A systematic cohort review of pheochromocytoma-induced typical versus atypical Takotsubo cardiomyopathy.

BACKGROUND: A rare presentation of pheochromocytoma (PCC) is catecholamine-induced-cardiomyopathy, or Takotsubo cardiomyopathy (TCM). PCC-induced TCM(PCC-TCM) can present as a typical or atypical type, based on the location of cardiac wall motion abnormalities. In this review, we sought to assess features and outcomes for PCC-TCM, and to compare typical and atypical subtypes. METHODS: A search was conducted on two databases (PubMed and Embase) for case series or reports on PCC-TCM from 2006 to 2020. RESULTS: One-hundred-and-two papers with a total of 104 cases of PCC-TCM were retrieved: 67(64.4%) typical and 37(35.6%) atypical subtypes. Overall median age was 50[range:23-86] years, the atypical group about a decade younger(p < 0.001). A female preponderance was seen for either subtype (∼75%). The most common presentations were chest pain(n = 60;58%), dyspnoea(n = 46;44%), and headache(n = 41;39.4%). Those with atypical subtype more often presented with fluid overload (typical:3% versus atypical:60%); acute pulmonary oedema (35% versus 60%); and cardiogenic shock (22% versus 43%) (all p < 0.05). Six patients (6%) died pre-operatively (typical:8% versus atypical:3%; p = 0.32). Non-fatal pre-operative complications occurred more among those with atypical TCM(p < 0.001), specifically cardiac arrest (typical:5% versus atypical:32%) and respiratory failure (9% versus 24%; both p < 0.05). Overall, 98 underwent surgery, majority undergoing laparoscopic adrenalectomy (81%); similar among the subtypes(p = 0.71). No robust data was provided on short-term outcomes, although two patients suffered from post-operative complications. CONCLUSION: Although quite similar in presentation to either standalone TCM or PCC, PCC-TCM seems to be associated with a higher degree of morbidity and mortality. The atypical PCC-TCM subgroup seems to have a more severe course with possibly a poorer outcome. Further research is needed to make more reliable inferences.

Cognitive deficits in primary hyperparathyroidism - what we know and what we do not know: A narrative review.

Classic symptoms of primary hyperparathyroidism (PHPT) are seen in approximately 20% of patients. While features such as kidney stones and skeletal disease are often highlighted as directly related to the disease, others can be even more prevalent. For example, cognitive dysfunction and reduced quality of life are common complaints in many patients, even among those who are classified as being asymptomatic. The pathophysiology of PHPT involves the impact of excess parathyroid hormone (PTH) on calcium metabolism. Referencing putative neurocognitive issues, many animal studies have illustrated the potential roles of PTH and PTH receptors in the brain. Functional imaging and pre-and post-parathyroidectomy studies have suggested a link between the neuronal impact of elevated PTH levels on specific functional aspects of the central nervous system, such as cognition. Confounding a direct role for PTH are hypercalcemia and vitamin D deficiency, both of which could conceivably alter CNS function in PHPT. The lack of strong evidence that parathyroidectomy improves cognition in patients with PHPT raises the question as to whether parathyroid surgery should be recommended on this basis alone. This narrative review summarizes the available literature on neurocognitive function in PHPT.

Sarcopenia is Associated with Reduced Survival following Surgery for Adrenocortical Carcinoma.

