Letter 2: Randomized clinical trial assessing impact of a lightweight or heavyweight mesh on chronic pain after inguinal hernia repair (Br J Surg 2005; 92: 166-170).
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Biomedical subjects
Publications and source records attributed to G B Doglietto.
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BACKGROUND AND STUDY AIMS: Outcomes following surgical treatment of patients with anal fistula are related to eradication of tracts and the internal opening. In this study, the results of surgery based on endoanal ultrasound (EAUS) findings were evaluated. PATIENTS AND METHODS: A total of 102 patients with primary cryptogenetic anal fistula were prospectively examined with EAUS, using a 360-degree rotating 10-MHz probe, equipped with a three-dimensional (3-D) imaging system. Injection of hydrogen peroxide through the external opening was also used. Patients underwent operation on the basis of the EAUS findings. The agreement between findings from EAUS and from surgery was calculated. Clinical results were reported as treatment success, fistula recurrence, and fecal incontinence. RESULTS: Amongst 102 patients, the overall concordance between EAUS and surgical findings was 94.1 % for primary tracts, 91.2 % for internal openings, 96.1 % for secondary tracts, 100 % for abscesses, and 96.1 % for horseshoe tracts. Diagnostic accuracy was improved when hydrogen peroxide injection or 3-D imaging were used. Fistulotomy was performed in 46 patients (45.1 %), fistulectomy in 17 (16.7 %), fistulotomy plus seton placement in 19 (18.6 %), fistulectomy plus seton in 18 (17.6 %), and mucosal flap advancement in 2 (2.0 %). The operation was curative in 100 patients (98.0 %), and unsuccessful in 2 (2.0 %) due to recurrence of the fistula. Fecal continence was preserved in all patients. CONCLUSIONS: These data highlight the diagnostic accuracy of EAUS, particularly when hydrogen peroxide injection or 3-D imaging are used. Basing our surgical decision making on EAUS findings allowed us to carry out curative operations in a significantly large number of patients; the recurrence rate was very low. The accurate EAUS assessment of the relationship between fistulas and sphincters has been the main factor in choosing a sphincter-saving surgical procedure, avoiding fecal incontinence.
Cachexia is a syndrome characterized by profound skeletal muscle wasting that frequently complicates malignancies. A number of studies indicate that protein hypercatabolism, largely mediated by classical hormones and cytokines, is the major component of muscle depletion. Impaired regeneration has been suggested to contribute to the reduction of muscle size. In particular, it has been shown that the expression of MyoD, a muscle-specific transcription factor, is down-regulated by cytokines such as TNFalpha and IFNgamma in a NF-kappaB-dependent posttranscriptional manner. The present study investigated whether modulations of the transcription factor MyoD are associated with the onset of muscle wasting in a well established model of cancer cachexia. Rats bearing the Yoshida AH-130 hepatoma develop a condition of muscle protein hypercatabolism, largely dependent on TNFalpha bioactivity. In the gastrocnemius of these animals the expression of MyoD was markedly reduced, paralleling the decrease of muscle weight. This pattern is associated with increased nuclear translocation of AP-1, while DNA-binding assays did not detect any change in NF-kappaB activity. This is the first observation demonstrating that muscle depletion in tumor-bearing rats is associated with a down-regulation of MyoD levels. Although the underlying mechanisms remain to be clarified, this change is compatible with the hypothesis that a reduced expression of molecules involved in the regulation of the regenerative response may concur to muscle wasting in cancer cachexia.
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BACKGROUND: Duodenal perforation occurs in 0.4-1 per cent of endoscopic procedures. The best therapeutic approach for periampullary injury is controversial; initially the treatment is generally conservative, but sometimes large retroperitoneal infections develop that require surgery. METHODS: Six patients with an extensive retroperitoneal collection and unstable sepsis as a consequence of periampullary duodenal perforation sustained during endoscopic retrograde cholangiopancreatography were treated by right posterior laparostomy through the bed of the 12th rib. RESULTS: The sepsis was managed effectively by an open posterior approach, resulting in spontaneous closure of the duodenal leak after a mean(s.d.) of 14.5(5.2) days. No hospital death or major complication was recorded. Late incisional hernia developed in one patient. CONCLUSION: The technique of posterior laparostomy through the bed of the 12th rib provided adequate debridement and drainage of upper and lower parts of the retroperitoneal space involved by infection following periampullary duodenal perforation. Good control of retroperitoneal sepsis and duodenal secretions resulted in spontaneous closure of the duodenal leak, avoiding the need for more complex intra-abdominal procedures.
