Hassan Z. Malik

Combined Ablation and Resection (CARe) as an Effective Parenchymal Sparing Treatment for Extensive Colorectal Liver Metastases

Background Combined intra-operative ablation and resection (CARe) is proposed to treat extensive colorectal liver metastases (CLM). This multicenter study was conducted to evaluate overall survival (OS), local recurrence-free survival (LRFS), hepatic recurrence-free survival (HRFS) and progression-free survival (PFS), to identify factors associated with survival, and to report complications. Materials and Methods Four centers combined retropectively their clinical experiences regarding CLM treated by CARe. CLM characteristics, pre- and post-operative chemotherapy regimens, surgical procedures, complications and survivals were analyzed. Results Of the 288 patients who received CARe, 210 (73%) had synchronous and 255 (88%) had bilateral CLM. Twenty-two patients (8%) had extrahepatic disease. Median follow-up was 3.17 years (95%CI 2.83–4.08). Median OS was 3.33 years (95%CI 3.08–4.17) and 5-year OS was 37% (95%CI 29–45). One- and 5-year LRFS from ablated lesions were 87.9% (95%CI 83.3–91.2) and 78.0% (95%CI 71–83), respectively. Median HRFS and PFS were 14 months (95%CI 11–18) and 9 months (95%CI 8–11), respectively. One hundred patients experienced complications: 29 grade I, 68 grade II–III–IV, and three deaths. In the multivariate models adjusted for center, the occurrence of complications was confirmed as a major independent factor associated with 3-year OS (HR 1.80; Pu200a=u200a0.008). Five-year OS was 25.6% (95%CI 14.9–37.6) for patients with complications and 45% (95%CI 33.3–53.4) for patients without. Conclusions Recent strategies facing advanced CLM include non-anatomic resections, portal-induced hypertrophy of the future remnant liver and aggressive medical preoperative treatments. CARe has the qualities of an approach that allows effective tumor clearance while maintaining good tolerance for the patient.

Evolution of surgical microwave ablation for the treatment of colorectal cancer liver metastasis: review of the literature and a single centre experience

Surgical resection is the gold standard treatment for colorectal liver metastasis, with reported five-year survival rates of 40xa0%. Unfortunately, despite progress in systemic therapies and surgical techniques, only 20–30xa0% of patients can be offered this potentially curative treatment modality. Ablative therapies have recently been suggested to treat unresectable lesions or to extend the margins of resectability. Additionally, cases of local recurrence after hepatic surgery might require alternative strategies and options for re-intervention. Microwave ablation (MWA) has recently become a matter of particular interest for such indications. We, herein, present a review of the literature published between January 1999 and June 2013 from a database search with the following keywords: microwave, ablation, liver metastases, colorectal neoplasm, resection, hepatectomy, colonic neoplasm, cancer. Furthermore, we provide insight based on our own data for 28 consecutive patients who underwent hepatic resection combined with MWA from 2005 to 2012 in a single centre.

Colorectal Liver Metastases: A Critical Review of State of the Art

Background: Over 50% of patients with colorectal cancer will develop liver metastases. Only a minority of patients present with technically resectable disease. Around 40% of those undergoing surgical resection are alive five years after their diagnosis compared with less than 1% for those with disseminated disease treated with systemic chemotherapy. Surgical resection remains the only possibility for long-term survival for these patients and great efforts have been made to increase the rates of resection whilst improving long-term outcomes. Summary: This review considers current technical and oncological criteria for resection, as well as targeted approaches to stratify underlying tumor biology in order to better predict long-term benefit. The role of neoadjuvant and perioperative systemic chemotherapy is critically reviewed, with suggestions for patient stratification in order to identify those who are likely to derive the greatest benefit. The key role of multidisciplinary assessment and decision making for these complex patients is also discussed. Key Messages: Surgery remains the optimal treatment for colorectal liver metastases (CRLM). Despite the curative intent of surgical resection, the majority of patients develop recurrence. Surgical strategies should therefore be adopted to maximize the potential for repeat resections in the event of recurrence. Although a number of preoperative prognostic markers have been identified, none are absolute contraindications to resection. In order to reduce postoperative recurrence, neo-adjuvant chemotherapy is now the standard of care in a number of countries. The evidence base for this approach is contentious, and the potential benefit of such a strategy is likely to be greatest in patients with high oncological risk disease. Multidisciplinary care is essential to ensure the optimal management of these complex patients. In addition, all patients with CRLM should be discussed with specialist hepatobiliary surgeons.

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

The risk of malignancy in ultrasound detected gallbladder polyps: A systematic review.

INTRODUCTIONnGallbladder polyps (GBPs) are a common incidental finding on ultrasound (US) examination. The malignant potential of GBPs is debated, and there is limited guidance on surveillance. This systematic review sought to assess the natural history of ultrasonographically diagnosed GBPs and their malignant potential.nnnMETHODSnThe keywords: Gallbladder AND (polyp OR polypoid lesion) were used to conduct a search in four reference libraries to identify studies which examined the natural history of GBPs diagnosed by US. Twelve studies were eligible for inclusion in this review.nnnRESULTSnOf the 5482 GBPs reported, malignant GBPs had an incidence of just 0.57%. True GBPs had an incidence of 0.60%. Sixty four patients of adenomatous and malignant polyps were reported. Only in one patient was a malignant GBP reported to be <6mm. Risk factors associated with increased risk of malignancy were GBP >6mm, single GBPs, symptomatic GBPs, age >60 years, Indian ethnicity, gallstones and cholecystitis.nnnCONCLUSIONnWith the reported incidence of GBP malignancy at just 0.57%, a management approach based on risk assessment, clear surveillance planning, and multi disciplinary team (MDT) discussion should be adopted. The utilization of endoscopic ultrasound(EUS) should be Only considered on the grounds of its greater sensitivity and specificity when compared to US scans.

