Marc I. Brand

Morbidity and Mortality in Octogenarians and Older Undergoing Major Intestinal Surgery

PURPOSE: The elderly constitute an increasing portion of the worlds population. Our study assessed morbidity, mortality, and outcome in octogenarians who have undergone lower intestinal operations, and compared outcome between subsequent decades. METHODS: A total of 138 octogenarians who underwent 157 operations were retrospectively studied (1995-2005). The American Society of Anesthesiologists Physical Status classification, blood loss, length of surgery, surgical intensive care unit admission, length of surgical intensive care unit and hospital stay, and complications were recorded. Emergency vs. elective and cancer vs. noncancer cases were compared. Results were compared for the years 1985 to 1994. RESULTS: Cancer comprised 63 percent of cases. The most common causes of mortality were sepsis and multiorgan failure. Differences (P < 0.05) were found for elective vs. emergent surgeries according to age, length of stay, complications, surgical intensive care unit admission, American Society of Anesthesiologists Physical Status classification, and mortality. Noncancer cases were more likely to be emergent, have a higher American Society of Anesthesiologists Physical Status classification, and a higher mortality rate. When emergency operations were excluded, there were no significant differences between cancer vs. noncancer cases. In a comparison of two decades (1985-1994 vs. 1995-2005), we found that the mortality rate in patients younger than aged 85 years decreased by more than 10 percent (P < 0.05). Patients older than aged 85 years demonstrated no significant differences between decades. The strongest determinants of outcome are emergency status and the presence of comorbid conditions. CONCLUSIONS: Elective surgery in the elderly is safe. Emergency surgery is accompanied by significant morbidity and mortality.

Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells.

Intestinal mucosa is constantly exposed to normal environmental antigens. A significant number of intestinal mucosal T cells are being deleted through apoptosis. In contrast, T cells from inflamed mucosa of ulcerative colitis patients did not undergo apoptosis. In this study, we determined whether the apoptosis of normal mucosal T cells was induced by antigen receptor stimulation and further determined pathways that mediated the apoptosis. Freshly isolated lamina propria T cells were stimulated with CD3 mAb and apoptosis was determined by Annexin V staining. Normal mucosal T cells underwent apoptosis upon CD3 mAb stimulation whereas the T cells from inflamed mucosa did not. The apoptosis in normal T cells was blocked by TRAIL‐R1:Fc and an inhibiting CD95 antibody. Interestingly, decoy receptor (DcR)1, DcR2, and DcR3 that compete with death receptor (DR)4/5 and CD95 were highly expressed by the T cells from inflamed mucosa, but much lower by T cells from normal mucosa. Our data suggest that normal mucosal T cells are constantly deleted in response to environmental antigens mediated through DR4/5 and CD95 pathways and mucosal T cells from ulcerative colitis resist to undergoing apoptosis due to highly expression of DcR1, DcR2, and DcR3.

Tumor scatter after neoadjuvant therapy for rectal cancer: are we dealing with an invisible margin?

BACKGROUND: After the impressive response of rectal cancers to neoadjuvant therapy, it seems reasonable to ask: can we can excise the small ulcer locally or avoid a radical resection if there is no gross residual tumor? Does gross response reflect what happens to tumor cells microscopically after radiation? OBJECTIVE: The aim of this study was to identify microscopic tumor cell response to radiation. DESIGN: This study is a retrospective review of a prospectively collected database. SETTING: This investigation was conducted at a single tertiary medical center. PATIENTS: Patients were selected who had elective radical resection for rectal cancer after preoperative chemotherapy and radiation performed by 2 colorectal surgeons between 2006 and 2011. MAIN OUTCOME MEASURES: The primary outcome measured was tumor presence after radiation therapy RESULTS: Of the 75 patients, 20 patients were complete responders and 55 had residual cancer. Of these patients, 28 had no tumor cells seen outside the gross ulcer, and 27 (49.1%) had tumor outside the visible ulcer or microscopic tumor present with no overlying ulcer. Of these tumors, 81.5% were skewed away from the ulcer center. The mean distance of distal scatter was 1.0 cm from the visible ulcer edge to a maximum of 3 cm; 3 patients had tumor cells more than 2 cm distal to the visible ulcer edge. Tumor scatter outside the ulcer was not associated with poor prognostic factors, such as nodal and distant disease, perineural invasion, or mucin; however, it was associated with lymphovascular invasion (&khgr;2 = 4.12, p = 0.038) LIMITATIONS: There was limited access to clinical information gathered outside our institution. CONCLUSIONS: Our study suggests that 1) after radiation, the gross ulcer cannot be used to determine the sole area of potential residual tumor, 2) cancer cells may be found up to 3 cm distally from the gross ulcer, so the traditional 2-cm margin may not be adequate, and 3) local excision of the ulcer or no excision after apparent complete response appears to be insufficient treatment for rectal cancer.

