Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. Methods Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). Results The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. Conclusion For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients

Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis

Purpose: Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. Methods: Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. Results: A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). Conclusions: In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset

Commment on the review entitled “A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer” by Chiva LM and Gonzalez-Martin A.

• We raised some methodological concerns and made some comments on the systematic review by Chiva and colleague. • To state that Cytoreduction & HIPEC is not beneficial in front line and platinum sensitive recurrence is highly disputable. • Anyway, the combined treatment should be offered in the context of clinical trial; randomized data are urgently needed

Early and long-term postoperative management following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Peritoneal surface malignancies have been traditionally regarded as end-stage conditions amenable to merely palliative options. The combination of aggressive cytoreductive surgery (CRS), involving peritonectomy procedures and multivisceral resections, with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC) and/or early postoperative intra-peritoneal chemotherapy (EPIC) to treat the microscopic residual tumor is a new concept. In recent years, promising results have been reported for peritoneal mesothelioma and carcinomatosis of gastrointestinal and gynaecologic origin treated by this combined protocol. However, CRS with HIPEC and/or EPIC is a complex procedure associated with high rates of potentially life-threatening complications. Furthermore, disease progression following comprehensive treatment is not uncommon and represents a relevant cause of treatment failure. The present paper reviews the available information on early postoperative management and long-term follow-up in patients treated with CRS and intraperitoneal chemotherapy. The peculiar clinical and biological alterations that can be expected during an uncomplicated postoperative course, as compared to standard digestive surgery, are discussed. Early recognition and appropriate management of the most common adverse events are addressed, in order to minimize the impact of treatment-related morbidity on survival and quality of life results. Since re-operative surgery with additional HIPEC, has proven to be useful in selected patients with recurrent disease, long-term surveillance aiming at early detection of postoperative disease progression has become a relevant issue. Current results on follow-up investigations are presented

Consensus statement on the loco-regional treatment of appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei)

Pseudomyxoma peritonei (PMP) is a rare condition mostly originating from low malignant potential mucinous tumours of the appendix. Although this disease process is minimally invasive and rarely causes haematogenous or lymphatic metastases, expectation of long-term survival are limited with no prospect of cure. Recently, the combined approach of cytoreductive surgery (CRS) and perioperative loco-regional chemotherapy (PLC) has been proposed as the standard of treatment for the disease. The present paper summarizes the available literature data and the main features of the comprehensive loco-regional treatment of PMP. The controversial issues concerning the indications and technical methodology in PMP management were discussed through a web-based voting system by internationally known experts. Results were presented for further evaluation during a dedicated session of "The Fifth International Workshop on Peritoneal Surface Malignancy (Milan, Italy, December 4-6, 2006)". The experts agreed that multiple prospective trials support a benefit of the procedure in terms of improved survival, as compared with historical controls. Concerning the main controversial methodological questions, there was an high grade of consistency among the experts and agreement with the findings of the literature.6 page(s

Preoperative investigations in the management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy : expert consensus statement

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on preoperative investigations for peritoneal surface malignancy was obtained through the Delphi process. The results showed that 100% of the voters considered that contrast-enhanced multisliced CT was the fundamental imaging modality, whereas MRI, PET, laparoscopy and serum tumor markers were regarded as useful, but not fundamental investigational modalities.4 page(s

Four scenarios of environmental risk of diclofenac in European groundwater ecosystems

Groundwater is the largest source of liquid freshwater on Earth. Groundwater ecosystems harbor a rich biodiversity, mainly consisting of microbes and invertebrates that provide substantial ecological services. Despite its importance, groundwater is affected by several anthropic pressures, including pollution from pharmaceutical compounds. Diclofenac is the non-steroidal drug most widely detected in freshwaters, both in surface waters (e.g., rivers, streams, lakes etc.) and groundwaters. Unlike surface waters, the environmental risk of diclofenac in European groundwaters has not yet been assessed by the competent Authorities. The environmental risk assessment refers to the analysis of the potential risk that a chemical compound poses to a given environment by comparing its measured environmental concentrations to its predicted no-effect concentration. In this study, we explored four environmental risk scenarios in European groundwaters using different methodologies. We obtained diverse risk expectations, some indicative of a moderately diffuse environmental risk for concentrations of diclofenac ≥42 ng/L and others indicative of a widespread environmental risk for concentrations ≥5 ng/L. The difference among the four scenarios mainly related to the methods of calculating the predicted no-effect concentration of diclofenac. We discussed the four scenarios in order to identify the most realistic risk expectations posed by diclofenac to European groundwater ecosystems.Fil: Di Lorenzo, T.. Consiglio Nazionale delle Ricerche; Italia. Romanian Academy. ”Emil Racovita” Institute of Speleology; RumaniaFil: Cifoni, M.. Consiglio Nazionale delle Ricerche; ItaliaFil: Baratti, M.. Consiglio Nazionale delle Ricerche; ItaliaFil: Pieraccini, G.. Università degli Studi di Firenze; ItaliaFil: Di Marzio, Walter Dario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Luján. Departamento de Ciencias Básicas. Programa de Investigación en Ecotoxicología; ArgentinaFil: Galassi, D. M. P.. Universita degli Studi dell'Aquila; Itali

Metabolic rates of a hypogean and an epigean species of copepod in an alluvial aquifer

Reduced metabolic rates of groundwater taxa, compared to those of surface water species, have long been inferred to be an adaptive trait where there is a low and discontinuous food supply and unpredictable shifts between hypoxic and normoxic conditions. However, there have been neither measurements of the respiratory rate of groundwater copepods nor a comparison of rates between closely related groundwater and surface water species. We measured the metabolic rates of two species of Cyclopoida: Cyclopidae, the stygobiotic (hypogean) copepod Diacyclops belgicus and the epigean Eucyclops serrulatus, which co-occur in the same alluvial aquifer. We expected the metabolic rate of the hypogean to be lower than that of the epigean species, irrespective of the ontogenetic stage, which would be consistent with the hypothesis that there is a generally lower metabolic rate in groundwater species. The metabolic rate of D. belgicus was significantly lower than that of the epigean E. serrulatus irrespective of the ontogenetic stage. We found an allometric relationship between oxygen consumption and body mass for E. serrulatus, an isometric one for D. belgicus juveniles and a rate of oxygen consumption that apparently does not change systematically with body mass for D. belgicus adults. The low metabolic rate of D. belgicus may be advantageous in oligotrophic groundwater habitats, where large fluctuations in oxygen availability occur. However, these physiological adaptations can put hypogean species at risk of replacement by more metabolically active epigean taxa, whenever the availability of organic matter increases, as happens with organic pollution. Moreover, the low metabolic rate of the hypogean species may entail an inability to cope with toxicants, rendering them more sensitive to pollutants. A higher metabolic rate in juvenile D. belgicus compared to that of adults allows copepodids to mature quickly when food is briefly abundant.Fil: Di Lorenzo, T.. Istituto Per Lo Studio Degli Ecosistemi; ItaliaFil: Di Marzio, Walter Dario. Universidad Nacional de Luján; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Spigoli, D.. Universita Degli Studi Di Firenze; ItaliaFil: Baratti, M.. Istituto Per Lo Studio Degli Ecosistemi; ItaliaFil: Messana, G.. Istituto Per Lo Studio Degli Ecosistemi; ItaliaFil: Cannicci, S.. Universita Degli Studi Di Firenze; ItaliaFil: Galassi, Diana M. P.. Universita Degli Studi Dell'aquila; Itali