Pharmacological principles of intraperitoneal and bidirectional chemotherapy.

Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.

Quality of life before and after laparoscopic sleeve gastrectomy. A prospective cohort study.

BACKGROUND: There is a lack of adequate prospective data on quality-of-life (QOL) and its predictors in patients undergoing laparoscopic sleeve gastrectomy (LSG). The aim of this study was to assess longitudinal changes in QOL after LSG with the use of the obesity-specific Moorehead-Ardelt II questionnaire (MAII) and to identify clinical parameters associated with QOL outcome. METHODS: Morbidly obese patients consecutively admitted for LSG, over a 30-month period, were prospectively studied. QOL was assessed using the validated Greek version of the MAII questionnaire and a visual analogueue scale (VAS), preoperatively and at 6, 12, and 24 months postoperatively. Anthropometric data and obesity-related co-morbidities were recorded. RESULTS: A total of 111 patients with a mean age 36.8±9.2 years were included. Mean preoperative body mass index (BMI) was 49.1±7.5 kg/m2. Percentage excess BMI loss (%EBL) was 51.1±14.9, 64.2±17.9 and 66.4±18.0 at 6, 12, and 24 months, respectively. Postoperatively, all obesity-related co-morbidities were significantly improved. MAII score increased from -.40±1.30 preoperatively to 1.75±.83, 2.18±.80, and 1.95±.71 at 6, 12, and 24 months postoperatively (trend P<.001). Preoperative median (interquartile range) VAS was 3 (1) increasing to 9 (2), 10 (1), and 9 (1) at 6, 12, and 24 months postoperatively (P<.001). %EBL and reduction in obesity-related co-morbidities, especially resolution of diabetes and sleep apnea, correlated significantly with higher QOL during the course of the study. CONCLUSION: LSG, a safe and effective bariatric operation, results in sustained weight loss and significant improvements in QOL. Both weight loss and amelioration of co-morbidities contribute to higher level of postsurgical QOL.

Complications and toxicity after abdominal and pelvic hypoxic stop-flow perfusion chemotherapy: incidence and assessment of risk factors.

BACKGROUND: Controversial results regarding the efficacy and toxicity of hypoxic abdominal and pelvic stop-flow perfusion chemotherapy (SFP) have been reported in relatively small series. Hence, because adequate assessment of its benefit in large homogenous cohorts is missing, acceptable morbidity should initially be assured in a series of adequate size. Additionally, risk factors should be assessed for eventual patient selection. METHODS: The morbidity of abdominal and pelvic SFP performed on a miscellaneous group of patients in our institute was analyzed and potential risk factors for adverse events were evaluated. RESULTS: Seventy abdominal (n = 42) and pelvic (n = 28) SFP were performed on 55 patients. In total, 28 adverse effects were observed after 30% of the procedures. Severe (grade 3) adverse events were recorded only after 4% of the procedures, while treatment-related life-threatening events and deaths were not present. Abdominal procedures when compared with pelvic ones were associated with increased systemic toxicity (36 vs. 7%, p = 0.005). Advanced age, gender, prior chemotherapy and/or radiotherapy, limited experience, repeated procedure, drug choice and omission of hemofiltration after SFP completion were not associated with statistically significant increase of procedures with overall or systemic adverse events. CONCLUSIONS: In the present series, abdominal and pelvic SFP was associated with an acceptable morbidity, which was mostly mild or moderate. Abdominal procedures were associated with increased toxicity. This procedure seems to be repeatable and also well tolerated both by elderly patients and by patients who had undergone prior chemotherapy and/or radiotherapy, while hemofiltration does not appear to decrease the incidence of systemic toxicity.

Cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy with paclitaxel: a clinical and pharmacokinetic study.

