Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for persistent and recurrent advanced ovarian carcinoma: a multicenter, prospective study of 246 patients.

BACKGROUND: Epithelial ovarian carcinoma is the main cause of death from gynaecological cancers in the western world. The initial response rate to the frontline therapy is high. However, the prognosis of persistent and recurrent disease remains poor. During the two past decades, a new therapeutic approach to peritoneal carcinomatosis has been developed, combining maximal cytoreductive effort with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A retrospective, multicentric study of 246 patients with recurrent or persistent ovarian cancer, treated by cytoreductive surgery and HIPEC in two French centers between 1991 and 2008, was performed. RESULTS: An optimal cytoreductive surgery was possible in 92.2 % of patients. Mortality and morbidity rates were 0.37 % and 11.6 %, respectively. The overall median survival was 48.9 months. There was no significant difference in overall survival in patients with persistent or recurrent disease. In multivariate analysis, performance status was a significant prognostic factor in patients with extensive peritoneal carcinomatosis (peritoneal cancer index >10). CONCLUSIONS: Salvage therapy combining optimal cytoreductive surgery and HIPEC is feasible and may achieve long-term survival in highly selected patients with recurrent ovarian carcinoma, including those with platinum resistant disease, with acceptable morbidity.

Capecitabine, irinotecan, oxaliplatin (CAPIRINOX) and concomitant irradiation in advanced rectal cancer: the Lyon R-02-01 phase I trial.

AIMS: To determine the feasibility of radiotherapy-associated capecitabine, irinotecan and oxaliplatin administration at five dose levels for the treatment of locally advanced rectal cancer, with or without metastasis. PATIENTS AND METHODS: This was a bicentric phase I trial, including patients with locally advanced rectal cancer, with or without metastasis. Chemotherapy comprised capecitabine (1100, 1300 or 1500 mg/m2/day, every day), irinotecan (30, 40 or 50mg/m2, once per week for 6 weeks) with the addition of oxaliplatin (40 mg/m2 at level 4 or 50 mg/m2 at level 5, once per week for 6 weeks). Radiotherapy at 46 Gy plus a boost of 4 Gy was administered concomitantly. RESULTS: Twelve patients received four levels of dose. As a supplement to radiotherapy, the combination of capecitabine and irinotecan at the respective doses of 1500 mg/m2/day and 50 mg/m2/week was feasible and well tolerated. The addition of oxaliplatin to this combination provoked toxicity (grade 3/4 vomiting, diarrhoea) for two-thirds of the patients. CONCLUSION: A treatment associating radiotherapy (46 Gy+4 Gy) with concomitant chemotherapy comprising capecitabine (1500 mg/m2/day, every day) and irinotecan (50 mg/m2/week, for 5 weeks) was feasible and well tolerated. The addition of oxaliplatin to these doses was prohibitory to the continuation of treatment due to unacceptable toxicity.

Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer.

HYPOTHESIS: The most common cause of palliative resection and recurrence in gastric cancer is peritoneal seeding. This study evaluates the efficacy of intraperitoneal chemohyperthermia after cytoreductive surgery in patients with peritoneal carcinomatosis arising from gastric cancer. DESIGN: Prospective clinical trial. SETTING: Surgical department at a university academic hospital. PATIENTS: Forty-nine consecutive patients with peritoneal carcinomatosis treated between January 1, 1989, and February 29, 2000. INTERVENTIONS: All patients underwent intraperitoneal chemohyperthermia with mitomycin C (40-60 mg); 21 patients had previously undergone extensive cytoreductive surgery. MAIN OUTCOME MEASURES: Clinicopathologic factors that affect overall survival rates. RESULTS: With median follow-up of 99 months, overall median survival was 10.3 months. Two factors were significant independent predictors of survival by multivariate analysis: preoperative ascites (P =.04) and completeness of cancer resection (CCR) by cytoreductive surgery (P<.001). Median survival was 21.3 months for patients with CCR-0 (macroscopic complete resection) or CCR-1 (diameter of residual nodules <5 mm) and 6.1 months for patients with CCR-2 (diameter of residual nodules >5 mm) (P<.001). Four patients survived longer than 5 years. CONCLUSIONS: An aggressive management strategy combining intraperitoneal chemohyperthermia with cytoreductive surgery is effective for patients with peritoneal carcinomatosis arising from gastric cancer. In highly selected patients (good general status, resectable primary tumor, resectable peritoneal carcinomatosis), this therapy may result in long-term survival.

Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures.

