Cholangiocarcinoma: advocate an aggressive operative approach with adjuvant chemotherapy.

Cholangiocarcinoma presents many challenges. Prognosis is thought to be determined by conventional predictors of survival; margin status, pathologic criteria, stage, and comorbid disease. Ninety-four patients, 57 males and 37 females, underwent resections for cholangiocarcinoma between 1989 and 2000. Thirty-two patients (34%) had distal tumors, 10 had midduct lesions, and 52 had proximal/intrahepatic lesions. Thirty-four patients underwent pancreaticoduodenectomies, 23 bile duct resections alone, and 37 bile duct and concomitant hepatic resections. Tumor location did not influence mean survival (distal, 28 months +/- 23; midduct, 28 months +/- 21; and proximal, 31 months +/- 36). Operation undertaken did not alter survival (bile duct resection, 30 months +/- 37; pancreaticoduodenectomy, 27 months +/- 23; and concomitant bile duct/hepatic resection, 32 months +/- 32). TNM stage failed to predict survival: 5 stage I (29 months +/- 22), 12 stage II (41 months +/- 33), 12 stage III (33 months +/- 19), and 64 stage IV (27 months +/- 32). Tumor size did not influence survival: T1-2 (32 months +/- 33) versus T3-4 lesions (29 months +/- 25). Mean survival with negative margin (n = 67) was 34 months +/- 33, whereas microscopically positive (n = 13, 23.9 months +/- 25) or grossly positive (n = 14, 20.4 months +/- 20) margins were predictive of significantly shorter survival (P < 0.03). Adjuvant treatment (n = 41) was associated with significantly longer survival (40.5 months +/- 36) than those who received no further therapy (n = 53; 24 months +/- 24) (P = 0.05). TNM stage, tumor size, operation undertaken, and location were not associated with duration of survival after resection. Margin status was associated with duration of survival, though extended survival is possible even with positive margins. Advanced stage should not preclude aggressive resection. Without specific contraindications, an aggressive operative approach is advocated followed by adjuvant therapy.

Location, not staging, of cholangiocarcinoma determines the role for adjuvant chemoradiation therapy.

The role of adjuvant chemoradiation therapy (CT/XRT) in the treatment of cholangiocarcinoma is controversial. We undertook this study to determine whether CT/XRT is appropriate after resection of cholangiocarcinomas. One hundred ninety-two patients with cholangiocarcinomas were treated from 1988 to 1999. After resection, patients were assigned a stage (TNM) and were stratified by location of the tumor as intrahepatic, perihilar, and distal tumors. Data are presented as mean +/- standard deviation. Of 192 patients 92 (48%) underwent resections of cholangiocarcinomas. Thirty-four patients had liver resections, 25 had bile duct resections, and 33 underwent pancreaticoduodenectomies. Thirty-four patients had adjuvant CT/XRT, three had adjuvant chemotherapy, four had neoadjuvant CT/XRT, and 50 had no radiation or chemotherapy. Mean survival of resected patients with adjuvant CT/XRT was 42 +/- 37.0 months and without CT/XRT it was 29 24.5 months (P = 0.07). Mean survival of patients with distal tumors receiving or not receiving CT/XRT was 41 +/- 21.8 versus 25 +/- 20.1 months, respectively, (P = 0.04). Adjuvant chemoradiation improves survival after resection for cholangiocarcinoma (P = 0.07) particularly in patients undergoing resection for distal tumors (P = 0.04). Benefits of adjuvant CT/XRT are apparent when stratified by location of cholangiocarcinomas rather than staging.

Local excision of T2 and T3 rectal cancers after downstaging chemoradiation.

