Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer in an Australian institution: lessons from 20 years' experience.

OBJECTIVES: We report the 20-year experience of the largest Australian unit performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer and reflect on learning opportunities. METHODS: A retrospective review of all cases of CRS for ovarian cancer at St George Peritonectomy Unit from Jan 1998 to Jan 2018 was performed. Prospectively collected data include age, stage, histology, disease extent (PCI), completeness of cytoreduction (CC score), HIPEC regime, 30-day surgical morbidity, disease recurrence, and death. Survival was computed using Kaplan-Meier method and analysed using log-rank tests and Cox-proportional hazards models. RESULTS: Forty-one women with advanced ovarian cancer (11 primary stage III/IV, 30 recurrent) underwent CRS, 29 (71%) with HIPEC. Most (68%) had high-volume disease (PCI > 15). In 98%, CC0/CC1 (residual < 2.5 mm) was achieved. Fourteen (34%) had grade 3/4 complications, 1 patient (2%) died within 30 days and 2 patients (5%) died within 90 days. Progression-free and median overall survival was 30.0 and 67.0 months for primary cancer, and 6.7 and 18.1 months for recurrent cancer. Survival was associated with platinum-sensitivity, PCI ≤ 15, and CC score 0, but not HIPEC. CONCLUSION: This study reports outcomes for patients with advanced ovarian cancer patients treated in an Australian centre offering CRS and HIPEC. Whilst survival and morbidity outcomes were good for primary disease, they were poorer than predicted from the literature for cases of recurrent disease. The incorporation of evidence-based predictors of survival and multidisciplinary input are essential to achieve the best survival outcomes.

Dietary fatty acid and starch content and supplemental lysine supply affect energy and nitrogen utilization in lactating Jersey cows.

The effects of dietary fatty acid (FA) and starch content as well as supplemental digestible Lys (sdLys) on production, energy utilization, and N utilization were evaluated. Each factor was fed at 5 different amounts, and factor limits were as follows: 3.0 to 6.2% of dry matter (DM) for FA; 20.2 to 31.3% of DM for starch, and 0 to 17.8 g/d of sdLys. Dietary FA and starch were increased by replacing soyhulls with supplemental fat and corn grain, respectively, and sdLys increased with rumen-protected Lys. Fifteen unique treatments were fed to 25 Jersey cows (mean ± SD; 80 ± 14 d in milk) across 3 blocks in a partially balanced incomplete block design. Each block consisted of 4 periods of 28 d, where the final 4 d were used to determine milk production and composition, feed intake, energy utilization (via total collection and headbox-style indirect calorimetry), and N utilization (via total collection). Response surface models were used to evaluate treatment responses. Increasing dietary FA decreased DM intake and milk protein yield. When dietary starch was less than 24%, milk protein concentration increased with increasing sdLys, but when dietary starch was greater than 26% milk protein concentration decreased with increasing sdLys. Digestibility of FA increased when dietary FA increased from 3.0 to 4.2% and decreased as FA increased beyond 4.2%. Although neutral detergent fiber digestibility decreased as dietary starch increased, energy digestibility increased. As dietary FA increased, metabolizable energy (ME) content quadratically increased. Supply of ME increased as dietary FA increased from 3.0 to 4.2% and decreased as FA increased beyond 4.2%. Increasing dietary FA and starch decreased CH4 production and urinary energy. Increasing dietary starch increased the efficiency of utilizing dietary N for milk N. Increasing sdLys quadratically decreased N balance as sdLys increased from 0 to 8 g/d and increased N balance as sdLys increased from 8 to 18 g/d. Increasing dietary FA can increase ME content, however, at high dietary FA, decreased DM intake and FA digestibility resulted in a plateau in ME content and a decrease in ME supply. Our results demonstrate that sdLys supply is important for milk protein when dietary starch is low, and some Lys may be preferentially used for muscle protein synthesis at the expense of milk protein when sdLys is high.