BACKGROUND: Intraperitoneal chemotherapy has been recommended as a treatment option for ovarian cancer with peritoneal dissemination. Although its treatment duration is significantly shorter, intraoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) has several advantages over simple intraperitoneal instillation chemotherapy. While platinum compounds have usually been used, only a few have administered paclitaxel during HIPEC. Its large molecular weight suggests a much more favorable pharmacokinetic profile than that of platinum compounds. The pharmacokinetics of paclitaxel during and after HIPEC have not been studied before. METHODS: Thirteen women, mainly with ovarian cancer, underwent cytoreductive surgery and HIPEC with 175 mg/m(2) paclitaxel for 2 h. Morbidity was noted. Peritoneal fluid samples and blood samples were harvested during and until 5 days after HIPEC for pharmacokinetic study in ten patients. RESULTS: No treatment-related mortality was noted. Overall morbidity was 38% (two wound infections, one deep venous thrombosis, two grade 1 thrombopenia, one grade 2 neutropenia, and one grade 3 pancytopenia). Mean maximal intraperitoneal paclitaxel concentration was 101 mg/L, which was an average of 1178 times higher than the peak plasma levels. The peritoneal fluid versus plasma AUC ratio was 1462 for the 2-h HIPEC duration and 366 for the total 5-day study period. Cytotoxic drug concentrations were detected in peritoneal fluid for a mean period of 2.7 days, despite drainage of the drug solution after 2 h of treatment. CONCLUSIONS: HIPEC with paclitaxel following cytoreductive surgery is feasible, relatively safe, and associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Larger studies with a more homogenous patient cohort and adequate follow-up should be performed to demonstrate its efficacy.

Ileal malignant melanoma causing intussusception: report of a case.

Cutaneous malignant melanoma (MM) often metastasizes to the gastrointestinal (GI) tract; however, primary MM of the small intestine is a controversial diagnosis. We report the case of a 76-year-old woman found to have a primary MM in the ileum. After clinical evaluation, the radiological workup, which included magnetic resonance enteroclysis (MRE), revealed a large polypoid intraluminal tumor. She underwent laparotomy and the lesion was excised. Histological examination of the resected specimen revealed morphological and immunohistochemical characteristics of MM and a detailed postoperative examination failed to identify a primary lesion on the skin, anus, oculus, or any other site. The patient died of brain metastasis 6 months after surgery. According to our review of the literature, this is the first case of primary MM of the small intestine diagnosed with the help of MRE.

Short-term exposure of cancer cells to micromolar doses of paclitaxel, with or without hyperthermia, induces long-term inhibition of cell proliferation and cell death in vitro.

BACKGROUND: During intraoperative hyperthermic intraperitoneal chemotherapy for primary or secondary peritoneal malignancies, tumor cells are exposed to high drug concentrations for a relatively short period of time. We investigated in vitro the effect of paclitaxel and hyperthermia on cell proliferation, cell cycle kinetics and cell death under conditions resembling those during intraoperative hyperthermic intraperitoneal chemotherapy. METHODS: Human breast MCF-7, ovarian SKOV-3 and hepatocarcinoma HEpG2 cells were exposed to 10 and 20 microM paclitaxel at 37, 41.5 or 43 degrees C for 2 h. Cell proliferation, cell cycle kinetics, necrosis and apoptosis were evaluated. RESULTS: Hyperthermia exerted a cytostatic effect to all cell lines and at 43 degrees C a cytotoxic effect on MCF-7 cells. MCF-7 and SKOV-3 cells treated under normothermic conditions with paclitaxel were arrested at G2/M or M phase for at least 3 days. Most of MCF-7 cells and approximately half of SKOV-3 cells were in interphase and became multinucleated without properly completing cytokinesis. Hyperthermia at 41.5 degrees C altered cell cycle distribution and affected the paclitaxel-related effect on cell cycle kinetics of MCF-7 and SKOV-3 cells. Analysis of the mode of cell death showed that cell necrosis prevailed over apoptosis. Hyperthermia at 43 degrees C increased paclitaxel-mediated cytotoxicity in MCF-7 cells and to a lesser extent in SKOV-3 and HEpG2 cells. CONCLUSIONS: Short-time treatment of carcinoma cells with high (micromolar) concentrations of paclitaxel in normothermic and hyperthermic conditions is highly efficient for cell growth arrest and could be of clinical relevance in locoregional chemotherapy.

Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: from laboratory bench to bedside.

