Sarah B. Fisher

MT1-MMP- and Cdc42-dependent signaling co-regulate cell invasion and tunnel formation in 3D collagen matrices

Complex signaling events control tumor invasion in three-dimensional (3D) extracellular matrices. Recent evidence suggests that cells utilize both matrix metalloproteinase (MMP)-dependent and MMP-independent means to traverse 3D matrices. Herein, we demonstrate that lysophosphatidic-acid-induced HT1080 cell invasion requires membrane-type-1 (MT1)-MMP-mediated collagenolysis to generate matrix conduits the width of a cellular nucleus. We define these spaces as single-cell invasion tunnels (SCITs). Once established, cells can migrate within SCITs in an MMP-independent manner. Endothelial cells, smooth muscle cells and fibroblasts also generate SCITs during invasive events, suggesting that SCIT formation represents a fundamental mechanism of cellular motility within 3D matrices. Coordinated cellular signaling events are required during SCIT formation. MT1-MMP, Cdc42 and its associated downstream effectors such as MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) and Pak4 (p21 protein-activated kinase 4), protein kinase Cα and the Rho-associated coiled-coil-containing protein kinases (ROCK-1 and ROCK-2) coordinate signaling necessary for SCIT formation. Finally, we show that MT1-MMP and Cdc42 are fundamental components of a co-associated invasion-signaling complex that controls directed single-cell invasion of 3D collagen matrices.

Laparoscopic distal pancreatectomy: trends and lessons learned through an 11-year experience.

BACKGROUND As compared with open distal pancreatectomy, laparoscopic distal pancreatectomy (LDP) is associated with lower morbidity and shorter hospital stays. Existing reports do not elucidate trends in patient selection, technique, and outcomes over time. We aimed to determine outcomes after LDP at a specialized center, analyze trends of patient selection and operative technique, and validate a complication risk score (CRS). STUDY DESIGN Patients undergoing LDP between January 2000 and January 2011 were identified and divided into 2 equal groups to represent our early and recent experiences. Demographics, tumor characteristics, operative technique, and perioperative outcomes were examined and compared between groups. A CRS was calculated for the entire cohort and examined against observed outcomes. RESULTS A total of 132 LDPs were attempted, of which 8 (6.1%) were converted to open procedures. Thirty-day overall and major complication rates were 43.2% and 12.9%, respectively, with mortality < 1%. Pancreatic fistulas occurred in 28 (21%) patients, of which 14 (11%) were clinically significant. Recent LDPs (n = 66) included patients with increasingly severe comorbidities (Charlson scores > 2, 40.9% vs 16.7%, p = 0.003), more proximal tumors (74.2% vs 26.2%, p < 0.001), more extended resections (10.6 vs 8.3 cm, p < 0.001), shorter operative times (141 vs 172 minutes, p = 0.007), and less frequent use of a hand port (25.8% vs 66.6%, p < 0.001). No significant differences were found in perioperative outcomes between the groups. As compared with the hand access technique, the total laparoscopic approach was associated with shorter hospital stays (5.3 vs 6.8 days, p = 0.032). Increasing CRS was associated with longer operative time, significant fistulas, wound infections, blood transfusions, major complications, ICU readmissions, and rehospitalizations. CONCLUSIONS This large, single-institution series demonstrates that despite a shift in patient selection to sicker patients with more proximal tumors, similar perioperative outcomes can be achieved with laparoscopic distal pancreatectomy. The CRS appears to be a reliable preoperative assessment tool for assessing other adverse perioperative outcomes in addition to predicting overall complications and fistulas as originally published.

Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma

Mixed lineage kinase domain‐like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC).

Laparoscopic pancreatectomy for malignancy.

Utilization of laparoscopic techniques for resection of the pancreas has slowly gained acceptance in specific situations and is now being applied to more challenging endeavors, such as pancreaticoduodenectomy for cancer. This review provides a summary of laparoscopic applications for pancreatic malignancy, with specific attention to the most common methods of pancreatic resection and their respective oncologic outcomes, including margin status, lymph node retrieval, and survival. J. Surg. Oncol. 2013;107:39–50.

