Contour prognostic model for predicting survival after resection of colorectal liver metastases: development and multicentre validation study using largest diameter and number of metastases with RAS mutation status.

BACKGROUND: Most current models for predicting survival after resection of colorectal liver metastasis include largest diameter and number of colorectal liver metastases as dichotomous variables, resulting in underestimation of the extent of risk variation and substantial loss of statistical power. The aim of this study was to develop and validate a new prognostic model for patients undergoing liver resection including largest diameter and number of colorectal liver metastases as continuous variables. METHODS: A prognostic model was developed using data from patients who underwent liver resection for colorectal liver metastases at MD Anderson Cancer Center and had RAS mutational data. A Cox proportional hazards model analysis was used to develop a model based on largest colorectal liver metastasis diameter and number of metastases as continuous variables. The model results were shown using contour plots, and validated externally in an international multi-institutional cohort. RESULTS: A total of 810 patients met the inclusion criteria. Largest colorectal liver metastasis diameter (hazard ratio (HR) 1.11, 95 per cent confidence interval 1.06 to 1.16; P < 0.001), number of colorectal liver metastases (HR 1.06, 1.03 to 1.09; P < 0.001), and RAS mutation status (HR 1.76, 1.42 to 2.18; P < 0.001) were significantly associated with overall survival, together with age, primary lymph node metastasis, and prehepatectomy chemotherapy. The model performed well in the external validation cohort, with predicted overall survival values almost lying within 10 per cent of observed values. Wild-type RAS was associated with better overall survival than RAS mutation even when liver resection was performed for larger and/or multiple colorectal liver metastases. CONCLUSION: The contour prognostic model, based on diameter and number of lesions considered as continuous variables along with RAS mutation, predicts overall survival after resection of colorectal liver metastasis.

Performance of a modified three-level classification in stratifying open liver resection procedures in terms of complexity and postoperative morbidity.

BACKGROUND: Traditional classifications for open liver resection are not always associated with surgical complexity and postoperative morbidity. The aim of this study was to test whether a three-level classification for stratifying surgical complexity based on surgical and postoperative outcomes, originally devised for laparoscopic liver resection, is superior to classifications based on a previously reported survey for stratifying surgical complexity of open liver resections, minor/major nomenclature or number of resected segments. METHODS: Patients undergoing a first open liver resection without simultaneous procedures at MD Anderson Cancer Center (Houston cohort) or the University of Tokyo (Tokyo cohort) were studied. Surgical and postoperative outcomes were compared among three grades: I (wedge resection for anterolateral or posterosuperior segment and left lateral sectionectomy); II (anterolateral segmentectomy and left hepatectomy); III (posterosuperior segmentectomy, right posterior sectionectomy, right hepatectomy, central hepatectomy and extended left/right hepatectomy). RESULTS: In both the Houston (1878 patients) and Tokyo (1202) cohorts, duration of operation, estimated blood loss and comprehensive complication index score differed between the three grades (all P < 0·050) and increased in stepwise fashion from grades I to III (all P < 0·001). Left hepatectomy was associated with better surgical and postoperative outcomes than right hepatectomy, extended right hepatectomy and right posterior sectionectomy, although these four procedures were categorized as being of medium complexity in the survey-based classification. Surgical outcomes of minor open liver resections also differed between the three grades (all P < 0·050). For duration of operation and blood loss, the area under the curve was higher for the three-level classification than for the minor/major or segment-based classification. CONCLUSION: The three-level classification may be useful in studies analysing open liver resection at Western and Eastern centres.

