Perioperative blood transfusions and survival in resected pancreatic adenocarcinoma patients given multimodality therapy.

BACKGROUND AND OBJECTIVES: The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection. METHODS: Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT). RESULTS: Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p < 0.001), perineural invasion (HR: 1.64, p = 0.050), postoperative pancreatic fistula (HR: 1.94, p = 0.018), and 24HR-BT (HR: 1.75, p = 0.001). CONCLUSIONS: Transfusions given within 24 h are associated with dose-dependent decreases in survival after pancreatectomy for PDAC.

Impact of Intraoperative Dexamethasone on Surgical and Oncologic Outcomes for Patients with Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Administration of dexamethasone to mitigate postoperative nausea and vomiting has been suggested to improve short- and long-term outcomes after pancreatic ductal adenocarcinoma (PDAC) resection. This study aimed primarily to evaluate these hypotheses in a contemporary patient cohort treated with multimodality therapy. METHODS: The clinicopathologic and perioperative characteristics of consecutive resected PDAC patients (July 2011 to October 2018) were analyzed from a prospectively maintained database. Intraoperative administration of dexamethasone (4-10 mg) was retrospectively abstracted from the electronic medical record. RESULTS: The majority of 373 patients (59.8%) received intraoperative dexamethasone. Most of these patients underwent neoadjuvant therapy (75.3%), were potentially resectable at presentation (69.7%), and underwent pancreaticoduodenectomy (79.9%). Women were more likely to receive dexamethasone than men (69.9 vs 30.1%; p < 0.001). The cohorts were otherwise clinically similar. Intraoperative dexamethasone was not associated with differences in postoperative major complications (PMCs) (21.1 vs 19.3%; p = 0.68), postoperative pancreatic fistulas (6.3 vs 6.7%; p = 0.88), or composite infectious complications (28.7 vs 24.7%; p = 0.39). Dexamethasone was not associated with any improvement in median recurrence-free survival (RFS) (17 vs 17 months; p = 0.99) or overall survival (OS) (46 vs 43 months; p = 0.90). After adjustment for clinical factors including margin status, clinical classification, tumor size, and dexamethasone, the only factors independently associated with OS were pathologic node-positivity (hazard ratio [HR], 1.80, 95% confidence interval [CI], 1.32-2.47), perineural invasion (HR, 2.02; 95% CI, 1.23-3.31), multimodality therapy (HR, 0.30; 95% CI, 0.13-0.70), and PMCs (HR, 1.64; 95% CI, 1.17-2.29) (all p < 0.006). CONCLUSIONS: Dexamethasone failed to demonstrate any protective advantage in terms of mitigating short-term PMCs or infectious complications, or to confer any long-term survival benefit. Tumor biology, multimodality therapy, and PMCs remain the main prognostic factors after PDAC resection.

Anesthetic and operative considerations for laparoscopic liver resection.

We enumerate the broad range of anesthetic considerations that affect the outcome of patients undergoing laparoscopic liver resection. Key elements for excellent outcomes after laparoscopic liver resection are careful patient selection and risk stratification, appropriate monitoring, techniques to reduce blood loss and transfusion, and active recovery management. Although some of these key elements are the same for open liver operation, there are specific anesthetic considerations of which both the surgical and anesthesia teams must be aware to achieve optimal patient outcomes after laparoscopic liver resection. While unique advantages of laparoscopic liver resection typically include decreased intraoperative bleeding, transfusion requirements, and a lower incidence of postoperative ascites, specific challenges include management of the complicated interplay between low-volume anesthesia and increased intraabdominal pressure due to pneumoperitoneum, with additional considerations regarding circulatory support to treat acute blood loss with need for emergent conversion in some cases. This article will address in detail the preoperative, intraoperative, and postoperative anesthetic considerations for patients undergoing laparoscopic liver resection that both the surgical and anesthesia team should be aware of to optimize outcomes.

A multidisciplinary cancer center maximizes surgeons' impact.