AIM: Adrenocortical cancer (ACC) is an aggressive malignancy and robust prognostic factors remain unclear. The presence of sarcopenia has been shown to negatively impact survival for other malignancies, but has not been extensively analyzed in ACC. METHODS: Patients who underwent resection of their ACC between 2010 and 2020 were identified; therapeutic, operative, and outcome data were analyzed. Sarcopenia was assessed by calculation of the skeletal muscle index (SMI) and was defined as an SMI <52.4cm2/m2 for males and <38.5cm2/m2 for females. RESULTS: Data on 35 patients (18 F: 17 M; median age 54 [range: 18-86]) who had primary surgical treatment were analyzed. Median tumor size was 10 cm [range:3-15]. In eleven patients (31%), the tumor was hormonally active (cortisol = 8;23%). Seventeen patients (49%) were classified as having sarcopenia on their pre-operative CT scan. The Intraclass Correlation Coefficient (ICC) for intra- and inter-observer variability showed very good agreement (0.99 and 0.98). There was no difference in incidence of sarcopenia stratifying for sex, BMI, or tumor-size, but incidence was higher with increasing age (p < .05). Overall median survival was 36 months, with 1- and 3-year survival rates of 77% and 52%. The presence of sarcopenia was strongly associated with a shorter overall survival (HR = 3.21; [95%CI: 1.06-9.69];p = .03) on unadjusted analyses. Moreover, age, higher T-stage, and presence of capsular invasion were also associated with poorer survival on univariable analyses. CONCLUSION: The presence of sarcopenia in patients undergoing surgery for ACC could be a predictor of reduced overall survival, although replications of these analyses should be performed in similar, larger cohorts. Specifically, the influence of a patient's hormonal status on the manifestation of sarcopenia should be further defined.

The use of computed tomography as a first-line imaging modality in patients with primary hyperparathyroidism.

BACKGROUND: The success of minimally invasive parathyroidectomy (MIP) relies on accurate localization of the abnormal parathyroid glands. Concordant findings on ultrasound (US) and 99mTc-scintigraphy (sestamibi) are currently considered the 'gold standard'. Computed tomography (CT) has also recently been used in preoperative planning. We sought to assess the accuracy of CT for localization of abnormal parathyroid glands in such patients. METHODS: An audit of 75 patients with primary hyperparathyroidism (PHPT) who underwent neck US and CT between 2017 and 2019 at our center as their first-line imaging. RESULTS: All 75 patients underwent US and CT and 54 (72.0%) also had sestamibi. CT alone identified a potential target in all patients, of which the location was correct in 63 (84.0%). The overall combined sensitivity of US and CT was 88% (95% CI 78-94) and was higher than the combined sensitivity of US and sestamibi (65% [95% CI 53-76]; p < 0.001). Twenty-one patients (28.0%) had an ectopic gland, and the sensitivity of US and CT was 86% (95% CI 64-96) versus US and sestamibi (57% [95% CI 34-77]; p = 0.016). For adenomas < 1.0 g (n = 36; 48%), the accuracy of CT was 81% (95% CI 64-91) compared with 62% (95% CI 44-77) for US and sestamibi (p = 0.04). The correct preoperative diagnosis of multiglandular disease (n = 9; 12%) seemed to be the most difficult, with similar accuracy for US and sestamibi (40% [95% CI 14-73]) and US and CT (50% [95% CI 20-80]) (p > 0.99). CONCLUSION: The combination of US and CT was able to correctly identify the location of the abnormal parathyroid in 88% of patients and, in comparison with US and sestamibi, had better diagnostic accuracy, especially for smaller and ectopic adenomas. This finding suggests that US and CT could be considered as a first-line imaging modality in patients with PHPT considered for MIP.

Treating papillary and follicular thyroid cancer in children and young people: Single UK-center experience between 2003 and 2018.

AIM: Differentiated thyroid cancer (DTC) in children and adolescents is rare and data about its presentation and management are not well known. The aim of this study was to provide evidence of the current practice in the United Kingdom before the launch of the Rare National Paediatric Endocrine Tumours Guidelines (to be published in 2020). METHODS: Seventy-two children and adolescents with DTC (<18 years) who were treated at our institution between 2003 and 2018 were identified and their presentation, treatment and outcomes were reviewed. RESULTS: Median age at presentation was 12.7 years [range: 1-18] and fifty-two (72%) were girls. Fifty (69.4%) children and adolescents presented with a thyroid nodule. Thirteen (18%) had cervical adenopathy and seven of them (54%) underwent an excision biopsy under GA. Eight patients (11%) had evidence of lung metastases at presentation. Twenty-four patients (33%) underwent a hemithyroidectomy and 22 of those had a completion thyroidectomy subsequently, ten (14%) a total thyroidectomy alone and 37 (51%) a total thyroidectomy with lymph nodes dissection. Seventy patients (97%) underwent adjuvant RAI at our institution. The median number of children and adolescents managed per year was five [range: 0-10]. After an overall median follow-up of 40 months, eight patients (11%) had developed recurrent disease. The 1- and 5-year recurrence-free-survival-rates were 93% and 87%, respectively. Overall survival was 100%, with eight children and adolescents (11%) being alive with disease. CONCLUSION: This study confirms that DTC in children and adolescents is uncommon, is frequently advanced at presentation and has considerable recurrence rates. Despite this, overall survival is excellent. Although the work-up was generally appropriate (image-guided cytology), open biopsy for the diagnosis of lymph node involvement was still employed. The introduction of a specific UK guideline for this age-group will likely result in more tailored-made treatment-pathways and thereby hopefully improve quality and outcomes even further. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level IV.

Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) as Possible Prognostic Markers for Patients Undergoing Resection of Adrenocortical Carcinoma.

AIM: Adrenocortical cancer (ACC) is a rare disease with a poor outcome, and robust prognostic factors remain unclear. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as markers of host inflammation have been found to be associated with decreased long-term outcomes in several tumour types, but have been scarcely analysed in ACC. METHODS: Patients who underwent resection of their ACC between 2000 and 2020 were identified; therapeutic, operative and outcome data were analysed. Pre-operative NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. RESULTS: Fifty-seven patients (30F:27 M) with an overall median age of 53 years [range: 18-86] presented with tumours of median size 11.5 cm [range: 3.0-22.0], of whom 26 (46%) were hormonally active. Majority of patients underwent an open resection (n = 48; 84%); more than half (n = 30; 53%) underwent multi-organ excision. Median NLR was 4.63 and median PLR was 186.21; these values were used for median split analyses (low vs. high). There were no differences with regard to age, sex or tumour characteristics and peri-operative data between the two groups (all p > 0.05). Overall, median recurrence-free survival (RFS) was 26 months (3-year: 45%) on Kaplan-Meier analysis. On univariate analyses, a high NLR did not influence RFS [HR = 1.57 (95%-CI: 0.73-2.38); p = 0.25], but patients with a high PLR had an increased risk of developing recurrence [HR = 2.39 (95%-CI: 1.08-5.31); p = 0.03]. The median overall survival (OS) was 33 months (3 years: 79%) on Kaplan-Meier analysis. Both a high NLR [HR = 2.24 (95%-CI: 1.07-4.70); p = 0.03] and a high PLR [HR = 4.02 (95%-CI: 1.80-8.98); p = 0.001] were strongly associated with a shorter OS on unadjusted analyses. CONCLUSION: Elevated pre-operative NLR and PLR are associated with shorter OS, while higher PLR was also associated with a shorter RFS for patients undergoing curative intent resection of ACC.

Late Recovery of Parathyroid Function after Total Thyroidectomy in Children and Adults: Is There a Difference?

BACKGROUND: Parathyroid failure after total thyroidectomy is the commonest adverse event amongst both children and adults. The phenomenon of late recovery of parathyroid function, especially in young patients with persistent hypoparathyroidism, is not well understood. This study investigated differences in rates of parathyroid recovery in children and adults and factors influencing this. METHODS: A joint dual-centre database of patients who underwent a total thyroidectomy between 1998 and 2018 was searched for patients with persistent hypoparathyroidism, defined as dependence on oral calcium and vitamin D supplementation at 6 months. Demographic, surgical, pathological, and biochemical data were collected and analysed. Parathyroid Glands Remaining in Situ (PGRIS) score was calculated. RESULTS: Out of 960 patients who had total thyroidectomy, 94 (9.8%) had persistent hypoparathyroidism at 6 months, 23 (24.5%) children with a median [range] age 10 [0-17], and 71 (75.5%) adults aged 55 [25-82] years, respectively. Both groups were comparable regarding sex, indication, extent of surgery, and PGRIS score. After a median follow-up of 20 months, the parathyroid recovery rate was identical for children and adults (11 [47.8%] vs. 34 [47.9%]; p = 0.92). Sex, extent, and indication for surgery had no effect on recovery (all p > 0.05). PGRIS score = 4 (HR = 0.48) and serum calcium >2.25 mmol/L (HR = 0.24) at 1 month were associated with a decreased risk of persistent hypoparathyroidism on multivariate analysis (p < 0.05). CONCLUSION: Almost half of patients recovered from persistent hypoparathyroidism after 6 months; therefore, the term persistent instead of permanent hypoparathyroidism should be used. Recovery rates of parathyroid function in children and adults were similar. Regardless of age, predictive factors for recovery were PGRIS score = 4 and a serum calcium >2.25 mmol/L at 1 month.

