Giovanni Battista Doglietto

Prognostic factors in colorectal cancer : Literature review for clinical application

PURPOSE: Identification of prognostic factors is a primary basis for planning the treatment and predicting the outcome of patients with colorectal cancer. Reviewing studies from the literature performed using univariate and multivariate analyses and their own study, the authors critically discuss the prognostic value of the clinicopathologic parameters of the tumor. METHODS: Among 853 patients with colorectal tumors seen at the Department of Clinical Surgery of the Catholic University of Rome, Italy, 690 cases that were curatively resected entered the study. Overall survival rate, related to the clinicopathologic variables, was calculated, and univariate and multivariate analyses were performed. RESULTS: Five-year and ten-year overall survival rates were 70 and 55 percent, respectively. Univariate and multivariate analyses showed that node involvement, distant metastases, bowel obstruction, and patient gender are factors independently related to outcome. CONCLUSIONS: Data from the literature and the present study suggest that only a few clinical parameters, particularly bowel obstruction, and some pathologic factors (tumor stage, vessels invasion, and tumor ploidy) are related to patient survival rate and are the most reliable prognostic criteria. In prospective clinical studies, any other new pathologic or molecular factors should be matched with these parameters to confirm their value in outcome prediction.

Increased muscle proteasome activity correlates with disease severity in gastric cancer patients

ObjectiveTo investigate the state of activation of the ATP-ubiquitin-dependent proteolytic system in the skeletal muscle of gastric cancer patients. Summary Background DataMuscle wasting in experimental cancer cachexia is frequently associated with hyperactivation of the ATP-dependent ubiquitin-proteasome proteolytic system. Increased muscle ubiquitin mRNA levels have been previously shown in gastric cancer patients, suggesting that this proteolytic system might be modulated also in human cancer. MethodsBiopsies of the rectus abdominis muscle were obtained intraoperatively from 23 gastric cancer patients and 14 subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin mRNA expression and proteasome proteolytic activities were assessed. ResultsMuscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin-like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased in gastric cancer patients with respect to controls. Advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher CTL activity but had no influence on TL and PGP activity. ConclusionsThese results confirm the involvement of the ubiquitin-proteasome proteolytic system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia. The observation that perturbations of this pathway in gastric cancer patients occur even before clinical evidence of body wasting supports the thinking that specific pharmacologic and metabolic approaches aimed at counteracting the upregulation of this pathway should be undertaken as early as cancer is diagnosed.

Thymoma in patients with MG: Characteristics and long-term outcome

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.

Ki-67 grading of nonfunctioning pancreatic neuroendocrine tumors on histologic samples obtained by EUS-guided fine-needle tissue acquisition: a prospective study

BACKGROUND Preoperative determination of Ki-67 expression, an important prognostic factor for grading nonfunctioning pancreatic endocrine tumors (NF-PETs), remains an important clinical challenge. OBJECTIVE To prospectively evaluate the feasibility, yield, and clinical impact of EUS-guided fine-needle tissue acquisition (EUS-FNTA) with a large-gauge needle to obtain tissue samples for histologic diagnosis and Ki-67 analysis in patients with suspected NF-PETs. DESIGN Prospective cohort study. SETTING Tertiary-care academic medical center. PATIENTS Consecutive patients with a single pancreatic lesion suspicious for NF-PET on imaging. INTERVENTION EUS-FNTA with a 19-gauge needle. MAIN OUTCOME MEASUREMENTS Feasibility and yield of EUS-FNTA for diagnosis and Ki-67 expression determination. RESULTS Thirty patients (mean [± SD] age 55.7 ± 14.9 years), with a mean (± SD) lesion size of 16.9 ± 6.1 mm were enrolled. EUS-FNTA was successfully performed without complications in all patients, with a mean (± SD) of 2.7 ± 0.5 passes per patient. Adequate samples for histologic examination were obtained in 28 of the 30 patients (93.3%). Ki-67 determination could be performed in 26 of these 28 patients (92.9%, 86.6% overall), 12 of whom underwent surgical resection. Preoperative and postoperative Ki-67 proliferation indexes were concordant in 10 patients (83.3%), whereas 2 patients were upstaged from G1 to G2 or downstaged from G2 to G1, respectively. LIMITATIONS Single center study with a single operator. CONCLUSION In patients with suspected nonfunctioning low-grade to intermediate-grade pancreatic neuroendocrine tumors (p-NETs), retrieval of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible, and highly accurate for both diagnosis and Ki-67 determination. A Ki-67 proliferative index acquired through this technique might be of great help for further therapeutic decisions.

