Laparoscopic cholecystectomy does not demonstrably decrease survival of patients with serendipitously treated gallbladder cancer.

BACKGROUND: The purpose of this study was to evaluate the possibility that laparoscopic cholecystectomy has worsened the prognosis of patients with resected gallbladder cancer; particularly for patients whose cancer was accidentally resected. STUDY DESIGN: We conducted a retrospective review of Connecticut Tumor Registry data and data extracted from individual patient records at 15 of 30 hospitals in Connecticut reporting data to the Registry, at two separate time points, 1985-1988 (immediate prelaparoscopic era) and 1992-95 (laparoscopic cholecystectomy well established). There were 194 and 208 patients in each 3-year period, respectively. Additional information was extracted from hospital records in 82 and 91 patients, respectively. Twenty-five percent of patients in both data sets presented with "local" or Tis, T1, T2 disease. RESULTS: Three-year survival for localized disease was 29% in the prelaparoscopic period and 34% once laparoscopic cholecystectomy was established. But analysis of individual patient records indicated that 36% of patients from the laparoscopic period did not actually undergo a laparoscopic procedure. Fifty-nine patients had their gallbladder cancer discovered in the specimen postoperatively (serendipitously treated). A higher proportion of cancers were discovered postoperatively in the laparoscopic era (44% versus 24%). Three-year survival for these patients was 25%. If the data from the two eras are grouped according to whether or not the cancer-bearing gallbladder was manipulated laparoscopically, 24 of 59 patients (41%) turned out to be at risk for the possibility of increased laparoscopic dissemination of tumor. Survival of these patients (11-month median survival) was not statistically different from survival of patients whose serendipitously discovered gallbladder cancer was never manipulated laparoscopically (16-month median survival); p = 0.54 by log rank test. CONCLUSIONS: The widespread adoption of laparoscopic cholecystectomy did not worsen the survival of patients with gallbladder cancer, and patients with serendipitously treated gallbladder cancers did not have a worse survival after laparoscopic manipulation than after a standard open cholecystectomy. The laparoscopic aspects of operative manipulation of a gallbladder with cancer in it do not appear to be a proximate cause of the poor prognosis in this disease.

What can we learn from the phenomenon of preferential lymph node metastasis in carcinoma?

Lymph nodes are the most common and earliest site of malignancies arising in epithelia. However, the reason for this pattern of preferential metastasis is not clear. This article reviews features of the metastatic process and lymph node microenvironment which might potentiate lymph node metastases. There is intriguing evidence that preferential lymph node metastasis is due to (1) the efficiency of lymph nodes as filters of the tumor cells which arrive there, and (2) the probability that adhesive interactions, normally governing the generation of different T-cell immune responses, are responsible for this efficiency and may also promote invasion and proliferation of tumor cells in the lymph node. Manipulation of the cytokine environment in a lymph node draining a primary epithelial tumor may alter both the expression of cell adhesion molecules within the node and the subsequent metastatic ability of the tumor cells arriving at it.

Lateral transperitoneal laparoscopic adrenalectomy.

Several laparoscopic approaches to the adrenal gland have been described. The lateral transperitoneal approach has several distinct advantages when contrasted with other techniques for laparoscopic adrenalectomy (LA). We present our technique and results obtained in 50 consecutive transperitoneal LAs. We review 50 consecutive laparoscopic adrenalectomies (28 female, 19 male) performed from 1993 to 1998 S.J. Shichman or R.E. Sosa was either the primary surgeon or the first assistant for all cases. The lateral transperitoneal approach described below was used in all cases. Indications for adrenalectomy included Cushing's syndrome (13), aldosteronoma (15), pheochromocytoma (7), nonfunctioning adenoma (11), hyperplasia (2), and 1 case each of Carney's syndrome and metastasis to the adrenal gland. We performed 5 bilateral, 22 left, and 18 right laparoscopic adrenalectomies. The average time needed for bilateral adrenalectomy was 503 min (range 298-690 min); for left adrenalectomy, 227 min (range 121-337 min); and for right LA, 210 min (range 135-355 min). We demonstrated a yearly trend in lower operative times. The largest adrenal gland removed measured 13.8 x 6.7 x 3.5 cm. Intraoperative blood loss was low. Only one patient received a blood transfusion. Conversion to open adrenalectomy was not required. Postoperative analgesic requirements were low. The average length of stay was 3.8 days for bilateral LA and 3 days for unilateral LA. Complications occurred in 5 patients (2 wound infections, 2 hematomas, and 1 pleural effusion). There was no mortality. Lateral transperitoneal adrenalectomy is a safe and efficient technique for the removal of functional and nonfunctional adrenal masses. This technique is associated with low morbidity, a minimal postoperative analgesic requirement, and a short hospital stay and, in our opinion, is more versatile than the retroperitoneal approach.

