, and HuDMECs could be cultured from the same skin biopsy. Initial studies culturing HuDMECs and other sources of endothelial cells with the tissue-engineered skin showed that these cells were capable of slowly entering the dermis under standard culture conditions in vitro. In conclusion, this provides us with a model in which to explore strategies for improving angiogenesis in vitro and also establishes the culture methodologies for the production of reconstructed skin containing autologous keratinocytes, fibroblasts, and endothelial cells.     

Os calcis fractures: Analysis of interobserver variability in using sanders classification

The os calcis is the most frequently fractured tarsal bone. In 1992 Sanders developed a classification system based on coronal and axial computed tomography (CT) scans of the calcaneus. This classification is the one used most frequently today in treatment decision making and reporting of results. The objective of this study was to assess the degree of interobserver variability in using this classification system. Thirty CTs of calcaneal fractures were chosen randomly from the past 5 years in 2 tertiary care centers. The CTs were reviewed by 3 orthopedic surgeons and one senior orthopedic resident who classified the fractures according to Sanders' classification. The results were first tabulated and analyzed by using a weighted kappa test including the subcategories. The weighted kappa value achieved was.56, with a 95% confidence interval of.45-.67. The subcategories of the classification were then further combined and a second weighted kappa test was performed to assess agreement between general classes. The weighted kappa value achieved was.48, with a 95% confidence interval of 0.37-0.59. We concluded that Sanders' classification system did prove to achieve moderate agreement among users, thus representing a useful classification system.