HIPECT4: multicentre, randomized clinical trial to evaluate safety and efficacy of Hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C used during surgery for treatment of locally advanced colorectal carcinoma.

BACKGROUND: Local relapse and peritoneal carcinomatosis (PC) for pT4 colon cancer is estimated in 15,6% and 36,7% for 12 months and 36 months from surgical resection respectively, achieving a 5 years overall survival of 6%. There are promising results using prophylactic HIPEC in this group of patients, and it is estimated that up to 26% of all T4 colon cancer could benefit from this treatment with a minimal morbidity. Adjuvant HIPEC is effective to avoid the possibility of peritoneal seeding after surgical resection. Taking into account these results and the cumulative experience in HIPEC use, we will lead a randomized controlled trial to determine the effectiveness and safety of adjuvant treatment with HIPEC vs. standard treatment in patients with colon cancer at high risk of peritoneal recurrence (pT4). METHODS/DESIGN: The aim of this study is to determine the effectiveness and safety of adjuvant HIPEC in preventing the development of PC in patients with colon cancer with a high risk of peritoneal recurrence (cT4). This study will be carried out in 15 Spanish HIPEC centres. Eligible for inclusion are patients who underwent curative resection for cT4NxM0 stage colon cancer. After resection of the primary tumour, 200 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously after the primary resection. Mitomycin C will be used as chemotherapeutic agent, for 60 min at 42-43 °C. Primary endpoint is loco-regional control (LC) in months and the rate of loco-regional control (%LC) at 12 months and 36 months after resection. DISCUSSION: We assumed that adjuvant HIPEC will reduce the expected absolute risk of peritoneal recurrence from 36% to 18% at 36 months for T4 colon-rectal carcinoma. TRIAL REGISTRATION: NCT02614534 ( clinicaltrial.gov ) Nov-2015.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei and appendix tumours in elderly patients: Is it justified?

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei and appendix tumours are widespread in the world. It is unclear what should be the attitude in elderly patients. METHODS: This retrospective multicenter study collected the database from ten Spanish centers from Spanish Group of Peritoneal Cancer Surgery. The study period was between November 2002 and March 2014. Seventeen patients with age greater than or equal to 75 years with peritoneal carcinomatosis from pseudomyxoma peritonei and appendix tumours met the selection criteria for the study. Outcomes in terms of morbidity and mortality such as disease-free and overall survival were analyzed. RESULTS: Median PCI was 16 (range 6-39). Ten postoperative adverse events were detected in nine patients (44.4%). 28% were grade I-II and 17% were grade III-IV. Disease-free survival at 1 and 3 years was 67 and 44%, respectively. Overall survival at 1 and 3 years was 100 and 88%, respectively. Only cytoreduction was related to worst disease free survival after univariate (p = 0.007) and multivariate (OR 11.639, 95% CI 1.24-109.74, p = 0.03) analyses. Cytoreduction was related to the worst overall survival after univariate analysis (p = 0.046). CONCLUSION: Cytoreductive surgery and HIPEC for pseudomyxoma peritonei and appendix tumours in elderly patients it is a procedure with feasible postoperative morbi-mortality and survival outcomes. TRIAL REGISTRATION: researchregistry1587 (retrospectively registered).

Morbidity and mortality outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients aged 75 years and over: Spanish group of peritoneal cancer surgery (GECOP) multicenter study.

BACKGROUND: The aim of this study is to report the perioperative outcomes of cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in patients ≥75 years from a Spanish multi-institutional experience. METHODS: This multi-institutional retrospectively analyzed a prospectively collected clinical data from 10 Spanish hospitals that are part of the Spanish Group Peritoneal Cancer Surgery (GECOP). We assessed postoperative morbidity rates and performed univariate and multivariate analyses of factors associated with overall (grade I-IV) and major (grade III-IV) postoperative morbidity. RESULTS: A total of 85 patients aged ≥75 years were included. Forty six postoperative adverse events were detected in 37 patients (43.5%). Twenty five complications in 20 patients (23.5%) were mild (grade I-II) and 16 complications in 12 patients (14.1%) were moderate-severe (grade III-IV). Five patients died in the first 90 days after the procedure (5.9%). After multivariate analysis, independent factors associated with postoperative complications were: PCI> 12 (OR: 4.14, 95% CI 1.22-14.12, p = 0.043) and the need for perioperative blood transfusion (OR: 14.91, 95% CI 3.87-57.46, p < 0.001). Regarding grade III-IV complications, after multivariate analysis, the presence of preoperative albumin levels <3.5 mgr/dl (OR: 9.15, 95% CI 1.38-60.57, p = 0.017), need for diaphragmatic peritonectomy procedures (OR: 11.32, 95% CI 1.40-91.32, p = 0.023) and perioperative blood transfusion (OR: 8.58, 95% CI 1.44-51.16, p = 0.018) were independent factors. CONCLUSIONS: Cytoreductive surgery and performing HIPEC by experienced groups in selected patients aged ≥75 years can be performed with morbidity and mortality similar to that described in the literature.

Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals.

Peritoneal carcinomatosis, considered years ago as a final stage of unresectable cancer, can now be managed with curative intention by means of a radical cytoreductive surgical procedure with associated peritonectomy and intraperitoneal chemotherapy, as described by Sugarbaker. Malignant neoplasms such as mesothelioma and pseudomyxoma peritonei, ovarian and colon cancer nowadays are experiencing some new therapeutical approaches. Higher survival rates can be reached in ovarian cancer, which is commonly diagnosed in the presence of peritoneal carcinomatosis, using an optimal cytoreductive radical surgery with intraperitoneal chemotherapy. An actualised review of the treatment of advanced ovarian cancer and a proposal of a national multicentre protocol for the treatment of peritoneal carcinomatosis from ovarian cancer has been performed by a group of Spanish surgeons and oncologists dedicated to a therapeutical approach to this pathology.

Management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy.

AIMS: A new treatment strategy combining maximal cytoreductive surgery for treatment of macroscopic disease and maximal perioperative intraperitoneal chemotherapy for residual microscopic disease, suggests that in a selected group of patients benefit is possible. The purpose of this study was to report our experience with this combined treatment and to identify the principal prognostic factors. METHODS: The study included 266 patients from 9 institutions operated on between July 1990 and July 2004. The median age was 55 years. RESULTS: The mortality rate was 7.8% and the morbidity rate 37.5%. The overall median survival was 13.7 months. Positive independent prognostic factors by multivariate analysis were gender, perioperative intraperitoneal chemotherapy and treatment by the second-look procedure. CONCLUSIONS: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with an acceptable morbidity and mortality.

Pancreatic function after severe acute biliary pancreatitis: the role of necrosectomy.

OBJECTIVES: To investigate the recovery of pancreatic function after severe acute biliary pancreatitis (ABP), especially the influence of necrosectomy on endocrine and exocrine functions. METHODS: Prospective cohort study including 39 patients with severe ABP. According to need or no need for surgical necrosectomy, patients were further subdivided into 2 groups. Functional pancreatic evaluation was carried out 12 months after the ABP episode. Endocrine function was evaluated by an oral glucose tolerance test and exocrine function by fecal fat excretion, fecal chymotrypsin (FQ), and secretin-cerulein tests (SCT). RESULTS: Most of the patients with necrosectomy had an abnormal exocrine pancreatic function, with steatorrhea in 25%. In the group without surgery, exocrine function was pathologic in only 13.3% and there were no cases of steatorrhea. Endocrine function was pathologic in 75% of patients undergoing necrosectomy versus 26.7% in the nonoperated group. In this latter group, the patients with abnormal endocrine function did not require insulin therapy, while in 33.3% of patient in the necrosectomy group insulin was necessary. CONCLUSIONS: In our homogeneous series of severe ABP, necrosectomy impaired significantly pancreatic endocrine and exocrine function. On the other hand, most patients with the same origin and severity index, but without surgical debridement, maintained normal pancreatic function.

Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis: therapeutical implications.

Severe acute pancreatitis causes a high incidence of mortality due to the systemic inflammatory response syndrome leading to multiple organ failure. At present, there is no treatment against severe acute pancreatitis, other than supportive critical care. The relationship between pancreatic injury and the uncontrolled systemic response is not completely understood. Nevertheless, experimental and clinical evidences have shown that pro-inflammatory cytokines and oxidative stress are critically involved in the development of local and systemic complications associated with severe acute pancreatitis. Serum levels of pro-inflammatory cytokines, such as TNF-alpha and IL-1beta, increase during the course of acute pancreatitis and they appear to be the driving force for the initiation and propagation of the systemic response. Accordingly, pretreatment with an antibody against TNF-alpha or blockade of TNF-alpha production with pentoxifylline ameliorates experimental acute pancreatitis. In addition, serum IL-6 and IL-8 levels appear to be correlated with severity of pancreatic inflammation. The role of oxidative stress in acute pancreatitis has been evidenced indirectly by beneficial effects of antioxidants as well as directly by pancreatic glutathione depletion and increased lipid peroxidation. Furthermore, circulating xanthine oxidase released by the damaged pancreas acts as a source of systemic oxidative stress contributing to lung inflammation. In conclusion, pancreatic injury seems to trigger at least two different pathways, i.e. pro-inflammatory cytokines and oxidative stress, both involved in the systemic effects of acute pancreatitis. Elucidation of these mechanisms and their interactions is critical to develop a treatment based on the pathophysiology of acute pancreatitis.

Bile duct injury during laparoscopic cholecystectomy: myth or reality of the learning curve?

