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Background: Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare., Methods: This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts., Results: Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%])., Conclusion: Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy., Competing Interests: Disclosure: Eileen M. O’Reilly reports research funding to Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, and Digestive Care, Break Through Cancer, as well as consulting/DSMB for Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus Agios (spouse), Genentech-Roche (spouse), Eisai (spouse), Servier (spouse). Jeffrey Drebin reports employment and leadership at American Regent (spouse) and stock and other ownership interests in Alnylam, Arrowhead Pharmaceuticals and Ions pharmaceuticals. Vinod P. Balachandran reports research funding from Genetech/Roche and was an inventor on patent applications related to antigen cross-reactivity and neoantigen quality modeling. Alice C. Wei reports consulting for Histosonics and clinical trial funding from Ipsen. The remaining authors have no conflicts of interest., (© 2024. Society of Surgical Oncology.)

Background: Management of intrahepatic cholangiocarcinoma (IHC) has advanced in recent decades, including randomized trial evidence supporting systemic therapy in the palliative and adjuvant setting. Mounting observational evidence suggests resection of IHC with multifocal disease (IHC-MF) or lymph node metastasis (IHC-LNM) should be limited. It is unknown how real-world practice has evolved in light of research advances. This study characterizes trends in management and outcomes of IHC without distant metastasis., Methods: We queried the National Cancer Database (NCDB) for patients treated for IHC without distant metastasis (M0) and identified subgroups with lymph node (cN1) or multifocal hepatic involvement (cT2b). Two-sided Cochran-Armitage tests evaluated trends in initial treating modality and perioperative chemotherapy. Logistic regression evaluated associations with choice of initial treating modality. Overall survival (OS) was evaluated by using Kaplan-Meier methods., Results: Between 2004 and 2020, 11,368 patients were treated for IHC without extrahepatic metastasis. Forty-three percent underwent resection. Initial management shifted from resection towards radiation or systemic therapy in IHC-MF and IHC-LNM. Use of perioperative chemotherapy increased from 39% pre-2010 to 70% in 2018-2020 (p < 0.001), most often delivered postoperatively. Across the entire cohort, median OS improved from 16 (95% confidence interval [CI] 15-18) to 27 months (95% CI 26-29). More modest improvements were observed in IHC-MF and IHC-LNM., Conclusions: Use of perioperative chemotherapy has been widely adopted, predating randomized trial evidence in the adjuvant setting. Initial management of IHC-MF and IHC-LNM has shifted from resection to systemic and/or radiation therapy. While OS has improved overall, outcomes of IHC-MF and IHC-LNM remain poor, warranting further investigation., (© 2024. Society of Surgical Oncology.)

Background: The incidence of young-onset colon cancer is increasing. This study investigated the extent to which financial hardships associated with colon cancer care are associated with patient age., Methods: A consecutive sample of patients with non-metastatic colon cancer who underwent resection at a comprehensive cancer center between 2017 and 2019 were retrospectively enrolled from a clinical database. Patients with one or more of the following events associated with their colon cancer care were categorized as having experienced financial toxicity: two or more bills sent to collections, application for a payment plan, settlement, bankruptcy, or enrollment in a financial assistance program., Results: Of 764 patients identified, 157 (21 %) experienced financial toxicity. In a univariable analysis, financial toxicity was significantly associated with younger age, female sex, nonpartnered marital status, and median income by ZIP code area (p < 0.05). A multivariable analysis showed that with each 10-year decrease in patient age, the odds of financial toxicity increased by 30 % (odds ratio [OR], 1.30; 95 % confidence interval [CI], 1.14-1.48). With each $50,000 decrease in median income by ZIP code area, the odds of financial toxicity increased by 35 % (OR, 1.35; 95 % CI, 1.05-1.74)., Conclusions: Younger patients with colon cancer are at greater risk for financial toxicity than older patients. As this population continues to grow, so will the need for timely and effective financial support mechanisms., (© 2023. Society of Surgical Oncology.)

Background: Immune checkpoint blockade (ICI) of programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1) can induce durable responses in patients who have colorectal cancer (CRC) with a high tumor mutational burden (TMB). Two recurring clinical dilemmas show how to manage oligoprogressive disease and stable disease after ICI., Methods: A cohort study was conducted to analyze patients with metastatic CRC who underwent PD-1 or PD-L1 blockade. Tumors were mismatch repair (MMR) deficient or had more than 25 mutations per megabase. Patients were identified who had local therapy (surgery, ablation, or radiotherapy) for one to three sites of progressive disease (PD) or surgery to consolidate SD. The study evaluated clinical and biologic factors associated with patient selection, outcomes, and pathologic response rates., Results: From 2014 to 2020, treatment was administered to 111 patients with ICI. Of these 111 patients, 19 (17%) survived fewer than 6 months, whereas to date, 50 have not had progression of disease. The remaining 42 patients experienced PD, and 16 (38%) were treated with local therapy for oligoprogression. Selection for local therapy was associated with response to ICI. The 2-year progression-free survival (PFS) after local therapy was 62%. Finally, 6 of the 50 patients without PD had consolidation of SD, and 5 had complete or near complete pathologic responses., Conclusions: Oligoprogression, a frequent pattern of failure after ICI, can be managed effectively with local therapy. In contrast, it may not be necessary to consolidate SD for selected patients. Further research is essential to define management algorithms better and to explore heterogeneity in response patterns., (© 2022. Society of Surgical Oncology.)

Background: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy., Methods: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis., Results: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001)., Conclusions: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy., (© 2022. Society of Surgical Oncology.)

Background: There is limited information about the long-term outcomes and patterns of progression in patients who have unresectable, liver-confined hepatocellular carcinoma (HCC) with complete response (CR) to transarterial embolization and do not undergo resection or transplantation (LT)., Methods: A retrospective review analyzed participants in a randomized trial comparing hepatic artery embolization (HAE) and drug-eluting bead transarterial chemoembolization (DEB-TACE) with doxorubicin who had CR according to modified response evaluation criteria in solid tumors (mRECIST). The overall survival (OS), incidence and patterns of progression, and factors associated with progression were assessed., Results: Of the 101 patients in the trial, 37 with CR were included in this study. This cohort had 17 patients treated with HAE (46 %), and 20 patients managed with DEB-TACE (54 %). The median age was 67 years (range, 42-82 years). Most of the cohort were male (86.5 %) and Caucasian (78 %). The median pre-treatment Model for End-Stage Liver Disease (MELD) score was 10, and 70 % of the cohort had Barcelona Clinic Liver Cancer (BCLC) stage B or C. The median follow-up period was 49 months (95 % confidence interval [CI], 9-108 months), and the median OS was 25 months (95 % CI, 18.9-30.9 months). The 3- and 5-year survival rates were respectively 31 % (95 % CI, 16.7-45.9 %) and 18 % (95 % CI, 6.8-32.1 %). The 1- and 2-year cumulative incidences of progression were respectively 76 % (95 % CI, 57.7-86.8 %) and 92 % (95 % CI, 74.5-97.6 %). The most common first site of progression was the previously treated hepatic site or local site (32 %, 12/37). The 3-year cumulative incidence of progression was 65 % (95 % CI, 46.4-78.4 %) for the local site., Conclusion: Patients with advanced-stage HCC and CR to embolization do not have durable responses and experience inevitable disease progression. Most patients with progression have liver-confined disease and should be evaluated for additional consolidative treatments., (© 2022. Society of Surgical Oncology.)

