Publications by authors named "Neda Amini"

61 Publications

The interplay of KRAS mutational status with tumor laterality in non-metastatic colorectal cancer: An international, multi-institutional study in patients with known KRAS, BRAF, and MSI status.

J Surg Oncol 2021 Mar 23;123(4):1005-1014. Epub 2020 Dec 23.

Department of General, Visceral and Vascular Surgery, Charitè Campus Benjamin Franklin, Berlin, Germany.

Background: Although the prognostic relevance of KRAS status in metastatic colorectal cancer (CRC) depends on tumor laterality, this relationship is largely unknown in non-metastatic CRC.

Methods: Patients who underwent resection for non-metastatic CRC between 2000 and 2018 were identified from institutional databases at six academic tertiary centers in Europe and Japan. The prognostic relevance of KRAS status in patients with right-sided (RS), left-sided (LS), and rectal cancers was assessed.

Results: Of the 1093 eligible patients, 378 had right-sided tumors and 715 had left-sided tumors. Among patients with RS tumors, the 5-year overall (OS) and recurrence-free survival (RFS) for patients with KRASmut versus wild-type tumors was not shown to differ significantly (82.2% vs. 83.2% and 72.1% vs. 76.7%, respectively, all p > .05). Among those with LS tumors, KRAS mutation was associated with shorter 5-year OS and RFS on both the univariable (OS: 79.4% vs. 86.1%, p = .004; RFS: 68.8% vs. 77.3%, p = .005) and multivariable analysis (OS: HR: 1.52, p = .019; RFS: HR: 1.32, p = .05).

Conclusions: KRAS mutation status was independently prognostic among patients with LS tumors, but this association failed to reach statistical significance in RS and rectal tumors. These findings confirm reports in metastatic CRC and underline the possible biologic importance of tumor location.
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http://dx.doi.org/10.1002/jso.26352DOI Listing
March 2021

Invasive and Non-Invasive Progression after Resection of Non-Invasive Intraductal Papillary Mucinous Neoplasms.

Ann Surg 2020 Nov 12. Epub 2020 Nov 12.

Departments of Surgery.

Objective: To define frequencies, pattern of progression (invasive versus non-invasive), and risk factors of progression of resected non-invasive IPMNs BACKGROUND:: There is a risk of progression in the remnant pancreas after resection of intraductal papillary mucinous neoplasms (IPMNs).

Methods: 449 consecutive patients with resected IPMNs from 1995-2018 were included to the study. Patients with invasive carcinoma or with follow-up < 6 months were excluded. Non-invasive progression was defined as a new IPMN, increased main pancreatic duct (MPD) size, and increased size of an existing lesion (5 mm compared to preoperative imaging). Invasive progression was defined as development of invasive cancer in the remnant pancreas or metastatic disease.

Results: With a median follow-up of 48.9 months, progression was identified in 124 patients (27.6%); 108(24.1%) with non-invasive and 16(3.6%) with invasive progression. Median progression follow-up was longer for invasive progression (85.4 vs. 55.9 months; P = 0.001). Five- and 10-year estimates for a cumulative incidence of invasive progression were 6.4% and 12.9% versus 26.9% and 41.5% for non-invasive progression. After risk-adjustment, multifocality (HR 4.53, 95%CI 1.34-15.26; P = 0.02) and high-grade dysplasia (HGD) in the original resection (HR 3.60, 95%CI 1.13-11.48; P = 0.03) were associated with invasive progression.

Conclusions: Progression to invasive carcinoma can occur years after the surgical resection of a non-invasive IPMN. HGD in the original resection is a risk factor for invasive progression but some cases of low-grade dysplasia also progressed to cancer. Patients with high-risk features such as HGD and multifocal cysts should be considered for more intensive surveillance and represent an important cohort for future trials such as anti-inflammatory or prophylactic immunotherapy.
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http://dx.doi.org/10.1097/SLA.0000000000004488DOI Listing
November 2020

Launaea acanthodes (Boiss) O. Kuntze mediates hepatic glucose metabolism and ameliorates impaired pancreatic function in streptozotocin-induced diabetic rats.

J Ethnopharmacol 2021 Mar 7;268:113577. Epub 2020 Nov 7.

Department of Biology, Kavian Institute of Higher Education, Mashhad, Iran.

Ethnopharmacological Relevance: Launaea acanthodes (Boiss.) O. Kuntze is native to semiarid regions of central Iran, traditionally used in the treatment of numerous disorders including diabetes.

Aim Of The Study: The current study aimed to explore hypoglycemic activity of Launaea acanthodes extract in streptozotocin-induced diabetic rats. Furthermore, gene expression study was carried out to examine expression levels of key glucose metabolism-related genes.

Methods: For in vitro study, Folin-Ciocalteus, DPPH and aluminum chloride colorimetric assays were used to determine the total phenolic content, antioxidant capacity and total flavonoid content of extracts, respectively. For in vivo study, streptozotocin-induced diabetic Wistar rats were orally administered with metformin (50 mg/kg) and various doses of extracts (100, 200 and 400 mg/kg body weight) for 28 days. Fasting blood glucose, body weight, food and water intake were assessed during the course of treatment. At the end of the intervention, oral glucose tolerance test (OGTT), lipid profile and glycated hemoglobin (HbA1c) were evaluated. Furthermore, functional liver enzymes, oxidative stress markers and histopathology of pancreas were examined. Lastly, quantitative real time polymerase chain reaction (qRT-PCR) was applied to explore the mRNA levels of genes relevant to glucose metabolism in the pancreas and liver tissues of diabetic rats.

Results: Based on the in vitro results, the hydroalcoholic extract revealed potential radical scavenging activity and contained highest amount of phenolic and flavonoid. The in vivo results demonstrated that the extract lowered fasting blood glucose level, increased the body weight, restored the alterations in the levels of water and food intake, attenuated HbA1c, improved lipid profile and ameliorated the OGTT in diabetic rats. The extract administration alleviated the histopathological changes in the pancreas, suppressed malondialdehyde (MDA) level and further restored attenuated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in diabetic rats. Analysis of real time PCR data showed that extract administration reversed the expression levels of hepatic glucokinase (GK), phosphenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Meanwhile, the extract upregulated the expression level of glucose transporter-2 (GLUT-2) and pancreatic-duodenal homeobox (PDX-1) in diabetic rats.

Conclusion: Collectively, the results demonstrate that Launaea acanthodes hydroalcoholic extract exerts hypoglycemic effect possibly via regulating key enzymes of glucose metabolism and ameliorating pancreatic dysfunction through its antioxidant properties.
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http://dx.doi.org/10.1016/j.jep.2020.113577DOI Listing
March 2021

The Interplay Between Innate Immunity (TLR-4) and sCD40L in the Context of an Animal Model of Colitis-associated Cancer.