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BACKGROUND: The rationale for combining cytotoxic agents, such as gemcitabine, and radiotherapy is based on their ability to act as radiation sensitizers and to improve overall response rate. Several studies on pancreatic or biliary carcinoma evaluated the maximum tolerated dose (MTD) of gemcitabine when combined with irradiation of the macroscopic tumor. However, most of these neoplasms metastasize to the regional lymph nodes. Aim of this report is to determine the MTD of weekly gemcitabine when combined with extended field irradiation (tumor plus nodal irradiation). PATIENTS AND METHOD: 15 patients entered the study. Of these 5 patients were treated with chemoradiation after radical surgical resection. External beam radiation (ERT) was delivered to the tumor (or tumor bed) and regional lymph nodes by using a three-field technique. The initial dose of gemcitabine was 100 mg/m(2) administered as short intravenous infusion once a week. At each dose level 3 patients were treated, and if no grade 3-4 toxicity (considered as dose-limiting toxicity, DLT) was recorded, dose escalation was applied with 50 mg/m(2) increments until the MTD was established. RESULTS: All patients were evaluable for acute toxicity. There were no treatment-related deaths. No DLT occurred at the first 4 dose levels (100-250 mg/m(2)). At the 5th dose level (300 mg/m(2)), 3 patients experienced DLT: 1 had grade 3 gastrointestinal toxicity (painful erosion of gastric mucosa), 1 had uncomplicated grade 3 leukopenia and 1 grade 3 change in liver biochemistry tests. In addition, all 10 unresected patients were evaluated for response, 4 of whom had progressive disease (1 local; 2 distant; 1 local and distant) and 6 had no change. The median follow-up was 21 months. CONCLUSION: Based on this study, the recommended dose for weekly short infusional gemcitabine combined with radiation therapy to the tumor and lymph nodes is 250 mg/m(2). This value is suggestive of a correlation between acute toxicity and inclusion of lymph nodes in the irradiated volume. Moreover, different infusion modalities, as continuous infusion gemcitabine, should be tested more accurately.
OBJECTIVE: To examine the characteristics of thymoma when associated with MG and to evaluate those conditions that can complicate management and affect survival. METHODS: The study includes 207 myasthenic patients who were operated on for thymoma, with at least 1-year follow-up from surgery. MG severity and response to treatment, the occurrence of paraneoplastic diseases and extrathymic malignancies, thymoma histologic types and stages, adjuvant therapy, tumor recurrences, and causes of death were recorded. RESULTS: MG-associated thymoma was predominantly of B type and was invasive in the majority of patients. MG was generally severe, and most patients remained dependent on immunosuppressive therapy. Other paraneoplastic disorders and extrathymic malignancies were found in 9.66 and 11.11% of patients. Thymoma recurrences occurred in 18 of 115 patients with invasive tumors (15.65%) and were often associated with the onset/aggravation of autoimmune diseases. On completion of the study, MG and thymoma accounted for a similar mortality rate. CONCLUSIONS: Thymoma should be considered as a potentially malignant tumor requiring prolonged follow-up. The presence of myasthenic weakness can still complicate its management. Thymoma-related deaths are bound to outnumber those due to MG in the future.
