Invasive and Noninvasive Progression After Resection of Noninvasive Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To define frequencies, pattern of progression (invasive vs noninvasive), and risk factors of progression of resected noninvasive intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: There is a risk of progression in the remnant pancreas after resection of IPMNs. METHODS: Four hundred forty-nine consecutive patients with resected IPMNs from 1995 to 2018 were included to the study. Patients with invasive carcinoma or with follow-up <6 months were excluded. Noninvasive progression was defined as a new IPMN, increased main pancreatic duct size, and increased size of an existing lesion (5 mm compared with 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 noninvasive 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 noninvasive 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 noninvasive 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.

Accuracy of National Surgical Quality Improvement Program Risk Calculator Among Elderly Patients Undergoing Pancreas Resection.

INTRODUCTION: A preoperative goals-of-care discussion is essential in maintaining the autonomy of older adults who require surgery. The purpose of this study was to determine the accuracy of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) risk calculator and its association with age for patients who underwent pancreatectomy. METHODS: Using the American College of Surgeons NSQIP database, patients who underwent pancreatectomy between 2012 and 2015 were identified. Age was categorized into three groups: 18-64, 65-79, and 80-89 y. Analysis of variance and Pearson correlation coefficients were employed to assess differences between age categories in predicted and actual mortality and morbidity. Covariate-adjusted logistic regression models were employed to evaluate associations while accounting for potential confounders. RESULTS: A total of 17,906 patients were included. The correlation between actual and predicted mortality was low (r = 0.14, P < 0.001). This correlation was weakest for the age category 80-89 y (r = 0.04, P = 0.07) and strongest for 65-79 y category (r = 0.14, P > 0.001). The correlation was weakest among patients who underwent pancreatoduodenectomy (r = 0.06, P = 0.08) and in this group mortality was overestimated for older adults in the age group 80-89 (actual mortality: 3.2% versus predicted mortality: 5.6%, P = 0.08). After adjusting for covariates, the interaction term between age and predicted mortality (P = 0.0021) indicated that the relationship between predicted and actual mortality is significantly influenced by patient age. CONCLUSIONS: The NSQIP risk calculator appears to overestimate mortality and morbidity risk for elderly patients undergoing pancreatoduodenectomy. These predictions should be used with caution in preoperative goals-of-care discussions with patients aged 80 y and older.

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.

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.

A Survey of Hospitalized Trauma Patients in Hemorrhage Control Education: Are Trauma Victims Willing to Stop the Bleed?

BACKGROUND: The Stop the Bleed (STB) campaign was developed in part to educate the lay public about hemorrhage control techniques aimed at reducing preventable trauma deaths. Studies have shown this training increases bystanders' confidence and willingness to provide aid. One high-risk group might be better solicited to take the course: individuals who have been a victim of previous trauma, as high rates of recidivism after trauma are well-established. Given this group's risk for recurrent injury, we evaluated their attitudes toward STB concepts. METHODS: We surveyed trauma patients admitted to 3 urban trauma centers in Baltimore from January 8, 2020 to March 14, 2020. The survey was terminated prematurely due to the COVID-19 pandemic. Trauma patients hospitalized on any inpatient unit were invited to complete the survey via an electronic tablet. The survey asked about demographics, prior exposure to life-threatening hemorrhage and first aid training, and willingness to help a person with major bleeding. The Johns Hopkins IRB approved waiver of consent for this study. RESULTS: Fifty-six patients completed the survey. The majority of respondents had been hospitalized before (92.9%) and had witnessed severe bleeding (60.7%). The majority had never taken a first aid course (60.7%) nor heard of STB (83.9%). Most respondents would be willing to help someone with severe bleeding form a car crash (98.2%) or gunshot wound (94.6%). CONCLUSIONS: Most patients admitted for trauma had not heard about Stop the Bleed, but stated willingness to respond to someone injured with major bleeding. Focusing STB education on individuals at high-risk for trauma recidivism may be particularly effective in spreading the message and skills of STB.