Angiogenesis in normal tissue adjacent to colon cancer.

BACKGROUND AND OBJECTIVES: Angiogenesis in malignant neoplasms, as measured by microvessel density, has been shown to correlate with survival or stage in some studies of breast, gastric, and colorectal cancer. We hypothesized that aggressive cancers promote angiogenesis in normal tissue adjacent to the invading neoplasm. METHODS: To test this hypothesis, 36 specimens of colon adenocarcinoma curatively resected between 1986 and 1990 were sectioned and stained for factor VIII-related antigen, vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8). Microvessel density was measured within the colon cancer and in adjacent, histologically normal tissue. Clinical/pathological variables were examined using multivariate analysis and Student t-test. RESULTS: Microvessel density was higher in the neoplasms (26.0+/-1.66/ 0.25 mm2) than in the surrounding normal tissue (22.3+/-1.88/0.25 mm2) (P=0.03). The difference was primarily due to smaller neoplasms (T1 and T2) which had vessel counts of 10.6+/-0.74/0.25 mm2 in the adjacent normal tissue compared to vessel counts of 18.9+/-3.02/0.25 mm2 within these tumors (P=0.02). T3 and T4 neoplasms had equivalent amounts of angiogenesis within the lesion (26.9+/-1.81/0.25 mm2) and in the histologically normal margin (24.2+/-1.98/0.25 mm2) (P=0.12). VEGF was present in the tumor microenvironment in 100% and IL-8 in 45% of specimens stained for these angiogenic cytokines. Microvessel density did not correlate with 5-year survival. CONCLUSIONS: Our data suggest that colon cancers that invade through the muscularis propria may have a greater ability to induce angiogenesis in adjacent normal tissue.

Management of bowel obstruction in patients with abdominal cancer.

OBJECTIVE: To determine the value of operation in patients with bowel obstruction caused by recurrent abdominal cancer. DESIGN: Retrospective case review. SETTING: The University of Connecticut Health Center, Farmington. PATIENTS: Ninety-eight patients admitted with a diagnosis of bowel obstruction and malignant neoplasm between November 1, 1987, and June 30, 1995. RESULTS: Data for 75 patients who developed a bowel obstruction within 5 years of a malignant diagnosis were analyzed. Forty-six patients (61%) were treated operatively and 29 (39%) were treated nonoperatively. The operative group included 32 patients (70%) whose obstruction was caused by carcinomatosis; 6 (19%) of these 32 patients had had at least 1 episode of previous obstruction requiring hospitalization. They had a 22% in-hospital mortality, stayed an average of 21 days in the hospital, and survived 7 +/- 6 months (mean +/- SD) after discharge; 5 (16%) had at least 1 episode of postoperative obstruction that required hospitalization. After discharge from the hospital, 53% had an excellent or good quality of life (assessed retrospectively). Of the 29 patients in the nonoperative group, 16 (55%) had carcinomatosis. These 16 patients had a 38% in-hospital mortality (6 of 16), stayed an average of 10 days in the hospital, and survived a mean of 13 +/- 9 months; 3 (19%) had at least 1 episode of recurrent obstruction requiring hospitalization. After discharge from the hospital, 6 (37%) had an excellent or good quality of life. CONCLUSION: The value of operative intervention for bowel obstruction in patients with cancer is derived from the possibility of a benign cause, not alleviation of the consequences of carcinomatosis.

