Kaplan Medical Center

BACKGROUND: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS: Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS: Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

BACKGROUND: Infectious diseases may rival cancer, heart disease, and chronic lung disease as sources of morbidity and mortality from smoking. We reviewed mechanisms by which smoking increases the risk of infection and the epidemiology of smoking-related infection, and delineated implications of this increased risk of infection among cigarette smokers. METHODS: The MEDLINE database was searched for articles on the mechanisms and epidemiology of smoking-related infectious diseases. English-language articles and selected cross-references were included. RESULTS: Mechanisms by which smoking increases the risk of infections include structural changes in the respiratory tract and a decrease in immune response. Cigarette smoking is a substantial risk factor for important bacterial and viral infections. For example, smokers incur a 2- to 4-fold increased risk of invasive pneumococcal disease. Influenza risk is severalfold higher and is much more severe in smokers than nonsmokers. Perhaps the greatest public health impact of smoking on infection is the increased risk of tuberculosis, a particular problem in underdeveloped countries where smoking rates are increasing rapidly. CONCLUSIONS: The clinical implications of our findings include emphasizing the importance of smoking cessation as part of the therapeutic plan for people with serious infectious diseases or periodontitis, and individuals who have positive results of tuberculin skin tests. Controlling exposure to secondhand cigarette smoke in children is important to reduce the risks of meningococcal disease and otitis media, and in adults to reduce the risk of influenza and meningococcal disease. Other recommendations include pneumococcal and influenza vaccine in all smokers and acyclovir treatment for varicella in smokers.

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: -mutation cohort), and the intention-to-treat population. RESULTS: -mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Abstract DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes 1 . Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells 2–5 . Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

We examined changes in spontaneously secreted growth hormone with aging by studying the 24-h integrated concentration of GH (IC-GH) of 173 nonobese subjects (height, greater than or equal to 5%; 7-65 yr of age). There was no significant difference in IC-GH on repeat testing of 13 men or in 23 women studied in the follicular and again in the luteal phase of the menstrual cycle. The level of IC-GH was strongly effected by age; children had the highest mean IC-GH, and there was a decline in IC-GH with increasing age after the second decade of life. The correlation of IC-GH with age was highly significant (r = 0.73; P less than 0.0001). There was no difference in IC-GH between males and females when matched for age. The mean IC-GH at Tanner stage 5 of puberty (7.4 +/- 2.0 ng/ml) was higher than that at stages 2-4 (5.7 +/- 1.4; P less than 0.0005) or that in prepubertal children (5.8 +/- 1.4; P less than 0.001). Thus, age and pubertal status must be carefully considered when interpreting the IC-GH for patients suspected of having deficient or excessive secretion of GH.

The prevalence of overweight and obesity is increasing worldwide.1 A comparison of data from 1976–802 with that from 1999–2000 shows that the prevalence of overweight (defined as body mass index, BMI, of 25–29.9 kg/m2) increased from 46% to 64.5%, and the prevalence of obesity (BMI ⩾ 30 kg/m2) doubled to 30.5%. The epidemic of obesity is not just isolated to the US, but is worldwide,3,,4 including less affluent countries.4 Obesity and overweight have many causes, including genetic, metabolic, behavioural and environmental. The rapid increase in prevalence suggests that behavioural and environmental influences predominate, rather than biological changes. We summarize data from many studies evaluating the impact of obesity on mortality and morbidity, discuss some controversies and provide practical guidelines for managing obese patients. Direct associations between obesity and several diseases, including diabetes mellitus, hypertension, dyslipidaemia and ischaemic heart disease, are well recognized. Despite this, the relationship between body weight and all-cause mortality is more controversial. A very high degree of obesity (BMI ⩾35 kg/m2) seems to be linked to higher mortality rates,5 but the relationship between more modest degrees of overweight and mortality is unclear. Initial data from actuarial studies of more than 4 million men and women showed a direct positive association between body weight and overall mortality rates.6 Subsequent studies confirmed increased mortality risk above a certain threshold, but found a U-shaped association between weight and mortality.7,,8 In the Build study,9 there was a higher mortality in lean subjects, but there was no adjustment for smoking. The American Cancer Society found a much stronger association between leanness and mortality, specifically cancer mortality, in the group of smokers compared to non-smokers.10 The Harvard Alumni Study11 was a prospective cohort study of more than 19 000 middle-aged … Address correspondence to Dr S.D.H. Malnick, Department of Internal Medicine C, Kaplan Medical Centre, Rehovot 76100, Israel. email: stevash{at}trendline.co.il