Survivin-Induced Aurora-B Kinase Activation: A Mechanism by Which APC Mutations Contribute to Increased Mitoses during Colon Cancer Development

APC mutations initiate most colorectal cancers (CRCs), but cellular mechanisms linking this to CRC pathology are unclear. We reported that wild-type APC in the colon down-regulates the anti-apoptotic protein survivin, and APC mutation up-regulates it, explaining why most CRCs display survivin overexpression and apoptosis inhibition. However, it does not explain another hallmark of CRC pathology--increased mitotic figures and cell proliferation. Because survivin activates aurora-B kinase (ABK) in vitro, catalyzing mitosis, we hypothesized that in normal colonic crypts, APC controls ABK activity, while in neoplastic APC-mutant crypts, ABK activity is up-regulated, increasing mitosis. We quantitatively mapped intracryptal distributions of survivin, ABK, and markers of activated downstream signaling and mitosis (INCENP, phospho-histone-H3, phospho-centromere-protein-A). In normal crypts, gradients for these markers, ABK:survivin:INCENP complexes, and ABK activity were highest in the lower crypt (inverse to the APC gradient). In neoplastic crypts that harbor APC mutations, proliferating (Ki-67+) cells and cells expressing survivin, ABK, and phospho-histone-H3 were distributed farther up the crypt. Hence, as cells migrate up neoplastic crypts, transitions between cell phenotypes (eg, from stem to proliferating) appear delayed. In CRC cell lines, increasing wild-type APC, inhibiting TCF-4, or decreasing survivin expression down-regulated ABK activity. Thus, APC mutation-induced up-regulation of the survivin/ABK cascade can explain delayed crypt cell maturation, expansion of proliferative cell populations (including mitotic figures), and promotion of colon tumorigenesis.

Preoperative Considerations and Creation of Normal Ostomies

Stomas provide fecal diversion in emergent and elective settings. Preoperative planning and counseling are extremely important to the creation of an acceptable and functional ostomy for the surgeon and patient. Proper site selection will help decrease the incidence of postoperative complications. Ileostomy, colostomy, and cecostomy indications and techniques are discussed.

Apoptosis and Inflammation: Role of Adipokines in Inflammatory Bowel Disease

OBJECTIVES:Leptin and adiponectin (APN) are adipokines produced by adipocytes that participate in the modulation of immune and inflammatory responses. In Crohns disease (CD), fat wrapping surrounding the inflamed intestine produces high levels of leptin and APN. In inflammatory bowel disease (IBD), apoptosis resistance of lamina propria T lymphocytes (LPL-T) is one of the mechanisms that maintains chronic inflammation. We addressed the mechanism by which leptin and APN regulate inflammation and apoptosis in IBD.METHODS:Immune cell infiltration, several factors expressed by adipose tissue (AT), and spontaneous release of cytokines by adipocytes were measured. The presence of APN and leptin in intestinal mucosa was detected and their effect on LPL-T apoptosis, signal transducer and activator of transcription 3 (STAT3), Suppressor of Cytokine Signaling 3 (SOCS3), Bcl-2 and Bcl-xL expression, and cytokine production was studied. In addition, the effects of globular and high-molecular-weight (HMW) APN on LPL-T cytokine production and apoptosis were studied.RESULTS:Higher levels of several chemokines, cytokines, and growth factors were present in AT near active than near inactive disease. A significantly higher amount of inflammatory infiltrate was present in AT near active CD than near ulcerative colitis, controls, and near the inactive area of CD. There were no changes in the ratios of APN molecular weight in control and IBD adipocyte products. Leptin and APN inhibited anti-CD3-stimulated-LPL-T apoptosis and potentiated STAT3 phosphorylation, Bcl-2, and Bcl-xL expression in IBD and control mucosa. However, SOCS3 expression was suppressed only in IBD. Both globular and HMW APN have similar effects on LPL-T cytokine production and apoptosis. Leptin and APN enhanced interleukin (IL)-10 production by anti-CD3-stimulated LPL-T in IBD only. APN, but not leptin, increased anti-CD3-induced IL-6 levels in LPL-T only in IBD patients. IL-10 exerts its anti-inflammatory activity in the presence of SOCS3 suppression by leptin or APN.CONCLUSION:Leptin and APN maintain the inhibition of anti-CD3-stimulated LPL-T apoptosis by enhancing Bcl-2 and Bcl-xL overexpression and promoting STAT3 phosphorylation while suppressing SOCS3.