Background: Liver metastasis (LM) after pancreatic ductal adenocarcinoma (PDAC) resection is common but difficult to predict and has grave prognosis. We combined preoperative clinicopathological variables and quantitative analysis of computed tomography (CT) imaging to predict early LM., Methods: We retrospectively evaluated patients with PDAC submitted to resection between 2005 and 2014 and identified clinicopathological variables associated with early LM. We performed liver radiomic analysis on preoperative contrast-enhanced CT scans and developed a logistic regression classifier to predict early LM (< 6 months)., Results: In 688 resected PDAC patients, there were 516 recurrences (75%). The cumulative incidence of LM at 5 years was 41%, and patients who developed LM first (n = 194) had the lowest 1-year overall survival (OS) (34%), compared with 322 patients who developed extrahepatic recurrence first (61%). Independent predictors of time to LM included poor tumor differentiation (hazard ratio (HR) = 2.30; P < 0.001), large tumor size (HR = 1.17 per 2-cm increase; P = 0.048), lymphovascular invasion (HR = 1.50; P = 0.015), and liver Fibrosis-4 score (HR = 0.89 per 1-unit increase; P = 0.029) on multivariate analysis. A model using radiomic variables that reflect hepatic parenchymal heterogeneity identified patients at risk for early LM with an area under the receiver operating characteristic curve (AUC) of 0.71; the performance of the model was improved by incorporating preoperative clinicopathological variables (tumor size and differentiation status; AUC = 0.74, negative predictive value (NPV) = 0.86)., Conclusions: We confirm the adverse survival impact of early LM after resection of PDAC. We further show that a model using radiomic data from preoperative imaging combined with tumor-related variables has great potential for identifying patients at high risk for LM and may help guide treatment selection., (© 2022. Society of Surgical Oncology.)

A prospective, multicentre observational cohort study of carbapenem-resistant Klebsiella spp. (CRK) bloodstream infections was conducted in Turkey from June 2018 to June 2019. One hundred eighty-seven patients were recruited. Single OXA-48-like carbapenemases predominated (75%), followed by OXA-48-like/NDM coproducers (16%). OXA-232 constituted 31% of all OXA-48-like carbapenemases and was mainly carried on ST2096. Thirty-day mortality was 44% overall and 51% for ST2096. In the multivariate cox regression analysis, SOFA score and immunosuppression were significant predictors of 30-day mortality and ST2096 had a non-significant effect. All OXA-48-like producers remained susceptible to ceftazidime-avibactam., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We aimed to describe the effect of aminoglycosides and tigecycline to reduce the mortality in colistin- and carbapenem-resistant Klebsiella pneumoniae (ColR-CR-Kp) infections. We included the studies with defined outcomes after active or non-active antibiotic treatment of ColR-CR-Kp infections. The active treatment was defined as adequate antibiotic use for at least 3 days (72 h) after the diagnosis of ColR-CR-Kp infection by culture. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and the checklist of PRISMA 2020 was applied. Crude and adjusted odds ratios (OR) with 95% confidence interval (CI) were calculated and pooled in the random effects model. Adding aminoglycosides to the existing treatment regimen reduced overall mortality significantly (OR 0.34, 95% CI 0.20-0.58). Overall mortality was 34% in patients treated with aminoglycoside-combined regimens and was 60% in patients treated with non-aminoglycoside regimens. Treatment with tigecycline is not found to reduce mortality (OR: 0.76, 95% CI: 0.47-1.23). Our results suggest that aminoglycoside addition to the existing regimen of colistin- and carbapenem-resistant Klebsiella pneumoniae infections reduces mortality significantly., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We performed a systematic review and meta-analysis for the effectiveness of Favipiravir on the fatality and the requirement of mechanical ventilation for the treatment of moderate to severe COVID-19 patients. We searched available literature and reported it by using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Until June 1, 2021, we searched PubMed, bioRxiv, medRxiv, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar by using the keywords "Favipiravir" and terms synonymous with COVID-19. Studies for Favipiravir treatment compared to standard of care among moderate and severe COVID-19 patients were included. Risk of bias assessment was performed using Revised Cochrane risk of bias tool for randomized trials (RoB 2) and ROBINS-I assessment tool for non-randomized studies. We defined the outcome measures as fatality and requirement for mechanical ventilation. A total of 2702 studies were identified and 12 clinical trials with 1636 patients were analyzed. Nine out of 12 studies were randomized controlled trials. Among the randomized studies, one study has low risk of bias, six studies have moderate risk of bias, and 2 studies have high risk of bias. Observational studies were identified as having moderate risk of bias and non-randomized study was found to have serious risk of bias. Our meta-analysis did not reveal any significant difference between the intervention and the comparator on fatality rate (OR 1.11, 95% CI 0.64-1.94) and mechanical ventilation requirement (OR 0.50, 95% CI 0.13-1.95). There is no significant difference in fatality rate and mechanical ventilation requirement between Favipiravir treatment and the standard of care in moderate and severe COVID-19 patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population., Methods: Consecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regression was used to determine whether laterality was an independent prognostic factor., Results: From 1993 to 2012, 487 patients [182 with right colon cancer (RCC), 305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5 years. Fifty-seven percent (n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%, P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%; P < 0.01) and LCC (73% vs. 55%; P < 0.01). On multivariable analysis, HAI remained associated with improved OS (HR 0.52; 95% CI 0.39-0.70; P < 0.01) but primary tumor site did not (HR 0.83; 95% CI 0.63-1.11; P = 0.21). Additional significant prognostic factors on multivariable analysis included age, number of tumors, node-positive primary, positive margins, RAS mutation, two-stage hepatectomy, and extrahepatic disease. Cox proportional hazard regression determined no significant interaction between HAI and laterality on OS [parameter estimate (SEM), 0.12 (0.28); P = 0.67]., Conclusions: Our data show an association of adjuvant HAI and increased OS in patients who underwent curative hepatectomy, irrespective of primary tumor location. Laterality should therefore not impact decision-making when offering adjuvant HAI.

In the time-to-event setting, the concordance probability assesses the relative level of agreement between a model-based risk score and the survival time of a patient. While it provides a measure of discrimination over the entire follow-up period of a study, the probability does not provide information on the longitudinal durability of a baseline risk score. It is possible that a baseline risk model is able to segregate short-term from long-term survivors but unable to maintain its discriminatory strength later in the follow-up period. As a consequence, this would motivate clinicians to re-evaluate the risk score longitudinally. This longitudinal re-evaluation may not, however, be feasible in many scenarios since a single baseline evaluation may be the only data collectible due to treatment or other clinical or ethical reasons. In these scenarios, an attenuation of the discriminatory power of the patient risk score over time would indicate decreased clinical utility and call into question whether this score should remain a prognostic tool at later time points. Working within the concordance probability paradigm, we propose a method to address this clinical scenario and evaluate the discriminatory power of a baseline derived risk score over time. The methodology is illustrated with two examples: a baseline risk score in colorectal cancer defined at the time of tumor resection, and for circulating tumor cells in metastatic prostate cancer.

