Development and External Validation of a Model to Predict Overall Survival in Patients With Resected Gallbladder Cancer.

OBJECTIVE: The aim of this study was to develop and validate a clinical prediction model to predict overall survival in patients with nonmetastatic, resected gallbladder cancer (GBC). BACKGROUND: Although several tools are available, no optimal method has been identified to assess survival in patients with resected GBC. METHODS: Data from a Dutch, nation-wide cohort of patients with resected GBC was used to develop a prediction model for overall survival. The model was internally validated and a cohort of Australian GBC patients who underwent resection was used for external validation. The performance of the American Joint Committee on Cancer (AJCC) staging system and the present model were compared. RESULTS: In total, 446 patients were included; 380 patients in the development cohort and 66 patients in the validation cohort. In the development cohort median survival was 22 months (median follow-up 75 months). Age, T/N classification, resection margin, differentiation grade, and vascular invasion were independent predictors of survival. The externally validated C-index was 0.75 (95%CI: 0.69-0.80), implying good discriminatory capacity. The discriminative ability of the present model after internal validation was superior to the ability of the AJCC staging system (Harrell C-index 0.71, [95%CI: 0.69-0.72) vs. 0.59 (95% CI: 0.57-0.60)]. CONCLUSION: The proposed model for the prediction of overall survival in patients with resected GBC demonstrates good discriminatory capacity, reasonable calibration and outperforms the authoritative AJCC staging system. This model can be a useful tool for physicians and patients to obtain information about survival after resection and is available from https:// gallbladderresearch.shinyapps.io/Predict_GBC_survival/.

Cost of treating metastatic colorectal cancer: a systematic review.

OBJECTIVE: The cost of treating metastatic colorectal cancer places a significant economic burden on individuals, populations, and health care. However, there is a paucity of information on the costs of the contemporary management of metastatic colorectal cancer. This systematic review aims to review the literature to estimate the direct cost of treating metastatic colorectal cancer. STUDY DESIGN: Systematic review. METHODS: MEDLINE, Embase, Web of Science, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database Guide, EconLit, and grey literature from the 1st of January 2000 to the 1st of February 2020 were all searched for studies reporting the direct costs of treating metastatic colorectal cancer. The methodological quality of the included studies was assessed using the Evers' Consensus on Health Economic Criteria checklist. RESULTS: In total, 39,489 records were retrieved, and 29 studies were included. Costs of treating metastatic colorectal cancer varied because of the heterogeneity of treatment. Studies reported average costs ranged from $12,346 to $293,461. Studies that included the cost of systemic therapy reported an estimated cost of almost $300,000. CONCLUSION: The existing evidence indicates that the cost of treating metastatic colorectal cancer places a significant economic burden on healthcare systems despite differences in methodology and treatment heterogeneity. Future research needs to define the cost components of treating metastatic colorectal cancer to improve comparability and examine the relationship between spending, overall survival, and quality of life. Identifying these costs and their impact on health care budgets can help policymakers plan health system expenditure.

Propensity score analysis of non-anatomical versus anatomical resection of colorectal liver metastases.

