New insights in the neuroanatomy of the human adult superior hypogastric plexus and hypogastric nerves.

BACKGROUND: The superior hypogastric plexus (SHP) is an autonomic plexus, located ventrally to the abdominal aorta and its bifurcation, innervating pelvic viscera. It is classically described as being composed of merely sympathetic fibres. However, post-operative complications after surgery damaging the peri-aortic retroperitoneal compartment suggest the existence of parasympathetic fibres. This immunohistochemical study describes the neuroanatomical composition of the human mature SHP. MATERIAL AND METHODS: Eight pre-determined retroperitoneal localizations including the lumbar splanchnic nerves, the SHP and the HN were studied in four human cadavers. Control tissues (white rami, grey rami, vagus nerve, splanchnic nerves, sympathetic ganglia, sympathetic chain and spinal nerve) were collected to verify the results. All tissues were stained with haematoxylin and eosin and antibodies S100, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP) and myelin basic protein (MBP) to identify pre- and postganglionic parasympathetic and sympathetic nerve fibres. RESULTS: All tissues comprising the SHP and hypogastric nerves (HN) showed isolated expression of TH, VIP and MBP, revealing the presence of three types of fibres: postganglionic adrenergic sympathetic fibres marked by TH, unmyelinated VIP-positive fibres and myelinated preganglionic fibres marked by MBP. Analysis of control tissues confirmed that TH, VIP and MBP were well usable to interpret the neurochemical composition of the SHP and HN. CONCLUSION: The human SHP and HN contain sympathetic and most likely postganglionic parasympathetic fibres. The origin of these fibres is still to be elucidated, however surgical damage in the peri-aortic retroperitoneal compartment may cause pelvic organ dysfunction related to both parasympathetic and sympathetic denervation.

Tumour response to preoperative anthracycline-based chemotherapy in operable breast cancer: the predictive role of p53 expression.

The aim of this retrospective study was to identify markers capable of predicting pathological complete (pCR) and overall clinical tumour response to preoperative anthracycline-based chemotherapy and clinical outcome in women with operable breast cancer. Therefore, we used the pre-treatment core biopsies from 107 patients who were enrolled in the EORTC trial 10902 to analyse tumour characteristics and the oncogenic markers Bcl-2, p53, ER, PgR, HER2, and p21. Median follow-up was 7 years (95% confidence interval [CI], 6.89-7.45). pCR was seen in seven patients (6.5%) and was associated with improved overall survival (hazards ratio, 0.39; 95% CI, 0.05-2.56; P = 0.30). In multivariate logistic regression analysis, pCR was independently predicted by p53 overexpression estimated by immunohistochemistry (odds ratio [OR], 16.83; 95% CI, 1.78-159.33; P = 0.01). Fifty-eight patients showed clinical tumour response (>50% decrease in tumour size), however responders experienced no benefit in clinical outcome. Clinical tumour response was independently predicted by p53 overexpression (OR, 5.57; 95% CI, 1.58-19.65; P = 0.008) and small clinical tumour size (OR, 10.26; 95% CI, 2.01-52.48; P = 0.005). In multivariate Cox regression analysis, negative pathological lymph node status, low tumour grade and use of tamoxifen showed improved overall survival. In conclusion, our data suggest p53 expression is of predictive significance in anthracycline-containing chemotherapeutic regimens.

Low rectal cancer: a call for a change of approach in abdominoperineal resection.

PURPOSE: Despite the major improvements that have been made due to total mesorectal excision (TME), low rectal cancer still remains a challenge. METHODS: By investigating a prospective randomized rectal cancer trial in which surgeons had undergone training in TME the factors responsible for the poor outcome were determined and a new method for assessing the quality of surgery was tested. RESULTS: Survival differed greatly between abdominoperineal resection (APR) and anterior resection (AR; 38.5% v 57.6%, P = .008). Low rectal carcinomas have a higher frequency of circumferential margin involvement (26.5% v 12.6%, P < .001). More positive margins were present in the patients operated with APR (30.4%) compared to AR (10.7%, P = .002). Furthermore, more perforations were present in these specimens (13.7% v 2.5%, P < .001). The plane of resection lies within the sphincteric muscle, the submucosa or lumen in more than 1/3 of the APR cases, and in the remainder lay on the sphincteric muscles. CONCLUSION: We systematically described and investigated the pathologic properties of low rectal cancer in general, and APR in particular, in a prospective randomized trial including surgeons who had been trained in TME. The poor prognosis of the patients with an APR is ascribed to the resection plane of the operation leading to a high frequency of margin involvement by tumor and perforation with this current surgical technique. The clinical results of this operation could be greatly improved by adopting different surgical techniques and possibly greater use of radiochemotherapy.