Anticancer Res 2020 Oct;40(10):5457-5462

Memorial Sloan Kettering Cancer Center, Department of Surgery, New York, NY, U.S.A.

Background/aim: Several studies have found elevated soluble CD40 Ligand (sCD40L) in the serum of patients with malignancies as well as those with inflammatory bowel disease (IBD). Our goal was to determine the possible causal role of sCD40L in colitis-associated colorectal cancer (CAC) by using the well-established azoxymethane/dextran sulfate sodium (AOM/DSS) protocol.

Materials And Methods: Twelve wild type (WT) and twelve TLR4 knock out (KO) female C57BL6 mice were divided into 4 experimental groups. Six WT and six TLR4 KO mice were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three 7-day cycles of oral 2.5% DSS. The other two groups included 6 WT and 6 TLR4 KO mice that received only water and served as the control groups. The mice were sacrificed after 84 days.

Results: All mice in the AOM/DSS WT group developed CAC while all mice from the AOM/DSS TLR4 KO group were protected from CAC. We measured the serum and pathologic tissue levels of sCD40L with quantitative sandwich enzyme-linked immunoassay (ELISA) and found that serum sCD40L was significantly higher in wild-type mice that developed CAC compared to their healthy counterparts (wild-type and TLR-4 KO controls). In comparison, serum sCD40L levels were comparable between TLR-4 KO mice, which are protected from developing CAC, and their healthy counterparts (wild-type and TLR-4 KO controls). Of note, tissue levels of sCD40L were not affected by the development of CAC.

Conclusion: Our findings point to the presence of an axis between TLR-4 and sCD40L, which may lead to decreased immunosurveillance and the subsequent development of colitis-associated cancer.
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http://dx.doi.org/10.21873/anticanres.14556DOI Listing
October 2020

Minimal main pancreatic duct dilatation in small branch duct intraductal papillary mucinous neoplasms associated with high-grade dysplasia or invasive carcinoma.

HPB (Oxford) 2020 Sep 7. Epub 2020 Sep 7.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: The aim of this study was to determine the incidence of high-grade dysplasia (HGD) or invasive carcinoma in patients with small branch duct intraductal papillary mucinous neoplasms (BD-IPMNs).

Methods: 923 patients who underwent surgical resection for an IPMN were identified. Sendai-negative patients were identified as those without history of pancreatitis or jaundice, main pancreatic duct size (MPD) <5 mm, cyst size <3 cm, no mural nodules, negative cyst fluid cytology for adenocarcinoma, or serum carbohydrate antigen 19-9 (CA 19-9) <37 U/L.

Results: BD-IPMN was identified in 388 (46.4%) patients and 89 (22.9%) were categorized as Sendai-negative. Overall, 68 (17.5%) of BD-IPMN had HGD and 62 (16.0%) had an associated invasive-carcinoma. Among the 89 Sendai-negative patients, 12 (13.5%) had IPMNs with HGD and only one patient (1.1%) had invasive-carcinoma. Of note, older age (OR 1.13, 95% CI 1.03-1.23; P = 0.008) and minimal dilation of MPD (OR 11.3, 95% CI 2.40-53.65; P = 0.002) were associated with high-risk disease in Sendai-negative patients after multivariable risk adjustment.

Conclusion: The risk of harboring a high-risk disease remains low in small BD-IPMNs. However, Sendai-negative patients who are older than 65 years old and those with minimal dilation of MPD (3-5 mm) are at greater risk of high-risk lesions and should be given consideration to be included as a "worrisome feature" in a future guidelines update.
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http://dx.doi.org/10.1016/j.hpb.2020.08.004DOI Listing
September 2020

The Prognostic Impact of Primary Tumor Site Differs According to the KRAS Mutational Status: A Study By the International Genetic Consortium for Colorectal Liver Metastasis.

Ann Surg 2019 Aug 5. Epub 2019 Aug 5.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status.

Background: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors.

Methods: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status.

Results: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38).

Conclusions: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.
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http://dx.doi.org/10.1097/SLA.0000000000003504DOI Listing
August 2019

KRAS mutational status impacts pathologic response to pre-hepatectomy chemotherapy: a study from the International Genetic Consortium for Liver Metastases.

HPB (Oxford) 2019 11 9;21(11):1527-1534. Epub 2019 Apr 9.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address:

Background: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined.

Methods: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response.

Results: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023).

Conclusions: Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.
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http://dx.doi.org/10.1016/j.hpb.2019.03.368DOI Listing
November 2019

The Prognostic Value of Varying Definitions of Positive Resection Margin in Patients with Colorectal Cancer Liver Metastases.

J Gastrointest Surg 2018 08 9;22(8):1350-1357. Epub 2018 Apr 9.

Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Varying definitions of resection margin clearance are currently employed among patients with colorectal cancer liver metastases (CRLM). Specifically, a microscopically positive margin (R1) has alternatively been equated with an involved margin (margin width = 0 mm) or a margin width < 1 mm. Consequently, patients with a margin width of 0-1 mm (sub-mm) are inconsistently classified in either the R0 or R1 categories, thus obscuring the prognostic implications of sub-mm margins.

Methods: Six hundred thirty-three patients who underwent resection of CRLM were identified. Both R1 definitions were alternatively employed and multivariable analysis was used to determine the predictive power of each definition, as well as the prognostic implications of a sub-mm margin.

Results: Five hundred thirty-nine (85.2%) patients had a margin width ≥ 1 mm, 42 had a sub-mm margin width, and 52 had an involved margin (0 mm). A margin width ≥ 1 mm was associated with improved survival vs. a sub-mm margin (65 vs. 36 months; P = 0.03) or an involved margin (65 vs. 33 months; P < 0.001). No significant difference in survival was detected between patients with involved vs. sub-mm margins (P = 0.31). A sub-mm margin and an involved margin were both independent predictors of worse OS (HR 1.66, 1.04-2.67; P = 0.04, and HR 2.14, 1.46-3.16; P < 0.001, respectively) in multivariable analysis. Importantly, after combining the two definitions, patients with either an involved margin or a sub-mm margin were associated with worse OS in multivariable analysis (HR 1.94, 1.41-2.65; P < 0.001).

Conclusions: Patients with involved or sub-mm margins demonstrated a similar inferior OS vs. patients with a margin width > 1 mm. Consequently, a uniform definition of R1 as a margin width < 1 mm should perhaps be employed by future studies.
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http://dx.doi.org/10.1007/s11605-018-3748-3DOI Listing
August 2018

Frailty as a Risk Predictor of Morbidity and Mortality Following Liver Surgery.

J Gastrointest Surg 2017 May 6;21(5):822-830. Epub 2017 Mar 6.

Department of Surgery, Wexner Medical Center at The Ohio State University, Columbus, OH, USA.

Background: Given the increasing number of elderly and comorbid patients undergoing surgery, there is increased interest in preoperatively identifying patients at high risk of morbidity and mortality following liver resection. We sought to develop and validate the use of a frailty index (FI) to predict poor postoperative outcomes following liver surgery.

