Daniel Albo

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. Cancer 2009.

The Role of the Tumor Microenvironment in the Progression of Pancreatic Cancer

Pancreatic cancer is the most lethal abdominal malignancy due to its aggressive growth and rapid development of distant metastases, thus making treatment extremely difficult. Additionally, pancreatic adenocarcinoma is locally invasive, surrounded by a dense desmoplastic reaction which can involve adjacent vital structures, limiting the number of patients who are candidates for surgical resection at the time of diagnosis. Recently the tumor microenvironment in other adenocarcinomas has been determined to be an important mediator of cancer cell behavior; however, few studies have elucidated the tumor-stroma interactions in pancreatic cancer. This review summarizes the role of pancreatic stellate cells, perineural invasion, angiogenesis, and inflammatory cells in fostering pancreatic cancer cell growth and invasion. The importance of extracellular matrix proteins, growth factors, and cytokines is also presented. Finally we suggest ideas for new avenues of research into the pancreatic tumor microenvironment which may permit the development of novel, more effective treatments for pancreatic cancer.

The relationship of angiogenesis to biological activity in human squamous cell carcinomas of the head and neck.

Tumor angiogenesis has recently been related to tumor growth and metastasis, which determine the clinical outcome of the patient. This study was designed to determine the relationship between angiogenesis in primary squamous cell carcinomas (SSC) of the head and neck and the development of recurrent or metastatic disease, or both. Different SCC of the head and neck were studied. Microvessels were selectively stained using a monoclonal antibody for factor VIII. Microvessel counts were performed in the tumor, in the tissues immediately adjacent, and in normal tissues of similar topographies. Microvessel counts were then correlated with clinical outcome (development of recurrent or metastatic disease, or both). Recurrent or metastatic disease, or both, developed in patients with high microvessel counts (mean, 121.25) in the tissues adjacent to the tumor 7 to 16 months after initial treatment. Those with low microvessel counts (mean, 33.75) were disease-free for 16 months to 6 years (p < 0.01). Microvessel counts inside the tumor were also higher in those in whom recurrences or metastasis, or both, developed, but were not statistically significant. In this study, angiogenesis was directly related to clinical outcome. Thus, angiogenesis may be an independent predictor of recurrent or metastatic disease, or both, which could help in the selection of patients with SCC of the head and neck for aggressive therapy.

Novel approaches to perioperative assessment and intervention may improve long-term outcomes after colorectal cancer resection in older adults.

Colorectal cancer (CRC) is common among older adults and surgical resection with curative intent is the primary treatment of CRC. Despite the changing demographics of CRC patients and increasing prevalence of multiple comorbidities, surgery is increasingly performed in this complex aging population. Clinically important short-term outcomes have improved for this population, but little is known about long-term outcomes. We review the literature to evaluate trends in CRC surgery in the geriatric population and the outcomes of surgical treatment. We explore the specific gaps in understanding longitudinal patient-centered outcomes of CRC treatment. We then propose adaptations from the geriatrics literature to better predict both short and long-term outcomes after CRC surgery. Interventions, such as prehabilitation, coupled with comprehensive geriatric assessment may be important future strategies for identifying vulnerable older patients, ameliorating the modifiable causes of vulnerability, and improving patient-centered longitudinal outcomes. Further research is needed to determine relevant aspects of geriatric assessments, identify effective intervention strategies, and demonstrate their validity in improving outcomes for at-risk older adults.

Thrombospondin-1 and transforming growth factor-betal promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system