Inhibition of bladder tumor cell implantation in cauterized urothelium, without inhibition of healing, by a fibronectin-related peptide (GRGDS).

BACKGROUND: Local recurrence after transurethral resection of bladder tumors (TURB) is common and might be diminished if free tumor cells within the bladder are prevented from reattaching. METHODS: In vitro inhibition of murine bladder tumor cells to an approximation of urothelial matrix with agents that might block attachment to components of the extracellular matrix, and in vivo inhibition of attachment in cautery-injured murine bladder. RESULTS: GRGDS, (0.1-2.5 mg/ml), a fibronectin-related peptide, mannose-6-phosphate, (0.1-20 mg/ml), a carbohydrate, and heparin (1-625 units/ml) all inhibited attachment in vitro in a dose-dependent fashion. YIGSR (0.1-2 mg/ml), a laminin-related peptide, did not. Mannose (10 mg/ml) did not significantly inhibit attachment of tumor cells to cauterized urothelium in vivo, whereas there was a 77% reduction of attachment in bladders irrigated with GRGDS (6.25 mg/ml) (p < 0.05), and the appearance of subsequent tumors in the bladder was inhibited. Finally, GRGDS (6.25 mg/ml) did not inhibit healing of the cautery ulcer. CONCLUSIONS: RGD-containing peptides may be useful as adjuvant therapy to decrease local recurrence after TURB and perhaps in other circumstances in which tumor cells spilled into a wound or body cavity threaten surgical success.

Utility of routine chest radiographs in the surgical intensive care unit. A prospective study.

OBJECTIVES: To correlate patient condition and reasons for obtaining chest radiographs (CXRs) with the utility of CXRs in critical illness and to determine the potential impact of stricter criteria for obtaining a CXR in a surgical intensive care unit (ICU). DESIGN: Inception cohort study of 1003 CXRs examined prospectively. PATIENTS AND SETTING: A total of 157 consecutive patients admitted to the general surgical ICU of a 780-bed, urban, university-affiliated, tertiary care hospital. INTERVENTION: Nothing was done to influence the ordering of CXRs. OUTCOME MEASURES: Influence of CXR findings on clinical management. RESULTS: The likelihood of a clinically important finding was 17% for CXRs obtained for no clear clinical indication (routine), 26% for those obtained to verify the position of a medical device, and 30% for those obtained for suspected clinical conditions. By univariate analysis, suspected pathophysiologic condition, admission APACHE II (Acute Physiology and Chronic Health Evaluation II) score, presence of a central venous or Swan-Ganz catheter, and length of ICU stay were all predictors of a significant finding. By multivariate analysis, the only independent predictor of a finding was a suspected clinical condition, and the only indwelling medical device that was an independent predictor of a finding was a Swan-Ganz catheter. If the criterion that routine CXRs should only be obtained in patients with Swan-Ganz catheters had been used, 200 CXRs would have been avoided during the 3-month study period. The only findings missed by not obtaining those CXRs would have been two malpositioned nasogastric tubes and one malpositioned central venous catheter. CONCLUSIONS: Chest radiographs should only be obtained on surgical ICU patients for specific indications. Routine CXRs for ICU patients are justified only for patients with indwelling Swan-Ganz catheters.

Influence of a lymph node environment on invasiveness of metastatic tumor cells.