Is Nighttime Really Not the Right Time for a Laparoscopic Cholecystectomy?

Purpose: The impact of an out-of-hours laparoscopic cholecystectomy on outcome is controversial. We sought to determine the association between an out-of-hours procedure and postoperative complications within 90 days. Methods: Between 2014 and 2016, 1553 laparoscopic cholecystectomies were performed. Therapeutic, operative, and outcome data were prospectively collected and analyzed. We defined out of hours as during weekends, national holidays, and daily between 5PM and 8AM. Results: Most patients operated on were female (n=988; 63.6%) and the majority of procedures were electives (n=1341; 86.3%). Although all procedures were performed with a laparoscopic intent, 42 (2.7%) were converted to open procedure. In total, 145 (9.3%) procedures were out of hours, all nonelective, and in most cases for acute cholecystitis (n=111; 7.1%). Overall, there were 212 complications in 191 patients (12.3%), most (n=153; 9.9%) classified as minor. The conversion rate in the out-of-hours group was significantly higher (9.7% vs 2.0%; p<0.001). While univariate analyses revealed out-of-hours procedure (OR=1.83; p=0.008) to be associated with an increased risk of complications, when controlling for confounding factors by multivariate analysis, this association was not found. However, operation by surgical staff (OR=1.71) and conversion to laparotomy (OR=3.74) were found to be independently associated with an increased risk of complications (both p<0.05), while an emergency procedure tended to be associated with postoperative morbidity (OR=1.82; p=0.069). Conclusion: An out-of-hours laparoscopic cholecystectomy was not found to be an independent risk factor for developing postoperative morbidity and time of day should therefore only be a relative contraindication.

The liver-first approach for synchronous colorectal liver metastases: more than a decade of experience in a single centre.

BACKGROUND: The feasibility of the liver-first approach for synchronous colorectal liver metastases (CRLM) has been established. We sought to assess the short-term and long-term outcomes for these patients. METHODS: Outcomes of patients who underwent a liver-first approach for CRLM between 2005 and 2015 were retrospectively evaluated from a prospective database. RESULTS: Of the 92 patients planned to undergo the liver-first strategy, the paradigm could be completed in 76.1%. Patients with concurrent extrahepatic disease failed significantly more often in completing the protocol (67% versus 21%; p = 0.03). Postoperative morbidity and mortality were 31.5% and 3.3% following liver resection and 30.9% and 0% after colorectal surgery. Of the 70 patients in whom the paradigm was completed, 36 patients (51.4%) developed recurrent disease after a median interval of 20.9 months. The median overall survival on an intention-to-treat basis was 33.1 months (3- and 5-year overall survival: 48.5% and 33.1%). Patients who were not able to complete their therapeutic paradigm had a significantly worse overall outcome (p = 0.03). CONCLUSION: The liver-first approach is feasible with acceptable perioperative morbidity and mortality rates. Despite the considerable overall-survival-benefit, recurrence rates remain high. Future research should focus on providing selection tools to enable the optimal treatment sequence for each patient with synchronous CRLM.

Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans.