Methods: Patients undergoing a liver resection were identified using the National Surgical Quality Improvement Program Hepatectomy-targeted database for 2014 and randomized into a training or validation cohort. Multivariable logistic regression analysis was performed to develop a revised frailty index (rFI) to predict adverse postoperative clinical outcomes. Leave one out cross-validation was performed to validate the proposed rFI.

Results: A total of 2714 patients were identified who met the inclusion criteria. Postoperatively, 826 patients (30.4%) developed a postoperative complication, while 39 patients died within 30 days of surgery. Five preoperative variables (ASA class, BMI, serum albumin, hematocrit, underlying pathology, and type of liver resection) were used to develop the rFI. The rFI demonstrated good discrimination (AUROC = 0.68) and outperformed the previously proposed modified frailty index (mFI; AUROC = 0.53, p < 0.001) when evaluated among patients included in the training cohort. On validation, the rFI demonstrated good model discrimination (AUROC = 0.68) and was accurately able to risk-stratify patients within the validation cohort at risk for developing a postoperative complication, prolonged length-of-stay, and postoperative mortality (all p < 0.05).

Conclusion: Frailty, as measured by the rFI, was predictive of increased risk of morbidity and mortality following liver surgery and can be used to guide patient decision-making.
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http://dx.doi.org/10.1007/s11605-017-3373-6DOI Listing
May 2017

Prognostic impact of complications after resection of early stage hepatocellular carcinoma.

J Surg Oncol 2017 Jun 15;115(7):791-804. Epub 2017 Feb 15.

Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Resection is the most effective treatment for HCC. However, postoperative morbidity is common and its impact on long-term oncological outcome remains unclear.

Methods: Long-term outcomes of 774 patients who underwent curative resection for early stage HCC at Johns Hopkins Hospital and Toranomon Hospital were investigated after stratifying by the development of postoperative overall and infectious complications.

Results: A minor or major postoperative complication developed in 281 and 65 patients, respectively, while postoperative mortality was 1.3% (n = 10). The 5-year cumulative recurrence and overall survival(OS) rates were 57.2% and 76.4%, respectively. Overall postoperative complications independently predicted worse OS in multivariable analysis (HR = 1.42, P = 0.021). Complication severity did not correlate with OS (P > 0.05). While infectious complications were not independent predictors of OS, the combination of blood transfusion and infectious complications led to significantly worse OS (66.3% vs. 44.9%, P = 0.008). Postoperative complications also correlated with increased recurrence risk, but only in patients with non-cirrhotic parenchyma (55.0% vs. 47.7%, P = 0.035) or non-viral hepatitis (55.6% vs. 44.4%, P = 0.002).

Conclusions: Post-operative morbidity independently predicted poor OS following hepatectomy for early stage HCC. A similar effect on recurrence was noted only in patients with favorable etiopathologic factors. Finally, the combination of peri-operative transfusion and subsequent infectious complications was associated with a synergistic negative effect on prognosis.
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http://dx.doi.org/10.1002/jso.24576DOI Listing
June 2017

Vital Pulp Therapy with Calcium-Silicate Cements: Report of Two Cases.

Iran Endod J 2017 ;12(1):112-115

Dentist, Professional Trainee at University of Texas Health Science Center at Houston.

This article describes successful use of calcium-enriched mixture (CEM) cement and Biodentine in apexogenesis treatment in two 8-year-old patients, one with immature permanent molar diagnosed primarily with irreversible pulpitis and the other with partially vital maxillary central incisor. After access cavity preparation, partial pulpotomy in molar and full pulpotomy in central was performed, and the remaining pulps was capped with either Biodentine or CEM cement, in each tooth. The crowns were restored with composite filling material at the following visit. The post-operative radiographic and clinical examinations (approx. average of 16 months) showed that both treated teeth remained functional, with complete root development and apex formation. A calcified bridge was produced underneath the capping material. No further endodontic intervention was necessary. Considering the healing potential of immature vital pulps, the use of CEM cement and Biodentine for apexogenesis might be an applicable choice. These new endodontic biomaterials might be appropriate for vital pulp therapies in an immature tooth. However, further clinical studies with longer follow-up periods are recommended.
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http://dx.doi.org/10.22037/iej.2017.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282391PMC
January 2017

A comparison between effect of photodynamic therapy by LED and calcium hydroxide therapy for root canal disinfection against Enterococcus faecalis: A randomized controlled trial.

Photodiagnosis Photodyn Ther 2017 Mar 28;17:226-232. Epub 2016 Dec 28.

University of Texas Health Science Center, Houston, United States of America.

Background: Insufficient root canal disinfection is one of the main reasons for persistent periapical pathology. Photodynamic therapy (PDT) has been proven effective in disinfecting infected root canals. The aim of this study was to evaluate the antimicrobial effect of photo activated disinfection (PAD) when using toluidine blue as photosensitizer and a LED lamp after the conventional treatment, and comparing it with calcium hydroxide therapy in vivo.

Methods: This clinical trial includes 20 patients with molars requiring endodontic retreatment. After the conventional treatment, first microbiological samples were obtained using sterile rotary ProTaper F2 file and 3 paper points and transferred to a microbiology laboratory. Group 1 (n=10) specimens underwent PAD with photosensitizer (PS) solution (0.1mg/mL TB) and irradiation with Fotosan light emitting diode (LED) lamp (635nm, 200mW/cm2) for 60s. Creamy Ca(OH)2 paste was used in group 2 (n=10) for two weeks. A second sample was then obtained. The samples were cultured and then bacterial colonies were counted. Data included number of colony forming units (CFUs) before and after treatments, analyzed by t-test and analysis of covariance (ANCOVA) using SPSS vs.18.

Results: A significant difference between results of before and after treatment of both groups (calcium hydroxide therapy p=0.02<0.05, PAD p<0.0001) indicated the efficacy of both treatments. The mean numbers for log 10CFUs/mL before calcium hydroxide therapy and PAD with LED irradiation was 10.1968 and 11.3773. After treatment, the mean numbers were 9.4202 and 8.3772, respectively. The difference in results after treatment between groups was significant (p=0.01<0.05) and indicate that PAD was more effective.

Conclusion: PAD and calcium hydroxide therapy, as auxiliary methods adjunct to conventional root canal therapy, are both effective in root canal disinfection. In comparison with calcium hydroxide therapy, PAD leads to a greater reduction in enterococcus faecalis number in the infected root canals.
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http://dx.doi.org/10.1016/j.pdpdt.2016.12.009DOI Listing
March 2017

Age of Transfused Blood Impacts Perioperative Outcomes Among Patients Who Undergo Major Gastrointestinal Surgery.