The ascites hepatoma Yoshida AH-130 induces loss of body weight and tissue waste. Tumour necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of muscle wasting in this model system, but other cytokines, such as interleukin-6, may be involved. In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation, tumour bearing rats were treated with pentoxyfilline (PTX, an inhibitor of TNF-alpha synthesis), or with suramin (SUR, an antiprotozoal drug blocking the peripheral action of several cytokines including IL-6 and TNF-alpha), or both the drugs, and the effects on muscle proteolytic systems were assessed. Muscle protein loss in the AH-130-bearing rats was associated with increased activity of both the ATP-ubiquitin- and the calpain- dependent proteolytic pathways (246% and 230% of controls, respectively). Both PTX and SUR, either alone or in combination, prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems. In particular, treatment with SUR, either alone or with PTX, induced a decrease in enzymatic activities to values similar to those of controls. The results obtained in the present paper demonstrate that: (i) muscle depletion in this model is indeed associated with increased proteasome- and calpain-dependent proteolysis, as previously suggested by increased mRNA expression of molecules pertaining to both pathways; (ii) anticytokine treatments effectively reduce muscle protein loss by down-regulating the activity of at least two major proteolitic systems; (iii) SUR is more effective than PTX in reducing the activity of proteolytic systems, possibly because of its multiple anticytokine action.
PURPOSE: Mesorectal involvement is a common feature in rectal tumors. Neoplastic foci can be identified at pathologic examination of the mesorectum, but their incidence and prognostic significance remain to be defined. METHODS: A series of 77 patients with extraperitoneal rectal cancer, resected with total mesorectal excision, entered the study. After fixation, the excised specimens were submitted to serial transverse sections and staining. Direct tumor infiltration, lymph node involvement, and neoplastic microfoci in the mesorectum were investigated. Patients with mesorectal foci were compared with those without deposits with regard to clinical and pathologic parameters; different patterns of foci (endovasal, endolymphatic, perineural, isolated) were also considered. Univariate and multivariate analyses were used to evaluate the impact on survival rate. RESULTS: Neoplastic mesorectal involvement was found in 64 patients (83.1 percent). Direct tumor infiltration was detected in 66.2 percent, node involvement in 28.6 percent, microscopic foci in 44.2 percent of cases (endovasal in 11.7 percent, endolymphatic in 15.7 percent, perineural in 26 percent, isolated in 14.3 percent). In 7 cases (10.9 percent) microfoci alone (without any kind of other mesorectal involvement) were detected. Deposits were found in 18.8 percent of TNM Stage I tumors, in 46.9 percent of Stage II and in 59.3 percent of Stage III cancers. Similar incidence was found in patients treated with integrated therapies and surgery alone (43.3 vs. 44.7 percent, P = not significant). Poorer median (44.5 vs. 57 months, P = 0.04) five-year overall survival rate (43.4 vs. 63.3 percent, P = 0.016) and disease-free survival rate (43.3 vs. 57.7 percent, P = 0.048) were observed in patients with microscopic foci compared with those without deposits. Tumor configuration was found to be a independent prognostic factor for both overall and disease-free survival rates; furthermore, endolymphatic, perineural, and isolated foci significantly affected overall survival rate, while TNM staging affected disease-free survival rate. CONCLUSIONS: The incidence of neoplastic foci in the mesorectum is high, even in early staged tumors and despite aggressive preoperative treatment. They seem to affect prognosis. Such features should, therefore, be considered when local excision of the tumor is planned. Presence of mesorectal foci should modify conventional staging of the rectal tumor.
AIM: Pancreatic cancer is a near fatal disease. External beam radiotherapy and intraoperative radiation therapy (IORT) has been proposed with the aim to improve clinical outcome in resectable tumors. The aim of this study is to assess the feasibility and outcome in patients with cT1-3 pancreatic cancer, treated with surgery, external beam radiotherapy and IORT. METHODS: From 1990 to 1996, 17 patients with clinical stage T1-3N0-1M0 adenocarcinoma of the head of the pancreas were treated with pancreatectomy and pre- (nine patients: 5 Gy), intra- (all patients: 10 Gy) and post-operative (all patients: 50 Gy) radiotherapy. The pathologic T stages were: 4 pT2 and 13 pT3. The pathologic N stages were: 9 pN0 and 8 pN1. Minimum follow-up in living patients was 60 months. RESULTS: No perioperative mortalities were recorded. Two patients showed postoperative morbidity (11.8%) which required a subsequent laparotomy. The disease-free survival at 1, 3 and 5 years was 41, 23 and 18%, respectively (median: 9 months). The overall survival at 1, 3 and 5 years was 70%, 41% and 18%, respectively (median: 17.5 months). Three patients developed local failure (17.6%) and 12 patients showed distant metastases (70.6%). Univariate analysis (logrank) showed: a significant correlation between both N-stage and retroperitoneal involvement (RPI) with local control (N-stage: P=0.0155; RPI:P =0.0295), a significant correlation between maximum tumor size and metastases-free survival (P=0.0167) and overall survival (P=0.0241); the female gender was another predictor of prolonged survival (P= 0.0465). Multivariate analysis (Cox) showed a significant impact of N-stage and retroperitoneal involvement on local control and also a significant correlation between perineural involvement and tumor diameter with metastases-free survival. CONCLUSIONS: These results are similar to those of other published series and suggest that this approach is feasible with acceptable local control and survival, especially in patients with small tumors (<2.5 cm: 5 year survival=33.3%) and in female patients (5 year survival=30%). Due to the impact of gender, tumor diameter and N stage on prognosis, in the design of future trials a stratification of patients based on these categories should be considered. The search of effective chemotherapeutic agents is required, to reduce the high incidence of distant metastases, especially in larger tumors.
