The role of faecal diversion in low rectal cancer: a review of 1791 patients having rectal resection with anastomosis for cancer, with and without a proximal stoma.

AIM: The morbidity of anastomotic dehiscence may be mitigated by a defunctioning stoma, but it is unclear if it is required for most low rectal anastomoses. Preoperative risk factors leading to anastomotic complications and the indications for faecal diversion have yet to be clearly defined. METHOD: Using the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) participant-use file, patients were identified who underwent low anterior resection with anastomosis for cancer at the 211 participating hospitals in 2005-08. RESULTS: A total of 1791 patients underwent low anterior resection. Patients were subdivided into two groups based on the level of the anastomosis. Of these 1266 patients had a low pelvic anastomosis (LPA) and 525 a coloanal anastomosis (CAA). In the LPA group, 606 patients had a stoma and 660 had no stoma. There were no differences in wound complications, sepsis or septic shock. Patients who had a stoma were more likely to have postoperative acute renal failure (1.7 vs 0.5%, P = 0.0485, OR 3.674). In the CAA group, 352 had a stoma and 173 had no stoma. In patients without faecal diversion, there was a significantly greater incidence of sepsis (8.7 vs 3.7%, P = 0.022, OR 2.47), septic shock (3.5 vs 0.57%, P = 0.018, OR 6.29) and need for reoperation (11 vs 1.7%, P = 0.0001, OR 7.11). Hospital length of stay was significantly longer with CAA and no stoma. On multivariate analysis, not having a stoma with a CAA was a risk factor for serious postoperative morbidity. CONCLUSION: While a defunctioning stoma with a coloanal anastomosis seems to protect from postoperative sepsis, septic shock and need for reoperation, it is likely that it is overused in rectal cancer surgery.

The nuclear tyrosine kinase Rak associates with the retinoblastoma protein pRb.

Rak is a nuclear tyrosine kinase containing Src homology 2 and 3 domains at its NH2 terminus. We report here that the retinoblastoma tumor susceptibility gene product pRb associates with Rak in vivo and in vitro. Rak binds in the A/B pocket region of pRb, a region that is frequently mutated in human cancer, during the G1 and S phases of the cell cycle. Furthermore, Rak expression is elevated in G1, and transfection of Rak into NIH 3T3 cells results in a significant decrease in the number of emerging colonies. Thus, Rak is a tyrosine kinase with growth suppressing activity that may function, in part, through its interaction with pRb.

Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors.

The focal adhesion kinase (FAK) gene encodes a tyrosine kinase (p125FAK) thought to be involved in signal transduction pathways used in cell adhesion, motility, and anchorage-independent growth. Because alterations in these cellular processes occur in tumor invasion and metastasis, we studied the protein expression of FAK in a variety of human tumors and found that in the 119 samples studied, increased levels of p125FAK correlated with the invasive potential of a tumor. By comparing FAK expression in tumors with normal tissue from the same patient, we found that p125FAK was significantly elevated in 17 (100%) of 17 invasive and metastatic colonic lesions and in 22 (88%) of 25 invasive and metastatic breast tumors. Additional studies of FAK expression in 13 high grade sarcomas showed high levels in all samples compared to benign, noninvasive mesenchymal specimens. Furthermore, FAK protein levels were elevated in preinvasive lesions, such as large (> 2 cm) colonic villous adenomas, whereas noninvasive, yet hypercellular, neoplastic tissues such as parathyroid and hepatocellular adenomas did not overexpress FAK. These data provide evidence that both epithelial and mesenchymal tumor progression are accompanied by increased p125FAK expression and suggest that the level of FAK expression might be a marker for the invasive potential of a tumor.

Two novel human serine/threonine kinases with homologies to the cell cycle regulating Xenopus MO15, and NIMA kinases: cloning and characterization of their expression pattern.