Ann Surg 2017 01;265(1):103-110

*Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD †The Johns Hopkins University School of Medicine, Baltimore, MD ‡Department of Surgery, University of Illinois Hospital and Health Sciences System, Chicago, IL §Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, MD ¶Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: To evaluate the impact of transfused packed red blood cell (PRBC) age on perioperative morbidity among patients undergoing major gastrointestinal surgery.

Background: Patients undergoing major surgery often receive PRBC transfusions. The effect of PRBC age (ie, storage duration before transfusion) on perioperative surgical outcomes remains poorly defined.

Methods: In this study, 1365 patients were identified who underwent a hepato-pancreatic or colorectal resection and received ≥1 unit of PRBCs between 2009 and 2014 at the Johns Hopkins Hospital. Data regarding the storage duration of PRBCs, clinicopathologic characteristics, and perioperative outcomes were obtained and analyzed. Multivariable modified Poisson regression analyses were performed to assess the effect of PRBC age on perioperative morbidity.

Results: A total of 5901 PRBC units were transfused for a median of 2 (interquartile range 2-4) units transfused per patient. In all, 936 (68.6%) patients received only units of blood that had been stored for less than 35 days ("fresh" blood), whereas 429 (31.4%) patients received at least 1 unit of PRBC that had been stored for ≥35 days ("older" blood). Overall postoperative morbidity was 32.8%. The incidence of postoperative complications (42.7% vs 28.3%) was higher among patients who received "older" vs "fresh" blood (P < 0.001). After adjusting for confounders on multivariable analysis, transfusion of "older" blood remained independently associated with an increased risk of perioperative morbidity (Relative Risk 1.20, P = 0.03).

Conclusions: The use of "older" blood was an independent predictor of postoperative morbidity among patients undergoing hepato-pancreatic or colorectal procedures. Transfusion of "older" blood products may contribute to a higher risk of postoperative complications.
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http://dx.doi.org/10.1097/SLA.0000000000001647DOI Listing
January 2017

Combined resection and RFA in colorectal liver metastases: stratification of long-term outcomes.

J Surg Res 2016 11 4;206(1):182-189. Epub 2016 Jul 4.

Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland; Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Wexner Medical Center at the Ohio State University, Columbus, Ohio. Electronic address:

Background: Combined hepatic resection and radiofrequency ablation (resection-RFA) is a widely accepted multidisciplinary treatment for unresectable colorectal cancer liver metastases. Worse prognosis after resection-RFA is correlated to tumor morphology, although unfavorable morphology is inherent to this patient cohort. This study aimed to select patients who may or may not benefit from resection-RFA with the aid of tumor biology.

Method: Data from 485 patients who underwent curative hepatectomy with or without concurrent RFA were retrospectively collected and analyzed. Clinicopathologic characteristics, predictors of overall survival (OS), and OS of patients stratified by tumor biology in resection-RFA were analyzed.

Results: Combined resection-RFA was performed in 86 patients (17.7%) and a standalone resection in 399 patients. Baseline patients' characteristics of the resection-RFA group were significantly different in terms of median number of tumors (5 versus 2) and bilobar distribution (84.9% versus 29.1%) from those of the resection-only group. Multivariate analysis identified four independent predictors of decreased OS in the resection-RFA group. Three were related to tumor biology: primary tumor nodal metastases (hazard ratio [HR], 2.32; 95% confidence interval (95% CI), 1.16-4.64], Kirsten rat sarcoma viral oncogene homolog mutation (HR, 2.64; 95% CI, 1.36-5.14), and preoperative high carcinoembryonic antigen (HR, 2.33; 95% CI, 1.13-4.81), and one related to tumor morphology-ablated lesions ≥3 (HR, 2.05; 95% CI, 1.41-3.80; P = 0.023). To examine the prognostic influence of tumor biology, the resection-RFA group was stratified into two groups by number of predictors related to tumor biology (low risk: 0-1 risk factors; n = 56 and high risk: 2-3 risk factors; n = 30). Median OS of the low risk, high risk, and resection-alone groups were 61.8, 20.7, and 75.3 mo, respectively. The 5-y OS rate was similar between the low risk and resection-alone group (52.7% versus 58.7%, respectively; P = 0.323).

Conclusions: Patients with low-risk tumors undergoing a combined resection-RFA approach had roughly comparable OS to those who only underwent resection, irrespective of advanced tumor morphology. Combined resection-RFA procedures might be of value to these patients.
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http://dx.doi.org/10.1016/j.jss.2016.06.098DOI Listing
November 2016

Sorafenib as an adjuvant therapy for resectable hepatocellular carcinoma: A single center experience.

J BUON 2016 Sept-Oct;21(5):1189-1194

2nd Department of Propaedeutic Surgery, Laiko General Hospital, School of Medicine, University of Athens, Athens, Greece.

Purpose: Resectable hepatocellular carcinoma (HCC) is currently treated with surgical resection without any adjuvant therapy. We sought to assess the value of sorafenib as an adjuvant treatment in that clinical setting.

Methods: Of a total of 30 patients, 16 underwent curative- intent liver resection for HCC and subsequently received adjuvant sorafenib, while 14 underwent surgery alone. Clinicopathological characteristics were analyzed and the impact of adjuvant sorafenib on overall survival (OS) was assessed.

Results: The median follow up time was 38.2 months. The median patient age was 63.5 and 76.7% of them were male. The majority of patients had a solitary tumor (74.1%) with a median size of 7.75 cm. Five-year OS for the whole cohort was 60.2%. OS for patients who underwent only resection was 52.9 vs 68.1% for patients who underwent resection and received adjuvant sorafenib (p=0.19).

Conclusion: Sorafenib seems to be associated with an acceptable safety profile but does not confer any substantial clinical benefit in terms of survival in HCC patients who have undergone curative-intent liver resection.
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June 2017

Tumor Biology Rather Than Surgical Technique Dictates Prognosis in Colorectal Cancer Liver Metastases.

J Gastrointest Surg 2016 11 6;20(11):1821-1829. Epub 2016 Jul 6.

Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: The interplay of tumor biology and surgical margin status after resection for colorectal liver metastasis (CRLM) remains controversial. Consequently, we sought to determine the impact of surgical margin status on overall survival (OS) stratified by KRAS mutational status.

Materials And Methods: Four hundred eighty-five patients with known KRAS mutational status were identified. Clinicopathologic and long-term survival data were collected and assessed.

Results: On pathology, most patients (n = 380; 78.3 %) had an R0 margin, while 105 (21.7 %) had an R1. Roughly two thirds of tumors were KRAS wild type (wtKRAS) (n = 307, 63.3 %), while 36.7 % (n = 178) had KRAS mutations (mutKRAS). Median and 5-year OS of the entire cohort was 65.8 months and 53.8 %, respectively. An R1 resection was associated with worse 5-year OS compared with R0 (42.4 % vs. 57.1 %; hazard ratio (HR) 1.82, 95 % CI 1.28-2.57; P = 0.001). After controlling for KRAS status, the survival benefit associated with an R0 resection persisted only among patients with wtKRAS tumors (HR 2.16, 95 % CI 1.42-3.30; P < 0.001). In contrast, surgical margin had no impact on OS among patients with mutKRAS tumors (5-year OS R0, 40.7 % vs. R1, 46.7 %; HR 1.34, 95 % CI 0.73-2.48; P = 0.348).