BACKGROUND: We investigated the possibility that lymph nodes might increase metastatic efficiency of tumor cells lodged there by measuring changes in tumor cell invasiveness after physical contact with an in vitro approximation of a lymph node environment. STUDY DESIGN: The experimental model involved growing Lewis lung carcinoma (LL) or B16 melanoma cells on microcarrier beads, rolling them on a "lymph node endothelial surface," which was created by growing endothelial cells on a differentiating acid extract of lymph node biomatrix, and testing the ability of those tumor cells to invade across matrigel-coated filters at rest (buffer) and in response to a chemotactic stimulus (3T3 conditioned media). RESULTS: Compared with contact with plastic, LL invasiveness was increased fivefold (buffer or conditioned media) and B16 invasiveness fourfold (conditioned media). Tumor cell invasiveness was not increased by exposure to the acid extract of biomatrix alone. Invasiveness to buffer or conditioned media after exposure to endothelial cells alone was 70 and 54 percent (LL) and 42 and 80 percent (B16), respectively, of the invasiveness induced by exposure to both. Compared with invasiveness induced by exposure to lymph node (100 percent), exposure to a "lung endothelial surface" induced invasiveness of 63 and 85 percent (LL) and 40 and 52 percent (B16) to buffer and conditioned media, respectively. Exposure to a hepatic endothelial surface induced invasiveness similar to that induced by lymph node; 90 and 82 percent (LL) and 110 and 86 percent (B16) of lymph node-induced invasiveness. CONCLUSIONS: A lymph node environment may modulate the metastatic potential of tumor cells.

Recurrent and chronic appendicitis: the other inflammatory conditions of the appendix.

Episodic abdominal pain, a common clinical problem, can be a diagnostic and therapeutic conundrum when the surgeon encounters it acutely in the emergency department. Appendicitis is often excluded from the differential diagnosis because the natural history of appendicitis is usually appreciated as acute, progressing to some degree of peritonitis quite rapidly and inevitably. However, recurrent and chronic forms of appendicitis occur also and can mislead the clinician. Herein, we describe two patients with recurrent appendicitis that were misinterpreted as other abdominal conditions, and we review the literature implicating recurrent and chronic appendicitis as disease processes, distinct from acute appendicitis, that occur with an incidence of approximately 10 per cent and 1 per cent, respectively.

Inhibition of tumor cell adhesion to lymph nodes by laminin-related peptide and neuraminidase.

BACKGROUND: Adhesion to lymph nodes, rather than growth stimulation, accounted for preferential colonization of lymph nodes by a metastatic B16 melanoma. We investigated these adhesive interactions. METHODS: Four classes of molecules were tested for inhibition of melanoma adhesion to cryostat sections of lymph node. RESULTS: Calcium chelators ethylenediaminetetraacetic acid and ethyleneglycol-bis-(beta-aminoethylether)-N,N,N',N'-tetra ace tic acid completely inhibited adhesion (50% adhesion, half-maximal inhibition, at 1 to 3 mmol/L). Cytochalasin B, which impairs contractile microfilaments, inhibited adhesion (60% adhesion at .001 mmol/L, 28% at .01 mmol/L). Colchicine, which disaggregates microtubules, had a similar effect (20% at .01 mmol/L, lowest dose tested). Trypsin slightly increased adhesion (125% adhesion at 10 micrograms/ml). Neuraminidase, which removed sialic acid residues, inhibited it (50% adhesion at 5 micrograms/ml). Gly-arg-gly-asp-ser, a peptide with a cell binding sequence of fibronectin, did not consistently inhibit adhesion (69% adhesion at 0.1 mg/ml, 83% adhesion at 1 mg/ml) or substantially differ from gly-arg-gly-glu-ser-pro (59% adhesion at 0.1 mg/ml, 90% adhesion at 1 mg/ml). In contrast, a peptide with a cell binding region of laminin (tyr-ile-gly-ser-arg) inhibited adhesion (50% adhesion at .05 mg/ml). CONCLUSIONS: Tumor cell-lymph node adhesion is a calcium-dependent process, requiring a functional cytoskeleton, that is mediated by both sialic acid moieties and trypsin-resistant, laminin-related, adhesion molecules.

Locally increased metastatic efficiency as a reason for preferential metastasis of solid tumors to lymph nodes.