OBJECTIVE: To evaluate the safety and efficacy of local excision in patients with T2 and T3 distal rectal cancers that have been downstaged by preoperative chemoradiation. SUMMARY BACKGROUND DATA: T2 and T3 cancers treated by local excision alone are associated with unacceptably high recurrence rates. The authors hypothesized that preoperative chemoradiation might downstage both T2 and T3 lesions and significantly expand the indications for local excision. METHODS: Local excision was performed after preoperative chemoradiation on patients with a complete clinical response or on patients who were either ineligible for or refused to undergo abdominoperineal resection. Local excision was approached transanally by removing full-thickness rectal wall and the underlying mesorectum. RESULTS: From 1994 to 2000, 95 patients with rectal cancers underwent preoperative chemoradiation and surgical resection for curative intent. Of these, 26 patients (28%), 19 men and 7 women, with a mean age of 63 years (range 44-90), underwent local excision. Pretreatment endoscopic ultrasound classifications included 5 T2N0, 13 T3N0, 7 T3N1, and 1 not done. Pathologic partial and complete responses were achieved in 9 of 26 (35%) and 17 of 26 (65%) patients, respectively. Two of nine partial responders underwent immediate abdominoperineal resection. The mean follow-up was 24 months (median 19, range 6-77). The only recurrence was in a patient who refused to undergo abdominoperineal resection after a partial response. There was one postoperative death from a stroke. This treatment was associated with a low rate of complications. CONCLUSION: Local excision appears to be an effective alternative treatment to radical surgical resection for a highly select subset of patients with T2 and T3 adenocarcinomas of the distal rectum who show a complete pathologic response to preoperative chemoradiation.

Factors affecting morbidity, mortality, and survival in patients undergoing Ivor Lewis esophagogastrectomy.

OBJECTIVES: To examine the safety of transthoracic esophagogastrectomy (TTE) in a multidisciplinary cancer center and to determine which clinical parameters influenced survival and the rates of death and complications. SUMMARY BACKGROUND DATA: Although the incidence of cancer at the gastroesophageal junction has been rising rapidly in the United States, controversy still exists about the safety of surgical procedures designed to remove the distal esophagus and proximal stomach. Alternatives to TTE have been proposed because of the reportedly high rates of death and complications associated with the procedure. METHODS: Data from 143 patients treated by TTE by one author (1989-1999) were entered into a computerized database. Preoperative clinical parameters were tested for effect on death, complications, and survival. RESULTS: The patient population consisted of 127 men and 16 women. One hundred twenty-one patients had a history of tobacco abuse, and 118 reported the regular ingestion of alcohol. One hundred fifteen patients had adenocarcinoma, 16 had squamous cell cancer, 6 had another form of esophageal tumor, and 6 had high-grade dysplasia associated with Barrett epithelia. Fifty-six patients had adenocarcinomas arising in Barrett epithelium. Twenty-eight patients were treated with neoadjuvant chemoradiation before surgery. Three patients died within 30 days of surgery (mortality rate 2.1%). Five patients (3.5%) had a documented anastomotic leak; three died). Overall, 42 patients had complications (29%). Twenty-six had pulmonary complications (19%). The mean length of stay in the intensive care unit was 3.35 days; the mean hospital length of stay was 13.54 days. The overall 3-year survival rate was 29.6%. CONCLUSIONS: A high ASA score and the development of complications predicted an increased length of stay. The presence of diabetes predicted the development of complication and an increased length of stay. None of the other parameters tested predicted perioperative death or complications. Only disease stage, diabetes, and blood transfusion affected overall survival. From these results with a large series of patients with gastroesophageal junction cancers, TTE can be performed with a low death rate (2.1%), a low leak rate (3. 5%), and an acceptable complication rate (29%).

Captopril-associated cholestasis complicating the management of pancreatic cancer.

Cholestatic jaundice is a rare complication associated with the use of the angiotensin -converting enzyme inhibitor captopril. The severity of the disease may range from cholestasis on liver histology to overt fulminant hepatic failure. This diagnosis is seldom considered in patients with pancreatic or biliary tract malignancy. We present a patient with unresectable adenocarcinoma of the pancreas whose jaundice decreased slowly over many weeks despite establishment of adequate endoscopic biliary drainage. The presence of captopril-associated cholestasis confounded confirmation of adequate biliary drainage. The absence of observed hepatic bile secretion at duodenoscopy, as seen in this patient, is a previously unreported endoscopic feature of this syndrome.