Conclusion: The impact of margin status differed by KRAS mutation status. An R0 margin only provided a survival benefit to patients with wtKRAS tumors. Tumor biology and not surgical technique determined prognosis.
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http://dx.doi.org/10.1007/s11605-016-3198-8DOI Listing
November 2016

Pre-hepatectomy carcinoembryonic antigen (CEA) levels among patients undergoing resection of colorectal liver metastases: do CEA levels still have prognostic implications?

HPB (Oxford) 2016 12 18;18(12):1000-1009. Epub 2016 Oct 18.

Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA. Electronic address:

Background: The impact of prehepatectomy carcinoembryonic antigen (CEA) levels in the era of modern chemotherapy and expanded surgical indications for colorectal liver metastasis (CRLM) remains not well defined.

Methods: 484 patients were identified and divided into two groups by surgical time period (group 1: 2000-2007 vs. group 2: 2008-2015). The prognostic significance of pre-hepatectomy CEA was determined by assessing the HRs associated with various cut-off levels ranging from 5 to 200 ng/mL.

Results: Median CRLM number was comparable in both groups (group 1: 2 vs. group 2: 2, P = 0.504). Bilobar disease was more frequent in group 2 (30.1% vs. 42.5%, P = 0.006). The administration of modern chemotherapy and/or biologic agents increased over time (49.5% vs. 67.9%, P < 0.001). Preoperative CEA independently predicted OS in group 1, even with a cut-off as low as >5 ng/mL. However, in group 2 it predicted recurrence and survival only after exceeding 70 and 50 ng/mL, respectively. Of note, in group 2, CEA was strongly associated with survival when CEA levels exceeded 70 ng/mL (HR 4.84).

Conclusions: While pre-hepatectomy CEA level may still have prognostic utility in CRLM resection, the optimal cut-off value has increased in the era of modern chemotherapy.
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http://dx.doi.org/10.1016/j.hpb.2016.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144549PMC
December 2016

KRAS Mutation Status Dictates Optimal Surgical Margin Width in Patients Undergoing Resection of Colorectal Liver Metastases.

Ann Surg Oncol 2017 Jan 30;24(1):264-271. Epub 2016 Sep 30.

Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.

Background: The optimal tumor-free margin width remains controversial and may be inappropriate to investigate without considering differences in the underlying tumor biology.

Methods: R1 resection was defined as margin clearance less than 1 mm. R0 resection was further divided into 3 groups: 1-4, 5-9, and ≥10 mm. The impact of margin width on overall survival (OS) relative to KRAS status [wild type (wtKRAS) vs. mutated (mutKRAS)] was assessed.

Results: A total of 411 patients met inclusion criteria. Median patient age was 58 years (interquartile range, 49.7-66.7); most patients were male (n = 250; 60.8 %). With a median follow-up of 28.3 months, median and 5-year OS were 69.8 months and 55.1 %. Among patients with wtKRAS tumors, although margin clearance of 1-4 mm or more was associated with improved OS compared to R1 (all P < 0.05), no difference in OS was observed when comparing margin clearance of 1-4 mm to the 5-9 mm and the ≥10 mm groups (all P > 0.05). In contrast, among patients with mutKRAS tumors, all three groups of margin clearance (1-4, 5-9, and ≥10 mm) fared no better in terms of 5-year survival compared to R1 resection (all P > 0.05).

Conclusions: While a 1-4 mm margin clearance in patients with wtKRAS tumors was associated with improved survival, wider resection width did not confer an additional survival benefit. In contrast, margin status-including a 1 cm margin-did not improve survival among patients with mutKRAS tumors.
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http://dx.doi.org/10.1245/s10434-016-5609-1DOI Listing
January 2017

Perioperative Hyperglycemia and Postoperative Outcomes in Patients Undergoing Resection of Colorectal Liver Metastases.

J Gastrointest Surg 2017 02 27;21(2):228-237. Epub 2016 Sep 27.

Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: There is limited evidence characterizing the impact of glycemic alterations on short-term outcomes among patients undergoing resection of colorectal liver metastases (CRLM).

Methods: Hyperglycemia was defined as a glucose value >125 mg/dl according to WHO definition. The impact of early postoperative hyperglycemia on short-term postoperative outcomes was assessed.

Results: The mean postoperative glucose value was 128 mg/dl; 30 (9.8 %) patients had normal fasting glucose (<100 mg/dl), 106 patients had glucose intolerance (100-125 mg/dl), and 170 (55.5 %) patients had hyperglycemia (>125 mg/dl). A postoperative complication occurred in 101 patients (morbidity, 33.1 %); among patients who experienced a complication, an infectious complication was most common (38.6 %). After controlling for clinical factors, patients with hyperglycemia had an increased risk of overall complications [odds ratio (OR) 4.11; 95 % confidence interval (CI) 1.96-8.62, P < 0.001]. This was the case for both patients with and without diabetes (P < 0.05). Patients with hyperglycemia on the day of surgery were also at an increased risk of infections [OR 9.17; 95 % CI 2.26-37.13, P = 0.002] and had a longer hospital stay (normal glucose, 4 days vs. glucose 100-125 mg/dl, 4 days vs. glucose >125 mg/dl, 5 days, P < 0.001).

Conclusions: Early postoperative hyperglycemia was associated with adverse outcomes in patients with and without diabetes who underwent resection of CRLM. Perioperative glucose evaluation may be an important quality target.
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http://dx.doi.org/10.1007/s11605-016-3278-9DOI Listing
February 2017

Albumin-Bilirubin Score: Predicting Short-Term Outcomes Including Bile Leak and Post-hepatectomy Liver Failure Following Hepatic Resection.

J Gastrointest Surg 2017 02 12;21(2):238-248. Epub 2016 Sep 12.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: Post-operative bile leak (BL) and post hepatectomy liver failure (PHLF) are the major potential sources of morbidity among patients undergoing liver resection. We sought to define the incidence of BL and PHLF among a large cohort of patients, as well as examine the prognostic impact of model for end-stage liver disease (MELD) and albumin-bilirubin (ALBI) scores to predict these short-term outcomes.

Materials And Methods: Patients who underwent a hepatectomy between January 1, 2014 and December 31, 2014 were identified using the National Surgical Quality Improvement Program (NSQIP) liver-targeted database. Risk factors for BL and PHLF were identified using multivariable logistic regression.