BACKGROUND Pericellular proteolysis is crucial in tumor cell invasion. The plasminogen/plasmin system is one of the main protease systems involved in cancer progression. Thrombospondin-1 (TSP-1), through activation of transforming growth factor-beta 1 (TGF-beta 1), up-regulates the main plasminogen activator, the urokinase-type plasminogen activator (uPA). The objectives of this study were to determine the role of TSP-1 and TGF-beta 1 in the localization of the plasminogen/plasmin system to the tumor cell surface by the uPA receptor (uPAR) and to determine its effect in breast tumor cell invasion. METHODS The effect of TSP-1 and TGF-beta 1 in uPAR expression was determined in MDA-MB-231 human breast cancer cells by enzyme-linked immunosorbent assay and Western blot analysis. Their effect and the role of the plasminogen/plasmin system in breast tumor cell invasion were studied with a Boyden Chamber assay. RESULTS uPAR expression was up-regulated more than twofold by both TSP-1 and TGF-beta 1. The effect of TSP-1 involved its receptor and the activation of TGF-beta 1 by TSP-1. Breast tumor cell invasion was up-regulated sevenfold to eightfold by both TSP-1 and TGF-beta 1 compared with the control group. Antibodies against uPA or uPAR neutralized the TSP-1- and TGF-beta 1-promoted breast tumor cell invasion. CONCLUSIONS TSP-1, through the activation of endogenous TGF-beta 1, up-regulates the plasminogen/plasmin system and promotes tumor cell invasion in breast cancer cells.

Early predictors of anastomotic leaks after colectomy

BackgroundAn anastomotic leak after colorectal surgery is associated with significant morbidity and decreased survival. Our aim was to identify the early predictors of anastomotic leaks.MethodsThe records of patients undergoing restorative resection for colorectal disease from January 2000 to November 2005 were reviewed. Demographics, clinical events, and laboratory parameters were recorded.ResultsA total of 311 patients were included. An anastomotic leak was identified in 25 patients (8%). A leak was suspected and diagnosis confirmed at a mean of 10±1 days postoperatively. More respiratory and neurological events occurred in patients with an anastomotic leak (p<0.001). These events occurred early in the postoperative course and were usually the first signs and symptoms of a leak. More patients with a leak had absence of bowel activity by postoperative day 6 compared to patients without a leak (p<0.0001). Elevations of the white blood cell count or temperature were a late finding.ConclusionThe earliest clinical predictors of an anastomotic leak are pulmonary and/or neurological. Awareness of these findings might help in early diagnosis and treatment of an anastomotic leak.

Obesity increases wound complications in rectal cancer surgery

BACKGROUND Obesity increases the risk of wound infections following surgery for colon cancer. Considerably less data is available, however, regarding the impact of obesity on infections and wound complications after resection for rectal cancer. Additionally, the impact of minimally invasive surgery (MIS) on complications in rectal surgery remains unclear. We hypothesized that obesity is associated with prolonged operative time and more infectious complications in obese patients undergoing both MIS and open surgery for rectal cancer. MATERIALS AND METHODS Review of retrospective surgical database. RESULTS One hundred fifty patients underwent surgery for rectal cancer from 2002 to 2009. Open cases accounted for 72% (n = 108) and MIS for 28% (n = 42) of cases. BMI did not correlate with increased operative time in open rectal surgery, but in MIS patients, operative time increased from a median of 254 min in the lowest quartile of BMI to 333 min in the highest quartile (P < 0.004). Superficial wound infections in open rectal surgery increased from 17% to 52% with increasing BMI (P < 0.005). The increased rate of wound complications persisted in the MIS group. Rate of superficial wound infections and subsequent open packing in the MIS group increased from 0% in the lowest BMI quartile to 33% in the highest quartile (P < 0.029 and P < 0.007, respectively). CONCLUSIONS Elevated BMI is associated with increased wound complications in both minimally invasive and open rectal surgery. This trend may be related to prolonged operative time in obese patients, particularly in MIS. Our observations suggest that more aggressive techniques to prevent infection are warranted in obese patients undergoing rectal surgery.

More than 150 consecutive open umbilical hernia repairs in a major Veterans Administration Medical Center

BACKGROUND The purpose of this study was to determine the rate of surgical site infection for open elective umbilical hernia repairs and to identify the factors related to an increased risk of infection and/or recurrence. METHODS A retrospective analysis of 152 open elective umbilical hernia repairs between 2003 and 2007 was performed. RESULTS Overall, 19% of repairs became infected. Both high ASA classification (P = .01) and mesh repair (P = .01) significantly predicted wound infection, whereas age >60 years, body mass index >30, smoking, immunosuppression, diabetes, and hernia size did not. Only 2 of 17 infected mesh repairs required removal of the mesh. The recurrence rate was 1.5% for mesh and 9.2% for suture repairs. CONCLUSIONS Umbilical hernia repair is associated with a high rate of infection, and most superficial mesh infections can be treated with antibiotics alone. In addition, mesh repair of umbilical hernias decreased the rate of recurrence but increased the risk of infection compared with suture repairs.