The combination of a taxane, paclitaxel or docetaxel, and a platinum compound has become the systemic chemotherapy of choice for primary ovarian cancer and has demonstrated high efficacy. However, ultimately most patients will die from this disease. Hence, there is a need for even more effective systemic chemotherapy or different treatment strategies. Intraperitoneal chemotherapy with taxanes is such an alternative treatment option. Ovarian cancer is theoretically an attractive malignancy for this regional treatment, because the disease remains largely confined to the peritoneal cavity. The choice of taxanes for this kind of chemotherapy is rational, because of its high activity against ovarian cancer cells and expected favourable pharmacokinetics because of limited absorption from the peritoneal cavity due to their large molecular weight and first-pass effect in the liver. In animal model and human pharmacokinetic studies, very high intraperitoneal drug concentrations and exposure and high peritoneal tumour concentrations were achieved, while systemic drug levels were low. The combination of intraperitoneal chemotherapy with hyperthermia enhances the penetration and cytotoxic activity of many drugs. Although data concerning thermal enhancement of taxane cytotoxicity are inconsistent, experimental studies show that at high locoregional concentrations there seems to be such an effect. Recently, feasibility and efficacy of this treatment have evidently been demonstrated in various clinical studies. A large randomized trial revealed improvement of outcome by intraperitoneal instillation chemotherapy with paclitaxel and cisplatin as first-line treatment. Moreover, promising results have been observed after intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel for recurrent disease.

Factors associated with disease evolution in Greek patients with inflammatory bowel disease.

BACKGROUND: The majority of Crohn's disease patients with B1 phenotype at diagnosis (i.e. non-stricturing non-penetrating disease) will develop over time a stricturing or a penetrating pattern. Conflicting data exist on the rate of proximal disease extension in ulcerative colitis patients with proctitis or left-sided colitis at diagnosis. We aimed to study disease evolution in Crohn's disease B1 patients and ulcerative colitis patients with proctitis and left-sided colitis at diagnosis. METHODS: 116 Crohn's disease and 256 ulcerative colitis patients were followed-up for at least 5 years after diagnosis. Crohn's disease patients were classified according to the Vienna criteria. Data were analysed actuarially. RESULTS: B1 phenotype accounted for 68.9% of Crohn's disease patients at diagnosis. The cumulative probability of change in disease behaviour in B1 patients was 43.6% at 10 years after diagnosis. Active smoking (Hazard Ratio: 3.01) and non-colonic disease (non-L2) (Hazard Ratio: 3.01) were associated with behavioural change in B1 patients. Proctitis and left-sided colitis accounted for 24.2%, and 48.4% of ulcerative colitis patients at diagnosis. The 10 year cumulative probability of proximal disease extension in patients with proctitis and left-sided colitis was 36.8%, and 17.1%, respectively (p: 0.003). Among proctitis patients, proximal extension was more common in non-smokers (Hazard Ratio: 4.39). CONCLUSION: Classification of Crohn's disease patients in B1 phenotype should be considered as temporary. Smoking and non-colonic disease are risk factors for behavioural change in B1 Crohn's disease patients. Proximal extension is more common in ulcerative colitis patients with proctitis than in those with left-sided colitis. Among proctitis patients, proximal extension is more common in non-smokers.

Micromolar taxol, with or without hyperthermia, induces mitotic catastrophe and cell necrosis in HeLa cells.

PURPOSE: Although the mode of action of taxol, when used in nanomolar or micromolar concentrations during long periods, is extensively studied, there are few data available on taxol-mediated cytotoxicity when the drug is applied for a short time alone or in combination with hyperthermia. We studied the effect of taxol and hyperthermia on cell cycle kinetics, proliferation, and mode of cell death in human cervical carcinoma HeLa cells, following a scheme which resembles the one currently used in regional chemotherapy. METHODS: Cells were incubated with micromolar doses of taxol for two h under normothermic or hyperthermic conditions and then cultured in drug-free medium for several days. Cell viability was assessed via an MTT assay. Necrotic and apoptotic cell death was determined using Trypan blue staining and TUNNEL assay, respectively. Flow cytometry was used for the analysis of cell cycle kinetics and the counting of apoptotic cells. Mitotic index, nuclear morphology and nuclear envelope organization were analyzed by fluorescence microscopy. RESULTS: Cells exposed to micromolar doses of taxol for 2 h and then transferred to a drug-free medium for 24 h were arrested at G2/M or M phase. When treated cells were cultured in normal media for longer periods, most of them remained in a tetraploid state, became multinucleated without properly completing cytokinesis and died mostly by necrosis. Hyperthermia alone exerted a cytotoxic effect, inhibited proliferation and caused minor changes in cell cycle kinetics. When combined with taxol treatment, hyperthermia modified the cell cycle-arresting effects of the drug, but did not alter significantly taxol-mediated cytotoxicity. CONCLUSIONS: From these data we conclude that short time incubation of HeLa cells under normothermic or hyperthermic conditions with micromolar concentrations of taxol is sufficient enough to induce extended cell growth arrest and cell death by necrosis.