Background: There are concerns that non-anatomical resection (NAR) worsens perioperative and oncological outcomes compared with those following anatomical resection (AR) for colorectal liver metastases (CRLM). Most previous studies have been biased by the effect of tumour size. The aim of this study was to compare oncological outcomes after NAR versus AR. Methods: This was a retrospective study of consecutive patients who underwent CRLM resection with curative intent from 1999 to 2016. Data were retrieved from a prospectively developed database. Survival and perioperative outcomes for NAR and AR were compared using propensity score analyses. Results: Some 358 patients were included in the study. Median follow-up was 34 (i.q.r. 16-68) months. NAR was associated with significantly less morbidity compared with AR (31·1 versus 44·4 per cent respectively; P = 0·037). Larger (hazard ratio (HR) for lesions 5 cm or greater 1·81, 95 per cent c.i. 1·13 to 2·90; P = 0·035) or multiple (HR 1·48, 1·03 to 2·12; P = 0·035) metastases were associated with poor overall survival (OS). Synchronous (HR 1·33, 1·01 to 1·77; P = 0·045) and multiple (HR 1·51, 1·14 to 2·00; P = 0·004) liver metastases, major complications after liver resection (HR 1·49, 1·05 to 2·11; P = 0·026) or complications after resection of the primary colorectal tumour (HR 1·51, 1·01 to 2·26; P = 0·045) were associated with poor disease-free survival (DFS). AR was prognostic for poor OS only in tumours smaller than 30 mm, and R1 margin status was not prognostic for either OS or DFS. NAR was associated with a higher rate of salvage resection than AR following intrahepatic recurrence. Conclusions: NAR has at least equivalent oncological outcomes to AR while proving to be safer. NAR should therefore be the primary surgical approach to CRLM, especially for lesions smaller than 30 mm.

The integration of pharmacology and pathophysiology into locoregional chemotherapy delivery via mass fluid transfer.

The prevailing paradigm of locoregional chemotherapy has been centred around delivering chemotherapy as close to the tumour as possible and in some cases incorporating vascular isolation techniques. Strategically, the development of these techniques has been rudimentary without consideration for the interdependencies between macrovascular manipulation and the microvascular effects. This review focuses on how new capabilities offered by recent advances in vascular access technology could be exploited to facilitate the mass fluid transfer (MFT) of anticancer agents to solid tumours. A haemodynamic model of MFT is proposed using the physical laws of fluid flow, flux, and diffusion that describe the microvascular effects anticancer agents may have upon tumours through the manipulation of macrovascular blood flow control. Finally, the possible applications of this technique for several organs are discussed.

A pre-operative clinical model to predict microvascular invasion and long-term outcome after resection of hepatocellular cancer: The Australian experience.

BACKGROUND: Hepatocellular cancer (HCC) is a leading cause of mortality worldwide. Liver resection or transplantation offer the best chance of long-term survival. The aim of this study was to perform a survival and prognostic factor analysis on patients who underwent resection of HCC at two major tertiary referral hospitals, and to investigate a pre-operative prediction model for microvascular invasion (MVI). METHODS: Clinico-pathological and survival data were collected from all patients who underwent liver resection for HCC at two tertiary referral centres (Royal North Shore/North Shore Private Hospitals and Westmead Hospital) from 1998 to 2012. An overall and disease-free survival analysis was performed and a predictive model for MVI identified. RESULTS: The total number of patients in this series was 125 and the 5-year overall and disease-free survival rates were 56% and 37%, respectively. MVI was the only factor to be independently associated with a poor prognosis on both overall and disease-free survival. Age ≥64 years, a serum alpha-fetoprotein (AFP) ≥400 ng/ml (×40 above normal) and tumor size ≥50 mm were independently associated with MVI. An MVI prediction model using these three pre-operative factors provides a good assessment of the risk of MVI. CONCLUSION: MVI in the resected specimen of patients with HCC is associated with a poor prognosis. A preoperative MVI prediction model offers a useful way to identify patients at risk of relapse. However, more precise predictive models using molecular and genetic variables are needed to improve selection of patients most suitable for radical surgical treatment.

Systematic review of antibiotic treatment for acute calculous cholecystitis.