Metastases from solid tumors to lymph nodes do not portend as poor a prognosis as metastases to other sites. The authors wished to determine whether specific subpopulations of cells metastasized to lymph nodes and whether they have different properties than cells metastatic to visceral sites. Repetitive selection for "spontaneous" metastases of a B16 melanoma to either lung or lymph node increased the incidence of lymph node metastases. Cells derived from pulmonary and lymph node metastases were assayed for their ability to adhere to cryostat sections of lung and lymph node and respond to target organ-conditioned media in serum-free conditions. Both cell types were four times more adherent to lymph node than lung, and consistently attached to the hilar and subcapsular sinuses. Attachment of cells derived from pulmonary metastases to either tissue was threefold greater than that of cells derived from nodal metastases. Lung-conditioned media stimulated proliferation of both cell types, and transiently induced differentiated morphology in cells derived from lymph node metastases, but not in cells from pulmonary metastases. Neither effect was found in lymph-node-conditioned medium. These results suggest that cells metastasize to lymph nodes preferentially not because of a specific predilection for lymph node, but because it is an easy site to colonize. Adhesive interactions in the lymph node rather than trophic ones appear to account for this effect. Cells metastatic to lymph node may be less "malignant" than cells metastatic to visceral sites because less has been required for them to succeed as a metastatic focus.

Search for anti-metastatic therapy: effects of phenytoin on B16 melanoma metastasis.

The ability to metastasize requires that tumor cells be able to degrade matrix. Nontoxic compounds that inhibit matrix digestion might be useful as anti-metastatic agents. We have investigated whether phenytoin, a drug commonly used in clinical practice that inhibits the production of collagenase by some cells, inhibits metastases in a standard animal model of metastasis: In vitro, phenytoin inhibited the proliferative response of B16 F10 melanoma cells to serum-containing media (75% inhibition at 25 micrograms/ml) but had no effect on their ability to degrade a type I collagen gel (1-100 micrograms/ml). Treatment of these cells with phenytoin prior to inoculation in vivo did not inhibit tumor growth, implantation in a surgical wound, or incidence of spontaneous metastases from a primary tumor growing in the foot. Pretreatment of mice with phenytoin (15, 40, and 75 mg/kg/day) diminished pulmonary metastases following tail vein injection in a minimal but dose dependent fashion; mean number of pulmonary colonies 4.6 +/- 3.1 (75/mg/kg/day) vs. 10.2 +/- 9.9 (control). However, tumor growth, implantation, and spontaneous metastases were not inhibited by pretreating the mice with the same doses of phenytoin. It is concluded that phenytoin has an insignificant inhibitory effect on tumor growth and metastasis.

A proposed cause for the hepatic dysfunction associated with parenteral nutrition.

Total parenteral nutrition (TPN) is associated with cholestasis and hepatic steatosis, which can be lethal in infants who cannot be fed orally. It was determined that route of administration was not the critical variable in the development of hepatic steatosis. Two groups of young rats received equivalent amounts of a standard TPN solution either orally or intravenously for an 8- to 10-day period during which they received no other nutrition. Both groups gained equivalent weight and developed marked hepatic steatosis. To test whether the solution was toxic or deficient, three groups of rats were given TPN solution orally and a fraction of their usual daily intake of rat chow. Rats receiving less than 10% of their usual chow intake developed steatosis; rats receiving more than that did not. To determine the solubility of the protective material in chow, two groups of rats were given TPN solution orally and chow that been extracted with either water or the organic solvent chloroform. Rats eating the water-extracted chow developed steatosis, rats eating chloroform-extracted chow did not. Although the protective component in chow was apparently water soluble, addition of a water soluble extract of chow to the TPN solution fed another two groups of rats did not prevent steatosis at 0.1 mg/mL and only partially, if at all, at 10 mg/mL. TPN-related hepatic dysfunction, as measured by the development of hepatic steatosis in this model, may be due to a deficiency in the TPN solution. The missing constituent(s) appears to be present in rat chow and can be extracted with water, but not with an organic solvent.

Heparin-mediated release of fibroblast growth factor-like activity into the circulation of rabbits.