Hypercoagulable states in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) patients have an increased risk for venous thromboembolism, mainly portal venous thrombosis (PVT). The aim of this study was to assess the role of acquired and hereditary thrombotic risk factors in HCC patients. Thirty-one patients with HCC, 30 patients with cirrhosis but without HCC or PVT, and 48 matched healthy controls were studied. Mean levels of plasma protein C, protein S, antithrombin, and serum lipoprotein (a) were significantly lower in patients with HCC and in the cirrhotic group compared to the healthy controls. Mean serum homocysteine levels were significantly higher in patients with HCC compared to cirrhotics and healthy controls. The prevalence of activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation G20210GA, and C677T methylenetetrahydrofolate reductase polymorphism was not significantly different among the three groups. In conclusion, thrombophilic defects are common in HCC patients and they might contribute to the observed thrombotic complications in this malignancy.

Hidradenitis suppurativa associated with Crohn's disease and spondyloarthropathy: response to anti-TNF therapy.

An association of hidradenitis suppurativa with Crohn's disease is supported by previous repent. We here report a patient with hidradenitis suppurativa who subsequently developed peripheral arthritis, sacroiliitis, and Crohn's disease. A significant attenuation of bowel, cutaneous, and joint symptoms was achieved after treatment with monoclonal antibody against tumor necrosis factor (TNF). The pathogenetic aspects according to the literature and response to the various therapeutic measures applied are also presented.

Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel as second-line treatment for peritoneal carcinomatosis of gynaecological origin.

BACKGROUND: Cytoreductive surgery with continuous hyperthermic perfusion peritoneal chemotherapy (CHPPC) is a relatively new multimodality treatment for peritoneal malignancies. We studied the feasibility and outcome of CHPPC with docetaxel as second-line treatment for gynaecological peritoneal carcinomatosis. PATIENTS AND METHODS: Twenty times CHPPC with docetaxel was performed in 19 patients, mean age of 65 years (47-80), who demonstrated early recurrent or persistent peritoneal carcinomatosis mainly of ovarian origin. RESULTS: Treatment-related death was noted in 2 elderly patients with a high tumour load. Two other major complications, requiring re-operation, were recorded. Haematological docetaxel-induced toxicity was highly limited, while the wound complication rate was relatively high. Ascites disappeared in all patients. After a mean follow-up of 30 months, the actuarial overall 1- and 3-year survival rates after CHPPC were 79% and 63%. CONCLUSION: CHPPC with docetaxel following cytoreductive surgery for early recurrent or persistent peritoneal carcinomatosis from gynaecological malignancies seems feasible and might have a positive impact on survival. The outcome seems to be superior to that of CHPPC with other drugs.

A comparison of Child-Pugh, APACHE II and APACHE III scoring systems in predicting hospital mortality of patients with liver cirrhosis.