Expression of insulin-like growth factor-1 receptor in human colorectal cancer.

The activation of the insulinlike growth factor 1/IGF-1 receptor system (IGF1/IGF1-R) has recently emerged as critical event in transformation and tumorigenicity of several murine and human tumors. Expression of IGF1 and of IGF1-R has been demonstrated in normal and neoplastic intestinal cell lines of rats and humans. However, the modulation of IGF1-R expression during the progression from normal colonic mucosa to adenoma, to carcinoma, and to metastasis, has not been evaluated. In this retrospective study, we investigated the expression of IGF1-R in 12 colonic adenomas (AD), 36 primary colorectal adenocarcinomas (CA), and in 27 corresponding metastases (MT). Normal colonic mucosa (N) was adjacent to the CA in 34 cases. Formalin-fixed, paraffin-embedded tissues of each case were immunostained using the avidin-biotin-peroxidase method. We used an anti-IGF1-R rabbit polyclonal antibody (Santa Cruz Biotechnology, CA; dilution 1:100). Positive staining was quantitated by CAS-200. Moderate to strong cytoplasmic immunostaining was observed in 34 of 36 CA (96%), and in 25 of 27 MT (93%). In all of the positive MTs, the intensity of the staining was always strong. In 10 of 12 ADs (83%), only a faint cytoplasmic stain was identified. Normal mucosa when present was negative. Strong IGF1-R positivity correlated with higher grade and higher-stage tumors (P < .01). These data suggest a role of IGF1-R expression during the progression of colorectal adenoma to carcinoma. An increased number of IGF1-R receptors may favor the metastasis of colorectal cancer.

Significance of Fas and retinoblastoma protein expression during the progression of Barrett's metaplasia to adenocarcinoma.

BACKGROUND: Barrett's esophagus (BE) is a premalignant lesion characterized by replacement of normal squamous epithelium with columnar epithelium. This lesion can progress to dysplasia and adenocarcinoma. Recently, the Fas receptor and retinoblastoma (Rb) protein have been described as important mediators of apoptosis and tumor suppression, respectively. This study was undertaken to examine their expression during the progression of metaplasia to adenocarcinoma in BE. METHODS: In a review of 56 adenocarcinomas arising in BE, the specimen blocks were examined using the immunohistochemical avidin-biotin-peroxidase complex technique. For each specimen, areas of normal epithelium were compared with areas of metaplasia, dysplasia, or carcinoma (when present). Monoclonal mouse anti-human antibodies were used to identify Rb protein (Rb-Ab5, 1/50 dilution; Oncogene Science) and the 40-50-kDa cell membrane Fas protein (APO-1/Fas, 1/5 dilution; DAKO Corp.). RESULTS: Loss of Rb staining was observed as the metaplasia progressed to dysplasia and carcinoma, indicating accumulation of unstainable aberrant protein. Conversely, Fas protein staining was undetectable or weak in normal or metaplastic epithelium, increasing in the areas of high-grade dysplasia and carcinoma. These differences were statistically significant (P < .001). CONCLUSIONS: The accumulation of abnormal Rb protein during the progression of Barrett's metaplasia to carcinoma leads to unsuppressed tumor growth. Fas overexpression may represent a cellular attempt to balance the uncontrolled tumor proliferation by promoting apoptosis.

Electrically enhanced drug delivery for the treatment of soft tissue sarcoma.