ANTECEDENTES: Las clasificaciones tradicionales de la resección hepática abierta (open liver resection, OLR) por número de segmentos resecados, no siempre se asocian con la complejidad quirúrgica y la morbilidad postoperatoria. El objetivo de este estudio fue comprobar si una clasificación de 3 niveles para estratificar la complejidad quirúrgica en función de los resultados quirúrgicos y postoperatorios, ideada originalmente para la resección hepática laparoscópica, es superior a las clasificaciones basadas en una encuesta descrita previamente para estratificar la complejidad quirúrgica de los procedimientos de OLR, nomenclatura menor/mayor, o número de segmentos resecados. MÉTODOS: Se estudiaron pacientes sometidos a una primera OLR sin otros procedimientos quirúrgicos concomitantes en el hospital MD Anderson (cohorte de Houston) o en la Universidad de Tokio (cohorte de Tokio). Se compararon los resultados quirúrgicos y postoperatorios entre 3 grados: I (resección limitada para el segmento anterolateral o posterosuperior y seccionectomía izquierda); II (segmentectomía anterolateral y hepatectomía izquierda); III (segmentectomía posterosuperior, seccionectomía posterior derecha, hepatectomía derecha, hepatectomía central y hepatectomía ampliada izquierda/derecha). RESULTADOS: En ambas cohortes de Houston (n = 1.878) y Tokio (n = 1.202), el tiempo operatorio, las pérdidas estimadas de sangre, y el índice de complejidad integral (comprehensive complication index) variaba en los 3 grados (todos P < 0,05) y aumentaba paso a paso desde los grados I a III (todos P < 0,05). La hepatectomía izquierda se asociaba con mejores resultados quirúrgicos y postoperatorios que la hepatectomía derecha, hepatectomía derecha ampliada, y seccionectomía posterior derecha, aunque estos cuatro procedimientos fueron categorizados como de complejidad intermedia en la clasificación basada en la encuesta. Los resultados quirúrgicos de las OLRs menores también variaron en los 3 grados (todos P < 0,05). Para el tiempo operatorio y la pérdida sanguínea, el área bajo la curva fue mayor para la clasificación de 3 niveles en el estudio actual, que para la clasificación menor/mayor o la clasificación basada en los segmentos. CONCLUSIÓN: La clasificación en 3 niveles puede ser útil en estudios que analizan las resecciones hepáticas abiertas en centros occidentales y orientales.

Comparison of oncological outcomes after open and laparoscopic re-resection of incidental gallbladder cancer.

BACKGROUND: The safety and oncological efficacy of laparoscopic re-resection of incidental gallbladder cancer have not been studied. This study aimed to compare laparoscopic with open re-resection of incidentally discovered gallbladder cancer while minimizing selection bias. METHODS: This was a multicentre retrospective observational cohort study of patients with incidental gallbladder cancer who underwent re-resection with curative intent at four centres between 2000 and 2017. Overall survival (OS) and recurrence-free survival (RFS) were analysed by intention to treat. Inverse probability of surgery treatment weighting using propensity scoring was undertaken. RESULTS: A total of 255 patients underwent re-resection (190 open, 65 laparoscopic). Nineteen laparoscopic procedures were converted to open operation. Surgery before 2011 was the only factor associated with conversion. Duration of hospital stay was shorter after laparoscopic re-resection (median 4 versus 6 days; P < 0·001). Three-year OS rates for laparoscopic and open re-resection were 87 and 62 per cent respectively (P = 0·502). Independent predictors of worse OS were residual cancer found at re-resection (hazard ratio (HR) 1·91, 95 per cent c.i. 1·17 to 3·11), blood loss of at least 500 ml (HR 1·83, 1·23 to 2·74) and at least four positive nodes (HR 3·11, 1·46 to 6·65). In competing-risks analysis, the RFS incidence was higher for laparoscopic re-resection (P = 0·038), but OS did not differ between groups. Independent predictors of worse RFS were one to three positive nodes (HR 2·16, 1·29 to 3·60), at least four positive nodes (HR 4·39, 1·96 to 9·82) and residual cancer (HR 2·42, 1·46 to 4·00). CONCLUSION: Laparoscopic re-resection for selected patients with incidental gallbladder cancer is oncologically non-inferior to an open approach. Dissemination of advanced laparoscopic skills and timely referral of patients with incidental gallbladder cancer to specialized centres may allow more patients to benefit from this operation.