Lymphovascular and perineural invasion as selection criteria for adjuvant therapy in intrahepatic cholangiocarcinoma: a multi-institution analysis

OBJECTIVES Criteria for the selection of patients for adjuvant chemotherapy in intrahepatic cholangiocarcinoma (IHCC) are lacking. Some authors advocate treating patients with lymph node (LN) involvement; however, nodal assessment is often inadequate or not performed. This study aimed to identify surrogate criteria based on characteristics of the primary tumour. METHODS A total of 58 patients who underwent resection for IHCC between January 2000 and January 2010 at any of three institutions were identified. Primary outcome was overall survival (OS). RESULTS Median OS was 23.0 months. Median tumour size was 6.5 cm and the median number of lesions was one. Overall, 16% of patients had positive margins, 38% had perineural invasion (PNI), 40% had lymphovascular invasion (LVI) and 22% had LN involvement. A median of two LNs were removed and a median of zero were positive. Lymph nodes were not sampled in 34% of patients. Lymphovascular and perineural invasion were associated with reduced OS [9.6 months vs. 32.7 months (P= 0.020) and 10.7 months vs. 32.7 months (P= 0.008), respectively]. Lymph node involvement indicated a trend towards reduced OS (10.7 months vs. 30.0 months; P= 0.063). The presence of either LVI or PNI in node-negative patients was associated with a reduction in OS similar to that in node-positive patients (12.1 months vs. 10.7 months; P= 0.541). After accounting for adverse tumour factors, only LVI and PNI remained associated with decreased OS on multivariate analysis (hazard ratio 4.07, 95% confidence interval 1.60-10.40; P= 0.003). CONCLUSIONS Lymphovascular and perineural invasion are separately associated with a reduction in OS similar to that in patients with LN-positive disease. As nodal dissection is often not performed and the number of nodes retrieved is frequently inadequate, these tumour-specific factors should be considered as criteria for selection for adjuvant chemotherapy.

An analysis of human equilibrative nucleoside transporter‐1, ribonucleoside reductase subunit M1, ribonucleoside reductase subunit M2, and excision repair cross‐complementing gene‐1 expression in patients with resected pancreas adenocarcinoma

Tumor overexpression of excision repair cross‐complementing gene‐1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter‐1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authorss knowledge, their role in PAC is not defined.

Reply to an analysis of human equilibrative nucleoside transporter-1, ribonucleoside reductase subunit M1, ribonucleoside reductase subunit M2, and excision repair cross-complementing gene-1 expression in patients with resected pancreas adenocarcinoma: Implications for adjuvant treatment

BACKGROUND Tumor overexpression of excision repair cross-complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authorss knowledge, their role in PAC is not defined. METHODS A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS. CONCLUSIONS High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy.

Excision repair cross‐complementing gene‐1, ribonucleotide reductase subunit M1, ribonucleotide reductase subunit M2, and human equilibrative nucleoside transporter‐1 expression and prognostic value in biliary tract malignancy

Tumor expression of excision cross‐complementing gene‐1 (ERCC1), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2), is associated with the efficacy of platinum and gemcitabine chemotherapy. The authors of this report recently demonstrated that high ERCC1 and RRM2 expression levels are independent negative prognostic markers for survival in early stage pancreas cancer. The differential expression and prognostic value of these biomarkers in biliary tract malignancy (BTM) is unknown.