Background: Obesity and metabolic syndrome are associated with inflammatory hepatic parenchymal disease (HPD) and increased risk for recurrence after resection of colorectal liver metastases (CRLM). The independent impact of HPD on recurrence patterns has not been well defined., Methods: The nonalcoholic fatty liver disease activity score (NAS) was used to quantify HPD including steatosis and fibrosis for all patients with completely resected CRLM between April 2003 and March 2007. Clinicopathologic factors, perioperative history, and outcomes were compared with the NAS. Fisher's exact test was used to examine the association between severe HPD (NAS ≥ 3) with clinical and perioperative characteristics. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS). The cumulative incidences of recurrence [any intrahepatic recurrence (IHR), extrahepatic recurrence only (EHR), and death without recurrence (DWR)] were estimated using competing risks methods., Results: Among the 357 patients included in this study, microsteatosis was noted in 124 (35%) patients, severe HPD in 31 (9%), steatohepatitis in 14 (4%), and sinusoidal injury in 36 (10%). After median follow-up of 127 months (range 4-175 months), 10-year RFS was 22% [95% confidence interval (CI) 17-27%]. Ten-year cumulative incidence for IHR, EHR, and DWR was 37%, 30%, and 12%, respectively. After controlling for confounders, NAS ≥ 3 was independently associated with higher risk of IHR [hazard ratio (HR) 1.76, 95% CI 1.07-2.90, p = 0.027] and lower risk of EHR (HR 0.18, 95% CI 0.04-0.75, p = 0.019) on multivariable analysis., Conclusions: Severe HPD was associated with increased IHR risk and decreased EHR risk. Future investigation into whether improving HPD from reversible etiologies can reduce the risk for IHR is warranted.

Background: Although IPMN are thought to represent a whole-gland disease, segmental resection remains the most frequently performed treatment. We sought to determine the rates, patterns, and predictors of IPMN progression in the pancreatic remnant following segmental resection of noninvasive or microinvasive IPMN., Methods: A prospectively maintained database was queried to identify all patients who underwent resection of noninvasive or microinvasive IPMN (≤ 10 mm of invasive component) between 1989 and 2015. Progression (recurrence) was defined as either the development of cancer, a new IPMN cystic lesion > 1 cm or ≥ 50% increase in the diameter of residual IPMN lesions in the remnant. Univariate and multivariate cox regression models were created to determine predictors of progression., Results: A total of 319 patients underwent resection for noninvasive and microinvasive IPMN. The median age was 68, 53% had branch-duct (BD) IPMN, and 6% had microinvasive disease. After a median follow-up of 42 months, 71 patients (22%) experienced IPMN progression. Within this group of 71 patients, 11 (16% of recurrence) developed invasive cancer in the pancreatic remnant after a median of 28 months. Twelve patients (17%) experienced progression > 5 years following initial resection. On multivariate analysis, a distal location of the initial lesion was associated with an increased risk of progression (multivariate hazards ratio = 2.43, confidence interval 1.47-4.0, p < 0.001)., Conclusions: In this study, 22% of patients had disease progression following resection of noninvasive or microinvasive IPMN; 16% of these progressions represented invasive disease. These patients represent a high-risk group and should undergo long-term radiographic surveillance.

Background: Pancreatic cancer is a highly lethal cancer with no established a priori markers of survival. Existing nomograms rely mainly on post-resection data and are of limited utility in directing surgical management. This study investigated the use of quantitative computed tomography (CT) features to preoperatively assess survival for pancreatic ductal adenocarcinoma (PDAC) patients., Methods: A prospectively maintained database identified consecutive chemotherapy-naive patients with CT angiography and resected PDAC between 2009 and 2012. Variation in CT enhancement patterns was extracted from the tumor region using texture analysis, a quantitative image analysis tool previously described in the literature. Two continuous survival models were constructed, with 70% of the data (training set) using Cox regression, first based only on preoperative serum cancer antigen (CA) 19-9 levels and image features (model A), and then on CA19-9, image features, and the Brennan score (composite pathology score; model B). The remaining 30% of the data (test set) were reserved for independent validation., Results: A total of 161 patients were included in the analysis. Training and test sets contained 113 and 48 patients, respectively. Quantitative image features combined with CA19-9 achieved a c-index of 0.69 [integrated Brier score (IBS) 0.224] on the test data, while combining CA19-9, imaging, and the Brennan score achieved a c-index of 0.74 (IBS 0.200) on the test data., Conclusion: We present two continuous survival prediction models for resected PDAC patients. Quantitative analysis of CT texture features is associated with overall survival. Further work includes applying the model to an external dataset to increase the sample size for training and to determine its applicability.

Background: Recurrence after resection of colorectal liver metastases (CRLMs) occurs in up to 75% of patients. Preoperative prediction of hepatic recurrence may inform therapeutic strategies at the time of initial resection. Texture analysis (TA) is an established technique that quantifies pixel intensity variations (heterogeneity) on cross-sectional imaging. We hypothesized that tumoral and parenchymal changes that are predictive of overall survival (OS) and recurrence in the future liver remnant (FLR) can be detected using TA on preoperative computed tomography (CT) images., Methods: Patients who underwent resection for CRLM between 2003 and 2007 with appropriate preoperative CT scans were included (n = 198) in this retrospective study. Texture features extracted from the tumor and FLR, and clinicopathologic variables, were incorporated into a multivariable survival model., Results: Quantitative imaging features of the FLR were an independent predictor of both OS and hepatic disease-free survival (HDFS). Tumor texture showed significant association with OS. TA of the FLR allowed patient stratification into two groups, with significantly different risks of hepatic recurrence (hazard ratio 2.09, 95% confidence interval 1.33-3.28; p = 0.001). Patients with homogeneous parenchyma had approximately twice the risk of hepatic recurrence (41 vs. 20%)., Conclusion: TA of the tumor and FLR are independently associated with OS, and TA of the FLR is independently associated with HDFS. Patients with homogeneous parenchyma had a significantly higher risk of hepatic recurrence. Preoperative TA of the liver represents a potential biomarker to identify patients at risk of liver recurrence after resection for CRLM.