BACKGROUND: Intravenous antibiotics are frequently used in the initial management of acute calculous cholecystitis (ACC), although supportive care alone preceding delayed elective cholecystectomy may be sufficient. This systematic review assessed the success rate of antibiotics in the treatment of ACC. METHODS: A systematic search of MEDLINE, Embase and Cochrane Library databases was performed. Primary outcomes were the need for emergency intervention and recurrence of ACC after initial non-operative management of ACC. Risk of bias was assessed. Pooled event rates were calculated using a random-effects model. RESULTS: Twelve randomized trials, four prospective and ten retrospective studies were included. Only one trial including 84 patients compared treatment with antibiotics to that with no antibiotics; there was no significant difference between the two groups in terms of length of hospital stay and morbidity. Some 5830 patients with ACC were included, of whom 2997 had early cholecystectomy, 2791 received initial antibiotic treatment, and 42 were treated conservatively. Risk of bias was high in most studies, and all but three studies had a low level of evidence. For randomized studies, pooled event rates were 15 (95 per cent c.i. 10 to 22) per cent for the need for emergency intervention and 10 (5 to 20) per cent for recurrence of ACC. The pooled event rate for both outcomes combined was 20 (13 to 30) per cent. CONCLUSION: Antibiotics are not indicated for the conservative management of ACC or in patients scheduled for cholecystectomy.

Adverse tumor biology associated with mesenterico-portal vein resection influences survival in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Although pancreatoduodenectomy (PD) with mesenterico-portal vein resection (VR) can be performed safely in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the impact of this approach on long-term survival is controversial. PATIENTS AND METHODS: Analyses of a prospectively collected database revealed 122 consecutive patients with PDAC who underwent PD with (PD+VR) or without (PD-VR) VR between January 2004 and May 2012. Clinical data, operative results, and survival outcomes were analysed. RESULTS: Sixty-four (53 %) patients underwent PD+VR. The majority (84 %) of the venous reconstructions were performed with a primary end-to-end anastomosis. Demographic and postoperative outcomes were similar between the two groups. American Society of Anesthesiologists (ASA) score, duration of operation, intraoperative blood loss, and blood transfusion requirement were significantly greater in the PD+VR group compared with the PD-VR group. Furthermore, the tumor size was larger, and the rates of periuncinate neural invasion and positive resection margin were higher in the PD+VR group compared with the PD-VR group. Histological venous involvement occurred in 47 of 62 (76 %) patients in the PD+VR group. At a median follow-up of 29 months, the median overall survival (OS) was 18 months for the PD+VR group, and 31 months for the PD-VR group (p = 0.016). ASA score, lymph node metastasis, neurovascular invasion, and tumor differentiation were predictive of survival. The need for VR in itself was not prognostic of survival. CONCLUSIONS: PD with VR has similar morbidity but worse OS compared with a PD-VR. Although VR is not predictive of survival, tumors requiring a PD+VR have more adverse biological features.

The clinical impact of early complete pancreatic head devascularisation during pancreatoduodenectomy.

BACKGROUND: Early inferior pancreaticoduodenal artery (IPDA) ligation reduces intraoperative blood loss during pancreatoduodenectomy, but the impact on oncologic and long-term outcomes remains unknown. The aim of this study was to review the impact of complete pancreatic head devascularization during pancreatoduodenectomy on blood loss, transfusion rates, and clinicopathologic outcomes. METHODS: Clinicopathologic and outcome data were retrieved from a prospective database for all pancreatoduodenectomies performed from April 2004 to November 2010 and compared between early (IPDA+; n = 62) and late (IPDA-; n = 65) IPDA ligation groups. RESULTS: Early IPDA ligation was associated with reduced blood loss (394 ± 21 vs 679 ± 24 ml, P < .001) and perioperative transfusion (P = .031). A trend toward improved R0 resection was seen in patients with pancreatic adenocarcinoma (IPDA+ vs IPDA-, 100% vs 82%; P = .059), but this did not translate to improved 2-year (IPDA+ vs IPDA-, 76% vs 65%; P = .426) or overall (P = .82) survival. CONCLUSIONS: Early IPDA ligation reduces blood loss and transfusion requirements. Despite overall survival being unchanged, a trend toward improved R0 resection is encouraging and justifies further studies to ascertain the true oncologic significance of this technique.

Redefining the apical lymph node at right hemicolectomy.