Results: Among the 3064 patients identified, median age was 60 years (IQR 50-68). Most patients underwent surgery (78.9 %) for malignant lesions. Post-operatively, 250 (8.5 %) patients experienced a BL while PHLF occurred in 149 cases (4.9 %). Both MELD (MELD <10 4.9 %; MELD ≥10, 10 %; P = 0.001) and ALBI (grade 1, 4.0 %; grade 2, 7.2 %; grade 3, 10.0 %; P = 0.001) were associated with PHLF occurrence, while only ALBI predicted PHLF severity (P = 0.008). Moreover, ALBI was associated with BL (grade 1, 7.1 %; grade 2, 11.5 %; grade 3, 14.0 %; P < 0.001), whereas MELD was not (MELD <10, 8.4 %; MELD ≥10, 11.2 %; P = 0.13). On multivariable analysis, ALBI grade 2/3 was associated with PHLF (OR 1.57, 95 % CI 1.08-2.27; P = 0.02), PHLF severity (OR 3.06, 95 % CI 1.50-6.23; P = 0.003), and the development of a BL (OR 1.35, 95 % CI 1.02-1.80; P = 0.04).

Conclusion: The ALBI score was associated with short-term post-operative outcomes following hepatic resection and represents a useful pre-operative risk-assessment tool to identify patients at risk for adverse post-operative outcomes.
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http://dx.doi.org/10.1007/s11605-016-3246-4DOI Listing
February 2017

In vitro evaluation of actively targetable superparamagnetic nanoparticles to the folate receptor positive cancer cells.

Mater Sci Eng C Mater Biol Appl 2016 Dec 1;69:1147-58. Epub 2016 Aug 1.

Faculty of Biomedical Engineering, Universiti Teknologi Malaysia, Skudai, 81310 Johor Bahru, Johor, Malaysia.

Engineering of a physiologically compatible, stable and targetable SPIONs-CA-FA formulation was reported. Initially fabricated superparamagnetic iron oxide nanoparticles (SPIONs) were coated with citric acid (CA) to hamper agglomeration as well as to ameliorate biocompatibility. Folic acid (FA) as a targeting agent was then conjugated to the citric acid coated SPIONs (SPIONs-CA) for targeting the specific receptors expressed on the FAR+ cancer cells. Physiochemical characterizations were then performed to assure required properties like stability, size, phase purity, surface morphology, chemical integrity and magnetic properties. In vitro evaluations (MTT assay) were performed on HeLa, HSF 1184, MDA-MB-468 and MDA-MB-231cell lines to ensure the biocompatibility of SPIONs-CA-FA. There were no morphological changes and lysis in contact with erythrocytes recorded for SPIONs-CA-FA and SPIONs-CA. High level of SPIONs-CA-FA binding to FAR+ cell lines was assured via qualitative and quantitative in vitro binding studies. Hence, SPIONs-CA-FA was introduced as a promising tool for biomedical applications like magnetic hyperthermia and drug delivery. The in vitro findings presented in this study need to be compared with those of in vivo studies.
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http://dx.doi.org/10.1016/j.msec.2016.07.076DOI Listing
December 2016

From bench to bedside: Clinical implications of KRAS status in patients with colorectal liver metastasis.

Surg Oncol 2016 Sep 14;25(3):332-8. Epub 2016 Jul 14.

Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA. Electronic address:

Introduction: While the role of KRAS in the molecular genetics of colorectal cancer has been studied extensively, its prognostic impact in colorectal liver metastases (CRLM) has only recently been examined. This review aimed to summarize currently reported findings on the clinical implications of KRAS mutant (mut-KRAS) status for patients with CRLM.

Materials And Methods: The Pubmed database was searched for relevant articles published from 01/01/2010 to 02/01/2016. Overall survival (OS) and recurrence free survival (RFS) as well as patterns of recurrence were the primary endpoints, but consideration was given to secondary outcomes when the respective findings were of clinical interest.

Results: Out of the 266 studies screened, 15 were included in our review. Fourteen studies were retrospective cohorts while one was a systematic review/meta-analysis. Among the 14 retrospective studies, 12 reported OS with 9 detecting a negative association with mut-KRAS status. Similarly, 11 out of 14 retrospective cohorts reported RFS with 6 detecting a negative association with mut-KRAS status. Five studies examined patterns of recurrence, with 4 detecting increased extrahepatic recurrence in the mut-KRAS group. One study examined the different effects of codon-specific KRAS mutations on prognosis.

Conclusion: mut-KRAS status predisposes to worse RFS and OS in patients with CRLM, possibly as a result of aggressive tumor biology. Early unresectable extrahepatic recurrence is more frequent in this patient group and may underlie the unfavorable prognosis. Future research should focus on characterizing the distinct effects of codon-specific KRAS mutations as well their interplay with other less common genetic mutations.
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http://dx.doi.org/10.1016/j.suronc.2016.07.002DOI Listing
September 2016

Rates and patterns of recurrence after curative intent resection for gallbladder cancer: a multi-institution analysis from the US Extra-hepatic Biliary Malignancy Consortium.

HPB (Oxford) 2016 11 13;18(11):872-878. Epub 2016 Aug 13.

Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA; Department of Surgery, Ohio State University, Columbus, OH, USA. Electronic address:

Background: Gallbladder cancer is a relatively rare malignancy. The current study aimed to define the incidence and patterns of recurrence following gallbladder cancer resection.

Methods: Using a multi-institutional cohort we identified 217 patient undergoing curative intent surgery for gallbladder cancer. Patterns of recurrence were classified as locoregional and distant recurrence.

Results: At last follow-up, 76 patients (35.0%) had experienced a recurrence (locoregional only, n = 12, 15.8%; distant only, n = 50, 65.8%; locoregional and distant, n = 14, 18.4%). Median time to recurrence was 9.5 months (IQR 4.7-17.6) and was not associated with recurrence site (all p > 0.05). On multivariable analysis, T3 disease (HR = 8.44, p = 0.014), lymphovascular invasion (HR = 4.24, p < 0.001) and residual disease (HR = 2.04, p = 0.042) were associated with an increased risk of recurrence. Patients who recurred demonstrated a worse 1-, 3- and 5-year OS (1-year OS: 91.3% vs. 68.6%, p = 0.001, 3-year OS: 79.3% vs. 28.7%, p < 0.001, and 5-year OS: 75.9% vs. 16.0%, p < 0.001). After adjusting for other risk factors, recurrence was independently associated with a decreased OS (HR = 3.71, p = 0.006). Of note, receipt of adjuvant therapy was associated with improved OS (HR = 0.56, p = 0.027) among those patients who developed a tumor recurrence.

Discussion: Over one-third of patients experienced a recurrence after gallbladder cancer surgery. While chemotherapy did not decrease the rate of recurrence, patients who experienced recurrence after administration of adjuvant treatment faired better than patients who did not receive adjuvant therapy.
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http://dx.doi.org/10.1016/j.hpb.2016.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094487PMC
November 2016

Antioxidant Activity and ROS-Dependent Apoptotic Effect of Scurrula ferruginea (Jack) Danser Methanol Extract in Human Breast Cancer Cell MDA-MB-231.