BACKGROUND: Pulsed electric fields have been shown to increase the effectiveness of antineoplastic agents by temporarily increasing the permeability of cell membranes. This type of drug delivery is called electrochemotherapy, and it has been successful in the treatment of patients with cutaneous malignancies in clinical trials. This study focused on determining the applicability of electrochemotherapy to the treatment of soft tissue sarcoma, using an animal model bearing human sarcomas. The antitumor effects of single and multiple electrochemotherapy treatments were investigated using small (250 mm3) and large (4000 mm3) tumors. METHODS: Established tumors were injected with bleomycin, then electric pulses were administered to the tumor site. Animals were followed based on periodic tumor volume determinations, which were used to categorize treatment of each tumor as a complete response, a partial response, stable disease, or progressive disease. Histologic analysis was used to confirm response data. RESULTS: Animals were randomly assigned to one of four different treatment groups. These groups received no treatment, drug only, electric pulses only, or drug combined with electric pulses. A single electrochemotherapy treatment protocol for small tumors resulted in a 100% complete response rate and a 41.7% cure rate. Multiple treatments of small and large tumors resulted in complete response rates of 83.3% and 100%, respectively. These responses were identical to the cure rates. In contrast, tumors in the groups that received no treatment, electric pulses only, and drug only progressed for both single treatment and multiple treatment scenarios, regardless of tumor size. CONCLUSIONS: In this study, a single electrochemotherapy treatment had a strong cytoreductive effect on small tumors that lasted approximately 35 days, until recurrences began. Multiple treatment of small and large tumors resulted in high complete response rates that lasted at least 100 days after treatment. This indicates the feasibility of electrochemotherapy as a modality of limb-preserving treatment for patients with sarcoma of the extremities.

Analysis of p53, p21WAF1, and TGF-beta1 in human ductal adenocarcinoma of the pancreas: TGF-beta1 protein expression predicts longer survival.

Loss of p53 and p21WAF1 expression have previously been reported in pancreatic adenocarcinoma. Despite these findings in several reports of oncogene and tumor suppressor gene alterations in pancreatic cancer, the clinical significance of these changes is still poorly understood. In an attempt to detect molecular prognostic markers for pancreatic carcinoma, we studied the immunohistochemical expression of p53, p21WAF1, and TGF-beta1 proteins in 42 pancreatic adenocarcinomas of the ductal type. The results were correlated with clinicopathologic findings to identify the markers with prognostic significance. p53 nuclear immunoreactivity was seen in 20 (48%) of the cases, and it was strong to moderate in 14 (33%) of them. p21WAF1 cytoplasmic positivity was found in 16 (38%) of the tumors, with 72% staining strong to moderate. TGF-beta1 stained the cytoplasm of the tumor cells in 13 (31%). Of the p53-negative cases, 12 (54%) exhibited p21WAF1 expression. In 3 (30%) of cases, TGF-beta1 reactivity was seen in the absence of p53 and p21WAF1 p53 positivity identified tumors of higher grade, but did not correlate with stage or survival. TGF-beta1 expression, however, identified low-grade tumors and patients with longer survival. No correlation was found between the expression of any of these molecular markers and smoking history. We report a significant correlation between TGF-beta1 reactivity and low-grade tumors and between TGF-beta1 and better survival. This is a novel finding pointing to TGF-beta1 as a possible new stage-independent predictor of tumor survival in pancreatic ductal adenocarcinoma. In agreement with others, we also found p53 mutation in 20 (48%) of the tumors.

Biliary glycoprotein is overexpressed in human colon cancer cells with high metastatic potential.

Carcinoembryonic antigen (CEA) has been recently implicated in the process of human colon cancer liver metastasis by means of an adhesion mechanism. Based on the strong sequence and structural homology of biliary glycoprotein (BGP) to CEA, we hypothesized that BGP might be overexpressed at the RNA and protein level in tumor cells with high metastatic potential. We have found the BGP messenger RNA derived from highly metastatic colon cancer cells is constitutively overexpressed-nearly fourfold greater than poorly metastatic cells-and that BGP expression is induced by interferon-gamma. Similarly, we have demonstrated that BGP protein levels were constitutively elevated in highly metastatic human colon cancer cells when compared to poorly metastatic cells. Collectively these results suggest that the basal and interferon-stimulated expression of BGP transcripts may be regulated in a manner similar to CEA and that a potential role in the process of metastasis may be inferred.