BACKGROUND AND AIM: Animal studies indicated that systemic ophthalmic acid (OPH) is a biomarker for hepatic glutathione (GSH) homeostasis, an important determinant of liver function. We aimed to clarify whether OPH levels can be used as a read-out for hepatic GSH homeostasis after paracetamol (APAP) challenges during pylorus-preserving pancreaticoduodenectomy (PPPD) or partial hepatectomy (PH). METHODS: Nineteen patients undergoing PPPD (n=7, control group) or PH (n=12) were included. APAP (1000 mg) was administered intravenously before resection (first challenge), and six and twelve hours later, with sequential blood sampling during this period. Arterial, hepatic and portal venous blood samples and liver biopsies were taken on three occasions during the first APAP challenge. Plasma and hepatic OPH and GSH levels were quantified, and venous-arterial differences were calculated to study hepatic release. RESULTS: Systemic GSH levels decreased during the course of the APAP challenge in both surgical groups, without notable change in OPH levels. Hepatic GSH and OPH content was not affected within ˜3 hours after administration of the first APAP dose in patients undergoing PPPD or PH. In this period, net release of OPH by the liver was observed only in patients undergoing PPPD. CONCLUSION: The drop in circulating GSH levels following APAP administrations, did not result in an increase in plasma OPH in both patients with an intact liver and in those undergoing liver resection. Hepatic content of GSH and OPH was not affected during the first APAP dose. It is uncertain whether hepatic GSH homeostasis was sufficiently challenged in the present study. RELEVANCE FOR PATIENTS: In the present study, plasma OPH seemed not useful as a marker for GSH depletion because APAP administration during liver surgery did not lead to (immediate) GSH depletion or increased OPH levels. Based on stable levels of hepatic GSH, OPH and thiyl radicals during surgery, standard APAP administration seems to be safe in a postoperative care program with regards to GSH homeostasis in this specific population. However, no general statements can be made on the basis of the current experiment, since GSH homeostasis and susceptibility to xenobiotic toxicity are influenced by several metabolic and genetic factors.

Outcomes of extended versus limited indications for patients undergoing a liver resection for colorectal cancer liver metastases.

BACKGROUND: Currently, resection criteria for colorectal cancer liver metastases (CRCLM) are only limited by remnant liver function. Morbidity and survival after a partial hepatectomy with limited or extended indication criteria were compared. METHODS/DESIGN: Between 1991 and 2010, patients undergoing a liver resection for CRCLM with limited (n = 169) or extended indication criteria (n = 129) were retrospectively identified in a prospectively collected single-centre database. Limited indication criteria were defined as less than three unilateral, not centrally located liver metastases in the absence of extra hepatic metastases. The extended criteria were only limited by predicted remnant liver volume and patients fitness. Data on co-morbidity, resection margin, short- and long-term morbidity, disease-free (DFS) and overall survival were compared. RESULTS: Patients with limited indications had less major complications (19.5% vs. 33.1%, P < 0.01), longer overall survival of 68.8 months [confidence interval (CI) 46.5-91.1] vs. 41.4 months (CI 33.4-49.0, P ≤ 0.001) and longer median DFS of 22.0 months [confidence interval (CI) 15.8-28.2] vs 10.2 months (CI 8.4-11.9, P < 0.001) compared with the extended indication group. Cure rates, defined as 10-year DFS, were 35.5% and 15.8%, respectively. Fewer patients in the extended indication group underwent an R0 resection (92.9% vs. 77.5%, P < 0.001). Only 17% of all R1 resected patients had recurrences at the transection plane. CONCLUSION: A partial hepatectomy for CRCLM with extended indications seems justified but is associated with higher complication rates, earlier recurrence and lower overall survival compared with limited indications. However, the median 5-year survival was substantial and a cure was achieved in 15.8% of patients.

Systematic review of ophthalmate as a novel biomarker of hepatic glutathione depletion.

BACKGROUND: Sustainability of hepatic glutathione (GSH) homeostasis is an important cellular defense against oxidative stress. Therefore, knowledge of liver GSH status is important. However, measurement of plasma GSH and tissue is difficult due to its instability. Alternatively, ophthalmate (OPH), an endogenous tripeptide analog of GSH, has been suggested as a potential indicator to assess GSH depletion. AIM: To provide an overview of present knowledge with respect to the usefulness of OPH as a biomarker for oxidative stress and hepatic GSH homeostasis. METHODS: A systematic, computerized search combined with a cross-reference search of the literature described in PubMed (January 1975 to January 2012) was conducted, key words: 'ophthalmate' and 'ophthalmic acid'. RESULTS: Twenty-two articles were included. Hepatic OPH levels increase inversely proportional to a drop in hepatic GSH in mice with paracetamol (PCM) induced hepatotoxicity. Little is known about the stability of OPH in human plasma. To measure the very low physiological concentrations of plasma OPH, liquid chromatography-mass spectrometry techniques can be employed. OPH synthesis can be measured in humans, using stable isotope labeling with a deuterated water ((2)H2O) load. CONCLUSION: OPH may be a promising biomarker to indicate hepatic glutathione depletion, but the suggested biological pathways need further unraveling.