Sacral Neuromodulation in Treatment of Fecal Incontinence Following Anterior Resection and Chemoradiation for Rectal Cancer

PURPOSEFecal incontinence may occur in patients who have undergone anterior resection for rectal cancer without presenting sphincter lesions. Chemoradiation may contribute to disrupting continence mechanisms. Treatment is controversial. Assessment of fecal incontinence in patients who agreed to integrate treatment for rectal cancer and treatment with sacral neuromodulation are reported.METHODSFecal incontinence following preoperative chemoradiation and anterior resection for rectal cancer was evaluated in four patients. A good response was observed during the percutaneous sacral nerve evaluation test, and so permanent implant of sacral neuromodulation system was performed. Reevaluation was performed at least two months after implant.RESULTSAfter device implantation, the mean fecal incontinence scores decreased, and the mean number of incontinence episodes dropped from 12.0 to 2.5 per week (P < 0.05). Permanent implant resulted in a significant improvement in fecal continence in three patients, and incontinence was slightly reduced in the fourth. Manometric parameters agreed with clinical results: maximum and mean resting tone and the squeeze pressure were normal in three patients and reduced in one. In these same three patients, neorectal sensation parameters increased when the preoperative value was normal or below normal and decreased when the preoperative value was higher than normal, whereas in one patient in whom extremely low values were recorded all of the parameters decreased significantly.CONCLUSIONSFecal incontinence following anterior resection and neoadjuvant therapy should be carefully evaluated. If a suspected neurogenic pathogenesis is confirmed, sacral neuromodulation may be proposed. If the test results are positive, permanent implant is advisable. Failure of this approach does not exclude the use of other, more aggressive treatment.

Evaluation of Transanal Hemorrhoidal Dearterialization as a Minimally Invasive Therapeutic Approach to Hemorrhoids

PURPOSE: Transanal hemorrhoidal dearterialization is an innovative technique to treat hemorrhoids using a specially designed proctoscope for Doppler-guided transanal ligation of hemorrhoidal arteries. We analyzed results of experience at a single-institution with this transanal hemorrhoidal dearterialization device. METHODS: Overall, 170 patients were submitted to transanal hemorrhoidal dearterialization during the period July 2005 through October 2008. The operation consisted of hemorrhoidal dearterialization (of 6 arteries) in all patients, with major mucosal/submucosal pexy in 56 patients (32.9%). The first consecutive 11 patients (6.4%) were treated under general/spinal anesthesia, the remaining 159 (93.6%) by sedation with propofol, supported by analgesia with remifentanil. Following transanal hemorrhoidal dearterialization surgery, patients were regularly evaluated at 2 weeks, 1 and 3 months, and once a year after operation. RESULTS: The mean age of the 170 patients was 47.3 ± 13.0 years; 102 (60%) were men. Hemorrhoidal disease was grade II in 13 (7.6%); grade III in 141 (82.7%), and grade IV in 16 (9.6%). Postoperative bleeding requiring surgical hemostasis occurred in 2 cases (1.2%). Mean follow-up was 11.5 ± 12 (range, 1–41) months. Hemorrhoidal thrombosis occurred in 4 patients (2.3%), chronic pain and fecal incontinence in none. Hemorrhoidal prolapse was reported at follow-up by 50 patients (29.5%), but prolapse was confirmed only in 18 (10.5%) and was mild; some patients reporting prolapse were found to have skin tags. Overall, long-term control of bleeding was obtained in 159 patients (93.5%) and control of prolapse in 152 (89.5%). Recurrence of hemorrhoidal disease requiring surgery was found in 7 patients (4.1%). CONCLUSIONS: Transanal hemorrhoidal dearterialization appears to be a very effective minimally invasive option to treat hemorrhoids and can be performed in a day-surgery setting. Future controlled trials comparing transanal hemorrhoidal dearterialization with other procedures will show the real potential of transanal hemorrhoidal dearterialization and define adequate indications for this approach.