BACKGROUND: Colorectal cancer patients require care across different disciplines. Integration of multidisciplinary care is critical to accomplish excellent oncologic results. We hypothesized that the establishment of a dedicated colorectal cancer center (CRCC) around specialty-trained surgeons will lead to increased multidisciplinary management and improved outcomes in colorectal cancer patients. METHODS: We analyzed data from three periods: a baseline group, a period after the recruitment of specialty-trained surgeons, and a period after the creation of a dedicated multidisciplinary cancer center. Data analyzed included surrogate markers of surgical oncologic care, multidisciplinary integration, and oncologic outcomes. RESULTS: Recruitment of specialized surgeons led to improvements in surgical oncologic care; the establishment of the CRCC resulted in further improvements in surgical oncologic care and multidisciplinary integration. CONCLUSION: Our study suggests that although the recruitment of specialty-trained surgeons in a high volume center leads to improvement in surgical oncologic care, it is the establishment of a multidisciplinary center around the surgeons that leads to integrated care and improvements in oncologic outcomes.

Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes.

BACKGROUND: Colorectal cancer staging criteria do not rely on examination of neuronal tissue. The authors previously demonstrated that perineural invasion is an independent prognostic factor of outcomes in colorectal cancer. For the current study, they hypothesized that neurogenesis occurs in colorectal cancer and portends an aggressive tumor phenotype. METHODS: In total, samples from 236 patients with colorectal cancer were used to create a tissue array and database. Tissue array slides were immunostained for protein gene product 9.5 (PGP9.5) to identify nerve tissue. The correlation between markers of neurogenesis and oncologic outcomes was determined. The effect of colorectal cancer cells on stimulating neurogenesis in vitro was evaluated using a dorsal root ganglia coculture model. RESULTS: Patients whose tumors exhibited high degrees of neurogenesis had 50% reductions in 5-year overall survival and disease-free survival compared with patients whose tumors contained no detectable neurogenesis (P = .002 and P = .006, respectively). Patients with stage II disease and high degrees of neurogenesis had greater reductions in 5-year overall survival and disease-free survival compared with lymph node-negative patients with no neurogenesis (P = .002 and P = .008, respectively). Patients with stage II disease and high degrees of neurogenesis had lower 5-year overall survival and disease-free survival compared with patients who had stage III disease with no neurogenesis (P = .01 and P = .008, respectively). Colorectal cancer cells stimulated neurogenesis and exhibited evidence of neuroepithelial interactions between nerves and tumor cells in vitro. CONCLUSIONS: Neurogenesis in colorectal cancer appeared to play a critical role in colorectal cancer progression. Furthermore, the current results indicated that neurogenesis functions as an independent predictor of outcomes and may play a role in therapy stratification for patients with lymph node-negative disease.

Minimally invasive surgery improves short-term outcomes in elderly colorectal cancer patients.

BACKGROUND: Minimally invasive surgery (MIS) for colorectal resection has been shown to improve short-term outcomes compared with open surgery in patients with colorectal cancer. Currently, there is a paucity of data demonstrating similar efficacy between MIS and open colorectal resection in the elderly population. We hypothesized that minimally invasive surgery provides improved short-term outcomes in elderly patients with colorectal cancer. METHODS: A review of 242 consecutive elderly (≥ 65 y of age) patients who underwent either open or MIS colorectal resection for adenocarcinoma at one institution was conducted. Short-term and oncologic outcomes were analyzed. Continuous variables were analyzed by the Mann-Whitney U test. Categorical variables were compared by χ(2) tests. Survival was compared by the Kaplan-Meier method using the log rank test for comparison. RESULTS: Of the 242 elderly patients with colorectal cancer (median American Society of Anesthesiology score (ASA) scores of 3), 80% (n = 195) of patients underwent open and 20% (n = 47) had MIS colorectal cancer resections. Patients undergoing MIS had a faster return of bowel function, decreased days to nasogastric tube removal, decreased days to flatus and bowel movement, and quicker advancement to clear liquid and regular diets. The overall length of hospital stay in the MIS group was decreased by 40% as well as a trend towards a 50% decrease in SICU stay. Additionally, there was 66% decrease in cardiac complications in the MIS group. When evaluating for oncologic adequacy as measured by number of lymph nodes and surgical resection margins, MIS surgery offered equivalent results as open resection. Furthermore, there was no significant difference in overall survival for MIS versus open colorectal surgery. CONCLUSION: Minimally invasive colorectal cancer resection leads to improved short-term outcomes as demonstrated by decreased length of hospital stay and faster return of bowel function. Additionally, there appears to be no difference in oncologic outcomes in the elderly. On the basis of our data, age alone should not be a contra-indication to laparoscopic colorectal cancer resection.