ANTECEDENTES: No se conoce la seguridad y la eficacia oncológica de la re-resección laparoscópica del cáncer incidental de vesícula biliar. Este estudio tiene como objetivo comparar las re-resecciones del cáncer incidental de vesícula biliar por vía laparoscópica y vía abierta, minimizando el sesgo de selección. MÉTODOS: Estudio de cohortes observacional, retrospectivo y multicéntrico de pacientes con cáncer incidental de vesícula biliar que se sometieron a una re-resección con intención curativa en 4 centros entre 2000 y 2017. Se analizó la supervivencia global (overall survival, OS) y la supervivencia libre de recidiva (recurrence free survival, RFS) según intención de tratamiento. Se calculó la probabilidad inversa de la ponderación del tratamiento quirúrgico utilizando puntuación de propensión. RESULTADOS: Se incluyeron 255 pacientes con re-resección (190 por vía abierta y 65 por vía laparoscópica). Se convirtieron 19 pacientes del grupo laparoscópico. El único factor relacionado con la conversión fue la realización de la cirugía antes de año 2011. La mediana de la estancia hospitalaria fue más corta tras la re-resección laparoscópica (4 versus 6 días; P < 0,001). La OS a tres años fue del 87% y del 62% (P = 0,502) para las re-resecciones laparoscópicas y abiertas, respectivamente). Los factores predictivos independientes relacionados con una peor OS fueron el hallazgo de cáncer residual en el momento de la re-resección (cociente de riesgos instantáneos, hazard ratio, HR 1,91; i.c. del 95% 1,17-3,11), una pérdida hemática > 500 ml (HR 1,83; i.c. del 95% 1,23-2,74) y la presencia de ≥ 4 ganglios positivos (HR 3,11; i.c. del 95% 1,46-6,65). En el análisis de riesgo competitivo, la RFS fue mayor para la resección laparoscópica (P = 0,038), pero no hubo diferencias en la OS entre ambos grupos. Los factores predictivos independientes de peor RFS fueron la detección de 1-3 ganglios positivos (HR 2,16; i.c. del 95% 1,29-3,60), ≥ 4 ganglio positivos (HR 4,39; i.c. del 95% 1,96-9,82) y el cáncer residual (HR 2,42; i.c. de 95% 1,46-4,0). CONCLUSIÓN: En pacientes seleccionados, los resultados oncológicos de la re-resección laparoscópica de un cáncer incidental de vesícula biliar no son inferiores a los que se obtienen por vía abierta. Una mayor difusión de las técnicas laparoscópicas avanzadas y una oportuna derivación de los pacientes con cáncer de vesícula biliar incidental a centros especializados podrían permitir que un mayor número de pacientes se beneficiaran de este abordaje.

Biomarkers in colorectal liver metastases.

BACKGROUND: Despite a 5-year overall survival rate of 58 per cent after liver resection for colorectal liver metastases (CLMs), more than half of patients develop recurrence, highlighting the need for accurate risk stratification and prognostication. Traditional prognostic factors have been superseded by newer outcome predictors, including those defined by the molecular origin of the primary tumour. METHODS: This review synthesized findings in the literature using the PubMed database of articles in the English language published between 1998 and 2017 on prognostic and predictive biomarkers in patients undergoing resection of CLMs. RESULTS: Responses to preoperative chemotherapy define prognosis in patients undergoing CLM resection. There are differences by embryological origin too. Somatic mutations in the proto-oncogenes KRAS and NRAS are associated with positive surgical margins and tumour regrowth after ablation. Other mutations (such as BRAF) and co-occurring mutations in RAS/TP53 and APC/PIK3CA have emerged as important biomarkers that determine an individual patient's tumour biology and may be used to predict outcome after CLM resection. CONCLUSION: Knowledge of somatic mutations can guide the use of preoperative therapy, extent of surgical margin and selection for ablation alone.

Prognostic impact of perihepatic lymph node metastases in patients with resectable colorectal liver metastases.