Is malnutrition still a risk factor of postoperative complications in gastric cancer surgery

OBJECTIVE & AIMS The present study aimed at retrospectively evaluating the incidence of mortality and major and minor postoperative complications in patients who underwent surgery for gastric cancer between 2000 and 2006 stratified according to the preoperative percentage weight loss, serum albumin levels and body mass index (BMI). METHODS One hundred and ninety-six patients affected by gastric cancer admitted to the Division of Digestive Surgery of the Catholic University of Rome between January 2000 and December 2006 were considered eligible and were included in the study. According to the weight loss, patients were divided into three groups: (1) 0-5%; (2) 5.1-10%; (3) >10%. On the basis of serum albumin levels, were divided into three groups: (1) <3.0 g/dl; (2) 3.0-3.4 g/dl; (3) >3.5 g/dl. According to BMI, were divided into four groups: (1) <18.5 kg/m(2); (2) 18.5-24.9 kg/m(2); (3) 25.0-29.9 kg/m(2); (4) >30.0 kg/m(2). Postoperative complications and mortality were reported. Complications were classified by objective criteria as major or minor, and as infectious or non-infectious. RESULTS The postoperative mortality was 0%. Major infectious complications occurred in 20 patients (10.2%), major non-infectious in 18 (9.2%), minor infectious in 21 (10.7%), whereas minor non-infectious complications were absent. The rate of major infectious, major non-infectious and minor infectious postoperative complications was similar in patients with absent or light weight loss (8.8%, 8.8%, 10.6%, respectively), mild weight loss (15.3%, 11.5%, 9.6%, respectively), or severe weight loss (6.4%, 6.4%, 12.9%, respectively). Similarly, the rate of postoperative complications did not differ between patients with serum albumin <3.0 g/dl (10.8%, 8.1%, 8.1%, respectively); between 3.0 and 3.4 (8.8%, 13.3%, 17.7%, respectively) or > or =3.5 g/dl (10.5%, 7.9%, 8,7%, respectively). According to BMI, the rate of postoperative complications was: 11.7%, 5.8%, and 5.8% for BMI <18.5 kg/m(2); 9.4%, 8.2%, and 11.7% for BMI between 18.5 and 24.9 kg/m(2); 10.7%, 10.7%, and 9.2% for BMI between 25 and 29.9 kg/m(2); 10.3%, 10.3% and 13.7% for BMI >30 kg/m(2). Then, we evaluated the postoperative morbidity only in patients who underwent total gastrectomy or distal subtotal gastrectomy associated with extended lymphadenectomy. In this group of patients, the rate of postoperative complications was comparable in patients with 0-5% (8.8%, 7.7%, 10%, respectively), 5.1-10% (14.6%, 9.7%, 9.7%, respectively), and >10% (7.1%, 7.1%, 14.3%, respectively) weight loss. Also stratifying the patients according to the serum albumin levels, the rate of postoperative complications did not differ significantly (serum albumin <3.0 g/dl: 14.8%, 11.1%, 14.8%, respectively; serum albumin between 3.0 and 3.4 g/dl: 6.2%, 12.5%, 15.6%, respectively; serum albumin > or =3.5 g/dl: 10.4%, 5.8%, 7.0%, respectively). According to BMI, the rate of postoperative complications was: 7.6%, 0%, and 7.6% for BMI <18.5 kg/m(2); 9.5%, 9.5%, and 11.1% for BMI between 18.5 and 24.9 kg/m(2); 12.5%, 8.3%, and 10.4% for BMI between 25 and 29.9 kg/m(2); 9.5%, 9.5% and 9.5% for BMI >30 kg/m(2). CONCLUSION The present study suggests that weight loss and hypoalbuminemia are not associated with an increased risk of mortality and morbidity in patients who underwent surgery for gastric cancer. This study may represent a stimulus for further studies aiming at evaluating the actual role of malnutrition in the development of postoperative complications in major abdominal surgery.

Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases

BACKGROUND The purpose of this study is to analyze the pooled results of multimodality treatment of locally advanced rectal cancer (LARC) in four major treatment centers with particular expertise in intraoperative radiotherapy (IORT). PATIENTS AND METHODS A total of 605 patients with LARC who underwent multimodality treatment up to 2005 were studied. The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (aCT). In uni- and multivariate analyses, risk factors for local recurrence (LR), distant metastases (DM) and overall survival (OS) were studied. RESULTS Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). In all, 42% of the patients received aCT, independent of tumor-node-metastasis stage or radicality of the resection. LR rate, DM rate and OS were 12.0%, 29.2% and 67.1%, respectively. Risk factors associated with LR were no downstaging, lymph node (LN) positivity, margin involvement and no postoperative chemotherapy. Male gender, preoperatively staged T4 disease, no downstaging, LN positivity and margin involvement were associated with a higher risk for DM. A risk model was created to determine a prognostic index for individual patients with LARC. CONCLUSIONS Overall oncological results after multimodality treatment of LARC are promising. Adding aCT to the treatment can possibly improve LR rates.