Fibroblast growth factors (FGFs) are a family of structurally related proteins that influence the growth and differentiation of a variety of cell types, including the cells of the vascular system. Due to the lack of signal sequence, basic FGF is not actively secreted. However, it has been detected in the extracellular matrix bound, at least in some cases, via heparin-like molecules. Heparin has been shown to displace FGF from cells and matrices in vitro, and we have investigated the possibility that a similar phenomenon might occur in vivo. Heparin was infused intravenously into anesthesized rabbits; plasma samples taken 30 min later and monitored using [3H]thymidine incorporation into BALB/c 3T3 cells were found to contain 3-fold more stimulatory activity than control plasma samples. Addition of heparin directly to the 3T3 cells or to the plasma samples following their collection did not affect the level of stimulatory activity. A time course of stimulatory activity in rabbit plasma following heparin administration revealed that 3T3 cell stimulatory activity rapidly increased following heparin infusion, peaked at 30 min, and declined to control levels by 90-120 min. The anticoagulant action of heparin followed a different time course, providing evidence that these two effects of heparin are functionally distinct. The binding affinity of the plasma-derived stimulatory activity for heparin was used to demonstrate that the activity is FGF-like in nature. Additionally, administration of [125I]bFGF to rabbits that had been "precleared" by heparin infusion resulted in an immediate peak of circulating labeled bFGF that decreased to plateau level by 20-45 min following injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of tumor-cell attachment to extracellular matrix as a method for preventing tumor recurrence in a surgical wound.

Studies with four different transplantable murine tumors demonstrated that surgical instruments contaminated by contact with a tumor mass could produce tumors in a surgical wound. Eighty-seven per cent of mice with wounds made by invisibly contaminated scissors developed tumors. Irrigation with water did not prevent tumor growth. Before spilled tumor cells can invade and grow into a recurrence in the wound site, they must first attach to underlying extracellular matrix. We have devised a simple in vitro assay to identify inhibitors of tumor-cell attachment to develop therapeutic compounds that can prevent tumor-cell reimplantation. Various test compounds, including proteases (trypsin and Dispase), known modulators of matrix metabolism (proline analogues, cycloheximide, heparin, cortisone, cortexolone, and heparin-steroid combinations), large molecular weight polymers (agarose, dextran, polyethylene oxide), and synthetic fibronectin peptides were tested for their ability to inhibit mouse melanoma (B16-F10) cell attachment to gelatinized dishes. Most of these compounds had little or no effect on tumor-cell adhesion when cells were plated in serum-containing medium. However we identified three compounds that inhibited tumor-cell attachment in a reversible fashion: (1) a specific inhibitor of collagen deposition (L-azetidine-2-carboxylic acid); (2) a bacterial neutral protease (Dispase); and (3) synthetic fibronectin peptides that contained the arginine-glycine-asparate (RGD) sequence that is responsible for cell binding. Dispase and the RGD-containing peptides also inhibited cell implantation and prevented tumor formation in a surgical wound. We propose that inhibitors of attachment might be used either alone or with other biologic modifiers to prohibit implantation of free tumor cells at the time of surgery and thus, to prevent local tumor recurrence.

The fate of intravenously administered bFGF and the effect of heparin.

The fate and effects of intravascular bFGF are unknown. We have investigated the fate of bFGF administered intravenously to rats in the presence and absence of heparin, and evaluated the effect of a 3-day IV infusion of bFGF on proliferation of endothelial and vascular smooth muscle cells in situ. [125I]bFGF, administered as an IV bolus, was rapidly cleared from the circulation (t1/2 = 1.5 min) by the liver. Nevertheless, it was maintained at a constant, predictable concentration in the blood (9.7 +/- 4% of the amount infused) by continuous IV infusion. Heparin consistently altered the pattern: slowing the rate of clearance (t1/2 = 4.5 min), increasing the plateau concentration in the blood during continuous infusion (32.5 +/- 14.3% of the amount infused), and allowing intact (as determined by gel analysis) bFGF to cross from the circulation into the urine. A 3-day infusion of bFGF alone (2.5 ng/kg/min) and with adenosine (11.6 microM/kg/hr) did not increase [3H]thymidine incorporation in either endothelial cells or vascular smooth muscle cells, suggesting that they are refractory to this factor when it is administered intravascularly.

Perforation of gastric squamous carcinoma metachronous to laryngeal carcinoma: metastatic in origin?

The local and regional spread of squamous cancer of the head and neck is well described. We report a possible unusual pattern of spread from a primary laryngeal carcinoma, which presented as gastric perforation.