Neoadjuvant oxaliplatin and 5-fluorouracil with concurrent radiotherapy in patients with locally advanced rectal cancer: a single-institution experience.

PURPOSE: The aim of this study was to evaluate the rate of pathological response (PR), disease control and safety of neoadjuvant chemotherapy using oxaliplatin (OX) and 5-fluorouracil (5-FU) with concurrent radiotherapy for treating locally advanced rectal cancer. MATERIALS AND METHODS: Between November 2002 and December 2010, 90 patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) were retrospectively analysed. All patients underwent preoperative radiotherapy (45 Gy in 1.8-Gy fractions) with concurrent OX (80 mg/m(2) i.v., day 1) and a 120-h continuous infusion of 5-FU (1,000 mg/m(2) per day). Surgery was performed within 6 weeks after completion of CRT treatment. RESULTS: Complete pathological response was obtained in six patients (6.7%), and 39 (43.3%) had their disease downstaged. The median follow-up period was 4.7 years (6 months to 9 years). Local recurrence occurred in two patients (2.2%), one of whom developed also liver metastases. Distant metastases not associated with local relapse occurred in 23 (25.6%) patients. Overall (OS) and disease-free (DFS) survival were 62.9% and 52.8%, respectively. CRT was well tolerated, with only one grade 3 (1.2%) haematological toxicity (neutropaenia). CONCLUSIONS: Neoadjuvant systemic chemotherapy based on OX and 5-UC associated with radiotherapy is well tolerated, with good results in terms of pathological response, disease control and survival, in rectal cancer patients.

Resolving sphincter of Oddi incontinence for primary duodenal Crohn's disease with strictureplasty.

INTRODUCTION: Crohn's involvement of duodenum is a rare event and may be associated to proteiform symptoms and uncommon pathological aspects which make diagnosis and treatment complex. PRESENTATION OF CASE: The peculiar aspect of this case was a suspected duodeno-biliary fistula. The patient (female, 22 years old) was affected by duodenal Crohn's disease. Magnetic resonance imaging showed a dilated common bile duct, whose final part linked to a formation containing fluid, and characterized by filling of the contrast medium in the excretory phase. Abdominal ultrasound showed intra-hepatic and intra-gallbladder aerobilia. At surgery, the duodenum was mobilized showing an inflammatory stricture and a slight dilatation of the common bile duct, with no signs of fistulas. The opened duodenum was anastomized side to side to a transmesocolic loop of the jejunum. After surgery, the general condition of the patient improved. DISCUSSION: Only two cases of fistula between a narrow duodenal bulb and the common bile duct have been described in literature and the Authors were not be able to verify the occurrence of a duodenal biliary fistula at surgery. The association between duodenal Crohn's disease and Sphincter of Oddi incontinence is a very rare finding with different etiology: chronic intestinal pseudo-obstruction, common bile duct stones, progressive systemic sclerosis. CONCLUSION: The treatment to resolve Sphincter of Oddi incontinence for primary duodenal Crohn's disease is not clear. Strictureplasty could be the treatment of choice, because, resolving the stricture, the duodenal pressure is likely to decrease and the reflux through the incontinent sphincter can be avoided.

Prognostic factors in primary and iterative surgery of colorectal liver metastases.

The aim of this study was to evaluate the results of surgery of colorectal liver metastases and assess prognostic factors influencing the outcome. A total of 135 hepatic resections performed in 107 patients was reviewed. The following prognostic factors were analyzed: primary tumor localization, Dukes stage, number and presence of metastases in one or two lobes, synchronous or metachronous occurrence, type of resection, use and modality of chemotherapy. The perioperative morbidity rate was 6.5% and mortality was 1.9%. Overall survival was 41.2% and disease-free survival 31.5% at 5 years. Survival at 5 years was better for patients with metachronous than for those with synchronous lesions (60.9% vs 28.1%; p<0.05). There were no significant differences in terms of long-term survival between patients with synchronous metastases that were excised simultaneously or with a delay of 3-6 months (p=n.s.). Site of the primary tumor, Dukes stage, number of metastases and type of resection did not influence survival. A favorable survival trend was observed in those patients who underwent both neoadjuvant and adjuvant chemotherapy. The overall survival rate at 5 years was 45.3% for patients undergoing a second hepatic resection and 50% for those with a third or a fourth hepatic resection. Liver resection remains the "gold standard" for the treatment of patients with colorectal liver metastases, with metachronous type having a better outcome than synchronous. Simultaneous or delayed surgery for synchronous metastases does not influence prognosis. Iterative resection is very encouraging and justifies an aggressive surgical approach.

Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures.

BACKGROUND AND AIMS: In addition to its crucial role in dampening tissue-damaging immune responses in the gut, transforming growth factor beta (TGFbeta) is a potent profibrogenic agent inducing collagen synthesis and regulating the balance between matrix-degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). TGFbeta signalling was investigated by analysis of Smad proteins and MMPs/TIMPs in the mucosa overlying strictures in patients with Crohn's disease (CD). METHODS: Specimens were collected from macroscopically normal mucosa overlying strictured and non-strictured gut of patients with fibrostenosing CD. Isolated myofibroblasts were cultured with anti-TGFbeta blocking antibody or TGF beta 1. TGFbeta transcripts were analysed by quantitative reverse transcription-PCR (RT-PCR). Smad proteins and MMPs were determined by immunoblotting. MMP-12 activity was measured by a real-time MMP-12 activity assay. An in vitro wound-healing scratch assay was used to assess myofibroblast migration. RESULTS: TGFbeta transcripts, phosphorylated Smad2-Smad3 (pSmad2-3) and TIMP-1 proteins were higher in mucosa overlying strictures than in mucosa overlying non-strictured areas. In contrast, mucosa overlying strictured gut had lower expression of Smad7, MMP-12 and MMP-3. Myofibroblasts from mucosa overlying strictured gut showed higher TGFbeta transcripts, a greater pSmad2-3 response to TGFbeta, increased TIMP-1, lower Smad7, increased collagen production and reduced migration ability compared with myofibroblasts from mucosa overlying non-strictured gut. TGFbeta blockade increased myofibroblast MMP-12 production and migration, more obviously in myofibroblasts isolated from mucosa overlying non-strictured compared with strictured gut. CONCLUSIONS: Changes in TGF-beta signalling and MMP production were identified in the mucosa overlying strictures in CD which may give a window into the process of fibrosis.

Anastomotic leaks after anterior resection for mid and low rectal cancer: survey of the Italian Society of Colorectal Surgery.

BACKGROUND: The aim of the survey was to assess the incidence of anastomotic leaks (AL) and to identify risk factors predicting incidence and gravity of AL after low anterior resection (LAR) for rectal cancer performed by colorectal surgeons of the Italian Society of Colorectal Surgery (SICCR). METHODS: Information about patients with rectal cancers less than 12 cm from the anal verge who underwent LAR during 2005 was collected retrospectively. AL was classified as grade I to IV according to gravity. Fifteen clinical variables were examined by univariate and multivariate analyses. Further analysis was conducted on patients with AL to identify factors correlated with gravity. RESULTS: There were 520 patients representing 64% of LAR for rectal cancer performed by SICCR members. The overall rate of AL was 15.2%. Mortality was 2.7% including 0.6% from AL. The incidence of AL was correlated with higher age (p<0.05), lower (<20 per year) centre case volume (p<0.05), obesity (p<0.05), malnutrition (p<0.01) and intraoperative contamination (p<0.05), and was lower in patients with a colonic J-pouch reservoir (p<0.05). In the multivariate analysis age, malnutrition and intraoperative contamination were independent predictors. The only predictor of severe (grade III/IV) AL was alcohol/smoking habits (p<0.05) while the absence of a diverting stoma was borderline significant (p<0.07). CONCLUSION: Our retrospective survey identified several risk factors for AL. This survey was a necessary step to construct prospective interventional studies and to establish benchmark standards for outcome studies.