Improvements in quality of life after surgery for benign hepatic tumors: Results from a dual center analysis.

BACKGROUND: Outcomes after operative management of benign hepatic lesions are ill-defined. We sought to define patient-reported quality of life (QOL) postoperatively for benign hepatic tumors. METHODS: Patients who underwent surgery for benign liver lesions (n = 255) were invited to complete a QOL survey designed using validated assessment tools. Clinicopathologic data were collected from 2 participating hepatobiliary centers and correlated with QOL data. RESULTS: The response rate was 70.2%. Most patients had a benign cystic (41.9%) or solid (47.5%) tumor; 19 (10.6%) patients had an indeterminate lesion. The lesion was most often solitary (71.5%) and median size was 7.5 cm. Most benign lesions were either a simple cyst (35.8%), hemangioma (19.6%), focal nodular dysplasia (19.6%), or hepatic adenoma (16.9%). Presenting symptoms included abdominal pain (70.9%), nausea/vomiting (5.0%), and early satiety (5.0%). Surgery involved less than hemihepatectomy (68.2%); a laparoscopic approach was utilized in 40.8% of patients. Perioperative morbidity was 16%. Postoperatively, the proportion of patients who reported moderate-to-extreme pain decreased from 46.9% to 15.6% and 6.8% at 6 months and 1-year, respectively (P < .001). Patient self-reported mean pain scores also decreased over time (preoperative, 1.65 vs 6 months, 0.63 vs 1 year, 0.28; P < .001). Patients with "moderate-to-extreme" pain preoperatively were more likely to report an improvement in pain scores (odds ratio, 1.96; 95% confidence interval, 1.05-3.66; P = .03). Many patients reported overall improvement in general health (40.5%) and physical health (39.3%; P < .001). CONCLUSION: Surgery for benign liver lesions is associated with high patient satisfaction and improved QOL. Patients with significant preoperative symptoms derive the most benefit from surgery.

Ophthalmate detection in human plasma with LC-MS-MS.

Based on animal experimentations, ophthalmate (OPH) has recently been suggested as a potential plasma biomarker to probe hepatic GSH homeostasis. Up until now, the inability to accurately determine OPH concentrations in human plasma prohibited further studies of OPH metabolism in humans. This study therefore aimed to study the influence of delayed sample preparation on OPH concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Venous plasma samples from 5 healthy human volunteers were incubated for varying times (5, 30, 60 and 120 min) at temperatures of 4 °C and 37 °C to investigate potential enzymatic degradation. At 37 °C, the decrease in OPH reached significance after 120 min (74.6% (range: 56.2-100.0%; p<0.0001)). At 4 °C, the same trend was observed but did not reach significance. These findings indicate ongoing enzymatic activity, stressing the need for immediate sample deproteinization to obtain reliable plasma concentrations. To investigate the feasibility of the here developed method, baseline arterial plasma values of 21 patients scheduled for partial liver resection were determined to be 0.06±0.03 µmol/l (mean±s.d.). In addition, in pooled samples from 3 patients, an OPH calibration curve was spiked to arterial plasma, arterial whole blood and liver biopsy material, resulting in a linear calibration curve in all cases. Individual measurements of baseline samples revealed that both arterial whole blood and liver biopsy material contained significant levels of endogenous OPH, namely 16.1 (11.8-16.4) µmol/l and 80.0 (191.8-349.2) µmol/kg, respectively. In conclusion, the present LC-MS/MS assay enables the accurate measurement of OPH in human plasma, whole blood and liver biopsies. Freshly prepared samples and immediate deproteinization are mandatory to block enzymatic degradation.

Hepatectomy for noncolorectal non-neuroendocrine metastatic cancer: a multi-institutional analysis.