Effect of feeding hydrolyzed feather meal and rumen-protected lysine on milk protein and energy utilization in late-lactation Jersey cows.

Hydrolyzed feather meal (HFM) is a feed that is high in rumen undegradable protein; however, it is low in Lys compared with other high rumen undegradable protein sources. Additionally, processing methods differ by facility, which affects AA composition and protein digestibility. The objective of this study was to use lactating dairy cows to determine the effects of feeding 2 sources of HFM that differed by the amount of blood they contained and also to study the effects of supplementing rumen-protected (RP) Lys when these sources of HFM are fed. In this study, 12 multiparous Jersey cows were enrolled in a triplicated 4 × 4 Latin square with 4 periods 28 d in length. Cows were fed 2 total mixed rations that differed by source of HFM. The HFM was included at 4.5% of the diet dry matter, and one source was produced with the addition of poultry blood. Cows were randomly assigned to 1 of 4 treatment sequences. Treatments were as follows: HFM without added blood and no RP-Lys, HFM with added blood and no RP-Lys, HFM without blood and with RP-Lys (22 g of digestible Lys), and HFM with added blood and RP-Lys. The source of HFM containing blood tended to increase dry matter intake (18.3 vs. 17.3 ± 0.72 kg/d), and increased milk yield (20.5 vs. 18.4 ± 1.31 kg/d) and protein yield (0.788 vs. 0.694 ± 0.040 kg/d). The inclusion of RP-Lys did not affect milk or protein yield. In cows fed HFM containing blood, plasma concentration of Lys (82.1 vs. 70.8 ± 4.06 µM) and His (27.8 vs. 17.9 ± 3.15 µM) was higher. The addition of RP-Lys had no effect on the concentration of either plasma Lys or His. Gross energy intake tended to increase for HFM containing more blood (81.4 vs. 77.3 ± 3.29 Mcal/d); however, no difference was observed for intake of digestible energy (52.0 ± 2.20 Mcal/d) or metabolizable energy (46.4 ± 2.02 Mcal/d). Similar to dry matter intake, N intake increased with the inclusion of HFM containing blood, but crude protein digestibility decreased (61.6 vs. 66.0%). Results of this study highlight that source of HFM can be a factor that affects milk production and that this in part is due to differences in the profile of AA. Additionally, the observation that plasma His and milk protein increased with the consumption of HFM containing more blood suggests that His may have played a role in increasing milk and milk protein yield.

A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.

BACKGROUND: Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. METHODS: Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. FINDINGS: Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. CONCLUSION: Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

Effects of rumen-protected lysine and histidine on milk production and energy and nitrogen utilization in diets containing hydrolyzed feather meal fed to lactating Jersey cows.