Background: Tumor-associated macrophages (TAMs) support growth in most human cancers, with the notable exception of colorectal adenocarcinoma, in which TAM infiltration of primary tumors is correlated with a better outcome. The importance of TAMs in colorectal liver metastases (CLM) is unknown., Methods: Using a tissue microarray of CLM resected at their institution from 1998 to 2000, the authors quantified immune marker expression by immunohistochemistry (IHC) using Metamorph Image Analysis software. Findings showed that CD68, CD3, CD4, CD8, FoxP3, and MHC-I were correlated with overall survival (OS) and disease-free survival (DFS)., Results: Tumor cores from 158 patients were analyzed. The median follow-up period was 117 months for survivors (n = 39). The univariate analysis showed a significant positive association between DFS and CD4 + (p = 0.025) and CD68 + (p = 0.007). The findings showed a significant positive correlation of OS with CD4 + (p = 0.042), whereas the correlation with CD68 + was not significant (p = 0.17). Cutoffs were determined to dichotimize each marker for the highest log-rank statistic. Patients with CD4 high had a median OS of 115 months and DFS of 41 months (p = 0.007 compared with 40 and 16 months, respectively, for patients with CD4 low (p = 0.022). Patients with CD68 high had a median OS of 50 months and a median DFS of 25 months (p = 0.67) compared with 43 and 15 months (p = 0.028). In the multivariate analysis of factors affecting DFS, high CD68 was associated with longer DFS (hazard ratio [HR], 0.63, 95% confidence interval [CI], 0.43-0.94; p = 0.02), independently of clinicopathologic variables and CD4., Conclusions: High TAM infiltration in resected CLM is associated with better outcome, independently of known clinicopathologic and immune predictors. This suggests that TAM depletion, which is being tested clinically in other cancers, may be detrimental in CLM.

Background: Resection of hepatocellular carcinoma (HCC) offers a chance of cure, but recurrence is common and survival is often limited. The clinical and pathological characteristics of long-term survivors have not been well studied., Methods: We retrospectively reviewed 212 patients who underwent partial hepatectomy for HCC with curative intent from 1992 to 2006. Fifty patients who survived beyond 10 years were compared with 109 patients who died of recurrence within 10 years., Results: Multivariate analysis showed that tumors <5 cm (odds ratio [OR] 2.3, p = 0.04), solitary tumors (OR 3.2, p = 0.01), and absence of vascular invasion (OR 2.3, p = 0.04) were independently associated with actual 10-year survival. However, more than 20% of long-term survivors also possessed established poor prognostic factors, including α-fetoprotein >1000 ng/mL, unfavorable serum inflammatory indices, tumor size >10 cm, microvascular invasion, poor tumor differentiation, cirrhosis, and metabolic syndrome. None of the 10-year survivors had an R1 resection. While 77% of the short-term survivors developed recurrence within 2 years, 42% of the 10-year survivors developed recurrence during their decade of follow-up, although most of the recurrences among 10-year survivors were intrahepatic and amenable to further treatment. Among patients who survived beyond 10 years, 42% remained alive without recurrence., Conclusions: In this largest Western series of actual 10-year survivors after HCC resection, almost one in four patients survived over a decade, even though nearly half of this subset had developed recurrence. While many well-known variables were associated with a poor outcome, only a positive microscopic margin precluded long-term survival.

Background: The surgical management of duodenal gastrointestinal stromal tumors (DGIST) is poorly characterized. Limited resection may be technically feasible and oncologically safe, but anatomic considerations may compromise the resection margins due to the proximity of critical structures, thereby necessitating more extensive resections such as pancreaticoduodenectomy., Methods: Patients undergoing surgery for DGIST at two institutions from 1994 to 2014 were identified. Clinicopathologic and survival data were analyzed to compare outcomes in patients treated with limited or radical resection., Results: Sixty patients underwent surgery for DGIST. Pancreaticoduodenectomy was performed in 38 % while the rest underwent limited resections. The most common type of limited resection was wedge resection and primary closure (49 %) followed by segmental resection with an end-to-end or side-to-side duodenojejunostomy (27 %). The pancreaticoduodenectomy group tended to have larger tumors with the majority located in D2/3 (87 %) and at the mesenteric border (91 %). The pancreaticoduodenectomy group also had significantly greater intraoperative blood loss, longer operative time, longer hospital stay, and higher 90-day morbidity and readmission rates. The 5-year relapse-free survival, recurrence-free survival, and overall survival for the pancreaticoduodenectomy versus limited resection were 81 versus 56 % (p = 0.05), 64 versus 53 % (p = 0.5), and 76 versus 72 % (p = 0.6), respectively. A surgical algorithm based on the location and size of the tumor is proposed., Conclusions: Limited resection of DGIST is safe, but may be associated with lower 5-year relapse-free survival. Pancreaticoduodenectomy is recommended for selected patients with DGIST when an R0 resection cannot be performed without removing the ampulla or part of the pancreas.

Background: Age 45 years is used as a cutoff in the staging of well-differentiated thyroid cancer (WDTC) as it represents the median age of most datasets. The aim of this study was to determine a statistically optimized age threshold using a large dataset of patients treated at a comprehensive cancer center., Methods: Overall, 1807 patients with a median follow-up of 109 months were included in the study. Recursive partitioning was used to determine which American Joint Committee on Cancer (AJCC) variables were most predictive of disease-specific death, and whether a different cutoff for age would be found. From the resulting tree, a new age cutoff was picked and patients were restaged using this new cutoff., Results: The 10-year disease-specific survival (DSS) by Union for International Cancer Control (AJCC/UICC) stage was 99.6, 100, 96, and 81 % for stages I-IV, respectively. Using recursive partitioning, the presence of distant metastasis was the most powerful predictor of DSS. For M0 patients, age was the next most powerful predictor, with a cutoff of 56 years. For M1 patients, a cutoff at 54 years was most predictive. Having reviewed the analysis, age 55 years was selected as a more robust age cutoff than 45 years. The 10-year DSS by new stage (using age 55 years as the cutoff) was 99.2, 98, 100, and 74 % for stages I-IV, respectively., Conclusion: A change in age cutoff in the AJCC/UICC staging for WDTC to 55 years would improve the accuracy of the system and appropriately prevent low-risk patients being overstaged and overtreated.

Background: Reports show that FOLFIRINOX therapy for pancreatic ductal adenocarcinoma (PDAC) results in objective response rates two to threefold higher than those of other regimens. This study aimed to assess response and resection rates for locally unresectable (stage 3) patients initially treated with induction FOLFIRINOX., Methods: The institutional cancer database was queried for patients treated with induction FOLFIRINOX therapy between 2010 and 2013. Patients were included in the study if they were treated at the authors' institution for stage 3 PDAC (locally unresectable) that had been adjudicated at a weekly multidisciplinary tumor board., Results: The study identified 101 patients. The median age was 64 years (range 37-81 years), and the median follow-up period was 12 months (range 3-37 months). The patients received a median of six cycles (range 1-20 cycles) of induction FOLFIRINOX. No grade 4 or 5 toxicity was recorded. At the initial restaging (median of 3 months after diagnosis), 23 patients (23 %) had developed distant metastases, 15 patients (15 %) had undergone resection, and 63 patients (63 %) had proceeded to chemoradiation. In the group of 63 patients who had proceeded to chemoradiation (median of 9 months after diagnosis), an additional 16 patients (16 %) had undergone resection, and 5 patients (5 %) had developed metastases. A partial radiographic response was observed in 29 % of all the patients, which was associated with ability to perform resection (p = 0.004). The median overall survival time was 11 months for the group that progressed with FOLFIRINOX and 26 months for the group that did not progress., Conclusion: Nearly one third of the patients who had been initially identified as having stage 3 pancreatic carcinoma and had been treated with FOLFIRINOX responded radiographically and underwent tumor resection.

