Multicentre analysis of the learning curve for laparoscopic liver resection of the posterosuperior segments.

BACKGROUND: Laparoscopic liver resection demands expertise and a long learning curve. Resection of the posterosuperior segments is challenging, and there are no data on the learning curve. The aim of this study was to evaluate the learning curve for laparoscopic resection of the posterosuperior segments. METHODS: A cumulative sum (CUSUM) analysis of the difficulty score for resection was undertaken using patient data from four specialized centres. Risk-adjusted CUSUM analysis of duration of operation, blood loss and conversions was performed, adjusting for the difficulty score of the procedures. A receiver operating characteristic (ROC) curve was used to identify the completion of the learning curve. RESULTS: According to the CUSUM analysis of 464 patients, the learning curve showed an initial decrease in the difficulty score followed by an increase and, finally, stabilization. More patients with cirrhosis or previous surgery were operated in the latest phase of the learning curve. A smaller number of wedge resections and a larger number of anatomical resections were performed progressively. Dissection using a Cavitron ultrasonic surgical aspirator and the Pringle manoeuvre were used more frequently with time. Risk-adjusted CUSUM analysis showed a progressive decrease in operating time. Blood loss initially increased slightly, then stabilized and finally decreased over time. A similar trend was found for conversions. The learning curve was estimated to be 40 procedures for wedge and 65 for anatomical resections. CONCLUSION: The learning curve for laparoscopic liver resection of the posterosuperior segments consists of a stepwise process, during which accurate patient selection is key.

ANTECEDENTES: La resección hepática laparoscópica exige experiencia y una larga curva de aprendizaje. La resección de los segmentos posterosuperiores (PS) es un reto, y no hay datos acerca de la curva de aprendizaje (learning curve, LC). El objetivo de este estudio fue evaluar la LC de la resección laparoscópica de los segmentos PS. MÉTODOS: Se realizó un análisis CUSUM de la puntuación de dificultad (difficulty score, DS) de la resección en pacientes de 4 centros especializados. La técnica CUSUM se ajustó al riesgo (risk-adjusted CUSUM, RA-CUSUM) para el tiempo operatorio, la pérdida de sangre y las conversiones a cirugía abierta ajustando según la DS de los procedimientos. Se utilizó una curva ROC para identificar el momento en el que se consideró que la LC había sido completada. RESULTADOS: De acuerdo con el análisis CUSUM de los 464 pacientes incluidos, se observó una DS baja al inicio, que posteriormente se fue incrementando hasta llegar a una estabilización. En la última fase de la LC se operaron más pacientes con cirrosis o cirugía previa. De forma progresiva se fueron reduciendo el número de resecciones hepáticas en cuña y aumentando el de resecciones anatómicas. A lo largo del tiempo se introdujo el CUSA y la maniobra de Pringle con mayor frecuencia. El RA-CUSUM mostró una reducción progresiva del tiempo operatorio. La pérdida de sangre inicialmente aumentó ligeramente, luego se estabilizó y finalmente disminuyó con el tiempo. Una tendencia similar se observó para las conversiones. La LC se estimó en 40 casos para las resecciones en cuña y en 65 casos para las resecciones anatómicas. CONCLUSIÓN: La LC de la resección hepática laparoscópica de los segmentos PS es un proceso paso a paso durante el cual la selección del paciente es clave.

Current management of peritoneal carcinomatosis from colorectal cancer.

Approximately 5% of colorectal cancer (CRC) patients will develop peritoneal carcinomatosis (PC) in the absence of systemic disease. Iconographic staging is only moderately accurate, but may be improved by diffusion weighted MR imaging. Systemic chemotherapy prolongs survival in PC patients, but is less active than in patients with hepatic metastasis. Intraperitoneal chemotherapy is based mainly on pharmacokinetic and pharmacodynamic observations. An increasing number of patients is treated with cytoreductive surgery followed by hyperthermic intraperitoneal chemoperfusion (HIPEC). Provided a complete resection can be performed, a median survival of almost three years may be achieved. The combined procedure is, however, associated with potentially significant morbidity. In patients with resected CRC at high risk of peritoneal recurrence, planned repeat surgery with "prophylactic". HIPEC has been shown to significantly reduce the risk of peritoneal recurrence. Cytoreduction and HIPEC should be a component of a multimodal approach, including neoadjuvant and adjuvant therapeutic regimens. Several questions remain, such as the specific role of HIPEC versus surgery alone, and the results of ongoing randomized trials are expected to provide important answers.

The low-molecular-weight heparin, nadroparin, inhibits tumour angiogenesis in a rodent dorsal skinfold chamber model.