HYPOTHESIS: Despite aggressive approaches, locoregional tumor control and survival rates for patients with cancer of the pancreatic head remain disappointing. In the present study, we address whether intraoperative and adjuvant radiotherapy may improve the prognosis for these patients. DESIGN: A retrospective study. SETTING: University hospital. PATIENTS: From February 1985 to December 1995, 46 patients with an adenocarcinoma of the pancreatic head underwent pancreatic resection. The last 26 patients also received intraoperative radiotherapy (except 5 patients) and adjuvant external beam radiation therapy. MAIN OUTCOME MEASURES: Demographic data, tumor characteristics, surgical procedures, 5-year survival, and local control of disease were analyzed retrospectively. RESULTS: The morbidity rate was not increased by adjuvant radiation therapy; it was 43% in patients treated with surgery alone and 57% in patients treated with surgery and radiotherapy (P =.1); operative mortality was 8% (n = 2) and 9% (n = 2), respectively (P =.8). Overall 5-year survival and local control were 13% and 48.6%, respectively. The mean +/- SD 5-year survival was 5.5% +/- 5.3% (median, 10.8 months) in the surgery-alone group and 15.7% +/- 8.6% (median, 14.3 months) in the surgery plus radiotherapy group (P =.06); local control at 5 years was 29.8% +/- 16.9% and 58.4% +/- 19.9%, respectively (P<.01). Median metastasis-free survival was 8 and 9 months, respectively (P =.52). Multivariate analysis showed that adjuvant radiotherapy was an independent prognostic factor for survival (P<.01) and local control of the disease (P =.03). CONCLUSION: The present study supports the role of radiotherapy combined with pancreatoduodenectomy for treatment of cancer of the pancreatic head because even if the improvement in overall survival is moderate, it is effective in improving the local control of the tumor.
HYPOTHESIS: Immediate enteral feeding following major abdominal surgery reduces postoperative complications and mortality when compared with parenteral nutrition. DESIGN: A prospective multicenter randomized trial. SETTING: A university hospital department of digestive surgery. PATIENTS AND INTERVENTIONS: Two hundred forty-one malnourished patients undergoing major elective abdominal surgery were randomly assigned to receive, after surgery, either enteral (enteral nutrition group: 119 patients) or parenteral nutrition (total parenteral nutrition group: 122 patients). The patients were monitored for postoperative complications and mortality. RESULTS: The rate of major postoperative complications was similar in the enteral and parenteral groups (enteral nutrition group: 37.8%; total parenteral nutrition group: 39.3%; P was not significant), as were the overall postoperative mortality rates (5.9% and 2.5%, respectively; P was not significant). CONCLUSION: The present study failed to demonstrate that enteral feeding following major abdominal surgery reduces postoperative complications and mortality when compared with parenteral nutrition.