While colorectal cancer is increasingly common in western populations, anatomical concepts regarding the anatomy of resection have remained static. In attempting to maximise the chance of surgical cure, surgeons and pathologists are now focussing upon the quality of oncological resection. Amongst pathological indices of interest, lymph node yield and the apical lymph node specifically are increasingly being shown to be reliable markers of the adequacy of oncologic resection. However, the position of the apical node in particular, is highly subjective and may not always correlate with the anatomical boundaries ultimately defining resection. We argue that the present definition of the apical lymph node is overly subjective and requires re-defining based on fixed anatomical landmarks. We propose that this new definition include a block of tissue inferolateral to the Trunk of Henle (the anatomical apical lymph node compartment).

The infracolic approach to pancreatoduodenectomy for large pancreatic head tumours invading the colon.

BACKGROUND: Tumours arising from the head of the pancreas can invade both the proximal transverse colon and its mesocolon. At laparoscopy, this may be considered a contraindication to proceeding to pancreatoduodenectomy. However, in some patients, pancreatoduodenectomy can still be performed with an R0 resection using an en-bloc resection technique by an infracolic approach. METHODS: This technique relies on the infracolic control of the superior mesenteric vein (SMV) and is based on the presence of a normal fat cuff around the superior mesenteric artery (SMA) on pre-operative imaging. The dissection is maintained along the adventitial plane of the SMA. Pancreatoduodenectomy is performed in conjunction with en-bloc resection of the transverse colon. In the event of tumour invading the SMV, this is also resected en-bloc with the pancreatic head and transverse colon. We reviewed all such cases performed at our institution between April 2004 and April 2009. RESULTS: This technique was attempted in eleven patients. In two patients, the procedure had to be abandoned because of unexpected SMA encasement by tumour. In the remaining nine patients this procedure was carried out successfully. In this paper, the infracolic approach to pancreatoduodenectomy, and the associated limitations, are described in detail. CONCLUSION: The infracolic technique may be used to deal with large pancreatic head tumours and all pancreatic surgeons should be familiar with this technique. In the absence of metastatic disease, large pancreatic head tumours involving the colon can be resected en-bloc with the pancreatic head, as long as the SMA is not encased by the tumour.

Clinical care and technical recommendations for 90yttrium microsphere treatment of liver cancer.

Selective internal radiation therapy (SIRT) with (90)yttrium microspheres is a relatively new clinical modality for treating non-resectable malignant liver tumours. This interventional radiology technique employs percutaneous microcatheterisation of the hepatic arterial vasculature to selectively deliver radioembolic microspheres into neoplastic tissue. SIRT results in measurable tumour responses or delayed disease progression in the majority of eligible patients with hepatocellular carcinoma or hepatic metastases arising from colorectal cancer. It has also been successfully used as palliative therapy for non-colorectal malignancies metastatic to the liver. Although most adverse events are mild and transient, SIRT also carries some risks for serious and--rarely--fatal outcomes. In particular, entry of microspheres into non-target vessels may result in radiation-induced tissue damage, such as severe gastric ulceration or radiation cholecystitis. Radiation-induced liver disease poses another significant risk. By careful case selection, considered dose calculation and meticulous angiographic technique, it is possible to minimise the incidence of such complications to less than 10% of all treatments. As the number of physicians employing SIRT expands, there is an increasing need to consolidate clinical experience and expertise to optimise patient outcomes. Authored by a panel of clinicians experienced in treating liver tumours via SIRT, this paper collates experience in vessel mapping, embolisation, dosimetry, microsphere delivery and minimisation of non-target delivery. In addition to these clinical recommendations, the authors propose institutional criteria for introducing SIRT at new centres and for incorporating the technique into multidisciplinary care plans for patients with hepatic neoplasms.

Skills acquired on virtual reality laparoscopic simulators transfer into the operating room in a blinded, randomised, controlled trial.

Virtual reality surgical simulators have proven value in the acquisition and assessment of laparoscopic skills. In this study, we investigated skill transfer from a virtual reality laparoscopic simulator into the operating room, using a blinded, randomised, controlled trial design. Surgical trainees using the LapSim System performed significantly better at their first real-world attempt at a laparoscopic task than their colleagues who had not received similar training, as measured independently by a number of expert surgical observers using four criteria.