Role of computed tomographic arterial portography and intraoperative ultrasound in the evaluation of patients for resectability of hepatic lesions.

Computed tomographic arterial portography (CTAP) has been shown to be the most sensitive preoperative test for determining resectability of hepatic lesions but we have shown it to have low specificity. Intraoperative ultrasound (IOUS) evaluation of the liver has also been proposed as an accurate means of assessing resectability. We sought to compare the effectiveness of the two modalities. Fifty-six patients who had been deemed candidates for liver resection based on CTAP findings underwent systematic exploration, liver mobilization, and IOUS examination. Ultrasound findings were compared with results of CTAP. In 46 patients the IOUS findings were in complete agreement with those of CTAP. In 10 patients CTAP lesions could not be verified by IOUS and these patients did not undergo resection. Follow-up of these 10 patients revealed eight who did not have progression of malignancy at the CTAP-predicted site (CTAP false positive). Two patients did have progression at a CTAP-positive IOUS-negative site (IOUS false negative). Sensitivity for CTAP and IOUS was 100% and 96%, respectively. Specificity for IOUS was 100%. These findings demonstrate the high sensitivity of CTAP and the high sensitivity and specificity of IOUS. CTAP may "overcall" hepatic lesions but IOUS can correctly identify these false positives in most instances. Because CTAP is useful for determining which patients might benefit from surgical exploration, we conclude that the two modalities are complementary for the assessment of resectability of hepatic lesions. The false positive rate for CTAP implies that caution must be used when declining to operate on patients on the basis of this test.

Augmentation of carcinoembryonic antigen release from intact, viable tumor cells by a factor in human serum.

BACKGROUND: Measurement of carcinoembryonic antigen (CEA) levels in human serum is frequently used to detect tumor recurrence in patients with resected primary colorectal cancers. These levels are highly variable from patient to patient, and the mechanism that determines these levels is still poorly understood. METHODS: Using a 6-h in vitro CEA-release assay, we determined that a factor in human and fetal bovine sera significantly augments the release of CEA from the tumor cell surface into cell culture supernatants. RESULTS: As little as 1% serum admixed with tumor cells results in CEA release up to 200% greater than that of serum-free controls. It is not inhibited by 1,10-phenanthroline or heat inactivation (of serum) but is calcium dependent. The electrophoretic mobility and membrane linkage of CEA released by serum appear to be identical to those of CEA released by bacterial phospholipase C. Because bacterial phospholipase C is known specifically to cleave the phosphoinositol (PI) glycan moiety that anchors CEA to the tumor cell surface, a mechanism of action for serum cleaving this anchor is suggested. CONCLUSIONS: The large range of CEA levels observed in patients with colorectal cancers may be related to differential sensitivity of the CEA membrane anchor to the CEA-releasing factor in serum.

Molecular basis for chemoprevention of colorectal carcinogenesis.

Colorectal cancer is a common disease that frequently produces limited survival in afflicted patients. Recently a genetic model for tumorigenesis has been defined and has led to a better understanding of the interrelationships between environmental mutagens and genes. Epidemiologic studies have identified multiple chemopreventive agents that appear to reduce the risk of developing colorectal cancer. Their molecular mechanisms of action, as related to the genetic model for colorectal cancer, are discussed.

Validity of major cancer operations in elderly patients.