Using polymerase chain reaction (PCR)-based methods, we have isolated cDNA clones of two new members of serine/threonine kinases, STK1 and STK2, from a cDNA library constructed from the BT-20 human breast cancer cell line. STK1 is transcribed as a 1.4 kilobase (kb) mRNA encoding for a protein of 346 amino acids. Based on amino acid sequence analysis, STK1 is 86% identical to the Xenopus p40mo15, a cdc2-related serine/threonine kinase recently found to be the activating kinase for p34cdc2 and p33cdk2. Thus, STK1 is most likely the human homologue of MO15. An alternatively spliced STK1 message expressed variably in cell lines and in primary carcinomas generates a predicted 58 amino acid protein that lacks the kinase domain. STK2 is transcribed into a 4.0 kb mRNA encoding for an 841 residue protein which exhibits 50% identity in the kinase domain with the mouse nek1 gene product, the relative of the fungal G2-M regulator, nimA. STK1 and STK2 display a variable pattern of expression among a series of primary carcinomas as well as cancer cell lines. Both STK1 and STK2 were expressed at the highest levels in the heart but were also detected in all other organs tested. In embryonal tissues, lower levels of expression were noted. Using cell cycle inhibitors, we have shown that both STK1 and STK2 mRNA levels remain relatively invariant through the cell cycle. Chromosomal assignment has localized STK1 on chromosome 2pcen-2p15, a region implicated in hereditary non-polyposis colorectal carcinoma, and STK2 on chromosome 3p21.1, a region frequently showing chromosomal alterations in renal cells carcinomas.

Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes.

The focal adhesion kinase (FAK) is a protein tyrosine kinase linked to signaling events between cells and the extracellular matrix. Studies at the Western blot level have demonstrated up-regulation of FAK expression in invasive breast and colon cancers. To assess p125FAK expression at the cellular level, we developed monoclonal antibodies that specifically detected FAK in formalin-fixed, paraffin-embedded tissue sections and analyzed the levels of FAK expression in human breast and colon tissues. Monoclonal antibody 4.47 demonstrated FAK-specific focal adhesion staining by immunofluorescence assays on BT-474 breast cancer cells and detected a Mr 125,000 protein by both Western blotting and immunoprecipitation analyses. Using immunohistochemical techniques, the expression of p125FAK was analyzed in 36 normal and 43 preinvasive or invasive human breast and colon tissues from individual patients. FAK was weakly expressed in most benign breast epithelium but was up-regulated at moderate or strong levels in 14 of 18 invasive breast carcinomas. In seven samples of ductal carcinoma-in situ, FAK was overexpressed. Borderline-to-weak expression of FAK was detected in the normal colonic epithelium. In the invasive colon cancers, FAK was overexpressed at moderate or strong levels in 13 of 15 tumors. Furthermore, FAK expression was up-regulated in areas of dysplastic, premalignant colon epithelium. These results provide the first evidence at the cellular level that FAK expression is variably overexpressed in breast and colon cancer and suggest that up-regulation occurs at an early stage of tumorigenesis.

Transplantation of rat insulinoma allografts with cyclosporin A.

Cyclosporin A (CyA), an investigational immunosuppressive drug, was tested for its ability as a single agent to prevent rejection and maintain function of islet cell tumors transplanted across a major histocompatibility barrier. Lewis rats have previously been shown by our group to reject the KX insulinoma in 7 to 10 days. CyA was administered to Lewis rats intraperitoneally for 21 days beginning 1 day before subcutaneous KX insulinoma engraftment. Dosage of 8 and 12 mg/kg/day failed to suppress rejection, as no palpable tumor or blood glucose level changes were observed. A dosage of 17 mg/kg/day allowed full allograft function without serious drug-related side effects in this short-term study. blood glucose levels in the successfully engrafted recipients fell to an average of 43 +/- 13 mg/dl. When CyA treatment was stopped, the insulinoma allografts were rejected within 14 days, suggesting that continued presence of the drug is necessary to maintain immunosuppression. These experimental results suggest that CyA can be administered as a single immunosuppressive agent to prevent early rejection of insulinoma transplanted across a major histocompatibility barrier in the experimental animal.

Expression polymerase chain reaction: a sensitive method for analysis of gene expression in human tumours.

To analyse the expression of individual genes in small tumour samples, we have used the method of RNA polymerase chain reaction (PCR) to develop a technique which we have termed expression PCR. With this technique, specific cDNA sequences of a target gene are amplified, analysed by gel electrophoresis, and semi-quantitated using laser densitometry. Alpha-actin is amplified as a reference gene to control for template RNA and each target gene is analysed at several cycle numbers to optimize PCR dynamics. In this study, we have demonstrated expression PCR by analysing the levels of expression of tyrosine kinase genes in a panel of human tumours. We have compared expression PCR with Northern analysis to show that these techniques provide equivalent information on relative levels of gene transcription, with expression PCR requiring 100-fold less RNA. This technique is sufficiently sensitive to detect and compare the levels of expression of genes not seen on Northern analysis and is ideally suited for analysing the expression of multiple genes within the same portion of a tumour.