BACKGROUND: Although perihepatic lymph node metastases (PLNMs) are known to be a poor prognosticator for patients with colorectal liver metastases (CRLMs), optimal management remains unclear. This study aimed to determine the risk factors for PLNMs, and the survival impact of their number and location in patients with resectable CRLMs. METHODS: Data on patients with CRLM who underwent hepatectomy during 2003-2014 were analysed retrospectively. Recurrence-free (RFS) and overall (OS) survival were calculated according to presence, number and location of PLNMs. Risk factors for PLNM were evaluated by logistic regression analysis. RESULTS: Of 1485 patients, 174 underwent lymphadenectomy, and 54 (31·0 per cent) had PLNM. Ten patients (5·7 per cent) who had lymphadenectomy and 176 (13·4 per cent) who did not underwent repeat hepatectomy. Survival of patients with PLNM was significantly poorer than that of patients without (RFS: 5·3 versus 13·8 months, P < 0·001; OS: 20·5 versus 71·3 months; P < 0·001). Median OS was significantly better in patients with para-aortic versus hepatoduodenal ligament PLNMs (58·2 versus 15·5 months; P = 0·011). Patients with three or more PLNMs had significantly worse median OS than those with one or two (16·3 versus 25·4 months; P = 0·039). The presence of primary tumour lymph node metastases (odds ratio 2·35; P = 0·037) and intrahepatic recurrence requiring repeat hepatectomy (odds ratio 5·61; P = 0·012) were significant risk factors for PLNM on multivariable analysis. CONCLUSION: Patients undergoing repeat hepatectomy and those with primary tumour lymph node metastases are at significant risk of PLNM. Although PLNM is a poor prognostic factor independent of perihepatic lymph node station, patients with one or two PLNMs have a more favourable outcome than those with more PLNMs.

Prognostic value of carbohydrate antigen 19-9 in patients undergoing resection of biliary tract cancer.

BACKGROUND: The clinical significance of abnormally high levels of carbohydrate antigen (CA) 19-9 after resection of biliary tract cancer (BTC) is not well established. The aim of this study was to determine the prognostic value of CA19-9 normalization in patients undergoing resection of BTC with curative intent. METHODS: Patients with BTC undergoing resection with curative intent (1996-2015) were divided into those with normal preoperative CA19-9 level (normal CA19-9 group), those with an abnormally high preoperative CA19-9 level (over 37 units/ml) and normal postoperative CA19-9 level (normalization group), and those with an abnormally high preoperative CA19-9 level and abnormally high postoperative CA19-9 level (non-normalization group). Overall survival (OS) was analysed and predictors of OS were determined. RESULTS: The normal CA19-9 group (180 patients) and normalization group (74) had better OS than the non-normalization group (58) (3-year OS rate 70·4, 73 and 31 per cent respectively; both P < 0·001). The normal CA19-9 and normalization groups had equivalent OS (P = 0·880). On multivariable analysis, factors associated with worse OS were lymph node metastases (hazard ratio (HR) 1·78; P = 0·014) and abnormally high postoperative CA19-9 level (HR 3·16; P < 0·001). In the normalization group, OS did not differ after R0 versus R1 resection (3-year OS rate 69 versus 62 per cent respectively; P = 0·372); in the non-normalization group, patients with R1 resection had worse OS (3-year OS rate 36 and 20 per cent for R0 and R1 respectively; P = 0·032). CONCLUSION: Non-normalization of CA19-9 level after resection of BTC with curative intent was associated with worse OS. R1 resection was associated with a particularly poor prognosis when CA19-9 levels did not normalize.

Local tumour progression after percutaneous ablation of colorectal liver metastases according to RAS mutation status.

BACKGROUND: Percutaneous ablation is a common treatment for colorectal liver metastasis (CLM). However, the effect of rat sarcoma viral oncogene homologue (RAS) mutation on outcome after ablation of CLMs is unclear. METHODS: Patients who underwent image-guided percutaneous ablation of CLMs from 2004 to 2015 and had known RAS mutation status were analysed. Patients were evaluated for local tumour progression as observed on imaging of CLMs treated with ablation. Multivariable Cox regression analysis was performed to determine factors associated with local tumour progression-free survival. RESULTS: The study included 92 patients who underwent ablation of 137 CLMs. Thirty-six patients (39 per cent) had mutant RAS. Rates of local tumour progression were 14 per cent (8 of 56) for patients with wild-type RAS and 39 per cent (14 of 36) for patients with mutant RAS (P = 0·007). The actuarial 3-year local tumour progression-free survival rate after percutaneous ablation was worse in patients with mutant RAS than in those with wild-type RAS (35 versus 71 per cent respectively; P = 0·001). In multivariable analysis, negative predictors of local tumour progression-free survival were a minimum ablation margin of less than 5 mm (hazard ratio (HR) 2·48, 95 per cent c.i. 1·31 to 4·72; P = 0·006) and mutant RAS (HR 3·01, 1·60 to 5·77; P = 0·001). CONCLUSION: Mutant RAS is associated with an earlier and higher rate of local tumour progression in patients undergoing ablation of CLMs.

