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.

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.

Repeat cytoreductive surgery with or without intraperitoneal chemotherapy for recurrent epithelial appendiceal neoplasms.

BACKGROUND: With recurrence rates after primary cytoreductive surgery (CRS) in excess of 50 per cent, repeat CRS is being performed increasingly, but survival outcomes have not been reported widely. This study examined the outcomes following repeat CRS for appendiceal cancer with peritoneal surface malignancy (PSM), and evaluated its feasibility and safety. METHODS: A retrospective cohort of patients who had surgery between 1996 and 2018 were analysed. Patients who underwent a single CRS procedure with or without heated intraperitoneal chemotherapy (HIPEC) were compared with those who had multiple procedures with or without HIPEC. Perioperative morbidity and survival outcomes were analysed. RESULTS: Some 462 patients were reviewed, 102 of whom had repeat procedures. For high-grade tumours, patients who had a single CRS procedure had significantly reduced overall survival (OS) compared with those who had repeat CRS (55·6 versus 90·7 months respectively; P = 0·016). For low-grade tumours, there was no difference in OS (P = 0·153). When patients who had a single procedure were compared with those who had multiple procedures, there was no significant difference in major morbidity (P = 0·441) or in-hospital mortality (P = 0·080). For multiple procedures, no differences were found in major morbidity (P = 0·262) or in-hospital mortality (P = 0·502) when the first procedure was compared with the second. For low-grade cancers, the peritoneal carcinomatosis index was a significant prognostic factor for OS (hazard ratio (HR) 1·11, 95 per cent c.i. 1·05 to 1·17; P < 0·001), whereas for high-grade cancers repeat CRS (HR 0·57, 0·33 to 0·95; P = 0·033), complete cytoreduction score (HR 1·55, 1·01 to 2·40; P = 0·046) and presence of signet ring cells (HR 2·77, 1·78 to 4·30; P < 0·001) were all significant indicators of long-term survival. CONCLUSION: In selected patients presenting with PSM from epithelial appendiceal neoplasms, repeat CRS performed in high-volume centres could provide survival benefits.

ANTECEDENTES: En países de bajos y medianos ingresos (low- and middle-income countries, LMIC) hay que desarrollar estrategias de futuro para incrementar la disponibilidad de equipos quirúrgicos, adquisición, capacitación, uso, mantenimiento y complicaciones relacionadas con las unidades electroquirúrgicas (electrosurgical unit, ESU) y los equipos de laparoscopia. MÉTODOS: Se realizó una encuesta entre los cirujanos que asistieron a la reunión anual del Colegio de Cirujanos de África Oriental, Central y Meridional (College Of Surgeons of East, Central and Southern Africa, COSECSA) en diciembre de 2017 y a la reunión anual de la Sociedad Quirúrgica de Kenia (Surgical Society of Kenya, SSK) en marzo de 2018. Se encuestaron también a los técnicos de equipos biomédicos (Biomedical Equipment Technicians, BMET) y se recopilaron los registros de mantenimiento en Kenia entre febrero y marzo de 2018. RESULTADOS: Participaron 80 sujetos, 59 cirujanos de 11 países africanos y 21 BMET de Kenia. Se recopilaron 36 registros de mantenimiento. Todos los cirujanos de COSECSA y SSK disponían de ESU, pero menos de la mitad (49%) disponían de equipos de laparoscopia. Como principales problemas se detectaron la reutilización de accesorios desechables en las ESU y las dificultades para disponer de CO2. Más de las tres cuartas partes (78%) de los cirujanos contaban con equipos de mantenimiento para las ESU, pero solo el 59% disponía de mantenimiento para los equipos de laparoscopia en su centro. CONCLUSIÓN: A pesar de la disponibilidad de equipos quirúrgicos, en estos LMIC se detectaron serias dificultades en su mantenimiento, hecho que limita la implementación de la cirugía abierta y laparoscópica.

Percutaneous lung ablation of pulmonary recurrence may improve survival in selected patients undergoing cytoreductive surgery for colorectal cancer with peritoneal carcinomatosis.