BACKGROUND: Bile duct injury (BDI) is a severe complication of laparoscopic cholecystectomy (LC) that is probably related to the effects of the learning curve. The aim of this prospective, institutional, and longitudinal study is to compare the incidence of BDI during LC in relation to the progressive experience of surgeons. METHODS: A total of 784 LC were examined during a 6-year period. They were divided into the following three consecutive groups: group A (1993-94), group B (1995-96), and group C (1997-98). Incidence and type of BDI, experience of the surgeon, intra- or postoperative diagnosis, treatment performed to repair the injury, and early and late morbidity and mortality were evaluated. RESULTS: The overall incidence of BDI was 1.4%. There were three cases of transection of the common bile duct, four partial lesions of the bile duct, and four cystic leakages. The number of BDI was maintained over the three different time periods; there were no statistical differences in the proportion of injuries among groups. Most BDI were incurred by experienced surgeons. In all, 36% of BDI were recognized intraoperatively. Hepaticojejunostomy, direct suture over a T-tube, and closure of the cystic stump were done to repair BDI. There was no additional morbidity or mortality in the patients with BDI. CONCLUSIONS: No relation was found between the experience of the surgeon and the number of BDI over the different periods of time. Therefore, BDI during LC cannot be attributed solely to the learning curve.

Pentoxifylline ameliorates cerulein-induced pancreatitis in rats: role of glutathione and nitric oxide.

Reactive oxygen radicals, nitric oxide, and cytokines have been implicated in the initiation of pancreatic tissue damage and impairment of the pancreatic microcirculation in acute pancreatitis. Pentoxifylline is a methylxanthine derivative with rheologic and marked anti-inflammatory properties and inhibits the production of proinflammatory cytokines. We have examined whether pentoxifylline ameliorates interstitial edema, inflammatory infiltrate, and glutathione depletion associated with cerulein-induced pancreatitis. Cotreatment of animals with pentoxifylline significantly reduced cerulein-induced pancreatic inflammation and edema and attenuated the depletion of pancreatic glutathione and the increase in serum lipase activity, nitrate, and tumor necrosis factor-alpha levels. Pentoxifylline also prevented both mitochondrial swelling and damage to mitochondrial cristae caused by cerulein. Our findings provide an experimental basis for using pentoxifylline to attenuate inflammatory responses within the pancreas in acute pancreatitis and as an adjuvant in the treatment of acute pancreatitis.

Sensitivity and maximal response to methacholine in perennial and seasonal allergic rhinitis.

BACKGROUND: Airway hyperresponsiveness to pharmacological agonists is a common feature in subjects with allergic rhinitis. OBJECTIVE: The aim of this study was to investigate differences in threshold value and shape of the concentration-response curves to methacholine between subjects with perennial allergic rhinitis and subjects with seasonal rhinitis. METHODS: We studied a sample of 72 non-asthmatic patients with allergic rhinitis. They were subdivided into two groups: subjects with only seasonal symptoms and skin sensitization to grass and/or Parietaria pollen allergens (seasonal group, n = 38), and subjects with perennial symptoms and skin sensitization to house dust mite, alone or with other allergens (perennial group, n = 34). They were challenged with methacholine (up to 200 mg/mliter), and concentration-response curves were characterized by the threshold value (PC20 = provocative concentration of methacholine required to produce a 20% fall in FEV1) and maximal response plateau, if possible. The measurements in the seasonal group were done within the pollen season. RESULTS: The geometric mean methacholine PC20 for subjects of the perennial group was 6.9 mg/mliter, compared with 23.4 mg/mliter in subjects of the seasonal group (P < 0.01). A plateau response was detected in 16 subjects of the perennial group and in 28 subjects of the seasonal group (P < 0.05). Moreover, the level of plateau was higher in subjects of the perennial group when compared with subjects of the seasonal group (23.8 +/- 2.0% vs 19.2 +/- 1.6%, P < 0.05). CONCLUSION: In subjects with allergic rhinitis, sensitization to perennial allergens is associated not only with lower methacholine threshold values, but also with lower prevalence and higher level of plateau than sensitization to pollen allergens.

Relationship between airway responsiveness and peak expiratory flow variability in subjects with allergic rhinitis.