The multidisciplinary rectal cancer treatment: main convergences, controversial aspects and investigational areas which support the need for an European Consensus.

BACKGROUND AND PURPOSE: During the past decades staging and treatment of rectal cancer are used different in Europe and in North America. To promote a process to integrate the daily practice with the best evidence of the literature an International Conference was organized in Italy. Agreement between Experts, Centres, and specialists who participated in the Conference are reported. METHODS: Five aspects were analyzed and a questionnaire was tailored for this purpose. The questionnaire had 159 questions. During the Conference, at the beginning of each Session, the moderators showed the answers from the Experts and the Centres, and, at the end of the session, the audience voted in all controversial issues. Agreements were scored at three levels: minimum, if it was between 51 and 74% of votes for each group; moderate, between 75 and 94%; large, more than 94%. RESULTS: The main results are: staging: endoanal ultrasound was considered as mandatory in T staging, in the evaluation of sphincter infiltration, and in the restaging of T after chemoradiotherapy (chRT). Magnetic Resonance Imaging is mandatory in the evaluation of mesorectal fascia infiltration. Endoscopy had a moderate agreement for the definition of tumour location, and the barium enema as optional. Digital rectal examination is complementary for staging and PET-CT investigational for T, N and yT staging. Preoperative radiotherapy: for T4 stage chRT was always the preferred treatment, often with moderate agreement, for any tumour location and N status. For T3, chRT received the same agreement except for high location and N0-N1. For T2 stage, N2 and positive nodes outside the mesorectum, chRT received minimum agreement for low and middle tumours; for high tumours only positive nodes outside the mesorectum was agreed upon. Preoperative radiotherapy, negative specimen and sphincter preservation: chRT was agreed by many for all T stages and N presentations of lower third tumours, except for T1-2 N0-N1. Postoperative treatments: the selection for these treatments often received moderate agreement according to the infiltration of surrounding organs, positive nodal status and circumferential radial margins. Therapy of metastatic disease: an agreement was found for FOLFOX as first-line therapy and for FOLFIRI as second-line, although comparative studies show similar activity of FOLFOX and FOLFIRI regimens. CONCLUSIONS: This process represents an expertise opinion process that may contribute to increased scientific debate and to promote the development of 'guidelines', 'clinical recommendations' and ultimately a Consensus on the evolving approach to rectal cancer treatment.

Bcl-2 overexpression does not prevent but retards adriamycin toxicity in CC531 colon carcinoma cells.

BACKGROUND: The Bcl-2 protein is a critical regulator of susceptibility towards cell death induced by antineoplastic drugs. Reduced growth activity and increased glutathione (GSH) levels protect against adriamycin toxicity. We recently demonstrated statistically significantly reduced growth activity and elevated cellular GSH levels in exponentially growing rat CC531 colon carcinoma cells overexpressing the full-length human Bcl-2 protein (CCbcl2#A3). METHODS: To assess the importance of reduced growth activity or increased GSH levels, we determined the mitochondrial function, 24 h after adriamycin treatment, in CCbcl2#A3 cells, parental CC531 cells and cells overexpressing the Bcl-2 protein lacking the N-terminal BH4 domain (CC Delta BH4): these latter cells contained elevated cellular GSH levels but were not reduced in growth activity. RESULTS: CCbcl2#A3, but not CC Delta BH4, cells were 3-fold less susceptible than parental cells suggestive of a protective role for reduced growth but not for increased GSH levels in BCL-2 transfectants. This was confirmed in several growth-inhibited CC531 transfectants and in slowly proliferating (ca. 100% confluent) cell populations compared to exponentially growing (ca. 50% confluent) cell populations. Reduced growth activity might delay the onset of cell death. Therefore, we tested the effect of adriamycin five days after treatment. In this long-term assay we found no differences between the various cells. CONCLUSION: Reduction of growth activity, for instance by an overexpression of the Bcl-2 protein, only transiently reduced the susceptibility towards adriamycin treatment.