Hydrolyzed feather meal (HFM) is high in crude protein, most of which bypasses rumen degradation when fed to lactating dairy cows, allowing direct supply of AA to the small intestine. Compared with other feeds that are high in bypass protein, such as blood meal or heat-treated soybean meal, HFM is low in His and Lys. The objectives of this study were to determine the effects of supplementing rumen-protected (RP) Lys and His individually or in combination in a diet containing 5% HFM on milk production and composition as well as energy and N partitioning. Twelve multiparous Jersey cows (mean ± SD: 91 ± 18 d in milk) were used in a triplicated 4 × 4 Latin square with 4 periods of 28 d (24-d adaptation and 4-d collection). Throughout the experiment, all cows were fed the same TMR, with HFM included at 5% of diet DM. Cows were grouped by dry matter intake and milk yield, and cows within a group were randomly assigned to 1 of 4 treatments: no RP Lys or RP His; RP Lys only [70 g/d of Ajipro-L (24 g/d of digestible Lys), Ajinomoto Co. Inc., Tokyo, Japan]; RP His only [32 g/d of experimental product (7 g/d of digestible His), Balchem Corp., New Hampton, NY]; or both RP Lys and His. Plasma Lys concentration increased when RP Lys was supplemented without RP His (77.7 vs. 66.0 ± 4.69 µM) but decreased when RP Lys was supplemented with RP His (71.4 vs. 75.0 ± 4.69 µM). Plasma concentration of 3-methylhistidine decreased with RP Lys (3.19 vs. 3.40 ± 0.31 µM). With RP His, plasma concentration of His increased (21.8 vs. 18.7 ± 2.95 µM). For milk production and milk composition, no effects of Lys were observed. Supplementing RP His increased milk yield (22.5 vs. 21.6 ± 2.04 kg/d) and tended to increase milk protein yield (0.801 vs. 0.772 ± 0.051 kg/d). Across treatments, dry matter intake (18.5 ± 0.83 kg/d) and energy supply (32.2 ± 2.24 Mcal of net energy for lactation) were not different. Supplementing RP His did not affect N utilization; however, supplementing RP Lys increased N balance (25 vs. 16 ± 9 g/d). The lack of production responses to RP Lys suggests that Lys was not limiting or that the increase in Lys supply was not large enough to cause an increase in milk protein yield. However, increased N balance and decreased 3-methylhistidine with RP Lys suggest that increased Lys supply increased protein accretion and decreased protein mobilization. Furthermore, His may be a limiting AA in diets containing HFM.

Effects of high-starch or high-fat diets formulated to be isoenergetic on energy and nitrogen partitioning and utilization in lactating Jersey cows.

The objective of this study was to determine the effects of high-starch or high-fat diets formulated to be isoenergetic on energy and N partitioning and utilization of energy. Twelve multiparous Jersey cows (mean ± standard deviation; 192 ± 11 d in milk; 467 ± 47 kg) in a crossover design with 28-d periods (24-d adaptation and 4-d collection) were used to compare 2 treatment diets. Treatments were high starch (HS; 30.8% starch, 31.8% neutral detergent fiber, and 1.9% fatty acids) or high fat (HF; 16.8% starch, 41.7% neutral detergent fiber, and 4.1% fatty acids). Diets were formulated to have net energy for lactation (NEL) content of 1.55 Mcal/kg of dry matter according to the National Research Council (2001) dairy model. Nutrient composition was varied primarily by replacing corn grain in HS with a rumen-inert fat source and cottonseed hulls in HF. Gross energy content was lower for HS (4.43 vs. 4.54 ± 0.01 Mcal/kg of dry matter), whereas digestible (2.93 vs. 2.74 ± 0.035 Mcal/kg of dry matter) and metabolizable energy (2.60 vs. 2.41 ± 0.030 Mcal/kg of dry matter), and NEL (1.83 vs. 1.67 ± 0.036 Mcal/kg of dry matter) content were all greater than for HF. Tissue energy deposited as body fat tended to be greater for HS (4.70 vs. 2.14 ± 1.01 Mcal/d). For N partitioning, HS increased milk N secretion (141 vs. 131 ± 10.5 g/d) and decreased urinary N excretion (123 vs. 150 ± 6.4 g/d). Compared with HF, HS increased apparent total-tract digestibility of dry matter (66.7 vs. 61.7 ± 1.06%), organic matter (68.5 vs. 63.2 ± 0.98%), energy (66.0 vs. 60.4 ± 0.92%), and 18-carbon fatty acids (67.9 vs. 61.2 ± 1.60%). However, apparent total-tract digestibility of starch decreased for HS from 97.0 to 94.5 ± 0.48%. Compared with HF, HS tended to increase milk yield (19.7 vs. 18.9 ± 1.38 kg/d), milk protein content (4.03 vs. 3.93 ± 0.10%), milk protein yield (0.791 vs. 0.740 ± 0.050 kg/d), and milk lactose yield (0.897 vs. 0.864 ± 0.067 kg/d). In addition, HS decreased milk fat content (5.93 vs. 6.37 ± 0.15%) but did not affect milk fat yield (average of 1.19 ± 0.09 kg/d) or energy-corrected milk yield (average of 27.2 ± 1.99 kg/d). Results of the current study suggest that the HS diet had a greater metabolizable energy and NEL content, increased partitioning of N toward milk secretion and away from urinary excretion, and may have increased partitioning of energy toward tissue energy deposited as fat.

