Surgical management of peritoneal metastasis: Opportunities for pharmaceutical research.

Cytoreductive surgery (CRS) has emerged as a survival-extending treatment of peritoneal metastasis (PM); recent advances include using intraperitoneal chemotherapy (IPC) at normothermic or hyperthermic temperatures, or under pressure (CRS + IPC). Clinical CRS + IPC research has established its highly variable efficacy and suggested tumor size, tumor locations and presence of ascites as potential determinants. On the other hand, there is limited knowledge on the effects of pharmaceutical properties on treatment outcomes. The present study investigated the inter-subject variability of paclitaxel binding to proteins in patient ascites because some PM patients show accumulation of ascites and because activity and transport of highly protein-bound drugs such as paclitaxel are affected by protein binding. Ascites samples were collected from 26 patients and investigated for their protein contents using LC/MS/MS proteomics analysis and for the concentrations of total proteins and two major paclitaxel-binding proteins (human serum albumin or HSA and α-1-acid glycoprotein or AAG). The association constants of paclitaxel to HSA and AAG and the extent of protein binding of paclitaxel in patient ascites were studied using equilibrium dialysis. Proteomic analysis of four randomly selected samples revealed 288 proteins, >90% of which are also present in human plasma. Between 72% - 94% of paclitaxel was bound to proteins in patient ascites. The concentrations of HSA and AAG in ascites showed substantial inter-subject variations, ranging from 14.7 - 46.3 mg/mL and 0.13-2.56 mg/mL, respectively. The respective paclitaxel association constants to commercially available HSA and AAG were âˆ¼ 3.5 and âˆ¼ 120 mM. Calculation using these constants and the HSA and AAG concentrations in individual patient ascites indicated that these two proteins accounted for >85% of the total protein-binding of paclitaxel in ascites. The extensive drug binding to ascites proteins, by reducing the pharmacologically active free fraction, may lead to the diminished CRS efficacy in PM patients with ascites. Clinical advances in CRS + IPC have outpaced current knowledge of pharmaceutical properties in this setting. IPC, as a locally acting therapy, is subjected to processes different from those governing systemic treatments. This study, to our knowledge, is the first to illustrate the implications of drug properties in the CRS + IPC efficacy against PM. While drugs are now an integral part of PM patient management, there is limited pharmaceutical research in this treatment setting (e.g., effects of hyperthermia or pressure on drug transport or release from delivery systems, pharmacokinetics, pharmacodynamics). Hence, CRS + IPC of PM represents an area where additional pharmaceutical research can assist further development and optimization.

Living on the edge: Prospects for enhanced biological phosphorus removal at low sludge retention time under different temperature scenarios.

The design of new wastewater treatment plants with the aim of capturing organic matter for energy recovery is a current focus of research. Operating with low sludge residence time (SRT) appears to be a key factor in maximizing organic matter recovery. In these new configurations, it is assumed that phosphorus is chemically removed in a tertiary step, but the integration of enhanced biological phosphorus removal (EBPR) into these short-SRT systems seems to be an alternative worth studying. A key point of this integration is to prevent the washout of polyphosphate accumulating organisms (PAO) despite the low SRT applied. However, the minimum SRT required to avoid PAO washout depends on temperature, due to its effects on reaction kinetics, gas transfer rates, biomass growth and decay rates. This work includes a wide range of short and long-term experiments to understand these interactions and shows which combinations of SRT and temperature are detrimental to PAO growth. For example, an EBPR system operating at 20 °C and SRT = 5 d showed good performance, but EBPR activity was lost at 10 °C. EBPR operated at SRT = 10 d had 86% P removal at 20 °C but decreased to 71% at 15 °C and progressively lost its activity at lower temperature. The temperature coefficient obtained for PAO show a low degree of temperature dependence (θ = 1.047 ± 0.014), and should be considered when designing short-SRT systems with EBPR.

Enhanced Biological Phosphorus Removal at low Sludge Retention Time in view of its integration in A-stage systems.

The two-stage A/B WWTP configuration is being studied as a possible wastewater treatment with low energy consumption or even with a net energy generation. The first phase, A-stage, is designed to remove organic matter at very short Sludge Retention Time (SRT), while the B-stage is based on autotrophic nitrogen removal. However, P-removal in the A/B process usually only relies on precipitation. This work studies the potential inclusion of Enhanced Biological Phosphorus Removal (EBPR) in the A-stage phase. For this aim, the long-term operation of three different Sequencing Batch Reactors (SBR) enriched in Accumulibacter at low SRT was thoroughly monitored for more than three months each one. This work shows that EBPR can be sustained with a minimal SRT of 3.6 d at 25 °C. Lower values, SRT = 3 d, led to the PAO washout because of a reduction in P-release and P-uptake, an increase of the VSS/TSS ratio and a decrease of the P/C ratio. The Yobs could be related to the SRT with the parameters Y = 0.39 ± 0.05 gCODX·g-1CODS and kD = 0.06 ± 0.04 d-1 which leads to a 24% increase of biomass yield when SRT was reduced from 10 to 4 d.

Preclinical Evaluation of Cathepsin-Based Fluorescent Imaging System for Cytoreductive Surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a treatment option for peritoneal surface malignancies. The ability to detect microscopic foci of peritoneal metastasis intraoperatively may ensure the completeness of cytoreduction. In this study, we evaluated the suitability of a hand-held cathepsin-based fluorescent imaging system for intraoperative detection of appendiceal and colorectal peritoneal metastasis. METHODS: Peritoneal tumors and normal peritoneal tissues were collected from patients with appendiceal and colorectal peritoneal metastasis. Expression of different cathepsins (CTS-B, -D, -F, -G, -K, -L, -O, and -S) was determined by quantitative RT-PCR and immunohistochemistry. The hand-held cathepsin-based fluorescent imaging system was used to detect peritoneal xenografts derived from human colon cancer cells (HT29, LoVo and HCT116) in nu/nu mice. RESULTS: While the expression levels of CTS-B, -D, -L, and -S could be higher in peritoneal tumors than normal peritoneum with a median (range) of 6.1 (2.9-25.8), 2.0 (1.0-15.8), 1.4 (0.8-7.0), and 2.1 (1.6-13.9) folds by quantitative RT-PCR, respectively, CTS-B was consistently the major contributor of the overall cathepsin expression in appendiceal and colonic peritoneal tumors, including adenocarcinomas and low-grade appendiceal mucinous neoplasms. Using peritoneal xenograft mouse models, small barely visible colonic peritoneal tumors (<2.5 mm in maximum diameter) could be detected by the hand-held cathepsin-based fluorescent imaging system. CONCLUSIONS: Because cathepsin expression is higher in peritoneal tumors than underlying peritoneum, the hand-held cathepsin-based fluorescent imaging system could be useful for intraoperative detection of microscopic peritoneal metastasis during CRS-HIPEC and clinical trial is warranted.

A critical look at local-regional management of peritoneal metastasis.

For patients with stage IV colorectal cancer, the presence of peritoneal metastases is a poor prognostic feature. Despite the improvement in systemic therapy, long-term survival remains poor for patients with peritoneal carcinomatosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be associated with long-term survival in patients who have limited peritoneal disease, particularly those who can have complete cytoreduction. Whether the possible benefit of CRS and HIPEC is from the surgical resection of all disease or the combination of CRS and HIPEC remains unclear.