PURPOSE: There are several options in the treatment of fecal incontinence; it is often difficult to choose the most appropriate, adequate treatment. The consolidated experience gained in the urologic field suggests that sacral nerve stimulation may be a further option in the choice of treatment. The aim of our study was to evaluate the preliminary results of the peripheral nerve evaluation test obtained in a multicenter collaborative study on patients with defecatory and urinary disturbances. METHODS: Forty patients (9 males; mean age, 50.2; range, 26-79 years) underwent the peripheral nerve evaluation test, 28 (70 percent) for fecal incontinence and 12 (30 percent) for chronic constipation. Fourteen (35 percent) patients also had urinary incontinence; six had urge incontinence, two had stress incontinence, and six had retention incontinence. Associated diseases were scleroderma (2 patients), spinal injuries (4 patients), and syringomyelia (1 patient). All the patients underwent preliminary investigations with anorectal manometry, pudendal nerve terminal motor latency testing, anal ultrasound, defecography, and if required, urodynamic tests. The electrode for sacral nerve stimulation was positioned percutaneously under local anesthesia in the S2 (4), S3 (34), or S4 (1) foramen unilaterally (1 patient not accounted for because of no response to acute test), based on the best motor and subjective responses of paresthesia of the pelvic floor. Stimulation parameters were average amplitude, 2.8 (range, 1-6) V and average frequency, 15 to 25 Hz. RESULTS: The mean duration of the tests was 9.9 (range, 7-30) days; tests lasting fewer than seven days were not evaluated. There were four early displacements of the electrode. In 22 of the 25 evaluable patients with fecal incontinence, there was an improvement of symptoms (88 percent), and 11 (44 percent) were completely continent to liquid or solid stools, whereas in 7 symptoms were unchanged. Mean number of episodes of liquid or solid stool incontinence per week was 8.1 (range, 4-18) in the prestimulation period and 1.7 (range, 0-12) during the peripheral nerve evaluation test. (P = 0.001; Wilcoxon's signed-rank test). The most important manometric findings were: increase of maximum rest pressure (39.4 +/- 7.3 vs. 54.3 +/- 8.5 mmHg; P = 0.014, Wilcoxon's test) and maximum squeeze pressure (84.7 +/- 8.8 vs. 99.5 +/- 1.1 mmHg; P = 0.047), reduction of initial threshold (63.6 +/- 5.2 vs. 42.4 +/- 4.7 ml; P = 0.041) and urge sensation (123.8 +/- 0.6 vs. 78.3 +/- 8.9 ml; P = 0.05). An improvement was also found in patients with constipation, with reduction in difficulty emptying the rectum, with prestimulation at 7 (range, 2-21) episodes per week and end of peripheral nerve evaluation test at 2.1 (range, 0-6) episodes per week, P < 0.01) and in the number of unsuccessful visits to the toilet, which dropped from 29.2 (7-24) to 6.7 (0-28) per week (P = 0.01). The most important manometric findings in constipated patients were an increase in amplitude of maximum squeeze pressure during sacral nerve stimulation (prestimulation, 63 +/- 0 mm Hg; end of peripheral nerve evaluation test, 78 +/- 1 mm Hg; P = 0.009) and a reduction in rectal volume for urge threshold (prestimulation, 189 +/- 52 ml; end of peripheral nerve evaluation test, 139 +/- 45 ml; P = 0.004). CONCLUSIONS: In functional bowel disorders short-term sacral nerve stimulation seems to be a useful diagnostic tool to assess patients for a minor invasive therapy alternative to conventional surgical procedure.
PURPOSE: Sacral nerve modulation appears to offer a valid treatment option for some patients with fecal incontinence and functional defects of the internal anal sphincter or of the striated muscle. METHODS: Sixteen patients with fecal incontinence (4 males; mean age, 51.4 (range, 27-79) years) with intact or surgically repaired (n = 1) anal sphincter underwent permanent sacral nerve stimulation implant. Cause was traumatic in two patients, and associated disorders included scleroderma (2 patients) and spastic paraparesis (1 patient); eight (50 percent) of the patients also had urinary incontinence, and two (12.5 percent) had nonobstructive urinary retention. All patients were selected on the basis of positive findings from at least one peripheral nerve evaluation. The stimulating electrode was positioned in the S2 (1 patient), S3 (14 patients), or S4 (1 patient) sacral foramen. RESULTS: Mean follow-up was 15.5 (range, 3-45) months. Mean preimplant Williams score decreased from 4.1 +/- 0.9 (range, 2-5) to 1.25 +/- 0.5 (range, 1-2) (P = 0.01, Wilcoxon test), and the number of incontinence accidents for liquid or solid stool in 14 days decreased from 11.5 +/- 4.8 (range, 2-20) before implant to 0.6 +/- 0.9 (range, 0-2) at the last follow-up. Important manometric data were an increase in mean maximal pressure at rest of 37.7 +/- 14.9 mmHg (implantable pulse generator 49.1 +/- 18.7, P = 0.04) and in mean maximal pressure during squeeze (prestimulation 67.3 +/- 21.1 mmHg, implantable pulse generator 82.6 +/- 21.0, P = 0.09). CONCLUSIONS: Neuromodulation can be considered an option for fecal incontinence. However, an accurate clinical and instrumental evaluation and careful patient selection are required to optimize outcome.