BACKGROUND: Although hepatic metastasectomy is well established for colorectal and neuroendocrine cancer, the approach to hepatic metastases from other sites is not well defined. We sought to examine the management of noncolorectal non-neuroendocrine liver metastases. STUDY DESIGN: A retrospective review from 4 major liver centers identified patients who underwent liver resection for noncolorectal non-neuroendocrine metastases between 1990 and 2009. The Kaplan-Meier method was used to analyze survival, and Cox regression models were used to examine prognostic variables. RESULTS: There were 420 patients available for analysis. Breast cancer (n = 115; 27%) was the most common primary malignancy, followed by sarcoma (n = 98; 23%), and genitourinary cancers (n = 92; 22%). Crude postoperative morbidity and mortality rates were 20% and 2%, respectively. Overall median survival was 49 months, and 1, 3, and 5-year Kaplan-Meier survival rates were 73%, 50%, and 31%. Survival was not significantly different between the various primary tumor types. Recurrent disease was found after hepatectomy in 66% of patients. In multivariable models, lymphovascular invasion (p = 0.05) and metastases ≥5 cm (p = 0.04) were independent predictors of poorer survival. Median survival was shorter for resections performed between 1990 and 1999 (n = 101, 32 months) when compared with resections between 2000 and 2009 (n = 319, 66 months; p = 0.003). CONCLUSIONS: Hepatic metastasectomy for noncolorectal non-neuroendocrine cancers is safe and feasible in selected patients. Lymphovascular invasion and metastases ≥5 cm were found to be associated with poorer survival. Patients undergoing metastasectomy in more recent years appear to be surviving longer, however, the reasons for this are not conclusively determined.

The impact of portal vein resection on outcomes for hilar cholangiocarcinoma: a multi-institutional analysis of 305 cases.

UNLABELLED: BACKGROUND. Surgical strategy for hilar cholangiocarcinoma often includes hepatectomy, but the role of portal vein resection (PVR) remains controversial. In this study, the authors sought to identify factors associated with outcome after surgical management of hilar cholangiocarcinoma and examined the impact of PVR on survival. METHODS: Three hundred five patients who underwent curative-intent surgery for hilar cholangiocarcinoma between 1984 and 2010 were identified from an international, multi-institutional database. Clinicopathologic data were evaluated using univariate and multivariate analyses. RESULTS: Most patients had hilar cholangiocarcinoma with tumors classified as T3/T4 (51.1%) and Bismuth-Corlette type II/III (60.9%). Resection involved extrahepatic bile duct resection (EHBR) alone (26.6%); or hepatectomy and EHBR without PVR (56.7%); or combined hepatectomy, EHBR, and PVR (16.7%). Negative resection (R0) margin status was higher among the patients who underwent hepatectomy plus EHBR (without PVR, 64.2%; with PVR, 66.7%) versus EHBR alone (54.3%; P < .001). The median number of lymph nodes assessed was higher among the patients who underwent hepatectomy plus EHBR (without PVR, 6 lymph nodes; with PVR, 4 lymph nodes) versus EHBR alone (2 lymph nodes; P < .001). The 90-day mortality rate was lower for patients who underwent EHBR alone (1.2%) compared with the rate for patients who underwent hepatectomy plus EHBR (without PVR, 10.6%, with PVR, 17.6%; P < .001). The overall 5-year survival rate was 20.2%. Factors that were associated with an adverse prognosis included lymph node metastasis (hazard ratio [HR], 1.79; P = .002) and R1 margin status (HR, 1.81; P < .001). Microscopic vascular invasion did not influence survival (HR, 1.23; P = .19). Among the patients who underwent hepatectomy plus EHBR, PVR was not associated with a worse long-term outcome (P = .76). CONCLUSIONS: EHBR alone was associated with a greater risk of positive surgical margins and worse lymph node clearance. The current results indicated that hepatectomy should be considered the standard treatment for hilar cholangiocarcinoma, and PVR should be undertaken when necessary to extirpate all disease. Combined hepatectomy, EHBR, and PVR can offer long-term survival in some patients with advanced hilar cholangiocarcinoma.

Peri-operative chemotherapy for resectable colorectal liver metastasis: does timing of systemic therapy matter?