The effect of multiple roles on caregiver stress outcomes.

Some caregivers focus exclusively on the caregiving role; others try to balance caregiving responsibilities with a simultaneous work role outside the home. This study examined competing hypotheses about the impact that greater immersion in a work role would have on the stress outcomes of individuals who provide care for a person with a disability. The authors used national survey data to examine whether hours of work were associated with caregiver stress outcomes. The authors also investigated whether type of disability moderated the relationship between hours worked and stress outcomes. Results suggest that spending more time in a work role generally has no effect on caregiver stress outcomes. However, caregivers who were caring for a person with a mental disability experienced significantly fewer stress outcomes as they spent more hours engaged in outside work.

beta-catenin expression in primary and metastatic colorectal carcinoma.

beta-catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also functions in growth signalling events, independently of the cadherin-catenin complex, and these signalling pathways are disturbed in colorectal cancer. Mutations in either the APC or beta-catenin genes in colorectal cancer cells result in up-regulation of protein expression and subsequent cytoplasmic and nuclear distribution of beta-catenin. In this study, we examined beta-catenin expression in 47 primary colorectal tumors and the corresponding liver metastases. Immunohistochemical studies demonstrated loss of membranous beta-catenin expression in 26% of primary tumors and 60% of liver metastases and a concomitant increase in cytoplasmic and nuclear staining. Widespread nuclear expression of beta-catenin was found in 64% of primary tumors and 21% of liver metastases. No associations were found between any form of beta-catenin expression and either tumor stage or tumor grade. Cellular distribution of beta-catenin was also examined by detergent extraction and Western blot analysis in 16 primary tumors and 23 liver metastases. This analysis showed that most tumors demonstrated reduced beta-catenin in the cytoskeletal fraction and increased beta-catenin in the cytosolic fraction. Furthermore, 3 liver metastases were found to contain a truncated beta-catenin protein of approximately M(r) 80,000. Immunoprecipitation studies showed that the truncated beta-catenin proteins only bound weakly to E-cadherin and beta-catenin compared with non-truncated beta-catenin. These results demonstrate gross alterations in the cellular distribution of beta-catenin in primary colorectal cancers with metastatic potential, as well as in the metastatic tumors. These changes may be the consequence of APC or beta-catenin gene mutations, or possibly result from a post-translational modification of the E-cadherin-catenin complex.

Cadherin-catenin expression in primary colorectal cancer: a survival analysis.

Both cell adhesion and cell signalling events are mediated by components of the cadherin-catenin complex. Loss of expression of the components of this complex have been shown to correlate with invasive behaviour in many tumour types although their exact role in colorectal cancer remains unclear. Immunohistochemical analysis of the expression of components of the cadherin-catenin complex in colorectal cancers from 60 patients was undertaken. Loss of memberanous expression of E-cadherin, alpha-catenin and beta-catenin was demonstrated in 52%, 85% and 40% of tumours respectively. Focal nuclear expression of beta-catenin (< 75% of cells per section), usually associated with cytoplasmic expression, was clearly demonstrated in 19 (32%) tumours while widespread nuclear expression (> 75% of tumour cells per section) was seen in 11 (18%) tumours. Loss of membranous alpha-catenin expression significantly correlated with tumour de-differentiation (P = 0.009). There was a trend towards an association between advanced tumour stage and loss of membranous expression of alpha-catenin or beta-catenin, although these associations were not statistically significant. Univariate analysis revealed that advanced Dukes' stage, tumour de-differentiation, loss of membranous beta-catenin expression, cytoplasmic beta-catenin expression and widespread nuclear expression of beta-catenin all correlated with short survival following apparently curative resection of the primary tumour. However, only Dukes' stage (P = 0.002), tumour grade (P = 0.02) and widespread nuclear expression of beta-catenin (P = 0.002) were independent predictors of short survival. Disturbed growth signalling events in colorectal tumours are thought to result in nuclear accumulation of beta-catenin. Consequently, tumours with widespread nuclear expression of beta-catenin are likely to have severely abnormal growth characteristics, and which therefore might be predictive of short survival in these patients.