Transthoracic Port Placement Increases Safety of Total Laparoscopic Posterior Sectionectomy.

BACKGROUND: Anatomic posterior sectionectomy is performed infrequently due to the challenges of controlling the right posterior portal pedicle (RPPP) while preserving the anterior pedicle (RAPP), difficulty of visualizing the drainage of the right hepatic vein into the IVC, and the potential for significant blood loss during the caval and hepatovenous dissection. PATIENT: A 62-year-old woman with three liver metastases to SVI and SVII from sigmoid colon cancer underwent five cycles of neoadjuvant chemotherapy with FOLFOX and bevacizumab with good response. She underwent a "Primary First" robotic low anterior rectosigmoid resection followed by a laparoscopic posterior sectionectomy. TECHNIQUE: The patient was placed in a Modified French Position. As previously described, a transthoracic trocar was placed for optimal laparoscopic visualization and access of the superior retrohepatic IVC and drainage of the right hepatic vein into IVC. Intraoperative ultrasound was crucial to assess tumor location, define transection plane, and preserve flow to RAPP before division of RPPP. The parenchymal transection follows an oblique angle and exposes the right hepatic vein. CONCLUSIONS: Transthoracic port placement augments the safety of the dissection along the IVC inferiorly and the right hepatic vein superiorly due to direct visualization. Also, it provides a direct instrument-to-target axis without the typical fulcrum of dissecting the postero/superior liver. Laparoscopic ultrasound is critical to confirm preserved flow to the RPPP and guide the parenchymal transection. Liver volumetry should be obtained before surgery to determine adequate future liver remnant if conversion to a right lobectomy becomes necessary.

Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer.

BACKGROUND: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). METHODS: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. RESULTS: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. CONCLUSIONS: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.

Association between KRAS mutation and lung metastasis in advanced colorectal cancer.

BACKGROUND: KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development. METHODS: We retrospectively evaluated data from patients with mCRC whose tumour was tested for KRAS mutation from 2008 to 2010. The relationships of KRAS mutational status with time-to-lung metastasis (TTLM) and overall survival (OS) were analysed. RESULTS: Of the 494 patients identified, 202 (41%) had tumours with KRAS mutation. KRAS mutations were associated with a shorter TTLM (median 15.2 vs 22.4 months; hazard ratio=1.40; P=0.002) and a two-fold greater odds of developing lung metastases during the disease course in patients with liver-limited mCRC at diagnosis (72 vs 56%, P=0.007). Overall survival did not differ by KRAS status. CONCLUSIONS: Lung metastasis was more likely to develop during the disease course in patients whose tumour had a KRAS mutation than in those whose tumour did not have a KRAS mutation. This finding may have an impact on decision making for surgical resection of metastatic disease.

Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer.

BACKGROUND: High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations. METHODS: We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used. RESULTS: High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03-2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2Rα, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR. CONCLUSIONS: High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.

Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases.