Establishment of a minimally invasive program at a Veterans' Affairs Medical Center leads to improved care in colorectal cancer patients.

BACKGROUND: Despite significant advantages to patients, less than 5% of all colorectal surgeries for cancer are performed laparoscopically. A minimally invasive colorectal cancer program was created in our Veterans' Affairs hospital with the intent of increasing access and improving quality of patient care while maintaining patient safety and oncologic standards. METHODS: Sixty consecutive laparoscopic colorectal cancer resections and 60 age-matched open resections were identified. Our prospective database was queried for demographic, clinical outcomes, and oncologic data. RESULTS: Patients undergoing laparoscopic resections experienced a shorter hospital stay and a quicker return of bowel function. Both groups had similar intraoperative blood loss and surgical times. Laparoscopic resections achieved equivalent lymph node retrieval and resection completeness compared with open resections. Laparoscopic resections resulted in fewer wounds and fewer complications requiring reoperation. CONCLUSIONS: Establishment of a minimally invasive colorectal cancer program in a Veterans Affairs Medical Center leads to increased access to laparoscopic colorectal resections and improved patient care while maintaining patient safety.

The role of angiocidin in sarcomas.

BACKGROUND: Angiocidin, first identified as a tumor-associated thrombospondin-1 (TSP-1) receptor, is a key mediator of tumor progression. TSP-1, an extracellular protein produced by stromal cells, up-regulates gelatinases and tumor cell invasion in epithelial malignancies. The authors recently developed 2 angiocidin-inhibitory peptides that block angiocidin-TSP-1 binding. They hypothesized that angiocidin mediates increased gelatinase expression and tumor cell invasion in sarcomas through its interaction with TSP-1. METHODS: Angiocidin, TSP-1, and gelatinase expression was evaluated in low-grade and high-grade sarcoma specimens. The authors established 3 distinct cell lines from a patient with an extraskeletal osteosarcoma: EXOS-N (normal mesenchymal), EXOS-P (primary osteosarcoma), and EXOS-M (lung metastasis). Each was evaluated for angiocidin, gelatinase, and gelatinase inhibitor (tissue inhibitors of metalloproteinase) expression and for invasive capacity. Their responsiveness to TSP-1 was determined. The role of angiocidin in up-regulating gelatinase expression and invasion was studied using the authors' angiocidin-inhibitory peptides. RESULTS: Expression of angiocidin, TSP-1, and gelatinases correlated with tumor grade. Angiocidin expression, gelatinase activity, and invasiveness in the EXOS cell lines correlated with phenotype; EXOS-N cells did not express angiocidin or gelatinases and were not invasive; EXOS-M cells were 5 times more invasive than EXOS-P cells and exhibited greater angiocidin and gelatinase expression. EXOS cell gelatinase activity and invasiveness increased 4- to 5-fold in response to TSP-1. Inhibition of angiocidin with the authors' inhibitory peptides blocked TSP-1-promoted increases in gelatinase activity and tumor cell invasion. CONCLUSIONS: Angiocidin promotes gelatinase up-regulation and tumor cell invasion in sarcomas. Angiocidin-inhibitory peptides are potent inhibitors of sarcoma cell invasion in vitro, suggesting a potential therapeutic role for these peptides in the treatment of sarcomas.

Perineural invasion in cancer: a review of the literature.

Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. It is emerging as an important pathologic feature of many malignancies, including those of the pancreas, colon and rectum, prostate, head and neck, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival. PNI is a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion. It can be a source of distant tumor spread well beyond the extent of any local invasion; and, for some tumors, PNI may be the sole route of metastatic spread. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of molecular mechanisms behind PNI and, to date, no targeted treatment modalities aimed at this pathologic entity. The objectives of this review were to lay out a clear definition of PNI to highlight its significance in those malignancies in which it has been studied best. The authors also summarized current theories on the molecular mediators and pathogenesis of PNI and introduced current research models that are leading to advancements in the understanding of this metastatic process.

Rectal cancer patients benefit from implementation of a dedicated colorectal cancer center in a Veterans Affairs Medical Center.

