Functional results of robotic total intersphincteric resection with hand-sewn coloanal anastomosis.

BACKGROUND: In recent decades there has been an increasing trend toward sphincter-preserving procedures for the treatment of low rectal cancer. Robotic surgery is considered to be particularly beneficial when operating in the deep pelvis, where laparoscopy presents technical limitations. The aim of this study was to prospectively evaluate the functional outcomes in patients affected by rectal cancer after robotic total intersphincteric resection (ISR) with hand-sewn coloanal anastomosis. METHODS AND PROCEDURES: From March 2008 to October 2012, 23 consecutive patients affected by distal rectal adenocarcinoma underwent robotic ISR. Operative, clinical, pathological and functional data regarding continence or presence of a low anterior resection syndrome (LARS) were prospectively collected in a database. RESULTS: Twenty-three consecutive patients were included in the study: 8 men and 15 women. The mean age was 60.2 years (range 28-73). Eighteen (78.3%) had neoadjuvant radiochemotherapy. Conversion rate was nil. The mean operative time was 296.01 min and the mean postoperative hospital stay was 7.43 ± 1.73 days. According to Kirwan's incontinence score, good fecal continence was shown in 85.7% of patients (Grade 1 and 2) and none required a colostomy (Grade 4). Concerning LARS score, the results were as follows: 57.1% patients had no LARS; 19% minor LARS and 23.8% major LARS. CONCLUSIONS: Robotic total ISR for low rectal cancer is an acceptable alternative to traditional procedures. Extensive discussion with the patient about the risk of poor functional outcomes or LARS syndrome is mandatory when considering an ISR for treatment of low rectal cancer.

Differential insulin-like growth factor II (IGF-II) expression: A potential role for breast cancer survival disparity.

OBJECTIVE: Increased risk of cancer and other adult diseases have been associated with perinatal exposure to adverse conditions such as stress and famine. Recently, Insulin-like growth factor II (IGF-II) was identified as the first gene associated with altered expression caused by fetal exposure to poor nutrition. IGF-II regulates fetal development and breast cancer cell survival, in part, by regulating anti-apoptotic proteins through activation of the IGF-I and insulin receptors. African-American (AA) women have a lower overall breast cancer (BC) incidence, however, they present with advanced disease at diagnosis, poorer prognosis and lower survival than Caucasian (CA) women. The reasons for the BC survival disparity are not well understood. We hypothesize that IGF-II plays a role in the survival disparity observed among AA breast cancer patients by stimulating rapid tumor growth, inhibiting apoptosis, and promoting metastasis. DESIGN: This study examines IGF-II expression and regulation of the anti-apoptotic proteins Bcl-2, Bcl-X(L), and survivin in Hs578t (ER-), CRL 2335 (ER-), and CRL 2329 (ER+) breast cancer cells and compares with the expression of these proteins in paired breast tissue samples from AA and CA women by qRT-PCR and Western blotting. RESULTS: IGF-II expression was significantly higher in AA cell lines and tissue samples when compared to Caucasians. IGF-II siRNA treatment decreased anti-apoptotic protein levels in all cell lines (regardless of ER status). These effects were blocked by the addition of recombinant IGF-II. Of significance, IGF-II expression and regulation of Bcl-X(L) and survivin in cell lines correlated with their expression in paired breast tissues. CONCLUSIONS: IGF-II and the anti-apoptotic proteins differential expression among AA and CA patients may contribute to the breast cancer survival disparities observed between these ethnic groups.

Comparison between image and flow cytometry. A priori factors that influence technique.

Comparisons between flow cytometry (FCM) and image cytometry (ICM) have found a high concordance rate in pancreatic tissue, with some discrepancies between the two procedures. This study utilized 40 cases of chronic pancreatitis, primary pancreatic adenocarcinoma and metastatic pancreatic adenocarcinoma to determine the concordance rate between the two procedures. The reasons for discrepancies were identified and subsequently used to establish methods for a priori determination of which procedure to use. Using the FACSCAN flow cytometer and the CAS 200 on appropriately stained specimens that were disaggregated from 50-micron sections, we achieved a concordance rate of r = .878 (P < .01) after removing outliers. Thirty-one of 40 cases matched DNA content, and 9 cases had discrepant results. These discrepant cases were evaluated with factor analysis, in part because initial observations suggested that the variables evaluated could be combined into unifying concepts. The nine measured variables were compressed into three factors, which accounted for 68% of the variation observed between the two methods. Readily evaluated features, on a case-by-case basis, including tumor/nontumor ratios, accounted for the largest proportion of this variation. These findings suggest that tumor/nontumor cell ratios in hematoxylin-eosin-stained sections may provide adequate a priori information to direct the choice of either FCM or ICM to measure DNA ploidy in pancreatic tissue.

