Molecular Profiling in Colon Cancer: Where Are We Now?

Abstract

Purpose of Review

Despite intense investigation, colorectal carcinoma (CRC) remains the second leading cause of cancer-related mortality in both men and women in the USA. With the advent of biologics and targeted therapies in oncology, molecular characterization of tumors has become of critical importance. This review seeks to outline the recent advances in the molecular profiling of CRC by highlighting the basic science background that has led to the diagnostic ability to portend prognosis and alter therapy.

Recent Findings

Building on existing knowledge of driver mutations has led to a better understanding of the molecular phenotypes of CRC and a transition from cytotoxic chemotherapy alone to targeting one aberration and now to considering multiple distinct targets for concerted therapy.

Summary

Utilizing genomic and epigenomic alterations, collectively grouped into distinct transcriptomic subtypes, now plays a vital role from initial diagnosis to continued treatment of virtually all colorectal carcinomas.

http://ift.tt/2weCXXU

Curative-intent treatment of recurrent colorectal liver metastases: a comparison between ablation and resection

Publication date: Available online 26 August 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Aurélien Dupré, Robert P. Jones, Rafael Diaz-Nieto, Stephen W. Fenwick, Graeme J. Poston, Hassan Z. Malik
BackgroundLiver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases.MethodsWe retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty-three (51.6%) by ablation and 31 (48.4%) by repeat resection.ResultsPatient groups were well matched, with surgically resected patients showing higher pre-operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (p<0.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression-free survival was longer for patients treated with surgery (10.2 months) compared to ablation (4.3 months) (p=0.002).ConclusionsAblation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression-free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis.



http://ift.tt/2vyPraR

The toxic influence of dibromoacetic acid on the hippocampus and pre-frontal cortex of rat: involvement of neuroinflammation response and oxidative stress

Abstract

Dibromoacetic acid (DBA) exsits in drinking water as a by-product of disinfection as a result of chlorination or ozonation processes. Hippocampus and pre-frontal cortex are the key structures in memory formation and weanling babies are more sensitive to environmental toxicant than adults, so this study was conducted to evaluate the potential neurotoxicity effects of DBA exposure when administered intragastrically for 4 weeks to weanling Sprague-Dawley rats, at concentration of 0, 20, 50, 125 mg/kg via the neurobehavioral and neurochemical effects. Results indicated that animals weight gain and food consumption were not significantly affected by DBA. However, morris water maze test showed varying degrees of changes between control and high-dose group. Additionally, the level of malondialdehyde (MDA) and generation of reactive oxygen species (ROS) in the hippocampus and pre-frontal cortex of rats increased significantly. The activities of total superoxide dismutase (SOD) and the glutathione (GSH) content in the hippocampus and pre-frontal cortex of rats decreased significantly after treatment with DBA. Treatment with DBA increased the protein and mRNA expression of Iba-1, NF-κB, TNF-α, IL-6, IL-1β and HO-1 in the hippocampus and pre-frontal cortex of rats. These data suggested that DBA had a toxic influence on the hippocampus and pre-frontal cortex of rats, and that the mechanism of toxicity might be associated with the neuroinflammation response and oxidative stress.

http://ift.tt/2w7xYKn

The role of enteric neurons in the development and progression of colorectal cancer

Publication date: Available online 25 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Glenn Rademakers, Nathalie Vaes, Simone Schonkeren, Alexander Koch, Keith A. Sharkey, Veerle Melotte
The enteric nervous system (ENS) is the neural network belonging to the gastrointestinal tract, which is essential for regulating gut functions. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation and gut homeostasis. So far, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in the CRC field. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on CRC development and/or progression. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment.



http://ift.tt/2wHZGi4

High-dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival—The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) experience

Abstract

Background

Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high-dose chemotherapy with autologous stem-cell transplantation (HDSCT) in an intensive first-line treatment offers additional benefit is an ongoing discussion.

Methods

A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93-01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014.

Results

Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III—1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty-seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment-related complication. Mean time to the first event was 3.5 months. Two-year EFS/OS (where EFS is event-free survival) for the whole group was 37 ± 6%/38 ± 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2-year OS in this group was 60 ± 15% compared to 34 ± 8% in the non-HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem-cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (<90 days). Thus, 2-year EFS only for patients without progression until day 90 was 60 ± 16% consolidated by HDSCT compared to 62 ± 11% without (P = 0.8).

Conclusion

Our retrospective analysis suggests comparable outcomes for patients with and without HDSCT, if adjusted for early disease progression.

http://ift.tt/2gey8Ki

Sirolimus therapy in the treatment of pseudomyogenic hemangioendothelioma

Abstract

Pseudomyogenic hemangioendothelioma (PMH) is a rare, mostly indolent vascular tumor. Extensive cases are treated with amputation as chemotherapy seems to be ineffective. Recently, promising results were published using mammalian target of rapamycin (mTOR) inhibitors in tumors of vascular origin. Here, we present a case of a child with advanced PMH relapsing after surgery and chemotherapy. Sirolimus achieved significant clinical improvement and stabilization of the lesions without any remarkable toxicity. This case contributes to the growing evidence regarding the efficacy of mTOR inhibitors, such as sirolimus, in multifocal PMH.

http://ift.tt/2ixQCWQ

Exercise right heart catheterization for pulmonary hypertension identified on screening echocardiography in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort

Abstract

Pulmonary hypertension, determined noninvasively by tricuspid regurgitant jet velocity on Doppler echocardiography, was previously identified in 25% of long-term survivors who received chest-directed radiotherapy. To validate noninvasively defined pulmonary hypertension, survivors (mean age 48 years), exposed to chest radiotherapy, underwent right heart catheterization with planned cardiopulmonary exercise testing during catheterization. Eight participants had an elevated mean pulmonary artery pressure at rest (≥25 mm Hg) or with subsequent exercise (>30 mm Hg), evidence of hemodynamically confirmed pulmonary hypertension by right heart catheterization. Cardiopulmonary exercise testing further defined the magnitude and etiology of cardiopulmonary limitations in this life-threatening late effect.

http://ift.tt/2geSxPu