BACKGROUND: Peritoneal carcinomatosis has been regarded as a lethal clinical entity. Recently, aggressive treatments combining intraperitoneal chemohyperthermia (IPCH) with cytoreductive surgery have resulted in long-term survival in selected patients. The aim of this trial was to analyze the mortality and morbidity of 216 consecutive treatments of peritoneal carcinomatosis by IPCH by using a closed abdominal procedure combined with cytoreductive surgery. METHODS: Between February 1989 and August 2001, 207 patients who underwent 216 IPCH procedures using a closed abdominal procedure with mitomycin C, cisplatin, or both were prospectively studied. RESULTS: The postoperative mortality and morbidity rates were 3.2% and 24.5%, respectively. The most frequent complications were digestive fistula (6.5%) and hematological toxicity (4.6%). Morbidity was statistically linked with the carcinomatosis stage (P =.016), the duration of surgery (P =.005), and the number of resections and peritonectomy procedures (P =.042). Duration of surgery and carcinomatosis stage were the most common predictors of morbidity. CONCLUSIONS: The frequency of complications after IPCH and cytoreductive surgery was mainly associated with the carcinomatosis stage and the extent of the surgical procedure. The IPCH closed abdominal procedure has shown an acceptable frequency of adverse events.

Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II study.

PURPOSE: To evaluate the tolerance of peritonectomy procedures (PP) combined with intraperitoneal chemohyperthermia (IPCH) in patients with peritoneal carcinomatosis (PC), a phase II study was carried out from January 1998 to September 2001. PATIENTS AND METHODS: Fifty-six patients (35 females, mean age 49.3) were included for PC from colorectal cancer (26 patients), ovarian cancer (seven patients), gastric cancer (six patients), peritoneal mesothelioma (five patients), pseudomyxoma peritonei (seven patients), and miscellaneous reasons (five patients). Surgeries were performed mainly on advanced patients (40 patients stages 3 and 4 and 16 patients stages 2 and 1) and were synchronous in 36 patients. All patients underwent surgical resection of their primary tumor with PP and IPCH (with mitomycin C, cisplatinum, or both) with a closed sterile circuit and inflow temperatures ranging from 46 degrees to 48 degrees C. Three patients were included twice. RESULTS: A macroscopic complete resection was performed in 27 cases. The mortality and morbidity rates were one of 56 and 16 of 56, respectively. The 2-year survival rate was 79.0% for patients with macroscopic complete resection and 44.7% for patients without macroscopic complete resection (P =.001). For the patients included twice, two are alive without evidence of disease, 54 and 47 months after the first procedure. CONCLUSION: IPCH and PP are able to achieve unexpected long-term survival in patients with bulky PC. However, one must be careful when selecting the patients for such an aggressive treatment, as morbidity rate remains high even for an experienced team.

Regulation of the 75-kDa subunit of mitochondrial complex I by iron.

Iron homeostasis is tightly regulated, as cells work to conserve this essential but potentially toxic metal. The translation of many iron proteins is controlled by the binding of two cytoplasmic proteins, iron regulatory protein 1 and 2 (IRP1 and IRP2) to stem loop structures, known as iron-responsive elements (IREs), found in the untranslated regions of their mRNAs. In short, when iron is depleted, IRP1 or IRP2 bind IREs; this decreases the synthesis of proteins involved in iron storage and mitochondrial metabolism (e.g. ferritin and mitochondrial aconitase) and increases the synthesis of those involved in iron uptake (e.g. transferrin receptor). It is likely that more iron-containing proteins have IREs and that other IRPs may exist. One obvious place to search is in Complex I of the mitochondrial respiratory chain, which contains at least 6 iron-sulfur (Fe-S) subunits. Interestingly, in idiopathic Parkinson's disease, iron homeostasis is altered, and Complex I activity is diminished. These findings led us to investigate whether iron status affects the Fe-S subunits of Complex I. We found that the protein levels of the 75-kDa subunit of Complex I were modulated by levels of iron in the cell, whereas mRNA levels were minimally changed. Isolation of a clone of the 75-kDa Fe-S subunit with a more complete 5'-untranslated region sequence revealed a novel IRE-like stem loop sequence. RNA-protein gel shift assays demonstrated that a specific cytoplasmic protein bound the novel IRE and that the binding of the protein was affected by iron status. Western blot analysis and supershift assays showed that this cytosolic protein is neither IRP1 nor IRP2. In addition, ferritin IRE was able to compete for binding with this putative IRP. These results suggest that the 75-kDa Fe-S subunit of mitochondrial Complex I may be regulated by a novel IRE-IRP system.