The use of raltitrexed ('Tomudex') as concomitant chemotherapy during preoperative radiotherapy in chemonaïve patients with stage II/III rectal cancer has been examined in this study and its recommended dose in conjunction with radiotherapy investigated. Forty-five Gray (Gy) of radiotherapy (1.8 Gy daily, 5 days per week) was delivered to the posterior pelvis, followed by a 5.4 Gy boost. Single doses of raltitrexed (2.0, 2.5 and 3.0 mg/m(2)) were administered on days 1, 19 and 38. Only 1 of the 15 patients entered experienced a dose limiting toxicity (DLT) (grade 3 leucopenia) at the 3.0 mg/m(2) dose level. The overall response rate was 80% (five complete responses, seven partial responses). These preliminary data suggest that raltitrexed is a well tolerated and effective treatment when combined with preoperative radiotherapy in patients with stage II/III rectal cancer. The recommended dose of raltitrexed for future phase II studies will be 3.0 mg/m(2).
BACKGROUND: The number of hepatic resections for benign and malignant lesions has constantly increased over the past 20 years, as a consequence, surgical experience acquired over the past few years has decreased post-operative morbidity and mortality rates. AIMS: Analysing the relation between potential preoperative risk factors and the occurrence of severe post-operative complications, an attempt is made to identify the variables determining surgical risk in elective hepatic surgery both in normal and cirrhotic liver. PATIENTS AND METHODS: The hospital records of 254 patients who underwent elective liver surgical procedures for hepatic lesions in our department, between 1984 and 1999, were reviewed. The following variables were entered into univariate and multivariate analysis: age, sex, nature of liver lesion (benign or malignant), presence of cirrhosis or cholestasis, synchronous resection of other organs, disorders of blood coagulation, intraoperative blood requirement, the extent of surgical procedures and Pringle's manoeuvre. RESULTS AND CONCLUSIONS: The multivariate analysis of the 254 surgical operations on the liver indicates that the most powerful independent predictors favouring a serious adverse effect includes intra-operative blood transfusions, advanced age and cirrhosis. Scrupulous preoperative clinical evaluation and expert surgical skills minimize intra-operative bleeding and proved to be the most significant factors influencing morbidity and mortality rates.
The intramuscular ATP-dependent ubiquitin (Ub)-proteasome proteolytic system is hyperactivated in experimental cancer cachexia. The present study aimed at verifying whether the expression of the muscle Ub mRNA is altered in patients with cancer. Total muscle RNA was extracted using the guanidinium isothiocyanate/phenol/chloroform method from rectus abdominis biopsies obtained intraoperatively from 20 gastric cancer (GC) patients and 10 subjects with benign abdominal diseases (CON) undergoing surgery. Ub mRNA levels were measured by northern blot analysis. Serum soluble tumor necrosis factor receptor (sTNFR) was measured by ELISA. Ub mRNA levels (arbitrary units, means +/- SD) were 2,345 +/- 195 in GC and 1,162 +/- 132 in CON (P = 0.0005). Ub mRNA levels directly correlated with disease stage (r = 0.608, P = 0.005), being 1,945 +/- 786 in stages I and II, 2,480 +/- 650 in stage III, and 3,799 +/- 66 in stage IV. Ub mRNA and sTNFR did not correlate with age and nutritional parameters. This study confirms experimental data indicating an overexpression of muscle Ub mRNA in cancer cachexia. Lack of correlation with nutritional status suggests that Ub activation in human cancer is an early feature that precedes any clinical sign of cachexia.