Background: Hepatic resection is considered the standard of care for patients with resectable colorectal liver metastases (CRLM), but the benefits of using systemic chemotherapy for these patients have not been completely proven. Although systemic chemotherapy is likely to improve recurrence-free survival (RFS), no differences in overall survival (OS) have been demonstrated to date. This study aimed to compare surgery plus systemic chemotherapy, regardless timing of administration, with surgery alone, analyzing long-term outcomes for patients with CRLM who underwent liver resection with curative intent., Methods: Systematic review and meta-analysis of studies published from January 1991 to December 2013 were used to compare surgery alone and surgery plus chemotherapy for patients with CRLM who underwent liver resection with curative intent. All randomized clinical trials (RCTs) were included in the study. Selection of high-quality observational comparative studies (OCSs) was based on a validated tool, the Methodological Index for Nonrandomized Studies. Comparison of RFS and OS was performed using a fixed-effects model and the hazard ratio (HR)., Results: Concerning OS, 5 studies (3 RCTs and 2 OCSs) comprising 2,475 patients were analyzed, and chemotherapy (1,024 patients) relatively improved OS rates for 23 % of the patients versus surgery alone (HR, 0.77; 95 % confidence interval [CI] 0.67-0.88; p < 0.001). Four studies, totaling 1,592 patients, reported RFS (3 using RCTs and 1 using OCSs), showing that chemotherapy (702 patients) relatively improved RFS for 29 % of the patients (HR, 0.71; 95 % CI 0.61-0.83; p < 0.001)., Conclusion: This meta-analysis demonstrated that the use of chemotherapy for patients with CRLM who underwent resection with curative intent is a worthwhile strategy for improving both RFS and OS.

Background: The role of carcinoembryonic antigen (CEA) in surveillance and follow-up of patients with colorectal cancer continues to be debated. The objective of this study was to assess the utility of postoperative CEA as a predictor of recurrence for patients with resected colorectal liver metastases (CLM)., Methods: Patients were identified from a prospectively maintained CLM database, and were studied retrospectively. Patients with extrahepatic disease or initially unresectable CLM were excluded. All patients in this study received adjuvant systemic chemotherapy after resection., Results: Between 1997 and 2007, a total of 318 consecutive patients were studied, with 168 patients (53 %) experiencing recurrence within 2 years. Various postoperative CEA cutoffs were tested as independent predictors of recurrence. A postoperative CEA ≥15 ng/ml obtained the highest hazard ratio (1.87; 95 % CI 1.09-3.2; p = 0.023) and was chosen to be included in the survival analysis in the multivariate model. A postoperative CEA ≥15 ng/ml had a specificity of 96 % and positive predictive value of 82 % for recurrence. On multivariate analysis, age ≥70 years, the presence of positive lymph node at primary tumor resection, disease-free interval ≤12 months, number of lesions >1, largest lesion ≥5 cm, presence of positive margins, and postoperative CEA ≥15 ng/ml were independent predictors of recurrence within 2 years., Conclusion: This study demonstrates a postoperative CEA ≥15 ng/ml to be a predictive test for recurrence.

Purpose: Patients with recurrence after complete resection of colorectal liver metastases (CLM) are considered for repeat resection as a potential salvage therapy (PST). However, outcomes for this approach are not well defined. We sought to analyze the natural history of recurrence and PST in a large cohort of patients with long-term follow-up., Methods: Recurrence patterns, treatments, and outcomes in consecutive patients undergoing resection for colorectal liver metastases were analyzed retrospectively. PST was defined as repeat resection of all recurrent disease and effective salvage therapy (EST) as free of disease for 36 months after last PST. Factors associated with PST, EST, and outcomes were analyzed., Results: Of 952 patients who underwent resection, 594 (62 %) experienced recurrence (median interval = 13 months). Initial recurrences involved liver (n = 157,26 %), lung (n = 167,28 %), multiple sites (n = 171,29 %), and other single sites (n = 99,17 %). PST was performed in 160 (27 %) of 594, most commonly with a single site of recurrence (n = 149). Young age (p = 0.01), negative initial resection margin (p = 0.003), initial tumor size <5 cm (p = 0.006), and recurrence pattern (p < 0.001) were independently associated with PST. Thirty-six patients experienced EST (25 % of PSTs). Overall median survival was 61 and 43 months in those with recurrence. Median survival of patients undergoing PST was 87 months compared to 34 months for those who did not., Conclusions: Recurrence is common after CLM resection, but 27 % of patients were able to undergo PST. Approximately one-quarter of these experienced EST and may be cured. PST is associated with long-term survival and possible cure, and therefore active surveillance after CLM resection is justified.

Introduction: Primary pancreatic lymphoma (PPL) is a rare tumor that is often misdiagnosed. Clinicopathologic features, optimal therapy, and outcomes are not well defined. We reviewed our institutional experience with PPL., Methods: Search of our institutional database identified that between 1987-2012, 21,760 patients with lymphoma and 11,286 patients with a primary pancreatic tumor were evaluated. There were 44 patients with pathologically confirmed PPL. Clinical data were obtained by chart review and survival distributions were estimated using the Kaplan-Meier method and compared using the log-rank test., Results: At baseline, LDH was elevated in 55 % of the patients, CA 19-9 in 25 %, and CEA in 20 %. Imaging characteristics included large, unresectable tumors (67 %), and lymphadenopathy inferior to the renal vein (50 %). Twenty-three patients underwent surgery for resection (5), diagnosis (13), or palliation (5). Chemotherapy alone achieved a 75 % complete response rate. Eight patients experienced relapse, 88 % of which occurred at distant sites. Median overall survival was 6.1 years and 10-year disease-specific survival (DSS) was 69 %. Patients with a low risk International Prognostic Index (IPI) and those with a follicular histologic subtype demonstrated 5-year DSS of 100 %., Conclusions: Chemotherapy for PPL results in a high complete response rate and long DSS, which is similar to nodal non-Hodgkin's lymphoma (NHL). A favorable outcome is expected for IPI low risk patients and follicular histologic subtype. Systemic therapy should generally be the initial therapy when the diagnosis is known. Prolonged follow up is recommended to detect relapses. Surgery alone should be reserved for non-curative intent (i.e. diagnostic or palliative).