Effects of lysophospholipids on short-term production, nitrogen utilization, and rumen fermentation and bacterial population in lactating dairy cows.

An experiment was conducted to examine effects of supplemental lysophospholipids (LPL) in dairy cows. Eight ruminally cannulated lactating Holstein cows were used in a replicated 4 × 4 Latin square design. Dietary treatments were (1) a dairy ration [CON; 55% forage and 45% concentrate on a dry matter (DM) basis], (2) a positive control diet supplemented with monensin (MON; 16 mg/kg in dietary DM; Elanco Animal Health, Greenfield, IN], (3) a control diet supplemented with low LPL (0.05% of dietary DM; Lipidol Ultra, Easy Bio Inc., Seoul, South Korea), and (4) a control diet supplemented with high LPL (0.075% of dietary DM). Experimental periods were 21 d with 14-d diet adaptation and 7-d sample collection. Daily intake and milk yield were measured and rumen contents were collected for fermentation characteristics and bacterial population. Spot urine and fecal samples (8 samples/cow per period) were collected to determine nutrient digestibility and dietary N utilization. All data were analyzed using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC; group and cow within group were random effects and treatments, time, and their interaction were fixed effects). Preplanned contrasts were made to determine effect of MON versus CON, effect of LPL versus MON, and linear effect of increasing LPL. In the current study, responses to MON generally agreed with effects of monensin observed in the literature (increased milk yield and feed efficiency but decreased milk fat content). Supplementation of LPL to the diet did not alter DM intake but linearly increased milk yield, resulting in increases in feed efficiency (milk yield/DM intake) and milk protein and fat yields. However, total-tract digestibility of DM and organic matter tended to be lower (60.9 vs. 62.2% and 61.8 vs. 63.1%, respectively) for LPL compared with CON. Linear increases in milk N secretion and decreases in urinary N excretion were observed with increasing LPL in the diet. A slight decrease in acetate proportion in the rumen for LPL was found. Relative to MON, very few bacteria in the rumen were affected with increasing LPL. In conclusion, LPL is a potential feed additive that can increase milk yield and components and dietary N utilization. However, more studies with large numbers of animals are needed to confirm the effect of LPL on production. Similar positive effects on production were observed between LPL and MON, but individual mechanisms were likely different according to ruminal fermentation characteristics. Further studies are needed to explore the mode of action of LPL in dairy cows.

Validating and optimizing spot sampling of urine to estimate urine output with creatinine as a marker in dairy cows.

An experiment was conducted to validate and optimize the procedure of spot urine sampling with urinary creatinine as a marker to estimate urine outputs of dairy cows. Twelve lactating cows were used in a randomized complete block design. Cows were grouped and randomly assigned to 2 experimental diets: a corn silage-based diet and an alfalfa silage-based diet with supplemental potassium. The experiment lasted for 21 d and total collection (TC) of urine was conducted for the last 3 d. Twelve spot samples of urine from individual cows were collected over a 3-d period during TC to represent every 2-h sampling in a 24-h cycle. Creatinine excretion rate (mg/kg of body weight per d) was variable among cows from 16.7 to 34.5 with an average of 27.3. Creatinine concentrations of spot samples within cow were averaged to simulate urine samples obtained from various spot sampling frequencies (equally spaced 12, 6, 4, and 2 time points starting at feeding: 12TP, 6TP, 4TP, and 2TP, respectively). Large diurnal variation of urinary creatinine concentration was observed within cow. Creatinine concentration was greater (75 vs. 65 mg/dL) for 12TP compared with TC, resulting in underestimating (29.8 vs. 32.6 kg/d) urine outputs. When compared among 12TP, 6TP, 4TP, and 2TP, creatinine concentrations were different and urine outputs tended to be different for 2TP compared with 12TP, 6TP, and 4TP. In addition, despite underestimation of urine output, a regression analysis indicated strong linear relationships between 12TP, 6TP, or 4TP and TC, suggesting that this technique can successfully identify the differences in urine outputs altered by dietary treatments. However, 4TP failed to detect statistical differences in urine outputs between a corn silage-based diet and the alfalfa silage-based diet with supplemental potassium, indicating that a spot urine sampling frequency of at least 6 was required to identify dietary effects on urine outputs. According to the pattern of diurnal changes in urinary creatinine concentration, a spot sample at about 10 h after feeding may have potential to obtain a urine sample that is more representative (i.e., creatinine concentration) of TC urine compared with urine from multiple sampling frequencies. Overall, urinary creatinine as a marker with spot sampling of urine underestimated urine output. However, 12TP and 6TP were successful in identifying changes in urine outputs by dietary treatments.