Inflammation and cancer: What a surgical oncologist should know

Chronic inflammation is an aberrantly prolonged form of a protective response to a loss of tissue homeostasis and it is involved in several steps of the carcinogenesis process. As a result, many cancers are inflammation-related. The systemic inflammatory response is associated with survival in advanced and localized cancers. Two categories of scores have been proposed to monitor the systemic inflammatory response, those derived from protein measurement and those based on counting inflammatory cells. This review aims to provide a critical appraisal of these 2 categories of surrogate markers. The 3 scale modified Glasgow prognostic score (mGPS) is based on the combination of C-reactive protein and albumin and is graded 0 to 2. It has been validated worldwide showing an independent prognostic value in patients with cancer in a variety of tumour types and tumour stages. Leukocytes-based scores are mainly neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR). Elevated NLR and/or PLR and lower LMR seem to be associated with decreased survival, but the studies about these markers are very heterogeneous. The main limit is the variety of thresholds used to dichotomize patients, so that reproducibility and reliability of leukocytes-based scores can be questioned. Hence, there is no sufficient evidence to support their use in clinical practice. Comprehensive management of patients with operable and advanced cancer should integrate the host systemic inflammatory response by calculating the mGPS. It could be a helpful tool to tailor patients management.

Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer

Background:Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer.Methods:Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network.Results:We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54–4.98), P=0.001), N stage (HR 1.51 (1.01–2.26), P=0.04), curative intent surgery (HR 0.51 (0.34–0.76), P=0.001), tumour grade (HR 0.44 (0.30–0.65), P=0.001) and KRAS mutation (1.54 (1.23–2.12), P=0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27–2.43), P=0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15–4.25), P=0.01) and p.G12V (HR 1.69 (1.08–2.62), P=0.02) were predictive of overall survival.Conclusions:For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis.

Influence of the primary tumour location in patients undergoing surgery for colorectal liver metastases

BACKGROUNDnThe prognosis of patients undergoing liver resection for colorectal liver metastases (CLM) seems to be altered when the primary tumour is right-sided. However, data are lacking and conflicting. We aimed to evaluate the influence of the primary tumour location on oncologic outcomes following such surgery.nnnMETHODSnWe retrospectively analysed prospectively collected data from 376 consecutive patients who underwent liver surgery for CLM between June 2010 and August 2015. We compared the outcomes of patients with right colon tumours and those with left colorectal tumours. The splenic flexure was used as the cut-off point to determine the anatomic primary site.nnnRESULTSnAmong the 364 patients eligible, 74 (20.3%) had a right-sided primary tumour. These patients were older, had a poorer American Society of Anaesthesiologists status and had fewer node-positive primary tumours. The CLM characteristics were similar between both groups. Median PFS was not significantly different between the two groups at 9.9 months, as well as the pattern of recurrence. Median OS was shorter for patients with right-sided primary tumour (34.6 versus 45.3 months, pxa0=xa00.035). Similar results were observed when patients with rectal tumour were excluded from analysis (34.6 vs. 47.5 months, pxa0=xa00.007). Primary tumour site was an independent prognosis factor in multivariate analysis.nnnCONCLUSIONnRight-sided location of the primary tumour is associated with worse OS after surgery for CLM, but seems to have no influence on PFS, and on the pattern of recurrence.

Curative-intent treatment of recurrent colorectal liver metastases: A comparison between ablation and resection

BACKGROUNDnLiver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases.nnnMETHODSnWe retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty-three (51.6%) by ablation and 31 (48.4%) by repeat resection.nnnRESULTSnPatient groups were well matched, with surgically resected patients showing higher pre-operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (pxa0<xa00.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression-free survival was longer for patients treated with surgery (10.2xa0months) compared to ablation (4.3xa0months) (pxa0=xa00.002).nnnCONCLUSIONSnAblation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression-free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis.

Defining the Optimal Use of Ablation for Metastatic Colorectal Cancer to the Liver Without High-Level Evidence

Opinion statementThe role of physical interventions (surgical resection and surgical/radiological ablation) for liver metastases of colorectal cancer has changed dramatically over the last 10–15xa0years. Whereas in the 1990s, when only those patients with up to three unilobar metastases were considered for any form of such intervention, our present approach to these physical interventions is determined by how much viable disease-free liver can be preserved (most authorities accepting 25–30% disease-free future remnant liver volume) and the possibility of further such interventions if the disease recurs in the liver. There is increasing evidence that for smaller tumours (<3xa0cm diameter), ablation therapy may be therapeutically the equivalent of surgical resection and possibly safer in high-risk patients with multiple comorbidities. Therefore, we now consider the use of such ablation therapies (with or without surgical resection) to be clinically effective when treating patients with multiple bilobar metastases that have shown good radiologic response to prior systemic therapy.