BACKGROUND: Previous studies have demonstrated an increase in diurnal variation of peak expiratory flow (PEF) in subjects with allergic rhinitis who had decreased methacholine PC20 values. The relationship between PEF variability and some indices of the concentration-response curve to methacholine such as the position and level of the maximal response-plateau has not been studied. OBJECTIVE: The study was carried out to determine differences in PEF variability between subjects with allergic rhinitis who showed plateaus on the concentration-response curves to methacholine at mild degrees of airway narrowing, and patients in whom no plateau was detected. METHODS: Forty-three nonasthmatic patients with allergic rhinitis were included in the study. Subjects underwent methacholine challenge tests with doubling concentrations from 0.39 to 200 mg/mL and measured their PEF three times daily for the next seven days, using mini-Wright peak flow meters. The concentration-response curves to methacholine were characterized by the threshold value (PC20 = provocative concentration required to produce a 20% fall in FEV1) and, if possible, by the position (EC50 = concentration of methacholine that produced 50% of the maximal response) and maximal response-plateau (FEV1 falls < or = 5% after at least three of the highest concentrations). The variability of PEF was expressed as the amplitude percent mean. RESULTS: No correlations were observed between amplitude percent mean and PC20 (r = -.23, NS), EC50 (r = -.07, NS), or level of plateau (r = .02, NS). The amplitude percent mean was higher in subjects who had decreased methacholine threshold values without plateau (geometric mean = 8.3%; range = 3.8% to 14.2%) than in subjects who had decreased threshold values and plateaus (geometric mean = 4.5%; range = 2.4% to 9.9%; P < .01), or subjects who had normal threshold values and plateaus (geometric mean = 4.4%; range = 1.6% to 10.8%; P < .01). Although subjects who had decreased threshold values and plateaus showed higher methacholine responsiveness than subjects with normal threshold values and plateaus (geometric mean PC20 = 6.2 mg/mL versus 107.1 mg/mL, P < .01; geometric mean EC50 = 3.1 mg/mL versus 9.1 mg/mL, P < .01; mean +/- SEM level of plateau = 17.2 +/- 1.8% versus 28.8 +/- 1.1%, P < .001), the difference in amplitude percent mean was not significant. CONCLUSIONS: The loss of plateau on the concentration-response curves to inhaled methacholine at mild degrees of airway narrowing identifies those subjects with allergic rhinitis who show a greater PEF variability. The PEF variability and airway responsiveness are not interchangeable terms.

[Relations between nonspecific bronchial hyperreactivity, diurnal variation of peak expiratory flow and medication requirements in patients with mild asthma]. / Relación entre hiperrespuesta bronquial inespecífica, variación diaria del flujo espiratorio máximo y necesidades de medicación en pacientes con asma leve.

To assess the relation between non-specific bronchial hyperreactivity, we recorded diurnal peak expiratory flow variation (PFV) and asthma symptoms in 36 individuals with mild allergic asthma. The patients were challenged with methacholine to induce decreases greater than 40% in FEV1, or until a maximum of 200 mg/ml had been administered. Over the next 14 days, PFV was measured three times per day and symptoms and inhaled salbutamol requirements were recorded. In the 11 patients with complete dose-response curves, the geometric mean of diurnal PFV variation (% mean range) was 5.0%; this parameter was 8.3% (p < 0.01) in the 25 subjects whose curves did not reach a plateau. A correlation (r = -0.56, p < 0.001) was found between PC20 and % mean range. PFV for the sample as a whole. In the 11 patients with complete curves, however, no correlation (r = -0.31, p = NS) between % mean range of PFV and PC20 was found. Nor could the plateau (r = 0.19, p = NS) or EC50 (r = -0.26, p = NS) be found for these patients. The geometric mean for PC20 in the 12 subjects who needed salbutamol throughout the 14-day study period after methacholine challenge was 1.06 mg/ml; this parameter was 1.32 mg/ml (p = NS) for those with no symptoms. A plateau was reached by 2 of the 12 patients who experienced asthma symptoms and in 9 of the 24 who were asymptomatic (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

[Whole gut irrigation in pediatric patients: a comparative study]. / Irrigacion digestiva en el paciente pediatrico: estudio comparativo.

The observation of hydroelectric and pH changes, as well as the diminishing incidence of postoperative infections in pediatric patients, subjected to digestive irrigation (D.I.) before surgery, was the reason for carrying out this paper, fundamentally directed at two objectives: Firstly, to determine the hydro-ionic and clinical repercussions by means of a comparative study of the two most used irrigations solutions and secondly, to analyze the modifications that the D.I., itself and with the addition of antibiotics, is capable of producing on the fecal flora and the intestinal mucous membrane. To realize our aim, a prospective and double blinded study was designed on 124 patients irrigated with a saline solution (S-I), or with the Golytely solution (S-II). The analysis of the results showed that exist a marked predisposition to metabolic acidosis and dehydration after irrigation with S-II, compared with a tendency towards hyperhydration and alkalosis after irrigation with S-I. The effect of flushing with D.I. is capable of producing a significant lowering in the number of germs/ml found in the contents of the colon; a reduction which increases for the anaerobic group (p less than 0.001), when the antibiotics are added to the irrigation solution. Neither of the studied cases gave evidence of histomorphologic alterations in the colonic mucosa after irrigation with erythromycin and neomycin base.