Preoperative Evaluation and Oncologic Principles of Colon Cancer Surgery

Colorectal cancer is the third most common malignancy in men and women and accounts for 10% of all cancer deaths. The primary risk factor for colorectal cancer is advancing age, but other factors also play a role in its development, including genetic predisposition, smoking, alcohol consumption, obesity, and high-fat, low-fiber diet. Colon cancer survival is primarily related to the stage of disease at diagnosis. The main screening tests for colon cancer are fecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema, and colonoscopy. The pre-operative evaluation should include a complete blood count, carcinoembryonic antigen (CEA), colonoscopy, and chest radiograph. Other preoperative evaluations are patient specific or of unproven benefit. The operative procedure should include a bowel preparation, parenteral antibiotics, and deep venous thrombosis prophylaxis. The procedure performed must be tailored to the location of the colon cancer but should include complete, en bloc resection of the cancer and its lymphatic drainage, including locally invaded structures. The bowel margins of resection should be at least 5 cm from the tumor to minimize anastomotic recurrences. Laparoscopic colectomy has been shown to be as safe and effective as open colectomy for the treatment of colon cancer. The use of sentinel lymph node biopsy is feasible but has not yet been proved clinically useful. Surveillance after surgery for colon cancer is necessary to monitor for metastatic disease or local recurrence. Several groups have made surveillance recommendations including office visits, colonoscopy, and CEA monitoring.

A Review of the Treatment of Opioid-induced Constipation with Methylnaltrexone Bromide

Objectives: Review and summarize the mechanism of action of methylnaltrexone bromide (methylnaltrexone) and its effectiveness in the treatment of opioid-induced constipation. Data Source: A multi-database search was conducted using PubMed and MEDLINE databases, in addition to electronic links to related articles and references. Background: Opioids are effective medications for the management of moderate to severe pain, but they are associated with a number of side effects, especially within the gastrointestinal system. Constipation is a very common adverse reaction in patients with late-stage, adverse illness, who require long term administration of opioids on a chronic basis to help alleviate pain. In April 2008, the Food and Drug Administration approved the use of methylnaltrexone, a quaternary derivative of naltrexone which does not cross the blood brain barrier, for the management of patients with opioid-induced constipation. Methylnaltrexone acts as a selective peripheral Mu-receptor antagonist, without affecting the effects of opioids on central analgesia. Conclusions: Studies have been shown that methylnaltrexone can be used safely in the treatment of opioid-induced constipation without either interfering with opioid effects on central anesthesia or precipitating opioid withdrawal.

Cleft lift procedure for pilonidal disease: technique and perioperative management

Pilonidal disease is a common condition affecting young patients. It is often disruptive to their lifestyle due to recurrent abscesses or chronic wound drainage. The most common surgical treatment, “cystectomy,” removes useful tissue unnecessarily and does not address the etiology of the condition. Herein, we describe the etiology of pilonidal disease and our technique for definitive management of pilonidal disease using the cleft lift procedure. In this paper, we present our method of performing the cleft lift procedure for pilonidal disease including perioperative management and surgical technique. We have used the cleft lift procedure in nearly 200 patients with pilonidal disease, in both primary and salvage procedures settings. It has been equally successful in both settings with a high rate of success. It results in a closed wound with relatively minimal discomfort and straightforward wound care. We have described our current approach to recurrent and complex pilonidal disease using the cleft lift procedure. Once learned, the cleft lift procedure is a straightforward and highly successful solution to a chronic and challenging condition.

Genetic Predisposition to Colorectal Cancer

Colorectal cancer is the most common malignancy of the gastrointestinal tract and is the second leading cause of cancer death when both genders are considered. There are several risk factors associated with an increased incidence of colorectal cancer, such as advanced age, high animal fat and low fiber diet, tobacco smoking, pelvic irradiation, and inflammatory bowel disease. However, one must be aware of a special population of patients with increased risk of colorectal cancer due to hereditary syndromes and manage them accordingly. The first step in management of hereditary colorectal cancer syndrome (HCRCS) is recognizing when the condition is present. Some patients may be without symptoms and seen for an unrelated condition. Family cancer history and reviewing surgical and pathology reports are crucial components in recognizing HCRCS. However, some patients with HCRCS will be the first person in a family diagnosed with the syndrome. Other clues may suggest the presence of HCRCS, such as unusual symptoms (abdominal pain, change in bowel habits, blood in stool) or findings (desmoid tumor, skull osteomas, supernumerary teeth) in a young person.