The aetiology and management of hepatic metastases.

Hepatic metastases are a common event in the metastatic spread of primary tumours and indicate advanced disease. However, the presence of hepatic metastases does not necessarily imply incurability; in selected patients resection of hepatic metastases may result in 5-year survival rates of 25-35%, usually in patients with colorectal liver metastases in whom solitary metastases are more frequent than with other primary tumours. However, hepatic metastases from Wilm's tumours, adrenal tumours, renal cell carcinoma, and neuroendocrine tumours may also be resected with similar success rates. A poor prognosis after resection of hepatic metastases is likely when there are more than three metastatic deposits, involved resection margins (often as a result of 'wedge' resections), when there is extrahepatic disease, or nodal involvement at the primary tumour site. Cyto-reductive procedures may provide excellent palliation and possibly long-term survival in selected patients with hepatic metastases unsuitable for resection. However, further study is required to establish the appropriate role for these treatments.

Management strategies for colorectal liver metastases--Part I.

Colorectal cancer is a common malignancy and the incidence of this disease is increasing. Approximately 50% of patients with colorectal cancer die from recurrent disease following an apparently curative resection of the primary tumour and the liver is the most frequent site of relapse. Although only a small proportion of patients will benefit from resection of liver metastases, this form of treatment offers the only possibility of cure. In selected patients, 5-year survival rates of 25-35% may be achieved following liver resection. A poor prognosis after resection of hepatic metastases is likely when there are more than three metastatic deposits, involved resection margins often as a result of ¿wedge' resections, when there is extrahepatic disease, or when there is nodal involvement at the primary tumour site. Regional hepatic artery infusion chemotherapy may provide palliation and possibly even prolongation of survival for some patients with unresectable metastases. Cytoreductive techniques may also provide palliation in selected patients with hepatic metastases unsuitable for resection; cryotherapy is the most promising of these methods.

Management strategies for colorectal liver metastases--Part II.

Liver metastases are relatively common in colorectal cancer and a small proportion of patients may benefit from resection of these liver metastases. In a selected subgroup of patients, 5-year survival rates of 25-35% may be achieved following liver resection. These survival figures compare favourably with those of patients with untreated liver secondaries. In the second part of this review the surgical and non-surgical treatment options for treating colorectal liver metastases are examined in detail.

Childhood intussusception in a regional hospital.

This study reviews all childhood intussusceptions treated over a 6 year period in a regional centre with six visiting general surgeons and two paediatricians. Clinical presentation, management, complications and outcomes were noted and an attempt was made to follow up all cases. There were 20 patients, with a median age of 6 months (range 10 weeks to 17 months). Only one patient had all four classical features of intussusception (pain, vomiting, 'red currant jelly' stools and abdominal mass). Seven patients were managed successfully by barium enema reduction, but 14 required operation, four following failed radiological reduction. There was one intestinal perforation due to attempted barium enema reduction and one patient required a reoperation for ileal gangrene following operative reduction. There were no deaths and there have been no subsequent recurrent intussusceptions although three cases were lost to follow up. There was a delay in diagnosis in some cases (average duration from onset to diagnosis was 34 h). Although delay was incurred by parents in some cases and in peripheral hospitals in others, there is a need for greater awareness by surgeons of the significance of subtle features such as pallor and lethargy in a child with persistent vomiting. Delay in diagnosis is likely to lead to an increased need for primary surgical intervention. Adverse features (age > 3 months or < 2 years; symptoms > 24 h; small bowel obstruction; dehydration > 5%) were predictive of an increased likelihood of surgical resection, and may help avoid inappropriate attempts at radiological reduction.(ABSTRACT TRUNCATED AT 250 WORDS)