BACKGROUND: As the population ages, more elderly individuals will be at risk for the development of gastrointestinal malignancies traditionally treated with radical operation. In the past, many major cancer operations were reserved for patients < 65 or 70 years of age, but as the life expectancy for a 70-year-old has improved, this policy has been questioned. METHODS: We examined the records of 124 consecutive patients who underwent one of three major operations (esophagogastrectomy, major liver resection, pancreatoduodenectomy) for gastrointestinal cancer during the past 6 years to determine if preoperative risk factors, operative mortality, length of stay, length of procedure, estimated blood loss, rate of major complication, or Kaplan-Meier survival was different for patients > or = 70 years of age as compared with younger patients. RESULTS: For patients at our institution undergoing esophagogastrectomy, major liver resection, or pancreatoduodenectomy, we found no significant difference in any of the parameters measured. There was no significant difference in any parameter when comparing patients > or = 70 versus < 70 years of age. CONCLUSIONS: We conclude that patients > or = 70 years of age are not necessarily less suitable candidates for major cancer operations than are those < 70 years of age if other risk factors are acceptable. Elderly patients should be included in clinical trials.

Phospholipase C-gamma 1 is present on the surface of human colorectal cancer cells.

Using murine monoclonal antibodies, we have detected the novel signal transducing enzyme, phospholipase C-gamma 1, on the surface of cultured human colorectal cancer cells. We have also demonstrated the presence of this enzyme on the surface of fresh human tumor cells derived from primary and metastatic colorectal tumors. This enzyme has previously been described to be associated only with the inner face of the plasma membrane and the cell cytosol. The finding of an enzyme critical to the signal transduction pathway may have important implications for additional functions of this protein.

Laparoscopic management of cystic disease of the liver.

Laparoscopic surgical procedures are increasing in scope and in variety. The benefits of decreased wound morbidity and pain have been well documented for multiple procedures that have traditionally required laparotomy. Although there are few controlled studies to document them, these benefits may be evident from simple clinical observation. Cystic disease of the liver is a condition that is treated largely for symptomatic reasons. The so-called noninvasive or radiographic guided methods of treatment for cystic disease of the liver are fraught with high recurrence rates. We present four cases of cystic disease of the liver treated laparoscopically, followed with pertinent discussion.

Urological aspects of hemicorporectomy.

The indications for hemicorporectomy are few. However, with improvements in surgical techniques, anaesthesia and post-operative surgical care, hemicorporectomy may again become a reasonable treatment for certain patients with malignancies of the pelvis. A 2-stage procedure is described which consists of an initial staging celiotomy with urinary and faecal diversions. A non-refluxing colon conduit is the preferred form of urinary diversion. The hemicorporectomy is performed approximately 2 weeks later. No complications were encountered in the post-operative period. Our experience and a review of the literature suggest that hemicorporectomy is a reasonable salvage procedure for certain patients with pelvic malignancies.

Preoperative evaluation of patients for liver resection. Appropriate CT imaging.

OBJECTIVE: The authors determined which combination of computed tomography scans is most helpful for preoperative assessment of patients with liver tumors. SUMMARY BACKGROUND DATA: Multi-institutional studies have shown that the most important prognostic factors for selection of patients with metastatic colorectal cancer considered for liver resection are: Dukes' stage of primary tumor, the number of hepatic metastases if greater than 3, the presence of extrahepatic cancer, and the ability to resect tumors with an adequate margin (> 1 cm.) Therefore the ability to predict the presence of extrahepatic disease and the number and location of hepatic tumors are important in these patients. METHODS: One hundred and nine consecutive patients with evidence of hepatic tumors were evaluated by computed tomography with arterial portography (CTAP) and abdominal computed tomography after a 4-hour delay (CT-D). Results of these studies and conventional computed tomography (CT-C) were compared with findings at operation. RESULTS: CTAP proved to be the most sensitive test for assessing distribution of intrahepatic disease. CT-D was no more sensitive than CT-C for the detection of hepatic or extrahepatic disease. CONCLUSIONS: CT-C in concert with CTAP provides the most reasonable CT evaluation of patients considered for operation for the treatment of hepatic tumors.