Parathyroid hormone-related protein: primary osteolytic factor produced by breast tumor cells in vitro?

Tumor cells in bone metastases are thought to induce bone resorption primarily by releasing paracrine factors. Parathyroid hormone related protein (PTHrp) has been proposed to mediate osteolytic activity of many tumors. PTHrp is produced by 40% to 60% of breast tumors and is elevated in the serum of up to 50% of patients with breast cancer metastases to bone. Most biologic processes in humans are heterogeneous in nature, so the purpose of this study was to investigate the hypothesis that paracrine factors other than PTHrp could mediate bone resorption by breast tumor cells. Serum-free conditioned medium (CM) was collected from five human breast tumor cell lines and tested for bone resorption-stimulating activity (BRSA) in mouse calvaria organ cultures. CM from all tumor cells studied produced significant bone resorption, comparable to that produced by 10 nM PTH. Small amounts of immunoreactive PTHrp (1.4-12.5 pM) were produced by all breast tumor cell lines. When tested in vitro, equivalent amounts of human PTHrp [1-36] did not produce significant bone resorption. Indomethacin (1 microM) significantly blocked BRSA by CM from all cell lines but did not decrease BRSA by PTHrp. In contrast PTHrp antibody (130 micrograms/ml) completely blocked BRSA by 1 nM PTHrp but did not modify BRSA by CM of breast tumor cells. The results of this study support the hypothesis that breast cancer cells release paracrine factors in vitro that stimulate bone resorption by a mechanism that is partially dependent on prostaglandin synthesis and at least in part different from that of PTHrp.(ABSTRACT TRUNCATED AT 250 WORDS)

The impact of prior intra-abdominal surgery on laparoscopic cholecystectomy.

The presence of abdominal wall scarring and intra-abdominal adhesions following prior abdominal surgery has been proposed as a relative contraindication to the performance of laparoscopic cholecystectomy. The impact of prior abdominal surgery on the management of symptomatic gall bladder disease was retrospectively reviewed. Three groups were evaluated: open, laparoscopic, and laparoscopic converted to open cholecystectomy. Clinical factors analyzed included lengths of operative time, postoperative hospitalization stay, medical risk (ASA Classification), and postoperative complications. In addition, factors contributing to the conversion from a laparoscopic to open procedure were evaluated to determine the impact of prior surgery on conversion. The records of 504 consecutive patients undergoing open and laparoscopic cholecystectomy were reviewed. Individuals having additional intra-abdominal procedures were excluded. A total of 175 patients were identified who had prior abdominal surgery and underwent a cholecystectomy. In patients requiring cholecystectomy who have had prior abdominal surgery, the following observations can be made regarding laparoscopic cholecystectomy: 1) The operative time is less compared to open cholecystectomy. 2) The advantage of a shorter postoperative stay is realized. 3) The conversion rate (7/158) is low. Five of the seven conversions were due to the dense adhesion that prevented safe needle/trocar placement. 4) The complication rate is not increased. 5) The successful completion rate of laparoscopic cholecystectomy following prior intra-abdominal surgery (95.6%) is high.

Factors influencing survival in advanced gastric cancer.

Even though the incidence of gastric carcinoma is decreasing, the prognosis remains poor. A review of 88 patients with advanced gastric cancer was evaluated by univariate and multivariate analysis to determine prognostic factors. Univariate analysis showed that both "curative" resection (P = 0.006) and adjuvant chemotherapy (P = 0.02) were important therapy variables. These factors were not independent when evaluated by multivariate analysis. However, when they were combined and re-evaluated by multivariate analysis, the combination of "curative" surgery and adjuvant chemotherapy significantly improved survival in advanced gastric cancer (P = 0.04).

Expression of P-glycoprotein in normal muscle cells and myogenic tumors.