Cytoreductive surgery and HIPEC improve survival compared to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.

BACKGROUND: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. OBJECTIVE: To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. MATERIAL AND METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. RESULTS: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. CONCLUSION: Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.

The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Effects of corn feeding reduced-fat distillers grains with or without monensin on nitrogen, phosphorus, and sulfur utilization and excretion in dairy cows.

This study investigated effects of high inclusion of reduced-fat corn distillers grains with solubles (RFDG) with or without monensin on utilization and excretion of dietary N, P, and S. The experiment was conducted for 11 wk (2-wk diet adaptation, 9-wk experimental period of data collection) with 36 Holstein cows in a randomized complete block design. Cows were blocked by parity, days in milk, and milk yield and assigned to the following diets: (1) a control diet (CON); (2) CON with RFDG included at 28.8% (dry matter basis) by replacing soybean meal, soyhulls, and supplemental fat and phosphorus (DG); and (3) DG with monensin (Rumensin; Elanco Animal Health, Greenfield, IN) supplemented at a rate of 20 mg/kg of DM offered (DGMon). Contrasts were used to compare CON versus DG and DG versus DGMon. Inclusion of RFDG at 28.8% of dietary DM replacing mainly soybean meal did not change crude protein content (17.6% on a DM basis) but decreased rumen-degradable protein and increased rumen-undegradable protein. In addition, the DG diets increased P (0.48 vs. 0.36%) and S concentrations (0.41 vs. 0.21%; DM basis) compared with the CON diet. As a result, DG versus CON decreased plasma and milk urea N concentrations and urinary N excretion. However, the increase in P concentration when feeding the DG versus CON diet to lactating cows increased P intake, plasma P concentration, and urinary and fecal P excretion without affecting milk P secretion. Intake of S was greater for cows fed the DG versus CON diet, resulting in greater plasma total S and sulfate concentration and urinary and fecal S excretion. However, milk S secretion was not affected by DG compared with CON. Monensin supplementation to the DG diet did not affect N intake, utilization, and excretion except that apparent N digestibility was lower compared with DG. In addition, feeding the DGMon diet did not affect P and S utilization and excretion compared with DG. The study suggests that inclusion of high RFDG in a ration by replacing mainly soybean meal altered N, P, and S utilization and excretion, but monensin supplementation to a high-RFDG diet, overall, had minimal effects on N, P, and S utilization and excretion in lactating dairy cows.

Oxaliplatin versus Mitomycin C for HIPEC in colorectal cancer peritoneal carcinomatosis.