Background: Readmission rates have been targeted for cost/reimbursement control. Our goal was to identify causes for readmission and delineate the pattern of early and late readmission., Methods: Between 2011 and 2012, a total of 490 patients underwent pancreaticoduodenectomy, distal pancreatectomy or central pancreatectomy. Logistic regression was used to identify predictors of readmission. K-medoids clustering was performed to identify the major readmission subgroups., Results: Median postoperative length of stay (LOS) was 7 days, and the 30- and 90-day readmission rates were 23 and 29 %, respectively. The most common cause for 30-day readmissions was procedure-related infections (58 %), while the most common cause for 31-90-day readmissions was failure to thrive and chemotherapy-related symptoms (38 %). Independent predictors of 30-day readmissions were central pancreatectomy, discharge with a drain, pancreatic duct <3 mm, previous abdominal surgery, and postoperative LOS. Independent predictors for 31-90-day readmissions were age and preoperative serum carcinoembryonic antigen. Cancer-related covariates were more common in the 31-90-day readmission group. Postoperative carbohydrate antigen 19-9 levels were twofold higher in the 31-90-day readmission group compared with the no readmission group (p = 0.03). K-medoids clustering identified a subgroup where 74 % of readmissions occur at a median of 7 days after discharge., Conclusions: Readmissions after pancreatic operations are procedure-related in the first 30 days, but those after this period are influenced by the natural history of the underlying diagnosis. The readmission penalty policy should account for the timing of readmission and the natural history of the underlying disease and procedure. Early follow-up for patients at high risk for readmission may minimize early readmissions.

Background: For patients with unresectable intrahepatic cholangiocarcinoma (ICC), treatment options are limited and survival is poor. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine and dexamethasone (with or without bevacizumab) in advanced ICC., Methods: Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST). Pre-HAI dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) images were reviewed, and tumor perfusion data correlated with outcome., Results: Forty-four patients were analyzed (floxuridine, 26; floxuridine/bevacizumab, 18). At a median follow-up of 29.3 months, 41 patients had died of disease. Partial response by RECIST was observed in 48 %, and 50 % had stable disease. Three patients underwent resection after response, and 82 % received additional HAI after removal from the trials. Median survival was similar in both trials (floxuridine 29.3 months vs. floxuridine/bevacizumab 28.5 months; p = 0.96). Ten (23 %) patients survived ≥3 years, including 5 (11 %) who survived ≥5 years. Tumor perfusion measured on pre-treatment DCE-MRI [area under the gadolinium concentration curve at 90 and 180 s (AUC90 and AUC180, respectively)] was significantly higher in ≥3-year survivors and was the only factor that distinguished this group from <3-year survivors (mean AUC90 22.6 vs. 15.9 mM s, p = 0.025, and mean AUC180 48.9 vs. 32.3 mM s, p = 0.003, respectively). Median hepatic progression-free survival was longer in ≥3-year survivors (12.9 vs. 9.3 months, respectively; p = 0.008)., Conclusions: HAI chemotherapy can result in prolonged survival in unresectable ICC. Pre-HAI DCE-MRI may predict treatment outcome.

Background: The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein expression in GBCAs from three continents., Methods: Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez [FALP]), Japan (Yokohama City University [YCU]), and the United States (Memorial Sloan-Kettering Cancer Center [MSKCC]). Hierarchical clustering was used to partition the data based on protein-expression and treatment center., Results: Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (p < 0.0001). Absence of p21 (p = 0.03) and VEGFR2 (p = 0.018) were more common and p27 expression was less frequent (p = 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (p = 0.017) and those with early tumors (p = 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (p = 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached, p = 0.06)., Conclusions: Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.

Introduction: Staging laparoscopy (SL) can identify occult, subradiographic metastatic (M1) disease in patients with gastric or gastroesophageal (G/GEJ) cancer who are unlikely to benefit from gastrectomy. The purpose of this study is to determine the yield of repeat SL following neoadjuvant therapy for G/GEJ adenocarcinoma after initial negative pretreatment SL., Methods: Retrospective review of a prospective database identified patients with locoregionally advanced (T3-4Nany or TanyN+) G/GEJ adenocarcinoma who underwent pretreatment SL. The yield of repeat SL following neoadjuvant therapy was determined., Results: From 1994 to 2010, 276 patients with locoregionally advanced G/GEJ adenocarcinoma were identified, of whom 244 proceeded to operation after neoadjuvant therapy, at a median time of 105 days. One hundred sixty-four patients (67 %) underwent repeat SL, and 80 patients (33 %) proceeded directly to laparotomy. Occult M1 disease was identified in 12 (7.3 %) and 6 (7.5 %) patients, respectively. In the repeat SL cohort, M1 disease was identified at laparoscopy in nine patients (5.5 %). M1 disease not identified by laparoscopy was discovered at laparotomy in three patients (1.8 %). The median follow-up for the study population was 31 months. For patients with M1 disease, median overall survival was 15 months, versus 41 months for patients resected without M1 disease (p < 0.0001)., Conclusions: Occult, subradiographic M1 disease develops in approximately 7 % of patients following neoadjuvant therapy for locoregionally advanced G/GEJ adenocarcinoma. These patients have poor prognosis, and repeat SL can be a valuable tool in selecting patients with locoregionally advanced G/GEJ tumors for potentially curative resection after neoadjuvant therapy.

Introduction: Outcome after hepatic resection for colorectal cancer liver metastases (CRLM) is heterogeneous and accurate predictors of survival are lacking. This study analyzes the prognostic relevance of pathologic details of the primary colorectal tumor in patients undergoing hepatic resection for CRLM., Methods: Retrospective review of a prospective database identified patients who underwent resection for CRLM. Clinicopathological variables were investigated and their association with outcome was analyzed., Results: From 1997-2007, 1,004 patients underwent hepatic resection for CRLM. The median follow-up was 59 months with a 5-year survival of 47%. Univariate analysis identified nine factors associated with poor survival; three of these related to the primary tumor: lymphovascular invasion (LVI, p<0.0001), perineural invasion (p=0.005), and degree of regional lymph node involvement (N0 vs. N1 vs. N2, p<0.0001). Multivariate analysis identified seven factors associated with poor survival, two of which related to the primary tumor: LVI (hazard ratio (HR) 1.3, 95% confidence interval (CI) 1.06-1.64, p=0.01) and degree of regional lymph node involvement [N1 (HR 1.3, 95% CI 1.04-1.69, p=0.02) vs. N2 (HR 1.7, 95% CI 1.27-2.21, p<0.0005)]. A significant decrease in survival along the spectrum of patients ranging from LVI negative/N0 to LVI positive/N2 was present. Patients who were LVI-positive/N2 had a median survival of 40 months compared with 74 months for patients who were LVI-negative/NO (p<0.0001)., Conclusions: Histopathologic details of the primary colorectal tumor, particularly LVI and the detailed assessment of the degree of lymph node involvement, are strong predictors of survival. Future biomarker studies should consider exploring factors related to the primary colorectal tumor.