PLoS One 2016 13;11(7):e0158942. Epub 2016 Jul 13.

Bioprocess Engineering Department, Faculty of Chemical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia.

Scurrula ferruginea (Jack) Danser is one of the mistletoe species belonging to Loranthaceae family, which grows on the branches of many deciduous trees in tropical countries. This study evaluated the antioxidant activities of S. ferruginea extracts. The cytotoxic activity of the selected extracts, which showed potent antioxidant activities, and high phenolic and flavonoid contents, were investigated in human breast cancer cell line (MDA-MB-231) and non-cancer human skin fibroblast cells (HSF-1184). The activities and characteristics varied depending on the different parts of S. ferruginea, solvent polarity, and concentrations of extracts. The stem methanol extract showed the highest amount of both phenolic (273.51 ± 4.84 mg gallic acid/g extract) and flavonoid contents (163.41 ± 4.62 mg catechin/g extract) and strong DPPH• radical scavenging (IC50 = 27.81 μg/mL) and metal chelation activity (IC50 = 80.20 μg/mL). The stem aqueous extract showed the highest ABTS•+ scavenging ability. The stem methanol and aqueous extracts exhibited dose-dependent cytotoxic activity against MDA-MB-231 cells with IC50 of 19.27 and 50.35 μg/mL, respectively. Furthermore, the extracts inhibited the migration and colony formation of MDA-MB-231 cells in a concentration-dependent manner. Morphological observations revealed hallmark properties of apoptosis in treated cells. The methanol extract induced an increase in ROS generation and mitochondrial depolarization in MDA-MB-231 cells, suggesting its potent apoptotic activity. The present study demonstrated that the S. ferruginea methanol extract mediated MDA-MB-231 cell growth inhibition via induction of apoptosis which was confirmed by Western blot analysis. It may be a potential anticancer agent; however, its in vivo anticancer activity needs to be investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943642PMC
July 2017

Complication timing impacts 30-d mortality after hepatectomy.

J Surg Res 2016 06 27;203(2):495-506. Epub 2016 Apr 27.

Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland. Electronic address:

Background: To date, no study has specifically focused on the timing of complications after hepatectomy relative to patient outcomes. We sought to investigate the effect of complication timing on 30-d mortality.

Materials And Methods: A total of 3064 patients who underwent hepatic resection in 2014 were identified from American College of Surgeons National Surgical Quality Improvement Program database. Cox regression analysis was performed to determine the association of complication timing with 30-d mortality.

Results: Median patient age was 60 y (interquartile range, 50-68). Among all patients who experienced a complication, 16.6% had only a postdischarge complication. Wound disruption (64%) and surgical site infection (58.1%) occurred frequently after discharge. Organ space surgical site infection occurred at a later time after surgery among patients who underwent minimally invasive surgery (minimally invasive surgery, 16 d versus open 10 d; P = 0.008). Among 47 (1.5%) patients who died within 30 d from surgery, 21.3% of deaths occurred postdischarge. After adjusting for competing risk factors, patients who had experienced a postdischarge complication demonstrated an increased risk of 30-d mortality (referent, predischarge, hazard ratio 2.96, 95% confidence intervals 1.07-8.17; P = 0.04).

Conclusions: Postdischarge complications occurred less frequently after hepatectomy than predischarge complications; however, late complications were associated with a three-fold increased risk of mortality.
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http://dx.doi.org/10.1016/j.jss.2016.04.047DOI Listing
June 2016

Prognostic Implication of KRAS Status after Hepatectomy for Colorectal Liver Metastases Varies According to Primary Colorectal Tumor Location.

Ann Surg Oncol 2016 10 28;23(11):3736-3743. Epub 2016 Jun 28.

Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Right-sided and left-sided colorectal cancer (CRC) is known to differ in their molecular carcinogenic pathways. We sought to investigate the variable prognostic implication of KRAS mutation after hepatectomy for colorectal liver metastases (CRLM) according to the site of primary CRC.

Methods: A total of 426 patients who underwent a curative-intent hepatic resection and whose KRAS status was available were identified. Clinicopathologic characteristics and long-term outcomes were stratified by KRAS status (wild type vs. mutant type) and primary tumor location (right-sided vs. left-sided). Cecum, right and transverse colon were defined as right-sided, whereas left colon and rectum were defined as left-sided.

Results: Among patients with a right-sided CRC, 5-year recurrence-free survival (RFS) and overall survival (OS) were not correlated with KRAS status (wild type: 30.8 and 47.2 % vs. mutant type: 38.5 and 49.1 %, respectively) (both P > 0.05). Specifically, mutant-type KRAS was not associated with either RFS or OS on multivariable analysis (hazard ratio [HR] 1.51, 95 % confidence interval [CI] 0.73-3.14, P = 0.23 and HR 1.03, 95 % CI 0.51-2.08, P = 0.95, respectively). In contrast, among patients who underwent resection of CRLM from a left-sided primary CRC, 5-year RFS and OS were worse among patients with mutant-type KRAS (wild type: 23.7 and 57.2 % vs. mutant type: 19.6 and 38.2 %, respectively) (both P < 0.05). On multivariable analysis, mutant-type KRAS remained independently associated with worse RFS and OS among patients with a left-sided primary CRC (HR 1.57, 95 % CI 1.01-2.44, P = 0.04 and HR 1.81, 95 % CI 1.11-2.96, P = 0.02, respectively).

Conclusions: KRAS status has a variable prognostic impact after hepatic resection for CRLM depending on the site of the primary CRC. Future studies examining the impact of KRAS status on prognosis after hepatectomy should take into account the primary CRC tumor site.
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http://dx.doi.org/10.1245/s10434-016-5361-6DOI Listing
October 2016

Activating KRAS mutation is prognostic only among patients who receive preoperative chemotherapy before resection of colorectal liver metastases.

J Surg Oncol 2016 Sep 6;114(3):361-7. Epub 2016 Jun 6.

Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland.

Background And Objectives: While the prognostic role of KRAS status after resection of CRLM has been previously explored, the importance of KRAS status relative to the receipt of preoperative chemotherapy remains largely unknown.

Methods: A total of 430 patients who underwent curative-intent surgery for CRLM between 2000 and 2015 and who had available KRAS genotype data were identified. Data regarding KRAS mutation status, receipt of preoperative chemotherapy, and overall survival (OS) were assessed using univariable and multivariable analyses.