PURPOSE: To analyze the outcomes of patients developing pulmonary metastases (PM) following cytoreductive surgery (CRS) and perioperative intra-peritoneal chemotherapy (IPC) for colorectal cancer (CRC) with peritoneal carcinomatosis. PATIENTS AND METHODS: A retrospective analysis of patients undergoing CRS/IPC for CRC from 1996 to 2016 was performed. Lung-specific disease-free and patient overall survival was analyzed. Patients undergoing percutaneous lung ablative therapy (PLAT) for PM were compared to patients receiving systemic chemotherapy alone. RESULTS: 273 patients underwent CRS/IPC for CRC. Of these, 61 (22%) developed PM. Median time to development of PM was 8 months (range 0-52 months) and 41 patients (67%) had metachronous lesions. Twenty-one PM patients underwent PLAT, either by radio-frequency or micro-wave ablation, for an average of 3 lesions (range 1-12) and 13 (62%) had bilobar disease. The most common post-interventional complication was the development of pneumothorax (71%). Overall survival following development of PM was 18 months and higher in patients undergoing PLAT compared to those treated with systemic chemotherapy (26 vs. 14 months, p = 0.03). In eight cases (38%) local tumor recurrence developed post-PLAT. A peritoneal carcinomatosis index >10 (HR 3.48, 95% CI 1.69-7.19), presence of liver metastases (HR 2.49, 95% CI 1.24-5.03) and PLAT (HR 0.43, 95% CI 0.20-0.93) were identified as significant predictors of overall survival following diagnosis of PM. CONCLUSION: PM develop in approximately a fourth of patients undergoing CRS/IPC for CRC. Of these, about 1/3 may be eligible for PLAT. PLAT is a valuable treatment option providing good local control and potentially prolongation of overall survival.

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.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Methodology, Drugs and Bidirectional Chemotherapy.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) combined have been recognized as standard of care for treatment of a subset of patients with peritoneal carcinomatosis (PC). The aim of CRS is to eliminate all macroscopic disease through a series of visceral resections followed by targeting any residual microscopic disease with intraperitoneal chemotherapy, exposing the peritoneal surfaces to a high concentration of chemotherapy with a lower systemic toxicity. Different regimes of intraperitoneal chemotherapy include HIPEC, early postoperative intraperitoneal chemotherapy (EPIC) and bidirectional chemotherapy. The efficacy and modality of treatment with intraperitoneal chemotherapy is dependent on multiple factors including the chosen cytotoxic agent and its pharmacokinetics and pharmacodynamics. There is no standardized methodology for intraperitoneal chemotherapy administration. This review will discuss the pharmacological principles of the various intraperitoneal chemotherapy techniques.

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.

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.

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.

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.

Long term results of RFA to lung metastases from colorectal cancer in 157 patients.

INTRODUCTION: We evaluated the long-term outcomes of 157 patients receiving radiofrequency ablation (RFA) to colorectal cancer (CRC) lung metastases. METHODS: A total of 434 lesions were ablated in 199 procedures over 14 years. Thirty-two out of the 157 patients underwent multiple procedures. Our primary end-points were overall survival, disease free survival, procedure-related mortality and morbidity and various prognostic entities for survival. The survival in three subgroups were analysed: those that had undergone CRC resection and peritonectomy, CRC resection and liver resection and resection of their primary CRC alone. RESULTS: 105 patients (67%) underwent pre-RFA liver resections, 14 patients (9%) underwent pre-RFA peritonectomies and 58 patients underwent only resection of their primary tumour. There were no procedurally related deaths. The mean duration of follow up was 28 months. A chest drain was required in 18.6% of all procedures. The overall median survival was 33.3 months. Survival at 1, 3 and 5 years was 89, 44 and 19.9% respectively. RFA post liver resection, post peritonectomy and post primary CRC resection alone saw median survivals of 38 months, 26 months and 27 months respectively. Tumour free survival at 12 months, 3 years and 5 years was 60.5%, 14.4% and 7% respectively. Lesion size, lesion number and pre-RFA CEA levels were not prognostic factors for overall survival or disease free survival. CONCLUSION: RFA is now an accepted alternative treatment modality for CRC lung metastases in selected groups of patients. RFA has a reasonable morbidity profile and a demonstrated benefit for survival in these patients.