BACKGROUND: Recently, low-molecular-weight heparins (LMWHs) were found to confer a survival advantage in cancer patients. The mechanism underlying this observation is unclear, but may involve inhibition of tumour angiogenesis. We aimed to examine the effects of nadroparin on tumour angiogenesis using a dorsal skinfold window chamber model in the Syrian hamster. METHODS: AMel-3 and HAP-T1 tumours were grown in donor animals and fragments implanted in the window chambers. Animals (N=46) were treated with 200 IU of nadroparin or saline for 10 days. Repeated intravital fluorescence microscopy was performed to calculate functional microcirculatory parameters: number (N) and length (L) of microvessels, vascular area fraction (AF), and red blood cell velocity (V). Microvessel density (MVD), fractal dimension, and pericyte coverage were assessed histologically. RESULTS: Active angiogenesis was observed in control animals, resulting in a significant increase in N, L, and AF. In nadroparin-treated animals, however, N and L did not increase whereas AF decreased significantly. Both groups showed an initial increase in V, but nadroparin treatment resulted in an earlier decrease in red blood cell velocity over time. Compared with control animals, nadroparin-treated animals showed a significantly lower MVD and fractal dimension but significantly higher pericyte coverage index (PCI). CONCLUSIONS: Taken together, these results suggest that the LMWH nadroparin inhibits tumour angiogenesis and results in microvessel normalisation.

Surgical trauma, minimal residual disease and locoregional cancer recurrence.

The persistence of residual tumour is associated with the histology and stage of the primary cancer, the completeness and quality of surgery, and postoperative events such as anastomotic leakage or entrapment of cells in exudating wound surfaces. At present, there is no clinical evidence that the use of laparoscopic techniques adversely influences the risk of residual disease. The inflammatory process associated with surgery shares a number of central mediators and pathways with tumour growth and invasiveness. Both cellular components (mainly macrophages and fibroblasts) and humoral factors associated with inflammation have been shown to enhance tumour growth in numerous preclinical studies. Tumour foci at a distance from the main cancer are kept in a dormant state by a range of anti-angiogenic mediators produced by the main cancer. Preclinical studies have shown that removal of the primary cancer reactivates proliferative and metastatic pathways in the residual tumour. Clinically, this phenomenon has been proposed as underlying the observed rapid systemic relapse after surgery in young node positive breast cancer patients. Strategies proposed to prevent residual disease encompass avoidance of tumour spill and minimization of surgical trauma and related inflammation. Efforts to remove or kill free intraperitoneal cells by local antiseptic or cytotoxic regimens have met only limited clinical success. Specific targeted therapy aimed at inhibiting the inflammatory response, tumour cell adhesion, or the metastatic phenotype of dormant cells appears promising in preclinical models and needs to be addressed in future clinical trials.

Pharmacodynamic aspects of intraperitoneal cytotoxic therapy.

The rationale for ip administration as an adjunct to surgery is firmly based on theoretical and pharmacokinetic grounds. The superiority of combined ip and intravenous chemotherapy over intravenous chemotherapy alone has been established in randomized trials in stage IIIc ovarian cancer patients. Intraoperative ip cytotoxic therapy results in a definite pharmacological advantage, since high peritoneal concentrations are achieved with limited systemic absorption. At present, however, it is not clearly established to what extent this PK advantage will result in enhanced anticancer activity and, ultimately, in a survival benefit. Preclinical models show that direct penetration into tumour tissue is limited to a few millimeters. Furthermore, the limited exposure time of intraoperative chemoperfusion could limit cytotoxic activity despite high local concentrations. Among the cytotoxic agents currently used, the pharmacodynamic aspects of the platinum compounds are the best studied both with and without associated hyperthermia. Newer agents such as the taxanes and the camptothecins appear promising for ip chemoperfusion during or immediately after surgery. Pharmacodynamic aspects of HIPEC needing further preclinical study-including mathematical modeling - are the establishment of tumour tissue penetration of the newer agents and its relation to hyperthermia, the definition of the relative contribution of direct penetration versus vascular supply by absorbed drug, and the efficacy of combined ip and intravenous regimens. Ultimately, however, randomised trials of ip chemotherapy with surgery will have to provide the evidence base to further build upon.

Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer.

BACKGROUND: Surgical treatment of intra-abdominal cancer is often followed by local recurrence. In a subgroup of patients, local recurrence is the sole site of disease, reflecting biologically low-grade malignancy. These patients might, therefore, benefit from local treatment. Recently, debulking surgery followed by hyperthermic chemoperfusion has been proposed in the treatment of locally advanced or recurrent intra-abdominal cancer. This paper reviews the rationale and assesses the currently accepted indications for and results of this novel treatment. METHODS: A systematic web-based literature review was performed. Information was also retrieved from handbooks, congress abstracts and ongoing clinical trials. RESULTS: A growing body of experimental evidence supports the use of hyperthermia combined with chemotherapy as an adjunct to cytoreductive surgery. Randomized clinical trials are available to support its use in the treatment and prevention of peritoneal carcinomatosis following resection of pathological tumour stage pT3 or pT4 gastric cancer; several other phase III trials are ongoing. Numerous phase I and II trials have reported good results for various other indications, with acceptable morbidity and mortality rates. Case mix, limited patient numbers and absence of a standardized technique are, however, a drawback in many of these series. CONCLUSION: For a subgroup of patients with peritoneal cancer without distant disease, debulking surgery followed by hyperthermic chemoperfusion may offer a chance of cure or palliation in this otherwise untreatable condition. This novel therapy should, however, be considered experimental until further results from ongoing phase III trials become available.