We have analyzed the expression of the multidrug resistance (mdr-1) gene product, P-glycoprotein, by immunohistochemical staining of frozen tissue sections of human normal muscle fibers and 31 tissue specimens of cases of myogenic sarcomas. The objective of this study was to further characterize what appears to be a variety of responses to therapy in like-appearing but distinct tumors. We have used two mouse monoclonal antibodies that recognize two different epitopes of P-glycoprotein. Mouse monoclonal antibody HYB-241 detects an extracellular epitope of P-glycoprotein, whereas C219 detects a carboxy-terminal intracellular epitope and has recently been reported to cross-react with the mdr-3 gene product. Differential epitope expression was observed among normal muscle fibers with the two antibodies used. Smooth-muscle cells were unreactive for the two antibodies, whereas cardiac and a subgroup of skeletal muscle fibers were intensely stained by C219, but not by HYB-241. P-glycoprotein expression was observed in 23% of the 31 myogenic sarcomas analyzed. Our study was conducted mainly using adult myogenic sarcomas (28 out of 31 cases), with a few cases (three out of 31 cases) of childhood sarcomas. Nineteen tumors were leiomyosarcomas, seven cases were embryonal rhabdomyosarcomas, and five cases were rhabdomyosarcomas. We have considered expression of the mdr-1-coded P-glycoprotein when we observed either HYB-241 and C219 staining, or just HYB-241 immunoreactivities. Although P-glycoprotein expression can now be detected in human sarcomas, further studies are needed, mainly comparing tumor samples before, during, and after therapy, to establish the possible significance of the P-glycoprotein expression in clinical drug resistance.

Recombinant interleukin-4 enhances the chemiluminescent oxidative burst of murine peritoneal macrophages.

We evaluated the effects of murine recombinant interleukin-4 (rIL-4) on murine peritoneal macrophages. We showed a marked, dose-dependent stimulation of respiratory oxidative burst by IL-4 in peptone-elicited murine peritoneal macrophages. This effect was abolished by a neutralizing monoclonal antibody (mAb) to rIL-4 confirming that the enhanced chemiluminescence was due to IL-4. In contrast, rIL-4 depressed the respiratory oxidative burst of a transformed murine macrophage cell line, J774, in a dose-dependent mAb-reversible manner.

Maltose absorption as an indicator of small-intestinal allograft rejection.

Maltose and lactose absorption, which require an intact brush border for breakdown and absorption as glucose, was evaluated as a function test to monitor the integrity of the small-bowel graft. Using the rat model of accessory small-bowel transplantation, absorption tests (in the form of an oral glucose tolerance test) were performed on iso- and allografts with either portal (PP-A) or caval venous drainage (PC-A). In isografts the absorption of maltose was found to be reproducible and not influenced by the type of venous drainage. This was not the case with the use of lactose which thus was not studied further. Allografts with PC-A demonstrated a reduction in their capacity for maltose absorption on the fifth postoperative day, as the glucose peak at 30 min (T30) was significantly blunted in comparison to that for isografts with PC-A (167 mg% +/- 12 vs 204 mg% +/- 8). Functional impairment preceded histologic changes which did not arise before the sixth-to-seventh postoperative day in rats with PC-A. Allografts with PP-A absorbed maltose on the fifth postoperative day nearly as effectively as did isografts (T30 min: 185 mg% +/- 14 vs 213 mg% +/- 8). By the ninth postoperative day, the serum glucose curve after maltose administration was flattened for grafts with PC-A (T30 min: 137 mg% +/- 11) which were rejected acutely (host's death) after 11.8 days +/- 0.45. A similar impairment of maltose absorption was not seen in the PP-A group (chronic graft rejection after 22.8 days +/- 1.8) until the 15th postoperative day.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone decreases centrally induced hyperglycemia in dogs. Evidence for an opioid role in glucose homeostasis.

Intracerebroventricular (ICV) instillation of morphine and beta-endorphin causes centrally induced hyperglycemia. Locally active, endogenous opioids in the central nervous system may, therefore, also be involved in the elevation of blood sugar. This possibility was tested by examining the glucoregulatory response to central glucoprivation induced by ICV administration of 2-deoxy-D-glucose (2DG) in dogs. Administration of 2DG resulted in a rise in plasma glucose and immunoreactive glucagon (IRG) of 108 +/- 19 mg/dl and 70 +/- 20 pg/ml, respectively. These changes were attenuated by the simultaneous central infusion of the opiate antagonist naloxone: plasma glucose levels increased by 77 +/- 14 mg/dl and IRG by 43 +/- 3 pg/ml, both significantly different from the effect of 2DG alone (P less than 0.05-0.01). These findings suggest that opiate receptors participate in the counterregulatory response to central glucoprivation. They also provide a mechanism by which endogenous opioid peptides may play a role in the central regulation of glucose homeostasis.

Hormonal control of biliary lipid secretion in dogs.