Conditional Disease-Free Survival After Surgical Resection of Gastrointestinal Stromal Tumors A Multi-institutional Analysis of 502 Patients

IMPORTANCE Gastrointestinal stromal tumors (GISTs) are the most commonly diagnosed mesenchymal tumors of the gastrointestinal tract. The risk of recurrence following surgical resection of GISTs is typically reported from the date of surgery. However, disease-free survival (DFS) over time is dynamic and changes based on disease-free time already accumulated following surgery. OBJECTIVES To assess the comparative performance of established GIST recurrence risk prognostic scoring systems and to characterize conditional DFS following surgical resection of GISTs. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study of 502 patients who underwent surgery for a primary, nonmetastatic GIST between January 1, 1998, and December 31, 2012, at 7 major academic cancer centers in the United States and Canada. MAIN OUTCOMES AND MEASURES Disease-free survival of the patients was classified according to 5 prognostic scoring systems, including the National Institutes of Health criteria, modified National Institutes of Health criteria, Memorial Sloan Kettering Cancer Center GIST nomogram, and American Joint Committee on Cancer gastric and nongastric categories. The concordance index (also known as the C statistic or the area under the receiver operating curve) of established GIST recurrence risk prognostic scoring systems. Conditional DFS estimates were calculated. RESULTS Overall 1-year, 3-year, and 5-year DFS following resection of GISTs was 95%, 83%, and 74%, respectively. All the prognostic scoring systems had fair prognostic ability. For all tumor sites, the American Joint Committee on Cancer gastric category demonstrated the best discrimination (C = 0.79). Using conditional DFS, the probability of remaining disease free for an additional 3 years given that a patient was disease free at 1 year, 3 years, and 5 years was 82%, 89%, and 92%, respectively. Patients with the highest initial recurrence risk demonstrated the greatest increase in conditional survival as time elapsed. CONCLUSIONS AND RELEVANCE Conditional DFS improves over time following resection of GISTs. This is valuable information about long-term prognosis to communicate to patients who are disease free after a period following surgery.

Effect of Preoperative Renal Insufficiency on Postoperative Outcomes after Pancreatic Resection: A Single Institution Experience of 1,061 Consecutive Patients

BACKGROUND Chronic kidney disease (CKD) is known to adversely affect cardiac and vascular surgery outcomes. We examined the effect of preoperative renal insufficiency on postoperative outcomes after pancreatic resection. STUDY DESIGN All patients who underwent pancreatic resection between January 2005 and July 2012 were identified. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease formula. Severe CKD (stages 4-5) was defined as eGFR < 30 mL/min/1.73 m(2). Renal function also was analyzed using serum creatinine (sCr) dichotomized at 1.8 mg/dL. Primary outcomes were any complication, major complications, and respiratory failure. Multivariate models for each endpoint were constructed by including all variables with p value ≤ 0.10 on univariate analysis. RESULTS There were 1,061 patients identified; 709 underwent pancreaticoduodenectomy, 307 distal pancreatectomy, and 45 central or total pancreatectomy. Median sCr value was 0.86 mg/dL (range 0.30 to 14.1 mg/dL). Eighteen patients (1.7%) had severe CKD and 31 (2.9%) had sCr ≥ 1.8 mg/dL. Complications occurred in 622 patients (58.6%), major complications in 198 (18.7%), and respiratory failure in 48 (4.5%). Both severe CKD and sCr ≥ 1.8 mg/dL were associated with any complication, major complications, and respiratory failure on univariate analysis. On multivariate analysis, severe CKD was associated with increased complications (odds ratio [OR] 5.5; 95% CI 1.3 to 25.5; p = 0.02) and respiratory failure (OR 6.1; 95% CI 1.8 to 20.5; p = 0.03), but not major complications. Using sCr ≥ 1.8 mg/dL as a surrogate marker for renal insufficiency, patients with sCr ≥ 1.8 mg/dL had increased risk of any complication (OR 3.5; 95% CI 1.3 to 9.3; p = 0.01), major complications (OR 2.2; 95% CI 1.04 to 4.8; p = 0.04), and respiratory failure (OR 4.7; 95% CI 1.8 to 12.6; p = 0.002). CONCLUSIONS Few patients with significant renal insufficiency are candidates for pancreatic resection. Severe CKD (stages 4-5) is associated with increased risk of complication and respiratory failure. Serum creatinine ≥ 1.8 mg/dL may serve as a useful marker of renal insufficiency and identifies patients at significantly increased risk of any complication, major complication, and respiratory failure after pancreatic resection.