BACKGROUND: The benefit of pre-operative chemotherapy in patients with resectable colorectal liver metastases (CRLM) remains ill defined. We sought to evaluate the impact of peri-operative systemic chemotherapy timing on outcome following resection of CRLM. METHODS: 676 patients who underwent surgery for CRLM were identified from two hepatobiliary center databases. Data were collected and analyzed utilizing multivariate, matched, and propensity-score analyses. RESULTS: Median number of metastases was 2 and median tumor size was 3.3 cm. 334 patients (49.4%) received pre-operative chemotherapy while 342(50.6%) did not. Surgical treatment was resection only (n = 555; 82.1%; minor hepatectomy, n = 399; 59.1%). While there was no difference in morbidity following minor liver resection (pre-operative chemotherapy: 17.9% versus no pre-operative chemotherapy: 16.5%; P = 0.72), morbidity was higher after major hepatic resection (pre-operative chemotherapy: 23.1% versus no pre-operative chemotherapy: 14.2%; P = 0.06). Patients treated with pre-operative chemotherapy had worse 5-year survival (43%) as compared to patients not treated with pre-operative chemotherapy (55%)(P = 0.009). Controlling for baseline characteristics, pre-operative chemotherapy was not associated with outcome on multivariate (HR = 1.04, P = 0.87) or propensity-score analysis (HR = 1.40, P = 0.12). CONCLUSION: Pre-operative chemotherapy was associated with a trend toward increased morbidity among patients undergoing a major hepatic resection. Receipt of pre-operative chemotherapy was associated with neither an advantage nor disadvantage in terms of long-term survival.

The liver-first approach for synchronous colorectal liver metastasis: a 5-year single-centre experience.

BACKGROUND: For patients who present with synchronous colorectal carcinoma and colorectal liver metastasis (CRLM), a reversed treatment sequence in which the CRLM are resected before the primary carcinoma has been proposed (liver-first approach). The aim of the present study was to assess the feasibility and outcome of this approach for synchronous CRLM. METHODS: Between 2005 and 2010, 22 patients were planned to undergo the liver-first approach. Feasibility and outcomes were prospectively evaluated. RESULTS: Of the 22 patients planned to undergo the liver-first strategy, the approach was completed in 18 patients (81.8%). The main reason for treatment failure was disease progression. Patients who completed treatment and patients who deviated from the protocol had a similar location of the primary tumour, as well as comparable size, number and distribution of CRLM (all P > 0.05). Post-operative morbidity and mortality were 27.3% and 0% following liver resection and 44.4% and 5.6% after colorectal surgery, respectively. On an intention-to-treat-basis, overall 3-year survival was 41.1%. However, 37.5% of patients who completed the treatment had developed recurrent disease at the time of the last follow-up. CONCLUSIONS: The liver-first approach is feasible in approximately four-fifths of patients and can be performed with peri-operative mortality and morbidity similar to the traditional treatment paradigm. Patients treated with this novel strategy derive a considerable overall-survival-benefit, although disease-recurrence-rates remain relatively high, necessitating a multidisciplinary approach.

Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.

PURPOSE: To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. PATIENTS AND METHODS: From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. RESULTS: Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). CONCLUSION: Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.

Hilar cholangiocarcinoma: tumor depth as a predictor of outcome.

BACKGROUND: The American Joint Committee on Cancer staging system for hilar cholangiocarcinoma may be inaccurate because the bile duct lacks discrete tissue boundaries. OBJECTIVES: To examine the accuracy of the American Joint Committee on Cancer staging schemes and to determine the prognostic implications of tumor depth. DESIGN, SETTING, AND PATIENTS: From January 1, 1987, through December 31, 2009, there were 106 patients who underwent resection of hilar cholangiocarcinoma who had pathologic slides available for re-review. MAIN OUTCOME MEASURES: Tumor depth and overall survival. RESULTS: Overall median survival was 19.9 months. The 6th and 7th editions of the T-classification criteria were unable to discriminate among T1, T2, and T3 lesions (P > .05 for all). Median survival was associated with the invasion depth of the tumor (≥5 mm vs <5 mm): 18 months vs 30 months (P = .01). On multivariate analysis, tumor depth remained predictive of disease-specific death (hazard ratio, 1.70; P = .03). CONCLUSIONS: The American Joint Committee on Cancer T-classification criteria did not stratify patients with regard to prognosis. Depth of tumor invasion is a better predictor of long-term outcome.