Case of intraperitoneal sepsis secondary to rupture of the appendix on the background of pseudomyxoma peritonei.

INTRODUCTION: Pseudomyxoma peritonei (PMP) is characterised by gelatinous ascites and pools of mucin associated with neoplastic mucinous epithelium within the peritoneal cavity. It can rarely present as acute intraperitoneal sepsis, requiring urgent medical attention. PRESENTATION OF CASE: A 59-year old male was referred to our centre in February 2014 following a diagnostic laparotomy, which showed jelly-like material with occasional epithelial cells. He was listed for peritonectomy in a month's time at our centre. Three weeks later, he was admitted urgently to our hospital due to generalised abdominal pain and watery diarrhoea. Examination at admission was unremarkable. On the following day, he became haemodynamically unstable and was suspected to have intraperitoneal sepsis due to infected PMP. At emergency laparotomy, we found gross intraperitoneal sepsis and did extensive debulking of tumour, appendectomy and extensive division of adhesions. Another laparotomy was done 24 h later for washout. He was discharged three weeks after. DISCUSSION: Although we have done 780 peritonectomy procedures, this was the first patient with this presentation of widerspread intraperitoneal sepsis. Continuous mucous production of appendiceal adenoma can lead to appendiceal rupture. The appendix may decompress by perforation and then reseal. However, one episode of appendiceal rupture can cause bacterial contamination of PMP, leading to sepsis. CONCLUSION: Intraperitoneal sepsis secondary to appendiceal rupture is rare. Hence surgeons may face an emergency of intraperitoneal sepsis during waiting period of planned CRS or as a primary presentation. With combined therapy of CRS and PIC, the prognosis of mucinous appendiceal adenoma is excellent.

Evaluating surrogacy metrics and investigating approval decisions of progression-free survival (PFS) in metastatic renal cell cancer: a systematic review.

BACKGROUND: In metastatic renal cell cancer (mRCC) trials, progression-free survival (PFS) is increasingly used instead of overall survival (OS) as the approval end point. Unlike other solid tumors, there is no published demonstration of what PFS is needed across and by treatment class in mRCC. We determine this and evaluate drug approval decisions in mRCC targeted therapy. METHODS: We identified all randomized, controlled trials reporting PFS and OS in mRCC. Surrogacy metrics were the coefficient of determination and surrogate threshold effect (STE)-the PFS difference needed to predict, with 95% confidence, an OS difference. Data from regulatory commentaries, briefing documents and transcripts were extracted. RESULTS: No exclusively chemotherapy trial met criteria. Of 30 qualifying trials, 11 trials (13 comparisons) used targeted therapy. The all-trials and immunotherapy-only trials analysis failed to demonstrate a STE. The targeted trials, using the more conservative regression analysis demonstrated an STE of 3.9 months and an R(2) of 0.44. Crossover upon progression, control to active treatment, was common. Regulatory approval, accelerated or regular, labeling, interim analyses, and adjudication were context specific. CONCLUSIONS: A new targeted therapy trial showing a PFS difference of 3.9 months can claim an OS benefit in mRCC. PFS surrogacy for OS in metastatic renal cell is not generalizable across all drug classes.

Immigrants' perceptions of the quality of their cancer care: an Australian comparative study, identifying potentially modifiable factors.