[Management of "complicated" work fitness judgements among health care workers]. / La gestione delle "idoneità difficili" negli operatori della sanità.

The occupational physician, performing health surveillance within a hospital, may face to some difficulties due to the variety and complexity of the tasks and the health risk factors of the health care workers. One of the hardest issue for occupational physician is to provide judgement on worker's fitness. Moreover, this task could be more complicated when a impaired worker could represent an hazard for his patients and colleagues. The authors will illustrate three critical clinical cases examined in Occupational Health Unit of Luigi Sacco Hospital, Milan; furthermore, the authors will show the difficulties and the applied solutions in order to provide the judgement on worker's fitness.

[Clinical guidelines for the management of gastrointestinal stromal tumors]. / Raccomandazioni cliniche per la diagnosi, la terapia ed il follow-up dei tumori stromali gastrointestinali.

Treatment of gastrointestinal stromal tumors (GIST) has been revolutioned by the recently discovered molecular mechanism responsible for the oncogenesis of this disease. In addition, due to the rapid progress at molecular and clinical level observed in the last few years, there is a need to review the current state of the art in order to delineate appropriate guidelines for the optimal management of these tumors. A panel of experts from several specialities, including medical oncology, surgery, pathology, molecular biology and imaging, were invited to participate in a meeting to present and discuss a number of pre-selected questions, and to achieve a consensus according to the categories of the National Comprehensive Cancer Network (NCCN) and the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers. Generally, consensus points were from categories 2A of the NCCN and B2 of the SOR. Conventional histologic examination with immunohistochemistry for CD117, CD34, SMA, S-100 and desmin is considered standard. Molecular analysis for the identification of KIT and PDGFRA mutation may be indicated in CD117-negative GIST. Complete tumor resection with negative margins is the optimal surgical treatment. Adjuvant imatinib should be considered an experimental approach. Neoadjuvant imatinib is also experimental, although its use may be justified in unresectable or marginally resectable GIST. Imatinib should be started in metastatic or recurrent disease, and should be continued until progressive disease or drug intolerance. In these cases, sunitinib can be used. The optimal criteria for the assessment and monitoring of GIST undergoing imatinib therapy are not well known, but they should include reduction in tumor size and disease stabilization, as well as reduction of tumor density on CT scan and metabolic activity on PET scan.

Use of icodextrin 4% solution in the prevention of adhesion formation following general surgery: from the multicentre ARIEL Registry.

INTRODUCTION: Intra-abdominal adhesions occur in many patients following major abdominal surgery and represent a serious burden to patients and healthcare providers. The multicentre ARIEL (Adept Registry for Clinical Evaluation) Registry was established to gather clinical experiences in the use of icodextrin 4% solution, an approved adhesion-reduction agent, during routine general surgery. PATIENTS AND METHODS: General surgeons from five European countries completed anonymised data collection forms for patients undergoing laparotomy or laparoscopy. Surgeons recorded patient demographics, use of icodextrin 4% solution and adverse events, and made subjective assessments of ease of use and patient acceptability with the agent. RESULTS: The general surgery registry included 1738 patients (1469 laparotomies, 269 laparoscopies). Leakage of fluid from the surgical site did not appear to be affected by icodextrin 4% solution and was classified as 'normal' or 'less than normal' in most patients (laparotomies 86%, laparoscopies 88%). Overall, satisfaction with ease of use was rated as 'good' or 'excellent' by the majority of surgeons (laparotomies 77%, laparoscopies 86%). Patient acceptability was also good, with ratings of 'as expected' or 'less than expected' in most cases for both abdominal distension (laparotomies 90%, laparoscopies 91%) and abdominal discomfort (laparotomies 91%, laparoscopies 93%). Adverse events occurred in 30.6% of laparotomy patients and 16.7% of laparoscopy patients; the most common events were septic/infective events (4.2% and 3.4% in the laparotomy and laparoscopy groups, respectively). Anastomotic wound-healing problems were reported in 7.6% of patients in the subset of laparoscopy patients undergoing anastomotic procedures (n = 66). DISCUSSION: Volumes of icodextrin 4% solution used as an irrigant and instillate were in line with recommendations. Surgeons considered the agent to be easy to use and acceptable to patients. The reported frequencies of adverse events were in line with those published in the literature for surgical procedures, supporting the good safety profile of this agent. CONCLUSIONS: Icodextrin 4% solution can be used in a wide range of surgical procedures. In combination with good surgical technique, it may play an important role in adhesion reduction.