Five dogs were anesthetized, their cystic ducts were ligated, and their common bile ducts cannulated. The experiments were divided into four 1-hour periods. Taurocholic acid (18 mumol/min) and pipenzolate methylbromide (0.5 mg/kg body weight initially followed by 0.1 mg/kg body weight/20 minutes) were infused during all periods. Somatostatin (800 ng/kg/min) was infused during periods 2, 3, and 4 to suppress the endogenous secretion of peptide hormones. During periods 3 and 4, insulin was infused into a mesenteric vein at rates of 0.2 mU/kg/min and 0.8 mU/kg/min, respectively. These rates have been shown to produce fasting and postprandial portal vein insulin levels. Bile was collected during each period and the volume, bile acid concentration, and biliary lipid content were measured. Another five dogs were studied in a similar way, except that glucagon was infused in place of insulin at rates of 0.6 and 3.0 ng/kg body weight/min to produce fasting and postprandial portal vein levels. The results show that 1) the biliary secretion of cholesterol and phospholipid is increased by pharmacologic doses of somatostatin and 2) physiologic doses of glucagon, but not insulin , suppress the biliary secretion of cholesterol and phospholipid.

Pharmacological and physiological doses of insulin and determinants of bile flow in dogs.

The role of insulin in control of bile secretion is uncertain. To study the mechanism of choleresis produced by large doses of insulin, bile was collected through modified Thomas cannulas from dogs anesthetized with pentobarbital. Animals received pipenzolate methylbromide, sodium taurocholate, and [14C]erythritol. After bile flow had stabilized three animals received infusions of insulin at 2, 4, 13, 26, 35, and 70 mU . kg-1 . min-1 for 40 min each. Bile and [14C]erythritol clearance increased (P less than 0.005), but bile salt output remained constant, suggesting that the choleresis was mainly due to enhanced bile salt-independent canalicular flow. Plasma insulin and glucagon levels also rose when insulin was infused. To exclude the possible effects of glucagon three additional animals received somatostatin (800 ng . kg-1 . min-1) along with infusions of insulin. Bile flow and [14C]erythritol clearance again increased significantly, but glucagon levels remained low, suggesting that the effects on bile flow were due to insulin alone. To determine whether physiological doses of insulin altered bile flow dogs were anesthetized with pentobarbital and received pipenzolate methylbromide, taurocholate, [14C]erythritol, and somatostatin (800 ng . kg-1 . min-1). Insulin (0.2 and 0.8 mU . kg-1 . min-1) was infused through the portal vein for 1 h each. Bile flow and [14C]erythritol clearance increased with insulin (0.8 mU . kg-1 . min-1; P less than 0.02), suggesting that the choleresis may have been due to bile salt-independent canalicular flow. Plasma insulin rose to physiological postprandial levels. These studies demonstrate that pharmacological and physiological levels of insulin administered to dogs produce a significant choleresis. Thus insulin may play an important role in the regulation of bile secretion.

Central control of peripheral circulating somatostatin in dogs: effect of 2-deoxyglucose.

Circulating plasma somatostatin concentrations are known to fluctuate in response to nutrients and hormones. However, little is known about neural or central nervous system (CNS) control of somatostatin secretion. To test whether peripheral circulating somatostatin is influenced by a central stimulus, 2-deoxyglucose (37.5 mg/kg) was infused into a lateral cerebral ventricle of six conscious dogs over a period of 15 min. Plasma somatostatin levels rose from a base line of 105 +/- 6 pg/ml (mean +/- SE) to a peak of 154 +/- 10 pg/ml (P less than 0.005) at 30 min after the onset of the infusion. Somatostatin levels were still significantly elevated (P less than 0.025) at 60 min (119 +/- 6 pg/ml) and thereafter gradually returned toward base line. Plasma glucose and glucagon levels increased in response to intraventricular 2-deoxyglucose. Glucose concentrations rose from 105 +/- 5 mg/dl to peak at 203 +/- 16 mg/dl (P less than 0.005) at 80 min and remained elevated to 120 min. The concentration of plasma glucagon increased from 41 +/- 6 to 92 +/- 18 pg/ml at 60 min (P less than 0.05) and then declined. In marked contrast to intraventricular 2-deoxyglucose, similar concentrations of 2-deoxyglucose administered intravenously (n = 4) resulted in a slight fall in plasma somatostatin. Intraventricular saline did not result in a change in plasma somatostatin. It is concluded that peripheral circulating somatostatin may be susceptible to central nervous system control.

Is glucagon a choleretic hormone at physiologic blood levels?

The mechanism of action and possible physiologic implications of glucagon-induced choleresis were investigated in two groups of dogs. Group I demonstrated, in chronic animal models, that glucagon-induced choleresis was not associated with increased bile acid output and was not blocked by somatostatin or Piptal, suggesting a direct stimulatory effect on bile acid-independent canalicular flow. In acute animal models (group II), glucagon infusion at rates which produced postprandial levels in the portal vein induced significant choleresis, implying that glucagon may have a physiologic role in the regulation of bile secretion. No consistent relation between bile secretion and portal venous blood flow could be demonstrated.