BACKGROUND: In patients with advanced colorectal cancer, KRAS mutation status predicts response to treatment with monoclonal antibody targeting the epithelial growth factor receptor (EGFR). Recent reports have provided evidence that KRAS mutation status has prognostic value in patients with resectable colorectal liver metastases (CLM) irrespective of treatment with chemotherapy or anti-EGFR therapy. A meta-analysis was undertaken to clarify the impact of KRAS mutation on outcomes in patients with resectable CLM. METHODS: PubMed, Embase and Cochrane Library databases were searched systematically to identify full-text articles reporting KRAS-stratified overall (OS) or recurrence-free (RFS) survival after resection of CLM. Hazard ratios (HRs) and 95 per cent c.i. from multivariable analyses were pooled in meta-analyses, and a random-effects model was used to calculate weight and overall results. RESULTS: The search returned 355 articles, of which 14, including 1809 patients, met the inclusion criteria. Eight studies reported OS after resection of CLM in 1181 patients. The mutation rate was 27.6 per cent, and KRAS mutation was negatively associated with OS (HR 2.24, 95 per cent c.i. 1.76 to 2.85). Seven studies reported RFS after resection of CLM in 906 patients. The mutation rate was 28.0 per cent, and KRAS mutation was negatively associated with RFS (HR 1.89, 1.54 to 2.32). CONCLUSION: KRAS mutation status is a prognostic factor in patients undergoing resection of colorectal liver metastases and should be considered in the evaluation of patients having liver resection.

Portal vein embolization improves rate of resection of extensive colorectal liver metastases without worsening survival.

BACKGROUND: Most patients requiring an extended right hepatectomy (ERH) have an inadequate standardized future liver remnant (sFLR) and need preoperative portal vein embolization (PVE). However, the clinical and oncological impact of PVE in such patients remains unclear. METHODS: All consecutive patients presenting at the M. D. Anderson Cancer Center with colorectal liver metastases (CLM) requiring ERH at presentation from 1995 to 2012 were studied. Surgical and oncological outcomes were compared between patients with adequate and inadequate sFLRs at presentation. RESULTS: Of the 265 patients requiring ERH, 126 (47·5 per cent) had an adequate sFLR at presentation, of whom 123 underwent a curative resection. Of the 139 patients (52·5 per cent) who had an inadequate sFLR and underwent PVE, 87 (62·6 per cent) had a curative resection. Thus, the curative resection rate was increased from 46·4 per cent (123 of 265) at baseline to 79·2 per cent (210 of 265) following PVE. Among patients who underwent ERH, major complication and 90-day mortality rates were similar in the no-PVE and PVE groups (22·0 and 4·1 per cent versus 31 and 7 per cent respectively); overall and disease-free survival rates were also similar in these two groups. Of patients with an inadequate sFLR at presentation, those who underwent ERH had a significantly better median overall survival (50·2 months) than patients who had non-curative surgery (21·3 months) or did not undergo surgery (24·7 months) (P = 0·002). CONCLUSION: PVE enabled curative resection in two-thirds of patients with CLM who had an inadequate sFLR and were unable to tolerate ERH at presentation. Patients who underwent curative resection after PVE had overall and disease-free survival rates equivalent to those of patients who did not need PVE.

Effect of specialist decision-making on treatment strategies for colorectal liver metastases.

BACKGROUND: One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver-only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess. Improved surgical technique and better chemotherapeutic manipulation of metastatic disease has increased the number of patients eligible for potentially curative resection of colorectal liver metastases. The rapid evolution in this field suggests that non-specialist decision-making may lead to inappropriate management. This study aimed to assess the management of colorectal liver metastases by non-liver surgeons. METHODS: All patients who underwent chemotherapy with palliative intent for metastatic colorectal cancer at a regional oncology centre between 1 January and 31 December 2009 were identified from a prospectively maintained local database. Six resectional liver surgeons blinded to patient management and outcome reviewed pretreatment imaging and assigned each scan a score based on their own management choice. A consensus decision was reached on the appropriateness of palliative chemotherapy. RESULTS: One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver-only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess [corrected]. Tumours in 33 patients (63 per cent) were considered potentially resectable, with a high level of interobserver agreement (κ = 0 · 577). When individual approach to management was considered, interobserver agreement was less marked (κ = 0 · 378). CONCLUSION: Management of patients with colorectal liver metastases without the involvement of a specialist liver multidisciplinary team can lead to patients being denied potentially curative treatments. Management of these patients must involve a specialist liver surgeon to ensure appropriate management.

Hepatectomy for recurrent colorectal liver metastases after radiofrequency ablation.