Concomitant Colorectal Cancer and Abdominal Aortic Aneurysm: Evolution of Treatment Paradigm in the Endovascular Era

BACKGROUND Although the incidence of patients presenting with concomitant colorectal cancer (CRC) and abdominal aortic aneurysm (AAA) is low, current treatment strategies in patients with both lesions remains controversial. Given recent advances in endovascular aortic aneurysm repair (EVAR), we sought to analyze the surgical outcomes of patients with concomitant CRC and AAA. STUDY DESIGN A retrospective chart review was performed on all patients with CRC and AAA between December 1984 and July 2007. RESULTS A total of 108 patients with concomitant CRC and AAA were identified. Forty-six patients presented with symptomatic or obstructing CRC, which was treated with colectomy followed by either open AAA repair (n=35, group A) or EVAR (n=11, group B). Thirty-eight patients underwent either open AAA (n=26, group C) or EVAR (n=12, group D) first, followed by staged CRC resection. Eight patients underwent combined CRC and open AAA repair (group E). The time delays after CRC resection to AAA repair in groups A and B were 42 and 35 days (NS), respectively. The time delays after open AAA or EVAR procedures before CRC resection in groups C and D were 115 days and 12 days (p < 0.0001), respectively. Two patients in group B developed sigmoid ischemia after EVAR and were treated with sigmoid resection. Increased perioperative morbidity and mortality rates were noted in group C (p < 0.002). CONCLUSIONS In patients with concomitant colorectal cancer and AAA, the symptomatic lesion should be a treatment priority. Because EVAR results in early recovery and a shorter convalescence compared with open aneurysmorrhaphy, this modality offers potential treatment benefits in patients with suitable anatomy who have concomitant CRC. But EVAR treatment should be offered with caution because of the risk of sigmoid ischemia caused by inferior mesenteric artery occlusion.

Transforming growth factor–beta1 inhibits generation of angiostatin by human pancreatic cancer cells

Abstract Background: Angiostatin, a proteolytic fragment of plasminogen, is a potent inhibitor of angiogenesis. We have previously shown that the human pancreatic cancer cell line ASPC-1 produces enzymatic activity capable of generating angiostatin. In this study we sought to determine whether angiostatin production by ASPC-1 cells was regulated by the growth factor transforming growth factor–β 1 (TGF- β 1), a key mediator of tumor angiogenesis. Methods: ASPC-1 cells were grown to 70% to 80% confluence in 20% fetal calf serum–RPMI. Medium was changed to serum free. TGF- β 1 was added at concentrations of 0, 1, 5, and 10 ng/mL with or without plasminogen activator inhibitor type-1 (PAI-1) at concentrations of 0, 5, 10, 50, and 100 μg/mL. Cells were then cultured for an additional 24 hours. The serum-free conditioned medium was obtained. Angiostatin generation was determined by incubating 20 μg of plasminogen with 100 μL of serum-free conditioned medium for 0, 1, 2, 3, 6, 12, and 24 hours. Samples were run on 12% sodium dodecyl sulfate–polyacrylamide gel electrophoresis and transferred. The membrane was probed with a monoclonal antibody to the kringle 1-3 fragment of plasminogen and developed using enhanced chemiluminesence. Results: TGF-β 1 and PAI-1 inhibited the conversion of plasminogen into angiostatin in a time- and dose-dependent manner. Antibody to PAI-1 completely blocks TGF- β 1 mediated angiostatin inhibition. Conclusions: TGF- β 1 inhibits the generation of the antiangiogenic molecule angiostatin by human pancreatic cancer cells in a time- and dose-dependent manner. This effect is mediated through modulation of the plasminogen/plasmin system. (Surgery 1998;124:388-93.)