BACKGROUND: Recent data show a falling cancer mortality in the general population without a similar shift in immigrant outcomes, leading to a greater cancer burden and mortality for immigrants. Our aims were to compare perceived patterns of care in immigrants and native-born cancer patients. PATIENTS AND METHODS: This was a hospital-based sample of first-generation immigrants and Australian-born Anglo patients in the first year following diagnosis. It was restricted to Chinese, Arabic, or Greek speakers. Eligible participants, recruited via 16 oncology clinics, were over 18, with cancer (any type or stage), and having commenced treatment at least 1 month previously. Five hundred and seventy-one CALD patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. RESULTS: Immigrants had difficulty communicating with the doctor (73% versus 29%) and understanding the health system (38% versus 10%). Differences were found in 'difficulty knowing who to see' (P = 0.0002), 'length of time to confirm diagnosis' (P = 0.04), wanting more choice about a specialist and hospital (P < 0.0001); being offered the opportunity to see a counselor (P < 0.0001); and actually seeing one (P < 0.0001). There were no significant self-reported differences regarding how cancer was detected, time to see a health professional, or type first seen; however, immigrants reported difficulty knowing who to see. Previous studies showed differences in patterns of care according to socioeconomic status (SES) and educational level. Despite adjusting for age, sex, education, marital status, SES, time since diagnosis, and type of cancer, we did not find significant differences. Instead, we found that understanding of the health system and confidence understanding English were important factors. CONCLUSIONS: This study confirmed that immigrants with cancer perceive an inferior quality of cancer care. We highlight potentially modifiable factors including assistance in navigating the health system, translated information, and cultural competency training for health professionals.

Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases.

BACKGROUND: (90)Y microsphere radioembolization is performed by injecting the microspheres through a hepatic artery catheter placed percutaneously via the femoral or brachial artery. This study assessed the efficacy of (90)Y microsphere therapy for patients with unresectable neuroendocrine tumour liver metastases (NETLMs). Potential prognostic factors were analysed for their impact on overall survival. METHODS: A prospectively collected database for patients with NETLMs treated by (90)Y microspheres in two centres from 2003 to 2008 was examined retrospectively. Serial radiographic evidence was collected during follow-up to assess response. RESULTS: Fifty-eight patients were included, 51 of whom had evaluable disease at most recent follow-up. Six patients achieved a complete response, 14 a partial response, 14 had stable disease and 17 had disease progression. Overall survival rates at 1, 2 and 3 years were 86, 58 and 47 per cent respectively; median survival was 36 (range 1-61) months. Extent of tumour involvement, radiographic response to treatment, extrahepatic disease and tumour grade were significant prognostic factors for overall survival. CONCLUSION: (90)Y microsphere radioembolization achieved a radiographic response in a significant proportion of patients with NETLMs.

Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. EXPERIMENTAL APPROACH: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. KEY RESULTS: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. CONCLUSIONS AND IMPLICATIONS: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH: A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS: St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.

Phase I clinical trial of a human idiotypic p53 vaccine in patients with advanced malignancy.

BACKGROUND: The purpose of this study was to induce immunity to p53 by using an idiotypic vaccine, composed of a pool of eight peptides derived from the complimentarity determining regions (CDRs) of human anti-p53 antibodies. PATIENTS AND METHODS: Subjects with advanced malignancy received up to four, monthly intradermal injections of pooled peptides (500 microg of each) admixed with granulocyte-macrophage colony-stimulating factor (GM-CSF; 100 microg). In addition, two sheep and two rabbits were also vaccinated with the pooled peptides. RESULTS: Fourteen subjects were enrolled into the study and six of these completed the vaccination schedule. The vaccine was well tolerated by all subjects and no major adverse events were attributable to the vaccine. All subjects mounted in vivo delayed type hypersensitivity (DTH) responses to two or more of the individual vaccine peptides. Vaccine-induced antibodies specific for peptides 2, 5 or 8 were detected in four of six subjects, and two of these had vaccine-specific, cell-mediated responses. Increasing titers of p53-specific antibodies were found in one patient. No T-cell response to p53 was observed in any of the subjects. All animals developed humoral immunity to the peptides and one of the sheep developed rising serum titers of anti-p53 antibodies. CONCLUSIONS: Vaccination with human antibody CDR regions represents a novel method for inducing human antibodies, which may in turn serve as immunological mimics of p53.