BACKGROUND: The results of surgery for recurrent colorectal liver metastases (CLM) after radiofrequency ablation (RFA) have not been evaluated. METHODS: From 1993 to 2009, data on patients who underwent resection or RFA for recurrent CLM were collected prospectively. Inclusion criteria for this study were RFA as initial treatment for CLM and resection of recurrent CLM after RFA. Postoperative results and oncological outcomes were analysed. RESULTS: Twenty-eight patients (median number of tumours 1 (1-3), median size 2·8 (2·0-4·0) cm) met the inclusion criteria. Of these, 22 had recurrence at the site of RFA only, two developed new lesions, whereas four had both recurrent and de novo metastases. At the time of resection, patients had a median of 1 (1-13) CLM with a median maximum tumour diameter of 5·0 (1·8-11·0) cm, significantly larger than at the time of RFA (P = 0·021). Ninety-day postoperative morbidity and mortality rates were 46 per cent (13 of 28) and 7 per cent (2 of 28) respectively. After a median follow-up of 35 (0-70) months, 3-year overall and disease-free survival rates calculated by Kaplan-Meier analysis were 60 and 29 per cent respectively. Plasma carcinoembryonic antigen level over 5 ng/ml at the time of resection and a rectal primary tumour were associated with worse survival (P = 0·041 and P = 0·021 respectively). CONCLUSION: Resection for recurrence after RFA is associated with significant morbidity and modest long-term benefit.

A human tumor necrosis factor p75 receptor agonist stimulates in vitro T cell proliferation but does not produce inflammation or shock in the baboon.

Tumor necrosis factor (TNF) is a potentially useful adjunct to anticancer therapies. However, the clinical utility of TNF has been limited by generalized toxicity and hypotension. Recently, studies have begun to dissect the individual proinflammatory and immunologic responses that result from TNF binding to its two cellular receptors, p55 and p75, in an attempt to develop TNF receptor agonists with reduced systemic toxicity. To evaluate a p75 receptor selective TNF mutant (p75TNF), TNF and p75TNF were administered to healthy anesthetized baboons. Intravenous infusion of the p75TNF produced none of the hemodynamic changes seen after the infusion of TNF. Infusion of p75TNF also failed to induce the plasma appearance of interleukins 6 and 8. However, p75TNF enhanced in vitro baboon thymocyte proliferation to concanavalin A, and infusion of p75TNF resulted in increased soluble p55 and p75 receptor plasma concentrations. Local skin necrosis and tissue neutrophil infiltration were seen after subcutaneous injections of TNF and p55TNF. Subcutaneous injection of p75TNF did not result in skin necrosis but did result in a modest dermal infiltration of lymphocytes and macrophages. The findings suggest that p75TNF may stimulate T cell proliferation without the systemic and local toxicity seen with TNF.

The Addition of Bevacizumab to Oxaliplatin-Based Chemotherapy: Impact Upon Hepatic Sinusoidal Injury and Thrombocytopenia.

Background: Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI. Methods: Two cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test. Results: In the exploratory cohort, the bevacizumab-treated patients (n = 138) compared with the nonbevacizumab-treated patients (n = 46) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (<150 000/mm3, P = .04). In the confirmatory cohort (106 bevacizumab arm and 94 placebo arm), the median time to a spleen enlargement of 30% or more was 7.6 vs 5.4 (P = .01), and six-month cumulative incidence of thrombocytopenia (platelets < 100 000/mm3) was 19% vs 51% (P < .001) for bevacizumab compared with placebo. The development of an increasing spleen size was associated with the risk of either grade 1 or grade 2 thrombocytopenia (P < .001). The cumulative rate of grade 1 or grade 2 thrombocytopenia was statistically less in the bevacizumab arm, with six-month grade 2 thrombocytopenia rates of 4% vs 23% (P < .001). Patients with a large spleen prior to chemotherapy initiation appeared to be at highest risk of this toxicity. Conclusion: In metastatic CRC, the addition of bevacizumab to oxaliplatin-based chemotherapy reduces the frequency of splenic enlargement and the rate of thrombocytopenia.