Purpose: To evaluate the changes in the 7th edition American Joint Committee on Cancer (AJCC) staging system for stomach cancer compared to the 6th edition; to compare the predictive accuracy of the two staging systems., Methods: In a combined database containing 2,196 patients who underwent an R0 resection for gastric adenocarcinoma, differences between the two staging systems were evaluated and stage-specific survival estimates compared. Concordance probability and Brier scores were estimated for both systems to examine the predictive accuracy., Results: Nodal status cutoff values were changed, leading to a more even distribution for the redefined N1, N2, and N3 group. AJCC 6th edition stage II reflected a highly heterogeneous population, which is now adequately subdivided in the AJCC 7th edition into stages IIA, IIB, and IIIA. The predictive accuracy of N classification improved significantly as measured by concordance. Despite increased complexity, the predictive accuracy of AJCC 7th stage grouping was significantly worse than that of the AJCC 6th edition., Discussion: The increased complexity of the 7th edition staging system is accompanied by improvements in the predictive value of nodal staging as compared to the 6th edition, but it was no better in overall stage-specific predictive accuracy. Future refinements of the tumor, node, metastasis staging system should consider whether increased complexity is balanced by improved prognostic accuracy.

Introduction: The accurate intraoperative localization of malignant nodes can pose a challenge to the surgical oncologist. Positron emission tomography (PET) scanning has significantly increased our ability to detect suspicious lesions. We investigated the ability of a novel, handheld tool to evaluate suspicious nodes intraoperatively and to correlate its findings with those seen on preoperative PET scan., Methods: Ten nude rats were inoculated with a lymphogenic mesothelioma tumor line and followed weekly with PET scan studies. When suspicious lymph nodes were found, animals were dissected and the intraoperative amount of tissue radiation was analyzed as "tumor-to-background ratio" (TBR) using the PET probes., Results: The intraoperative probe was used to guide dissections and select high-risk nodes based on their specific radiotracer uptake. A total of 52 nodes were harvested; eight of these were suspicious on preoperative PET scan studies. Using a TBR of 2.5, the intraoperative probes were able to localize all suspicious nodes previously seen on PET scan. Both gamma (sensitivity: 100%; specificity: 86%; positive predictive value (PPV): 57%; negative predictive value (NPV): 100%) and beta (sensitivity: 88%; specificity: 91%; PPV: 64%; NPV: 98%) probes showed an excellent area under the curve (AUC) in the receiver operating characteristic analysis (ROC). Both probes had an AUC of 0.95 for localizing suspicious nodes on PET scan. Furthermore, the AUC for detecting malignancy for the gamma probe was 0.90 (95% confidence interval (CI), 0.83-0.99), and for the beta probe it was 0.97 (95% CI, 0.94-1.0), suggesting a better performance of the beta probe for detecting malignancy., Conclusions: This novel tool may be used synergistically with the PET scan examination to maximize intraoperative nodal selection and sampling.

Background: This study utilized the imaging data of primary liver cancer (PLC) treated with floxuridine (FUDR) and bevacizumab to test the hypothesis that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters correlate with tissue hypoxia markers and treatment outcome., Methods: Seventeen patients with PLC were treated with hepatic artery infusional (HAI) FUDR for 14 days followed by systemic bevacizumab therapy. DCE-MRI images were obtained at baseline and after HAI FUDR and bevacizumab therapy. The parameters (K(trans), AUC) pertaining to perfusion and vascular permeability of the tumor and adjacent liver parenchyma were measured with DCE-MRI. Tissue obtained at baseline was stained for hypoxia markers (anti-hypoxia inducible factor-1α, anti-carbonic anhydrase IX, and vascular endothelial growth factor). Changes in DCE-MRI parameters were correlated with tissue hypoxia and time to progression (TTP)., Results: The median TTP was 8.8 months. Significant decreases in AUC90 (P = 0.004), AUC180 (P = 0.004), and K(trans) (P = 0.05) were noted in tumors after bevacizumab but not in nontumor areas. TTP correlated inversely with changes in AUC90 and AUC180 after bevacizumab (P = 0.002 and P = 0.0001). Reductions in tumor perfusion (AUC90 and AUC180) were greater in tumors expressing anti-hypoxia inducible factor-1α (P = 0.02 and 0.03), vascular endothelial growth factor (P = 0.01 and P = 0.01), and anti-carbonic anhydrase IX (P = 0.009 and P = 0.009)., Conclusions: In patients with PLC, bevacizumab induces a reduction in tumor perfusion measured by DCE-MRI. These changes correlate with TTP and tissue markers of tumor hypoxia.

Background: Surgical resection for patients with hepatic and extrahepatic (EHD) colorectal metastases is controversial. We analyzed our experience with hepatic resection in patients with concomitant EHD. The aims were to characterize survival, recurrence rates, and factors associated with outcome., Methods: From 1992 to 2007, 1,369 patients underwent resection of hepatic colorectal metastases, of whom 127 (9%) had concurrent resection of EHD. Survival and recurrence were compared between patients with and without EHD. Survival data were stratified by site of metastatic involvement. Variables potentially associated with survival were analyzed in univariate and multivariate analyses., Results: Median follow-up was 24 months (range 3-152 months). The 3- and 5-year survival for patients with concomitant EHD were 47% and 26%, respectively, compared with 67% and 49%, for those without EHD (P < 0.001). Among the patients with EHD, multivariate analysis identified higher clinical risk score, incomplete resection of all EHD, EHD detected intraoperatively, and having received neoadjuvant chemotherapy to be independently associated with a worse survival. Patients with portal lymph node metastases had worse survival than those with lung or ovarian metastases. Among patients who had a complete resection of all disease, 95% recurred., Conclusion: Concurrent resection of hepatic and EHD in well-selected patients is associated with a possibility of long-term survival. The presence of limited and resectable EHD should not be an absolute contraindication to resection. The site of EHD and the nearly universal recurrence rate must be taken into consideration.

While sentinel lymph node biopsy (SLN) is a highly accurate and well-tolerated procedure for patients with cutaneous melanoma, the role of the completion lymph node dissection (CLND) for patients with positive SLN biopsy remains unknown. This study aimed to look at the prognostic value of a positive nonsentinel lymph node (NSLN). A prospectively maintained database identified 222 patients with cutaneous melanoma and a positive SLN biopsy, without evidence of distant disease. All of these patients underwent CLND, and 37 patients (17%) had positive NSLN. With median follow-up of 33 months, patients with negative NSLN had median survival of 104 months, while patients with positive NSLN had median survival of 36 months (p < 0.001). There were no survivors in the patients with positive NSLN beyond 6 years. When patients with an equal number of positive nodes were analyzed, the presence of a positive NSLN was still associated with worse melanoma-specific survival (66 months for NSLN- versus 34 months for NSLN+, p = 0.04). While increasing age, tumor thickness, and male sex were associated with an increased risk of death on multivariate analysis, a positive NSLN was the most important predictor of survival (hazard ratio 2.5). We conclude that positive NSLN is an independent predictor of disease-specific survival in patients with cutaneous melanoma.