OBJECTIVE: Compare long-term outcomes in colorectal cancer (CRC) patients with peritoneal carcinomatosis (PC) treated with peritonectomy/HIPEC using oxaliplatin versus MMC. BACKGROUND: Peritonectomy and heated intraperitoneal chemotherapy (HIPEC) greatly improves patient survival in CRC PC. This procedure is not uniform across centres and the optimal choice of HIPEC chemotherapeutic is unclear. Oxaliplatin and Mitomycin C (MMC) are the most commonly used agents and comparative studies have reported varying results. METHOD: 201 patients were retrospectively selected from the St George Hospital database, all of which had undergone peritonectomy/HIPEC for CRC PC. Oxaliplatin and MMC were used in 106 and 96 patients, respectively. Each patient's baseline characteristics, operative details, choice of chemotherapeutic agent and survival were noted. RESULTS: The two groups did not differ significantly at baseline. Patients receiving oxaliplatin had significantly greater unadjusted median survival compared to MMC (56.0 ± 8.1 vs. 29.0 ± 3.4 months) which translated into a hazards ratio of 0.59 (95% CI 0.37-0.91, p = 0.017). Subgroup analysis further confirmed an advantage with oxaliplatin in females, moderate-well differentiated tumours, tumours without signet ring pathology and PCI 10-15. CONCLUSION: Our study suggests oxaliplatin offers a survival advantage over MMC when used for HIPEC in CRC PC. Further studies to understand its efficacy, complications and ideal preparation are required. A Phase III randomised control trial comparing oxaliplatin and MMC would enhance decision-making.

High risk features of primary colorectal carcinomas which subsequently undergo peritonectomy.

OBJECTIVE: Determine what portion of colorectal cancer (CRC) patients with peritoneal metastases (PM) undergoing peritonectomy would have been identified/treated if second-look surgery protocol existed for high-risk primary tumours. BACKGROUND: The prognosis of CRC PM greatly improves following peritonectomy/HIPEC. Survival remains dependent upon stage of PM and there is some knowledge of high-risk factors for its development. Subsequently, there is interest in routine second-look laparotomy to follow-up high-risk CRC patients so to 'prevent' PM. METHODS: Patients were retrospectively selected from the St George database, all of whom had had PM recurrence after primary CRC resection thus underwent peritonectomy/HIPEC. Each patient's primary tumour pathology was obtained with incidence of high-risk stage (T4), macroscopic (peritoneal involvement, ovarian metastases, perforated primary) and microscopic (mucinous, signet ring) features noted. RESULTS: 125 patients were included. At primary diagnosis, 34.4%, 46.4% and 19.2% were of T3, T4a and T4b stage. Primary tumour macroscopic features included 41.1%, 12.6% and 23.7% with synchronous peritoneal involvement, perforated primary and ovarian metastases. Primary tumour microscopic features included 8.1%, 44.0% and 5.6% with signet ring, mucinous and both pathologies. Individually T4 status, macroscopic and microscopic features would have identified 65.6%, 56.8% and 46.5% of patients. Any high-risk factor would have identified 85.6%. CONCLUSION: Our study suggests that T4 stage, high-risk macroscopic and high-risk microscopic features at time of primary diagnosis identifies the majority of CRC patients who later develop PM. This provides support for a selective second-look protocol in such patients to enable early identification and, potentially, 'prevention' of CRC PM.

Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer: A systematic review and meta-analysis.

PURPOSE: Emerging evidence suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) shows a survival benefit over CRS alone for patients with epithelial ovarian carcinoma (EOC). This systematic review and meta-analysis will assess the safety and efficacy of HIPEC with CRS for EOC. DESIGN: Searches of five databases from inception to 17/02/15 was performed. Clinical outcomes were synthesised, with full tabulation of results. RESULTS: A total of 9 comparative studies and 28 studies examining HIPEC + CRS for primary and/or recurrent EOC were included. Meta-analysis of the comparative studies showed HIPEC + CRS + chemotherapy had significantly better 1-year survival compared with CRS + chemotherapy alone (OR: 3.76, 95% CI 1.81-7.82). The benefit of HIPEC + CRS continued for 2-, 3-, 4-, 5- and 8-year survival compared to CRS alone (OR: 2.76, 95% CI 1.71-4.26; OR: 5.04, 95% CI 3.24-7.85; OR: 3.51, 95% CI 2.00-6.17; OR: 3.46 95% CI 2.19-5.48; OR: 2.42, 95% 1.38-4.24, respectively). Morbidity and mortality rates were similar. Pooled analysis of all studies showed that among patients with primary EOC, the median, 1-, 3-, and 5-year overall survival rates are 46.1 months, 88.2%, 62.7% and 51%. For recurrent EOC, the median, 1-, 3-, and 5-year overall survival rates are 34.9 months, 88.6%, 64.8% and 46.3%. A step-wise positive correlation between completeness of cytoreduction and survival was found. CONCLUSION: The addition of HIPEC to CRS and chemotherapy improves overall survival rates for both primary and recurrent EOC.

Laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) for refractory malignant ascites in patients unsuitable for cytoreductive surgery.

INTRODUCTION: Malignant ascites (MA) is the abnormal accumulation of fluid in the peritoneal cavity of patients with intraperitoneal dissemination of their disease and is associated with a short life expectancy. The most common clinical feature is a progressive increase of abdominal distention resulting in pain, discomfort, anorexia and dyspnoea. Currently, no treatment is established standard of care due to limited efficacy or considerable toxicity. The objective was to examine the efficacy of laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) in the palliation of refractory MA in patients who were unsuitable for cytoreductive surgery. METHODS: From May 2009 to June 2015, 12 patients with MA due to their peritoneal malignancy were treated with laparoscopic HIPEC. The time between operation and repeat paracentesis, in-hospital data, and the proportion of patients that did not require repeat paracentesis was analyzed. RESULTS: One patient (8%) was admitted to ICU for 1 day. The mean operating time and hospital stay was 149.3 min (range 79-185) and 4.6 days (range 2-11) respectively. Neither high-grade morbidity nor mortality was observed. The median OS was 57 days. In our experience, a complete and definitive disappearance of MA was observed in 83% of patients. Two patients (17%) developed recurrent MA 124 days and 283 days post-HIPEC. CONCLUSION: Laparoscopic HIPEC is a beneficial treatment for the management and palliation of refractory MA and results in an excellent clinical and radiological resolution in patients with a complete resolution observed in selected patients.

Repeat cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent diffuse malignant peritoneal mesothelioma.

INTRODUCTION: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). PATIENTS AND METHODS: This is a retrospective study of prospectively collected data of 44 consecutive patients with DMPM who underwent CRS and HIPEC by the same surgical team at St George Hospital in Sydney, Australia. A total of 58 operations were performed. Clinical data were divided according to the number of operation and HIPEC the patient had undergone (Group 1 = initial CRS and HIPEC; Group 2 = 2nd CRS and HIPEC; Group 3 included 3rd CRS and HIPEC; Group 4 = 4th CRS and HIPEC). A significant difference was defined as p < 0.05. RESULTS: There were no significant differences in mortality and morbidity results among the four groups. The median survival for those who only had one operation was 22 months (95% confidence interval (CI) = 0-47.2), whereas the median survival for those who had a second operation was 62 months (95% CI = 22.9-101.1). However, such a difference did not translate into a statistical significance (p = 0.141). CONCLUSION: We report an encouraging median survival of 62 months in patients who had recurrence of disease and had repeat CRS and HIPEC with similar morbidity and mortality with the initial operation. Due to the learning curve of this technique, patients with recurrent mesothelioma should be referred to specialised tertiary care centres for evaluation. Selected patients may experience prolonged survival after repeat CRS and HIPEC.

Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be complicated by pulmonary emboli (PE). Patients are at high risk due to surgery, underlying malignancy, immobility and indwelling lines. OBJECTIVES: This paper aims to identify clinically significant signs and symptoms preceding acute PE in post CRS-HIPEC patients, assess the PE investigative approach in this population and the significance of PE on patient management. METHOD: 25 cases with a positive and 50 controls with a negative CTPA for PE were isolated from the peritonectomy database at St George Hospital Sydney, January 2006 to July 2013. Vital signs, patient symptoms, adjunct investigation findings and patient outcomes were collected and graphed in Microsoft Excel. P values and 95% confidence intervals were calculated using GraphPad Prism version 6. RESULTS: 25 of 562 (4.4%) CRS-HIPEC patients were diagnosed with acute PE. Raised body temperature was the only statistically significant clinical finding that differentiated cases from controls (p value 0.02). Arterial blood gas results did not correlate with PE (p values 0.62; 0.29; 0.55, 0.84). Troponin, ECG and CXR were not routinely conducted. CXR and CTPA findings were similar between cases and controls (Table 4). PE patients required lower supplementary oxygen and escalation of care. CONCLUSION: Body temperature is the only statistically significant clinical finding observed with PE. We recommend a standardised investigative approach consisting of troponin, ECG and CXR. PE in CRS-HIPEC does not cause significant cardio-respiratory dysfunction, or escalation of care. PE rates are higher than other major surgeries, thus we propose a trial with increased chemical prophylaxis in CRS-HIPEC patients.

Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei.

BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal.

Repeat cytoreductive surgery (CRS) for recurrent colorectal peritoneal metastases: yes or no?

PURPOSE: To clarify the role of repeat CRS for recurrent colorectal carcinoma (CRC) through: (i) Systematic review of the literature (ii) Analysis of survival outcomes in a prospective cohort. METHODS: (i) Pubmed and MEDLINE from 1980 to July 2013 searched using terms: colorectal carcinoma, peritonectomy, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), redo, repeat, and iterative. (ii) Kaplan-Meier Survival analysis of consecutive patients undergoing repeat CRS at St George Hospital between Jan 2000 and July 2013. RESULTS: (i) The search strategy yielded 309 articles, 5 meeting inclusion criteria, reporting on 91 patients. Median overall survival from first CRS ranged from 39 to 57.6 months with 3-yr survival of 50%, and 5-year survival of 30%. Median survival from second CRS was 20-months with 1-yr survivals of 72% and 66% and 2-year survivals of 50% and 44%. (ii) Repeat CRS performed on 18 patients found median survival from first CRS was 59 months, with 1, 3, and 5-year survival of 100%, 52% and 26% respectively. Median survival from repeat CRS was 22.6 months with 1, 2, and 3-year survival of 94%, 48% and 12% respectively. CONCLUSION: The current data on repeat CRS in CRC is relatively immature and more data is required before drawing clear conclusions. Patient selection should be on a case by case basis conducted through a MDT process with emphasis on surrogate markers for favourable outcomes.

Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma: non-mucinous tumour associated with an improved survival.

AIMS: Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has been reported as a treatment option for patients with peritoneal carcinomatosis from colorectal carcinoma. METHODS: Thirty patients with colorectal peritoneal carcinomatosis underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy. All appendiceal cancers were excluded. All patients were followed until January 2006 or death. Univariate analysis was performed to evaluate significant prognostic factors for overall survival, defined from the time of surgery. RESULTS: There were 13 male patients. The mean age at the time of surgery was 54years. There was no hospital mortality. The mean duration of hospital stay was 27days. The overall median survival was 29months, with 1- and 2-year survival of 72% and 64%, respectively. Twenty-one patients had complete cytoreduction and their 1- and 2-year survival rates were 85% and 71%, respectively. Univariate analysis demonstrated that patients with non-mucinous colorectal adenocarcinoma, Peritoneal Cancer Index (PCI) < or =13, and complete cytoreduction were associated with an improved survival. CONCLUSIONS: This study reported on 30 patients who underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis. Patients with mucinous tumour had relatively more extensive intraperitoneal disease. Non-mucinous colorectal adenocarcinoma, PCI < or =13, and complete cytoreduction were associated with an improved survival.