The chemokine SDF-1 plays a central role in the repopulation of the bone marrow (BM) by circulating CD34(+) progenitors, but the mechanisms of its action remain obscure. To extravasate to target tissue, a blood-borne cell must arrest firmly on vascular endothelium. Murine hematopoietic progenitors were recently shown in vivo to roll along BM microvessels that display selectins and integrins. We now show that SDF-1 is constitutively expressed by human BM endothelium. In vitro, human CD34(+) cells establish efficient rolling on P-selectin, E-selectin, and the CD44 ligand hyaluronic acid under physiological shear flow. ICAM-1 alone did not tether CD34(+) cells under flow, but, in the presence of surface-bound SDF-1, CD34(+) progenitors rolling on endothelial selectin rapidly developed firm adhesion to the endothelial surface, mediated by an interaction between ICAM-1 and its integrin ligand, which coimmobilized with SDF-1. Human CD34(+) cells accumulated efficiently on TNF-activated human umbilical cord endothelial cells in the absence of SDF-1, but they required immobilized SDF-1 to develop firm integrin-mediated adhesion and spreading. In the absence of selectins, SDF-1 also promoted VLA-4-mediated, Gi protein-dependent tethering and firm adhesion to VCAM-1 under shear flow. To our knowledge, this is the first demonstration that SDF-1 expressed on vascular endothelium is crucial for translating rolling adhesion of CD34(+) progenitors into firm adhesion by increasing the adhesiveness of the integrins VLA-4 and LFA-1 to their respective endothelial ligands, VCAM-1 and ICAM-1.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

BACKGROUND: Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required. METHODS: A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting. RESULTS: The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests. CONCLUSIONS: The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.

n 1998, Mowat et al 1 delineated a syndrome with Hirschsprung disease (HSCR) or severe constipation, microcephaly, mental retardation, and a distinctive facial appearance. 1 Because two of the patients had a cytogenetically visible deletion of 2q22-q23, 1 2 and all patients were sporadic cases, a contiguous gene syndrome or a dominant single gene disorder involving this locus were suggested. 1 Two similar patients with cytogenetically balanced translocation t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively, allowed Wakamatsu et al 3 and Cacheux et al 4 to narrow down the critical interval to 5 Mb and to one single gene respectively, which led both groups independently to the detection of intragenic mutations in the gene coding for Smad interacting protein-1 (formerly SIP1, now called zinc finger homeobox 1B (ZFHX1B)) in patients with so called "syndromic HSCR". However, because HSCR is not an obligatory symptom and patients with and without HSCR can be recognised by other features, especially their distinct facial gestalt, 5 6 we suggested that "Mowat-Wilson syndrome" (MWS) is a more appropriate name. 6 Although the developmental ZFHX1B expression pattern fully explains the clinical spectrum observed in patients with Mowat-Wilson syndrome by haploinsufficiency of this gene alone, 5 7 Wakamatsu et al 3 initially stated that their deletion patient would have a more severe phenotype and therefore would have a contiguous gene syndrome. Amiel et al 8 reported that the phenotype was similar in patients with "syndromic HSCR" caused by mutations and cytogenetically non-visible large scale deletions of the ZFHX1B locus, respectively, but the deletion sizes were not delineated. We therefore analysed deletion size and genotype-phenotype correlation in four new patients with cryptic deletions of the ZFHX1B locus.

Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease of unknown cause that usually affects middle-aged women and eventually leads to liver failure and the need for liver transplantation. It is diagnosed more frequently now than it was a decade ago because of its greater recognition by physicians and the widespread use of automated blood testing and the antimitochondrial-antibody test, which is relatively specific for the disease.1 Important advances have been made in our understanding of the natural history, pathogenesis, and treatment of primary biliary cirrhosis since the subject was last reviewed in the Journal.2 Little has changed . . .

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.

Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP/PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated beta-amyloid, and characterized as CD11b(+)/CD11c(-)/MHC class II(-)/TNF-alpha(+) cells, impeded neurogenesis from adult neural stem/progenitor cells, whereas CD11b(+)/CD11c(+)/MHC class II(+)/TNF-alpha(-) microglia, a phenotype induced by IL-4, counteracted the adverse beta-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.

The L1 adhesion molecule plays an important role in axon guidance and cell migration in the nervous system. L1 is also expressed by many human carcinomas. In addition to cell surface expression, the L1 ectodomain can be released by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be detected in tumors and in the developing mouse brain. The shedding of L1 involved a disintegrin and metalloproteinase (ADAM)10, as transfection with dominant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and laminin, which was blocked by antibodies to alpha v beta 5 and L1. Migration of L1-CHO cells, but not the basal migration of CHO cells, was blocked by a metalloproteinase inhibitor, indicating a role for L1 shedding in the migration process. CHO and metalloproteinase-inhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by alpha v beta 5-specific antibodies and required Arg-Gly-Asp sites in L1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell migration. We propose that ectodomain-released L1 promotes migration by autocrine/paracrine stimulation via alpha v beta 5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.

Dietary fibers, major phenolics, main minerals, and trace elements in persimmons and apples were analyzed and compared in order to choose a preferable fruit for an antiatherosclerotic diet. Fluorometry and atomic absorption spectrometry following microwave digestion were optimized for the determination of major phenolics and minerals. Total, soluble, and insoluble dietary fibers, total phenols, epicatechin, gallic and p-coumaric acids, and concentrations of Na, K, Mg, Ca, Fe, and Mn in whole persimmons, their pulps, and peels were significantly higher than in whole apples, pulps, and peels (P < 0.01-0.0025). Conversely, the contents of Cu and Zn were higher in apples than in persimmons. In persimmons and apples all of the above components were higher in their peels than in whole fruits and pulps. The relatively high contents of dietary fibers, total and major phenolics, main minerals, and trace elements make persimmon preferable for an antiatherosclerotic diet.

In Brief Objective: To assess feasibility, risks, and long-term outcome of 2-stage hepatectomy as a means to improve resectability of colorectal liver metastases (CLM). Summary Background Data: Two-stage hepatectomy uses compensatory liver regeneration after a first noncurative hepatectomy to enable a second curative resection. Methods: Between October 1992 and January 2007, among 262 patients with initially irresectable CLM, 59 patients (23%) were planned for 2-stage hepatectomy. Patients were eligible when single resection could not achieve complete treatment, even in combination with chemotherapy, portal embolization, or radiofrequency, but tumors could be totally removed by 2 sequential resections. Feasibility and outcomes were prospectively evaluated. Results: Two-stage hepatectomy was feasible in 41 of 59 patients (69%). Eighteen patients failed to complete the second hepatectomy because of disease progression (n = 17) or bad performance status (n = 1). The 41 successfully treated patients had a mean number of 9.1 metastases (mean diameter, 48.5 mm at diagnosis). Chemotherapy was delivered before (95%), in between (78%), and after (78%) the 2 hepatectomies. Mean delay between the 2 liver resections was 4.2 months. Postoperative mortality was 0% and 7% (3/41) after the first and second hepatectomy, respectively. Morbidity rates were also higher after the second procedure (59% vs. 20%) (P < 0.001). Five-year survival was 31% on an intention to treat basis, and all but 2 patients who did not complete the 2-stage strategy died within 19 months. After a median follow-up of 24.4 months (range, 3.7–130.3), overall 3- and 5-year survivals for patients that completed both hepatectomies were 60% and 42%, respectively, after the first hepatectomy (median survival, 42 months from first hepatectomy and 57 months from metastases diagnosis). Disease-free survivals were 26% and 13% at 3 and 5 years, respectively. Conclusions: Two-stage hepatectomy provides a 5-year survival of 42% and a hope of long-term survival for selected patients with extensive bilobar CLM, irresectable by any other means. The long-term benefit of 2-stage hepatectomy as a strategy to increase the resectability of multiple bilobar colorectal liver metastases remains unclear. Treatment outcomes and survival were analyzed in 59 patients selected for this procedure. A 2-stage strategy is able to provide a 5-year survival of 42% in up to 70% of selected patients with otherwise irresectable multinodular bilobar metastases.