Results: Median patient age was 58 years (IQR, 50.4-66.4 years). A total of 258 patients (60.0%) received preoperative chemotherapy, while 172 (40.0%) had upfront surgery. Median and 5-year OS in the entire cohort was 65.1 months and 53.2%, respectively. KRAS mutation was associated with a worse 5-year OS compared with wild-type tumors (HR 1.41; P = 0.042). After stratifying by the receipt of preoperative chemotherapy, the prognostic value of KRAS mutation only persisted among patients who had received preoperative chemotherapy (HR 1.67; P = 0.012). In contrast, KRAS mutation status had no impact on OS among patients who had not received preoperative chemotherapy (P = 0.597).

Conclusions: KRAS mutation status was an independent predictor of OS among patients undergoing liver resection of CRLM. However, after stratifying by receipt of preoperative chemotherapy, KRAS was informative relative to prognosis only among patients who received preoperative chemotherapy. J. Surg. Oncol. 2016;114:361-367. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jso.24319DOI Listing
September 2016

Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.

Cancer 2016 09 31;122(17):2698-707. Epub 2016 May 31.

Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland.

Background: Investigations regarding the impact of tumor biology after surgical management of colorectal liver metastasis have focused largely on overall survival. We investigated the impact of codon-specific KRAS mutations on the rates and patterns of recurrence in patients after surgery for colorectal liver metastasis (CRLM).

Methods: All patients who underwent curative-intent surgery for CRLM between 2002 and 2015 at Johns Hopkins who had available data on KRAS mutation status were identified. Clinico-pathologic data, recurrence patterns, and recurrence-free survival (RFS) were assessed using univariable and multivariable analyses.

Results: A total of 512 patients underwent resection only (83.2%) or resection plus radiofrequency ablation (16.8%). Although 5-year overall survival was 64.6%, 284 (55.5%) patients recurred with a median RFS time of 18.1 months. The liver was the initial recurrence site for 181 patients, whereas extrahepatic recurrence was observed in 162 patients. Among patients with an extrahepatic recurrence, 102 (63%) had a lung recurrence. Although overall KRAS mutation was not associated with overall RFS (P = 0.186), it was independently associated with a worse extrahepatic (P = 0.004) and lung RFS (P = 0.007). Among patients with known KRAS codon-specific mutations, patients with codon 13 KRAS mutation had a worse 5-year extrahepatic RFS (P = 0.01), whereas codon 12 mutations were not associated with extrahepatic (P = 0.11) or lung-specific recurrence rate (P = 0.24). On multivariable analysis, only codon 13 mutation independently predicted worse overall extrahepatic RFS (P = 0.004) and lung-specific RFS (P = 0.023).

Conclusions: Among patients undergoing resection of CRLM, overall KRAS mutation was not associated with RFS. KRAS codon 13 mutations, but not codon 12 mutations, were associated with a higher risk for overall extrahepatic recurrence and lung-specific recurrence. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2698-2707. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30085DOI Listing
September 2016

Impact of Chemotherapy and External-Beam Radiation Therapy on Outcomes among Patients with Resected Gallbladder Cancer: A Multi-institutional Analysis.

Ann Surg Oncol 2016 09 11;23(9):2998-3008. Epub 2016 May 11.

Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Use of adjuvant chemotherapy (CTx) and chemoradiation therapy (cXRT) for the treatment of gallbladder cancer (GBC) remains varied. We sought to define the utilization and effect of adjuvant therapy for patients with GBC.

Methods: Using a multi-institutional national database, 291 patients with GBC who underwent curative-intent resection between 2000 and 2015 were included. Patients with metastasis or an R2 margin were excluded.

Results: Median patient age was 66.6 years. Most patients had a T2 (46.2 %) or T3 (38.6 %) lesion, and 37.8 % of patients had lymph node (LN) metastasis. A total of 186 (63.9 %) patients underwent surgery alone, 61 (21.0 %) received CTx, and 44 (15.1 %) patients received cXRT. On multivariable analysis, factors associated with worse overall survival (OS) included T3/T4 stage [hazard ratio (HR) 1.82], LN-metastasis (HR 1.84), lymphovascular invasion (HR 2.02), perineural invasion (HR 1.42), and R1 surgical margin status (HR 2.06); all P < 0.05). In contrast, receipt of CTx/cXRT was associated with improved OS (CTx, HR 0.38; cXRT, HR 0.26; P < 0.001) compared with surgery alone. Similar results were observed for disease-free survival (DFS) (CTx, HR 0.61; cXRT, HR 0.43; P < 0.05). Of note, only patients with high-risk features, such as AJCC T3/T4 stage (HR 0.41), LN metastasis (HR 0.45), and R1 disease (HR 0.21) (all P < 0.05) derived an OS benefit from CTx/cXRT.

Conclusions: Adjuvant CTx/cXRT was utilized in 36 % of patients undergoing curative-intent resection for GBC. After adjusted analyses, CTx/cXRT were independently associated with improved long-term outcomes, but the benefit was isolated to only patients with high-risk characteristics.
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http://dx.doi.org/10.1245/s10434-016-5262-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456271PMC
September 2016

Prognostic Implications of Lymph Node Status for Patients With Gallbladder Cancer: A Multi-Institutional Study.

Ann Surg Oncol 2016 09 5;23(9):3016-23. Epub 2016 May 5.

Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Although the American Joint Committee on Cancer (AJCC) classification is the most accepted lymph node (LN) staging system for gallbladder adenocarcinoma (GBA), other LN prognostic schemes have been proposed. This study sought to define the performance of the AJCC LN staging system relative to the number of metastatic LNs (NMLN), the log odds of metastatic LN (LODDS), and the LN ratio (LNR).

Methods: Patients who underwent curative-intent resection for GBA between 2000 and 2015 were identified from a multi-institutional database. The prognostic performance of various LN staging systems was compared by Harrell's C and the Akaike information criterion (AIC).

Results: Altogether, 214 patients with a median age of 66.7 years (interquartile range [IQR] 56.5-73.1) were identified. A total of 1334 LNs were retrieved, with a median of 4 (IQR 2-8) LNs per patient. Patients with LN metastasis had an increased risk of death (hazard ratio [HR] 1.87; 95 % confidence interval [CI] 1.24-2.82; P = 0.003) and recurrence (HR 2.28; 95 % CI 1.37-3.80; P = 0.002). In the entire cohort, LNR, analyzed as either a continuous scale (C-index, 0.603; AIC, 803.5) or a discrete scale (C-index, 0.609; AIC, 802.2), provided better prognostic discrimination. Among the patients with four or more LNs examined, LODDS (C-index, 0.621; AIC, 363.8) had the best performance versus LNR (C-index, 0.615; AIC, 368.7), AJCC LN staging system (C-index, 0.601; AIC, 373.4), and NMLN (C-index, 0.613; AIC, 369.5).

Conclusions: Both LODDS and LNR performed better than the AJCC LN staging system. Among the patients who had four or more LNs examined, LODDS performed better than LNR. Both LODDS and LNR should be incorporated into the AJCC LN staging system for GBA.
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http://dx.doi.org/10.1245/s10434-016-5243-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450040PMC
September 2016