Background: Staging laparoscopy for patients with radiographically resectable pancreatic adenocarcinoma has been reported to yield an 8-15% finding of unresectable disease. Factors associated with the likelihood of subradiographic unresectable disease have not been clearly defined., Methods: A prospectively maintained pancreatic database was reviewed and patients were identified who underwent staging laparoscopy for radiographically resectable pancreatic adenocarcinoma between January 2000 and December 2006. Preoperative carbohydrate antigen 19-9 (CA 19-9) values were assessed for their association with the presence of subradiographic unresectable disease., Results: Four hundred ninety-one patients underwent staging laparoscopy. Resection was performed in 80% (n = 395). Of the 96 patients with unresectable disease, 75 (78%) had metastases either in the liver (n = 60) or peritoneum (n = 15). Preoperative CA 19-9 values were available for 262 of the 491 patients. Fifty-one of these patients had unresectable disease, of which 78% were due to distant disease. The median preoperative CA 19-9 value for patients who underwent resection was 131 U/ml versus 379 U/ml for those patients with unresectable disease (P = 0.003). A receiver operating characteristics (ROC) curve was developed for preoperative CA 19-9 value and tumor resectability. The statistically optimal cutoff value was determined to be 130 U/ml. Unresectable disease was identified in 38 of the 144 patients (26.4%) with a preoperative CA 19-9 >or= 130 U/ml, and in 13 of the 118 patients (11%) with a CA 19-9 < 130 U/ml (P = 0.003). CA 19-9 values greater than 130 U/ml remained a predictor of tumor unresectability on multivariate regression analysis [hazard ratio (HR) 2.70, 95% confidence interval (CI) 1.34-5.44; P = 0.005]., Conclusion: In this study, preoperative CA 19-9 values were strongly associated with the identification of subradiographic unresectable disease. Preoperative CA 19-9 values may allow surgeons to better select patients for staging laparoscopy.

Background: Frozen section analysis of bile duct margins is often used to guide the extent of surgical resection for hilar cholangiocarcinoma (HCCA), but the usefulness of this practice is unknown., Methods: The association between disease-specific survival (DSS) and pathologic margin status determined during and after surgical resection for HCCA was assessed retrospectively for 101 patients between 1992 and 2005. Final histopathology identified three subgroups on the basis of resection margin status: wide margin (bile duct and specimen margins negative for adenocarcinoma), narrow margin (bile duct margin negative but specimen margins positive), and positive margin (bile duct and specimen margins positive)., Results: On the basis of frozen section analysis alone, 90 patients were thought to have a disease-negative bile duct margin intraoperatively. Final histopathology showed that eight patients (9%) had invasive adenocarcinoma in the cuff of bile duct submitted for frozen section analysis. Of the 82 patients with negative final bile duct margins, 54 patients were categorized as having wide margins, and 28 patients had narrow margins. The median DSS for patients with wide margins was 56 months compared with 38 months for patients with narrow margins and 32 months for margin-positive patients (P = .01)., Conclusion: Frozen section analysis of the proximal bile duct margin is misleading in 9% of patients. Among patients with HCCA who are determined to have negative duct margins intraoperatively, only 60% will have margins adequately wide enough to be associated with an improvement in DSS.

Background: Use of laparoscopy for isolated adrenal metastases is controversial. The aims of this study were to characterize patients with isolated adrenal metastases; compare operative characteristics of the laparoscopic adrenalectomy (LA) versus open adrenalectomy (OA) approach; and compare long-term oncological and surgical outcomes., Methods: Our adrenal resection database (1995-2006) identified 63 OA and 31 LA cases done for isolated adrenal metastases. Subset analysis was performed for all patients from isolated lung metastases (n = 39) and for all tumors smaller than 4.5 cm (n = 49)., Results: Overall, local recurrence was 17%, median survival 30 months and 5-year estimated survival 31%. The only independent predictor of survival for all (n = 94) was adrenal tumor size less than 4.5 cm (P = 0.01). When comparing LA with OA, no differences in local recurrence, margin status, disease-free interval or overall survival were observed for the entire group, or for patients with metastases only from lung cancer (n = 39) or for those with tumors smaller than 4.5 cm (n = 49). LA provided significantly shorter operative time (175 vs 208 min, P = 0.04), lower estimated blood loss (EBL) (106 vs 749 cc, P < 0.0001), shorter length of hospital stay (2.8 vs 8.0 days, P < 0.0001) and fewer total complications (P < 0.0001)., Conclusions: LA is equivalent to OA in terms of margin status, local recurrence, disease-free interval and overall survival. LA for metastatic adrenal lesions is safe, with equivalent long-term oncological outcomes providing the additional benefits of a minimally invasive technique. LA can be recommended as an appropriate initial approach for isolated adrenal metastases.

Background: There is little information to determine prognosis or to guide clinical care for patients with duodenal adenocarcinoma. We have hypothesized that survival following resection of duodenal cancer is similar to survival following resection of distal gastric cancer. We tested the utility of a nomogram created for determining disease-specific survival (DSS) after R0 resection of gastric cancer in estimating DSS for patients with resected duodenal cancer., Methods: Review of a prospective database identified 106 patients who underwent R0 resection of duodenal cancer. Comparison was made to 459 patients with distal gastric cancer. The Student t test, Fisher exact test, Pearson chi-square test, and log-rank test were used to assess statistical significance. Concordance probabilities and calibration plots were used for nomogram validation., Results: Duodenal cancers were more deeply invasive than gastric cancer (P < .01). The rate of lymph node positivity was not statistically different between the two tumors; however, there were differences in the rate of nodal positivity for certain depths of penetration. Younger age (P = .002), negative regional lymph nodes (P = .03), and tumors confined to the bowel wall or subserosa (P = .03) were associated with improved DSS for duodenal cancer. When applied to patients with duodenal cancer, the nomogram had a concordance probability of 0.70, and calibration appeared to be accurate., Conclusions: A nomogram created for determining DSS after resection of gastric cancer predicts outcome for duodenal cancer patients and may prove to be useful for research and in guiding clinical care.

Background: Treatment of metastatic GIST with imatinib mesylate results in a 2-year survival of approximately 72%. The outcome of patients with metastatic GIST not treated with tyrosine kinase inhibitors is not well defined., Methods: One hundred nineteen patients with metastatic GIST diagnosed prior to July 1, 1998 (approximately 2 years prior to the use of imatinib for GIST) were identified from an institutional database of patients with pathologically confirmed GIST. Mutational analysis was performed in cases with available tissue. The log rank test and Cox regression models were used to assess prognostic factors., Results: Median survival was 19 months with a 41% 2-year survival and a 25% 5-year survival. Resection of metastatic GIST was performed in 81 patients (68%), while 50 (42%) received conventional chemotherapy. Twelve patients (10%) were eventually started on imatinib. Primary tumor size <10 cm, <5 mitoses/50 HPF in the primary tumor, epithelioid morphology, longer disease-free interval, and surgical resection were independent predictors of improved survival on multivariate analysis. Mutational status did not predict outcome. In patients who underwent resection, the 2 year survival was 53%, and negative microscopic margins also independently predicted improved survival., Conclusions: Treatment with imatinib appears to improve 2-year survival of metastatic GIST by approximately 20% when compared to surgery alone. The combination of imatinib and surgery for the treatment of metastatic GIST therefore warrants investigation.