Serum total gangliosides and TA90-IC levels: novel immunologic markers in colorectal cancer.

BACKGROUND: Because of the challenge in defining prognostic markers predictive of recurrence or progression, carcinoembryonic antigen (CEA) remains the most frequently used marker in colorectal cancer, despite its low sensitivity. We hypothesized that TA90-IC status and serum ganglioside levels might be useful markers and might be of prognostic significance in colorectal cancer. METHODS: Serum samples from 68 patients undergoing surgical treatment for histologically proven colorectal cancer were analyzed for the presence of CEA, serum gangliosides, and TA90-IC. Forty-one patients had node-negative disease, whereas 27 patients had limited metastatic disease. The intent was curative resection, even for patients with metastatic disease. Cryopreserved serum specimens were analyzed in a blinded fashion for total serum ganglioside levels (by an assay that detects lipid-associated sialic acids), for CEA, and for TA90-IC (by a murine monoclonal antibody-based enzyme-linked immunosorbent assay). A positive value for TA90-IC levels was defined as an optical density (OD) of more than 0.410 at 405 nm. RESULTS: Serum ganglioside levels were elevated more frequently than CEA concentrations (84% vs 44%). The combination of serum ganglioside and CEA values was more sensitive (88%) than CEA value alone (44%) in identifying patients with early-stage colorectal cancer. TA90-IC levels were elevated more frequently than CEA concentrations (56% vs 32%). The combination of TA90-IC and CEA values was more sensitive (72%) than CEA value alone (32%) in identifying patients with advanced-stage colorectal cancer. At an enzyme-linked immunosorbent assay cutoff level of 0.410, 15 (56%) patients had positive TA90-IC values. Fourteen patients alive with residual disease had a median OD TA90-IC level of 0.879, and only three patients had levels below the OD cutoff value of 0.410. Thirteen patients with no evidence of disease had a median level of 0.277, and only four patients had OD levels > or = 0.410. TA90-IC was significantly higher in the alive with residual disease patients than those rendered no evidence of disease (P = 0.02). CONCLUSIONS: We speculate that a multiple-marker analysis that combines CEA values with serum ganglioside and TA90-IC values may be more sensitive than CEA value alone for detecting colorectal cancer. The potential prognostic significance of TA90-IC status in advanced disease warrants further investigation.

Will we need lymph node dissection at all in the future?

Traditionally in the treatment of primary breast cancer, axillary lymph node dissection (ALND) plays an important role. However, a substantial and increasing percentage of patients appear to have no nodal involvement and have been subjected to ALND unnecessarily. The first reason to perform an ALND is axillary nodal staging. After reviewing the literature, it can be concluded that in clinically node-negative patients an adequately conducted lymphatic mapping by sentinel node procedure is equal to ALND for this purpose. The second reason to perform an ALND is to establish the extent of nodal involvement, which might have an impact on adjuvant treatment recommendations. However, there is no evidence available that patients with extensive nodal involvement (= 4 positive nodes) benefit more from adjuvant systemic treatment (either standard or high dose) in terms of reduction of odds of recurrence and mortality compared to patients with limited nodal involvement and optimally administered so-called standard adjuvant treatment. The third reason to perform an ALND is to ensure axillary tumor control. Reviewing the different treatment options, it can be concluded that in clinically node-negative patients axillary control after axillary radiotherapy appears to be similar to axillary control after ALND. In clinically overt axillary involvement, ALND (with or without adjuvant radiotherapy) may result in an improved regional control. In the near future, ALND will not be the standard of care but will be reserved for those patients with proven axillary lymph node involvement. In microscopic disease, radiotherapy may be an alternative with equal control and less morbidity.