A comparison of methods for the analysis of low abundance proteins in desmoid tumor cells.

The desmoids are a group of rare clinically diverse, deep-seated fibrous neoplasms. The exact etiology is unknown, but several factors are considered to be positively correlated with their development and growth, i.e., genetic and hormonal factors and trauma. These tumors may be sporadic or associated with a genetic disease such as familial adenomatous polyposis (FAP). Devoid of metastatic potential, they tend to form large, infiltrative masses which, if not completely excised, recur repeatedly. Although surgery is widely accepted as the first-line treatment for extra-abdominal and abdominal wall desmoids, a proportion of cases are successfully palliated with either estrogen antagonists (tamoxifen, toremifene, and raloxifene) or nonsteroidal anti-inflammatory drugs. We describe and compare four methods for evaluating the expression of estrogen receptors alpha/beta and COX-1 and COX-2 in desmoid tumor-derived cells and tissues: immunocytochemistry, immunohistochemistry, RT-PCR, and two-color Western blot detection with the Odyssey infrared imaging system. Through this comparative analysis, Western blot with Odyssey was recognized as the best method to analyze the expression particularly of low expressed proteins in desmoid-derived cells. The use of a specific and reliable assessment method becomes fundamental in the evaluation of the presence and modulation of proteins which are important but weakly expressed in these rare tumors.

Characterization of the functional and growth properties of long-term cell cultures established from a human somatostatinoma.

In somatostatinoma, a rare malignant somatostatin (SST)-secreting neoplasia, tumour regression is rarely observed, implying the need for novel antiproliferative strategies. Here, we characterized a long-term culture (SST-secreting cancer (SS-C cells)) established from a human somatostatinoma. High concentrations of SST and chromogranin A were released by SS-C cells and SST release was stimulated by depolarizing stimuli and inhibited by the SST analogue, octreotide. SS-C cells expressed mRNA for SST receptor (SSTR) subtypes 1, 2 and 4, being also able to bind native SST. Moreover, SS-C cells were positively stained with an antibody to SSTR2. SS-C cells also expressed interferon-gamma (IFN-gamma) receptor mRNA and measurable telomerase activity. Our findings indicate that in vitro exposure of SS-C cells to native SST-28, to octreotide, to IFN-gamma, or to 3'-azido-3'deoxythymidine (AZT), a telomerase inhibitor, results in inhibition of SS-C cell proliferation. Concomitant with growth inhibition, apoptosis was detected in SST-, octreotide-, IFN-gamma- or AZT-treated SS-C cell cultures. Taken together our results characterized native SST, SST analogues, IFN-gamma and a telomerase inhibitor as growth-inhibiting and proapoptotic stimuli in cultured human somatostatinoma cells. Based on these findings, the potential of SST analogues, IFN-gamma and AZT, alone or in combination, should be further explored in the medical treatment of somatostatinoma.

Intraoperative positive fluid balance improves tissue diffusion of ceftizoxime.