Dietary iron, animal fats, and risk of Parkinson's disease.

BACKGROUND: Recent studies have proposed a role for diet in Parkinson's disease (PD). PD is characterized by a high deposition of iron and a low concentration of ferritin in the substantia nigra. Few data in the literature are available on the possible role of dietary iron in the development of PD. METHODS: In a population-based, case-control study, we addressed the hypothesis that high dietary iron intake was associated with PD. We assessed dietary iron intake with a semiquantitative food-frequency questionnaire in 104 PD patients and 352 control subjects, frequency matched for age and gender. We also studied the association of PD and dietary iron and animal fat intake in the presence of different iron stores measured by transferrin saturation. RESULTS: No significant differences were observed between patients' and control subjects' dietary intake of iron from food or supplements (odds ratio [OR] for the highest quartile of intake, 0.9; 95% confidence interval [95% CI], 0.6, 1.3; p for trend = 0.60). Among those with low transferrin saturation levels (lower 50%), the odds ratio for PD associated with animal fat intake was ninefold higher than the risk of those with low intake (OR, 9.0; 95% CI, 2.7-29.9). Among those with high transferrin saturation, risk of PD was two times higher (relative risk, 1.9; 95% CI, 0.5-7.2) for those who reported high intake of animal fat compared with those who reported low intake. CONCLUSION: Dietary iron intake after caloric adjustment was not associated with an increased risk of PD. However, the previously described association between animal fat intake and PD was modified by iron level stores as measured by transferrin saturation. These observations suggest that dietary fat and a systemic defect in iron metabolism may act synergistically in the process of lipid peroxidation in PD.

Characterization of the human mitochondrial aconitase gene (ACO2).

We have cloned and characterized the ACO2 gene on human chromosome 22q13, which encodes the essential iron-dependent metabolic enzyme mitochondrial aconitase. We determined that the ACO2 gene comprises 18 translated exons distributed over approximately 35 kilobasepairs (kbp) of DNA. We have shown that the ACO2 mRNA is 2.7kb in length and is expressed ubiquitously, and we can detect multiple isoforms of the ACO2 protein. As others had reported the existence of biochemically active electrophoretic variants of mitochondrial aconitase, we wished to find common ACO2 gene allozymes, functional polymorphisms that might be associated with susceptibility to human genetic diseases. We looked for ACO2 allozymes by DNA sequencing and genotyping in a population of 217 subjects, many of which had idiopathic Parkinson's disease (IPD). We studied patients with IPD because this movement disorder is thought to arise from defects in neuronal iron and energy metabolism, two properties with which aconitase is involved. Furthermore, reports of associations between alleles of the CYP2D6 locus (nearby on 22q13) and IPD, although inconsistent, indicated that an IPD susceptibility locus might be in strong linkage disequilibrium with CYP2D6. We found three functionally silent single nucleotide polymorphisms (SNPs) present in transcribed sequences that exist in similar frequencies in IPD patients and healthy controls. These ACO2 SNPs are in linkage disequilibrium with each other, providing evidence for distinct ACO2 haplotypes. We have, as yet, not detected polymorphisms that would lead to ACO2 allozymes, nor have we observed differences in ACO2 isoform prevalence or distribution in our population of IPD patients and controls. We conclude it is unlikely that polymorphism in the ACO2 gene or post-translational modification of the enzyme predispose to IPD.

Quality of final care for terminal cancer patients in a comprehensive cancer centre from the point of view of patients' families.

The aim of this study was to evaluate the quality of care for terminal cancer patients at our institution, as assessed by families in a questionnaire sent 6 months after the death of the patient. We evaluated the quality of information given to the patients and to their families, the patients' "comfort" at the end of their lives (nursing, pain, psychological support) and the families' opinions about the practical conditions at the time of death (in our institution or at home). A total of 105 consecutive patients who died in our institution between January and June 1989 were included in the study; the vast majority had breast or head and neck cancers. We obtained a total of 48 answers from the 105 families that received the questionnaire. Of these, 87.5% were satisfied with the terminal nursing care, 77% were satisfied with the information given to patients and 60% with the information given to families. The treatment for pain was considered to be inefficient or incomplete by 21% of the families; 32 families (67%) considered that the death of terminal cancer patients should occur in the hospital where the patient had been treated and 12% felt that it should occur at home. This study led us to examine various means for improving the quality of care for our terminal cancer patients.