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.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Curative Resection of Adrenocortical Carcinoma: Rates and Patterns of Postoperative Recurrence.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy. The aim of this study was to determine the incidence and patterns of recurrence after curative-intent surgery for ACC. METHODS: Patients who underwent curative-intent resection for ACC between 1993 and 2014 were identified from 13 academic institutions participating in the United States ACC study group. Patients with metastasis or an R2 margin were excluded. Patterns and rates of recurrence were determined and classified as locoregional and distant recurrence. RESULTS: A total of 180 patients with a median age of 52 years (interquartile range 43-61) were identified. Most patients underwent open surgery (n = 111, 64.5 %) and had an R0 resection margin (n = 117, 75.0 %). At last follow-up, 116 patients (64.4 %) had experienced recurrence (locoregional only, n = 41, 36.3 %; distant only, n = 51, 45.1 %; locoregional and distant, n = 21, 18.6 %). Median time to recurrence was 18.8 months. Several factors were associated with locoregional recurrence, including left-sided ACC location (odds ratio [OR] 2.71, 95 % confidence interval [CI] 1.06-6.89) and T3/T4 disease (reference T1/T2, OR 3.04, 95 % CI 1.19-7.80) (both p < 0.05). Distant recurrence was associated with larger tumor size (OR 1.11, 95 % CI 1.01-1.24) and T3/T4 disease (reference T1/T2, OR 5.23, 95 % CI 1.70-16.10) (both p < 0.05). Patients with combined locoregional and distant recurrence had worse survival (3- and 5-year survival: 39.5, 19.7 %) versus patients with distant-only (3- and 5-year survival 55.1, 43.3 %) or locoregional-only recurrence (3- and 5-year survival 81.4, 64.1 %) (p = 0.01). CONCLUSIONS: Nearly two-thirds of patients experienced disease recurrence after resection of ACC. Although a subset of patients experienced recurrence with locoregional disease only, many patients experienced recurrence with distant disease as a component of recurrence and had a poor prognosis.

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

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.

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

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.

Blood loss and outcomes after resection of colorectal liver metastases.

BACKGROUND: The influence of intraoperative blood loss (IBL) on long-term outcomes of patients undergoing liver resection for colorectal cancer liver metastases (CRLM) remains not well defined. MATERIALS AND METHODS: A total of 433 patients who underwent curative-intent hepatic resection for CRLM between 2000 and 2013 at Johns Hopkins were identified. Demographics, IBL data, and long-term outcomes were collected and analyzed. Clinicopathologic predictors of IBL and the association of IBL and outcomes were assessed. RESULTS: The median patient age was 54 y (interquartile range, 44-64), most patients were male (58.9%; n = 255). At surgery, the median IBL was 400 mL (range, 10-5100 mL). Two-hundred eighty-seven patients (66.3%) had an IBL of >250 mL. Factors associated with increased IBL (>250 mL) on multivariate analysis were male sex (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.68-4.09; P < 0.001), tumor size >3 cm (OR, 1.88; 95% CI, 1.18-2.99; P = 0.008), and major hepatic resection (OR, 3.08; 95% CI, 1.92-4.92; P < 0.001). At a median follow-up time of 30.6 mo, the median survival times were 70.5, 56.4, and 36.9 mo for IBL <250, 250-1000, and >1000 mL, respectively (P = 0.004). IBL >250 mL remained an independent prognostic factor of overall survival in multivariate analysis (hazard ratio, 1.41; 95% CI, 1.01-1.97; P = 0.04) after adjusting for other factors including the receipt of blood transfusion. CONCLUSIONS: The magnitude of IBL during CRLM resection was related to biologic characteristics of the tumor and the extent of surgery. Increased IBL during CRLM resection was an independent prognostic factor for worse patient survival. Furthermore, a dose-response relationship between increasing IBL and worsening survival was evident.

Complication timing impacts 30-d mortality after hepatectomy.

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.

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

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.

Synthesis, characterization and in vitro evaluation of exquisite targeting SPIONs-PEG-HER in HER2+ human breast cancer cells.

A stable, biocompatible and exquisite SPIONs-PEG-HER targeting complex was developed. Initially synthesized superparamagnetic iron oxide nanoparticles (SPIONs) were silanized using 3-aminopropyltrimethoxysilane (APS) as the coupling agent in order to allow the covalent bonding of polyethylene glycol (PEG) to the SPIONs to improve the biocompatibility of the SPIONs. SPIONs-PEG were then conjugated with herceptin (HER) to permit the SPIONs-PEG-HER to target the specific receptors expressed over the surface of the HER2+ metastatic breast cancer cells. Each preparation step was physico-chemically analyzed and characterized by a number of analytical methods including AAS, FTIR spectroscopy, XRD, FESEM, TEM, DLS and VSM. The biocompatibility of SPIONs-PEG-HER was evaluated in vitro on HSF-1184 (human skin fibroblast cells), SK-BR-3 (human breast cancer cells, HER+), MDA-MB-231 (human breast cancer cells, HER-) and MDA-MB-468 (human breast cancer cells, HER-) cell lines by performing MTT and trypan blue assays. The hemolysis analysis results of the SPIONs-PEG-HER and SPIONs-PEG did not indicate any sign of lysis while in contact with erythrocytes. Additionally, there were no morphological changes seen in RBCs after incubation with SPIONs-PEG-HER and SPIONs-PEG under a light microscope. The qualitative and quantitative in vitro targeting studies confirmed the high level of SPION-PEG-HER binding to SK-BR-3 (HER2+ metastatic breast cancer cells). Thus, the results reflected that the SPIONs-PEG-HER can be chosen as a favorable biomaterial for biomedical applications, chiefly magnetic hyperthermia, in the future.