AIM OF STUDY: To demonstrate that administration of fluids and the consequent improvement of fluid balance during a surgical procedure can modify the tissue diffusion of ceftizoxime. METHODS: Twenty-eight patients (30-79 years) undergoing major abdominal surgery of the colon were administered ceftizoxime 30 mg/kg i.v. at induction of anesthesia. A sample of arterial blood was taken before administration of the drug (t0) and then again at the time of vascular occlusion of the colon segment to be removed (t1). A sample of the segment of removed colon was taken. The patients were divided into two groups on the basis of the fluid balance between t0 and t1: group A (n = 17) with a fluid balance <1,000 ml and group B (n = 11) with a fluid balance >1,000 ml. The parameters evaluated in each group were: weight, height and age of the patients, serum and tissue antibiotic concentration, percent ratio of serum and tissue concentration, time elapsed between t0 and t1, volume of administered fluids between t0 and t1, diuresis and hourly diuresis between t0 and t1 and body fluid distribution, obtained using a bioelectrical impedance analyzer. The mean results obtained in the two groups were then compared using Student's t test. RESULTS: The balance of fluids calculated up to t1 was 675 +/- 308 ml for group A and 1,411 +/- 405 ml for group B (p < 0.01). The means of the recorded values that showed statistically significant differences were: mean percent concentration ratio (43.6 +/- 8.4 vs. 84 +/- 16%; p < 0.05), concentration in the colonic segment (16.3 +/- 7.9 vs. 37.2 +/- 25.9 mg/ml; p < 0.05), urinary volume gathered up to t1 (538 +/- 557 vs. 169 +/- 104 ml; p < 0.05), hourly urinary volume up to t1 (311.1 +/- 296 vs. 97.6 +/- 77.9 ml/h; p < 0.05), percent variation of resistance (95.1 +/- 5.1 vs. 89.7 +/- 8.6; p < 0.05). The other means did not show any significant statistical differences. CONCLUSIONS: A higher tissue water level seems to facilitate the penetration of the antibiotic into the tissue according to the pharmacokinetic characteristics of ceftizoxime: high amount of free drug (not bound to plasma proteins) and high hydrosolubility.

Different role of the colonic pouch for low anterior resection and coloanal anastomosis.

BACKGROUND: Functional outcome after sphincter-saving operations can be improved by colonic pouch compared to the straight procedure. However, it is not clear whether the colonic pouch has a different behavior in patients treated by low anterior resection with colorectal (LAR) or coloanal anastomosis (CAA). METHODS: We evaluated the 1-year results of 75 patients who underwent a sphincter-saving operation for rectal carcinoma or villous tumor of the middle or lower third of the rectum: 18 patients underwent coloanal anastomosis (CAA), in 13 patients we performed a coloanal anastomosis with a colonic pouch (PCAA), 20 patients had low anterior resection (LAR) and 24 had LAR with pouch construction (PLAR). The two groups of patients were similar in terms of age and gender. Anorectal function was assessed 12 months after the initial operation by an interview and anorectal manometry. RESULTS: One year after surgery, the daily mean number of defecations was significantly higher in the LAR group than in the other groups (2.0+/-1.5 in CAA group, 2.2+/-1.0 in PCAA, 2.3+/-1.8 in PLAR, 4.1+/-0.7 in LAR; p<0.05). Frequent soiling was observed in all the groups except PLAR. A lower degree of incontinence and a lower frequency of urgency were found in PCAA than in CAA. There were no differences in anal resting pressure and squeeze pressure among the various groups. Greater distensibility and compliance of the neorectum were observed in CAA, PCAA and PLAR compared to LAR, respectively 8.5+/-7.0 ml air/mmHg for CAA, 8.7+/-5.0 ml air/mmHg for PCAA, 6.3+/-4.0 ml air/mmHg for PLAR and 3.1+/-2.7 ml air/mmHg for LAR. A significant inverse linear correlation was present between the mean daily number of defecations and compliance. No difference in sense of incomplete evacuation was observed among the groups of patients. CONCLUSIONS: Colonic J-pouch provides an advantage over straight anastomosis in sphincter-saving operations by reducing the daily number of defecations, and the frequencies of fecal soiling and urgency. The role of the pouch seems to be different in LAR compared to CAA. In fact, in LAR the pouch increases compliance and consequently decreases the daily number of defecations. In CAA, the pouch does not reduce the number of defecations or the compliance, but reduces the frequency of fecal soiling and urgency.