BACKGROUND: A dedicated colorectal cancer (CRC) center was created in a Veterans Affairs Medical Center with the intent of improving quality of patient care and multidisciplinary cooperation. METHODS: Retrospective and prospective databases before and after creation of the CRC center, respectively, were created. Patients entered in each database included those requiring surgical intervention for CRC treatment. Statistical analyses included Fisher's exact, chi-square, and unpaired Student t tests as well as analysis of variance. RESULTS: The overall quality of care of CRC patients has improved as evidenced by a larger percentage of complete, margin-negative resections (P <.05) as well as an increase in the number of lymph nodes excised at surgery (P <.0001). Furthermore, a multidisciplinary approach is clearly beneficial as evidenced by the increased number of CRC patients receiving appropriate multidisciplinary therapy (P <.0001). CONCLUSIONS: A dedicated CRC center has significantly improved quality of care for CRC patients.

Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection.

BACKGROUND: Thoracic aortic aneurysmal diseases are characterized by degeneration of elastin within the aortic wall. Although proteinases, such as matrix metalloproteinase, appear to contribute to elastin degradation, little is known about the role of elastic fiber assembly in such diseases. Fibulin-5 is an extracellular protein that is expressed in the vascular basement membrane and regulates elastic fiber assembly by microfibril machinery. In this study, we examined whether thoracic aortic dissection (TAD) is associated with abnormal fibulin-5 expression. METHODS: Intraoperative aortic samples were obtained from 21 patients with proximal aortic dissection. Control aortic tissue was obtained from 11 organ donors, heart transplant recipients, and patients undergoing coronary artery bypass. An in vitro culture of vascular smooth muscle cells was obtained from 2 TAD patients and 1 control subject. To evaluate elastin expression, we stained tissue sections with Verhoeff-Van Gieson stain. Fibulin-5 messenger RNA (mRNA) expression was determined by quantitative real-time reverse-transcriptase-polymerase chain reaction. RESULTS: Aortic fibulin-5 mRNA and elastin content were decreased in TAD patients, compared with controls (P=.001 and P=.02, respectively). Decreased fibulin-5 expression strongly correlated with decreased amounts and fragmentation of elastin in aortic samples from patients with TAD (r=0.83, P < .0001 and F=20.7, P < .0001 respectively). The fibulin-5 mRNA in aortic vascular smooth muscle cells collected from TAD demonstrated a 38% decrease in expression, compared with the control. CONCLUSIONS: Patients with proximal aortic dissection exhibited significantly decreased expression of aortic fibulin-5. Decreased fibulin-5 may contribute to the pathogenesis of aortic dissection by impairing elastic fiber assembly.

Matrix metalloproteinases in ascending aortic aneurysms: bicuspid versus trileaflet aortic valves.

BACKGROUND: Abnormal matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression contributes to the development of abdominal aortic aneurysms. Recent data suggest that MMP-2 and MMP-9 may also play a role in thoracic aortic disease. We sought to determine (1) whether ascending aortic aneurysms are associated with increased MMP expression and (2) whether aortic inflammation and MMP expression differ between patients with congenital bicuspid aortic valves (BAVs) and those with trileaflet aortic valves (TAVs). MATERIALS AND METHODS: Samples of ascending aortic aneurysms were obtained from 29 patients; 14 patients had BAVs and 15 had TAVs. Control ascending aorta was obtained from 14 organ donors or heart transplant recipients. Aortic histology and immunohistochemistry were performed to evaluate elastin degradation, inflammatory changes, and MMP-2 and MMP-9 expression. Aortic levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured using ELISA. RESULTS: Aneurysms in the TAV patients exhibited marked inflammation, high CD68 expression, diminished elastin content, increased MMP-9 expression, and normal MMP-2 levels. In contrast, BAV aneurysms were characterized by a relative lack of inflammation, preservation of elastin content, normal MMP-9 levels, and elevated MMP-2 expression. TIMP-1 and TIMP-2 levels were not significantly different among the three groups. CONCLUSIONS: Ascending aortic aneurysms exhibited increased MMP expression. The pattern of MMP expression and the degree of inflammation, however, differed between aneurysms associated with BAVs and those with TAVs. Variations in the molecular mechanisms underlying different types of thoracic aortic aneurysms warrant further investigation.