Sacral nerve stimulation is a valid approach in fecal incontinence due to sphincter lesions when compared to sphincter repair.

PURPOSE: Anal sphincter lesions represent the major cause of fecal incontinence, particularly in women. Sphincteroplasty with overlap is the traditional treatment, but a significant reduction in benefits within 5 years of surgery has been reported. More recently, sacral nerve stimulation has been suggested following sphincteroplasty or as primary treatment. METHODS: Overall, 24 women with fecal incontinence in the presence of anal sphincter lesions underwent sphincteroplasty (14 patients, mean age 47.6 ± 15.6 years, range 26–70) or definitive implant of sacral nerve stimulation (10 patients, mean age 60.7 ± 17.6 years, range 26–73), using identical selection criteria. At baseline, patients were studied with clinical evaluation, 3-dimensional endoanal ultrasound, and anorectal manometry (ARM), repeated at follow-up (median 60.0 months, range 6–96 in sphincteroplasty group; median 33.0 months, range 6–84 in sacral nerve stimulation group). RESULTS: At baseline, both groups presented similar characteristics. Two sphincteroplasty patients (14.3%) experienced relapse of fecal incontinence at 6 and 19 months after treatment, whereas good to excellent continence was observed in all of the sacral nerve stimulation patients. Compared to baseline, both groups showed a significant improvement in clinical parameters, and ARM data remained unchanged. In 12 of 14 sphincteroplasty patients, the repaired sphincter at endoanal ultrasound was found to overlap. At follow-up, comparison between sphincteroplasty and sacral nerve stimulation showed no significant differences in clinical and ARM parameters, if related to lesion of internal, external, or both sphincters. CONCLUSIONS: These data appear to confirm that sacral nerve stimulation could represent a valid alternative in the treatment of fecal incontinence patients presenting with sphincter lesion that was not preceded by sphincteroplasty.

Combined-modality therapy in locally advanced primary rectal cancer.

AbstractPURPOSE: Patients with unresectable, locally advanced rectal cancer are reported to have a dismal prognosis. The aim of this study was to analyze the effect of combined-modality therapy on clinical outcome. METHODS: From March 1990 to December 1997, 43 patients (28 males; median age, 62 years; median follow-up, 74 months) with locally advanced (T4 and/or N3) nonmetastatic rectal cancer received external-beam radiation (23.6 plus 23.6 Gy (split course), 8 patients; 45 Gy, 35 patients) plus 5-fluorouracil (96-hour continuous infusion, Days 1–4, at 1,000 mg/m2/day) and mitomycin C (10 mg/m2, intravenous bolus, Day 1). Concomitant chemotherapy was repeated at the beginning of the second course (split-course group) or in the last week of radiotherapy (continuous-course group). After 6 to 8 weeks, patients were evaluated for surgical resection and intraoperative radiation therapy (10 to 15 Gy). Thereafter, adjuvant chemotherapy (5-fluorouracil plus leucovorin, 6–9 courses) was prescribed. RESULTS: During chemoradiation, 5 patients (11.6 percent) developed Grade 3 to 4 hematologic toxicity. After chemoradiation, 29 patients (67.4 percent) had an objective clinical response (complete response, 2.3 percent; partial response, 65.1 percent). Thirty-eight patients underwent radical surgery (anterior resection, 24 patients; abdominoperineal resection, 14 patients; intraoperative radiation therapy boost on the tumor bed, 19 patients), and 2 patients had partial tumor resection. No perioperative deaths occurred in the patient group. Five-year survival and local control rates were 59.9 and 69.1 percent, respectively. Distant metastasis occurred in 44.2 percent of patients. Statistically significant relationships between intraoperative radiation therapy and local control (P = 0.0104), radical surgery and survival (P = 0.0120), and adjuvant chemotherapy and disease-free survival (P = 0.0112) were observed. CONCLUSIONS: Our data suggest that combined-modality therapy was relatively well tolerated and resulted in good local control and survival. With regard to the impact of surgical resection on survival, additional studies aimed at improving the local response rate are necessary, whereas the positive impact of intraoperative radiotherapy on local control appears to justify the inclusion of this therapeutic modality in prospective multi-institutional trials.