[Rectal cancer: locoregional recurrence in relation to surgical and complementary treatment]. / Il cancro del retto: le recidive locoregionali in rapporto alle terapie chirurgiche e complementari adottate.

Much recent data have been published on the risk of local recurrence (LR) following curative surgery for rectal cancer and the impact of adjuvant therapy. On the other hand, improvements in surgical techniques, as the total mesorectal excision, have apparently reduced the risk of LR. Furthermore, in selected cases, neoadjuvant therapy seems to reduce much more the incidence of LR. A list of prognostic factors which affect the onset of LR, other than the different procedures, was considered. To investigate such evidences a retrospective analysis was undertaken in our series, focusing on examination of the employed techniques as potential predictors of local recurrence. Thus, in a 18-yr-period (1986-2003), two hundred and ninety-five patients who had undergone elective curative surgical resection of rectal cancer were included in the study. The demographic, operative and follow-up data were collected retrospectively. All patients underwent total mesorectal excision, whereas neoadjuvant therapy was performed in a selected series of patients, according to defined entry criteria patterns. Results evidenced LR in 7.1% of patients and occurred between 6 months to 8 year following surgery. Comparisons were made between patients who had different surgical procedures; indeed sphyncter saving procedures correlated with a higher incidence of LR rather than abdomino-perineal resection. Pelvic recurrences were observed more frequently compared to the anastomotic ones. A limited number of patients with LR underwent surgery due to the associated condition of metastatic lesions; the follow-up related to such series evidenced a mortality rate of 57% within 3 year from reoperation. A low local recurrence rate can be achieved after total mesorectal excision (TME) without preoperative radiotherapy. Our results suggest that preoperative radiotherapy may be employed only for those patients who are at a higher risk for local recurrence.

[Major and repeated liver surgery in the multimodal treatment of synchronous and metachronous metastasis of colorectal cancer]. / La chirurgia epatica maggiore e iterativa nel trattamento multimodale delle metastasi sincrone e metacrone da cancro colorettale.

At the present, surgical treatment still represents the only chance of cure for liver metastases from colorectal cancer. Moreover in the last years the new chemotherapic adjuvant and neoadjuvant regimens and the use of radioablative techniques as radiofrequency have improved resectability and even survival. Besides, iterative surgery seems to show more and more encouraging results in terms of disease-free and overall survival, sometimes even in patients already resected for extrahepatic disease. The golden rule is in fact to try to perform every time an R0 resection, with no macro- and possibly microresidual disease.

Anal carcinoma occurring in Crohn's disease patients with chronic anal fistula.

This paper reports six patients with perianal Crohn's disease (CD), who developed anal cancer in chronic anal fistulas. Tumors have been often diagnosed at an advanced stage and had a worse prognosis than cancers arising in the general population as tumor symptoms may mimic symptoms of CD, resulting in delay in diagnosis. Patients with perianal CD should undergo a careful surveillance program for ano-rectal carcinoma, including routine biopsy of any suspected lesion. When malignancy is found, an aggressive surgical approach and complementary therapy are mandatory.

[Surgical treatment of hepatocellular carcinoma: prognostic factors for long-term disease-free survival and tumor recurrence]. / La terapia chirurgica del carcinoma epatocellulare: fattori prognostici per la sopravvivenza a lungo termine libera da malattia e la recidiva tumorale.

Hepatocellular carcinoma mainly develops in a cirrhotic liver; in the majority of the patients chronic hepatitis or cirrhosis are virus-related and/or postalcoholic. Liver resection is the gold standard treatment when there is no multifocality of the tumor and liver disease is not advanced (patients with Child-Pugh A score, or B in selected cases). In our experience the presence of vascular invasion and satellite nodules is clearly related to a decreased rate of disease-free survival and a higher percentage of intrahepatic recurrence.