BACKGROUND: The aim of this study was to assess the prognostic accuracy of Child-Pugh and APACHE II and III scoring systems in predicting short-term, hospital mortality of patients with liver cirrhosis. METHODS: 200 admissions of 147 cirrhotic patients (44% viral-associated liver cirrhosis, 33% alcoholic, 18.5% cryptogenic, 4.5% both viral and alcoholic) were studied prospectively. Clinical and laboratory data conforming to the Child-Pugh, APACHE II and III scores were recorded on day 1 for all patients. Discrimination was evaluated using receiver operating characteristic (ROC) curves and area under a ROC curve (AUC). Calibration was estimated using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Overall mortality was 11.5%. The mean Child-Pugh, APACHE II and III scores for survivors were found to be significantly lower than those of nonsurvivors. Discrimination was excellent for Child-Pugh (ROC AUC: 0.859) and APACHE III (ROC AUC: 0.816) scores, and acceptable for APACHE II score (ROC AUC: 0.759). Although the Hosmer-Lemeshow statistic revealed adequate goodness-of-fit for Child-Pugh score (P = 0.192), this was not the case for APACHE II and III scores (P = 0.004 and 0.003 respectively) CONCLUSION: Our results indicate that, of the three models, Child-Pugh score had the least statistically significant discrepancy between predicted and observed mortality across the strata of increasing predicting mortality. This supports the hypothesis that APACHE scores do not work accurately outside ICU settings.

Balthazar computed tomography severity index is superior to Ranson criteria and APACHE II and III scoring systems in predicting acute pancreatitis outcome.

BACKGROUND AND GOALS: Acute pancreatitis runs an unpredictable course. We prospectively analyzed the prognostic usefulness of four different scoring systems in separately assessing three variables; acute pancreatitis severity, development of organ failure and pancreatic necrosis. STUDY: 78 patients with acute pancreatitis were studied prospectively. Data pertinent to scoring systems were recorded 24 hours (APACHE II and III scores), 48 hours (Ranson score) and 72 hours (Balthazar computed tomography severity index) after admission. Statistical analysis was performed by using receiver operating characteristic curves and by comparing likelihood ratios of positive test (LRPT) for all three outcome variables. RESULTS: 44 patients were classified as mild and 34 as severe pancreatitis. When we compared LRPT, only that for the Balthazar score (11.2157) was able to generate large and conclusive changes from pretest to post-test probability in acute pancreatitis severity prediction. LRPT were 2.4157 for Ranson, 4.0980 for APACHE II and 3.6670 for APACHE III score. The APACHE II and III scores and Ranson criteria performed slightly better than the Balthazar score in predicting organ failure (LRPT: 4.0667, 3.2892, 3.0362 and 1.7941 respectively), while when predicting pancreatic necrosis the APACHE II and III performed slightly better than the Ranson score (LRPT: 2.0769, 2.7500 and 1.7813 respectively). CONCLUSIONS: In all outcome measures the APACHE scores generate small and of similar extent changes in probability. The Balthazar score is superior to other scoring systems in predicting acute pancreatitis severity and pancreatic necrosis. However the Ranson and APACHE scores perform slightly better with respect to organ failure prediction.

Pharmacokinetic study of docetaxel in intraoperative hyperthermic i.p. chemotherapy for ovarian cancer.

The purpose of this study was to evaluate the pharmacokinetics and toxicity of docetaxel in continuous hyperthermic perfusion peritoneal chemotherapy (CHPPC) after cytoreductive surgery for peritoneal involvement of gynecological malignancies, mainly ovarian cancer. Eighteen patients, with a mean age of 64 years (range 51-80), underwent cytoreductive surgery and subsequent CHPPC with 75 mg/m2 docetaxel at 41-43 degrees C. One patient was treated twice. In eight cases, peritoneal fluid and blood samples were obtained for pharmacokinetic analysis. Death occurred in two heavily pretreated elderly patients with a high volume i.p. tumor recurrence, probably reflecting poor patient selection (mortality rate 10.5%). Other complications, mainly minor, were recorded after 63% of the procedures. Hematological docetaxel-induced toxicity was limited, while the incidence of wound complications was relatively high and probably caused by the direct exposure of the wound to docetaxel during CHPPC. The maximal i.p. versus plasma concentration ratio ranged from 17 to 95 (average 45), while the i.p. versus systemic exposure ratio varied between 105 and 555 (average 207). We conclude that the use of docetaxel in CHPPC following cytoreductive surgery seems feasible and results in a high i.p. versus systemic exposure ratio. The AUC for the peritoneal cavity is on average 13-27 times higher after i.p. administration of 75 mg/m2 during CHPPC than the AUC achieved in the systemic compartment after i.v. administration of the recommended dose of 100 mg/m2, while docetaxel-induced systemic toxicity is highly limited.