Insulinoma: pitfalls in preoperative localization.

In patients with biochemical evidence of insulinoma, many techniques have been advocated as the procedures of choice for diagnostic localization without a clear-cut consensus as to their utility. Despite the small size of insulinomas, 90% are solitary and nearly 100% are intrapancreatic. A commonly held belief is that once the diagnosis of autonomous hyperinsulinism is confirmed, it is necessary to secure as much information as possible about the precise location prior to surgery. Although frequently used, preoperative localization studies are expensive, potentially morbid, and worse yet, may be misleading. We present a case study in which the preoperative studies falsely localized the insulinoma to the pancreatic head. Since the introduction of intraoperative ultrasound (IOUS), it is now unusual not to identify and excise the insulinoma in patients undergoing exploration for functioning beta-islet cell lesions. Our experience, along with support from the literature, led us to recommend a simplified localization approach, namely IOUS combined with surgical palpation.

Molecular mechanisms involved in tumorigenesis and their surgical implications.

Our understanding of normal and malignant cell growth has rapidly advanced in the last two decades as new technologies have accelerated the ability to resolve the underlying molecular mechanisms. The speed and complexity of this advance, as well as the inadequate and confused nomenclature of molecular oncology, has made this field difficult to follow. Nevertheless, many future therapies will be targeted to a genomic level and clinicians will be called upon to communicate with basic scientists in implementing them. To facilitate the surgeon's part in this dialogue, we present a broad review of the molecular genetics of cancer. The selected bibliography contains many review articles by leading researchers in this field. Particular emphasis has been placed on the themes that are emerging, such as oncogenic mechanisms, tumor suppressor genes, signal transduction, the multistage concept of carcinogenesis, and molecular diagnostics and therapies.

Retroperitoneal fibrosis treated with tamoxifen.

Retroperitoneal fibrosis, although histologically benign, has a malignant course due to encasement and compression of tubular retroperitoneal structures, particularly the urinary system. The etiology of this neoplastic process is unclear, but clinical symptoms result from fibroblast proliferation with excessive collagen deposition. Because of the diffuse nature of this disease, surgical resection is technically impossible, and past medical therapies have been inconsistent. Tamoxifen has been shown to be effective in the treatment of desmoid tumors, and we present a patient with retroperitoneal fibrosis who was treated successfully with this anti-estrogen. Because of its minimal side effects and simplicity of dosing, tamoxifen may be a useful treatment in this disease.

Protein kinases in human breast cancer.

The family of protein kinases includes many oncogenes and growth factor receptors, many of which have been linked to the pathogenesis and progression of cancer. Protein tyrosine kinases such as HER-2/c-erbB-2 and the epidermal growth factor receptor (EGFR) have been linked specifically to breast cancer, and perturbations of HER-2 affect response to chemotherapy. We have reviewed the biology of protein kinases in human breast cancer, as well as their translational applications to breast cancer patients. We have studied the spectrum of protein kinases expressed in human breast cancer cells and have identified four protein kinases with potentially important functions in breast cancer: rak (src-related), TK5 (which we now designate JAK3), the focal adhesion kinase (FAK), and STK1 (human M015/CAK). We describe the potential significance of these genes in breast cancer, as well as our methodology for identifying and characterizing novel genes in breast cancer.

The National Cancer Data Base Report on treatment patterns for hepatocellular carcinomas: improved survival of surgically resected patients, 1985-1996.

BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) has previously reported data evaluating time trends in various cancers, including such elements as stage of disease at diagnosis, treatment, and survival for multiple tumor sites. In this report, data collected from 1985, 1986, 1990, 1991, 1995, and 1996 for primary hepatocellular carcinoma (HCC) tumors are presented. METHODS: The data presented in this review were collected from hospital cancer registries from across the U.S. Eight calls for data have yielded a total 6.9 million cases for the years 1985-1996, including 1158 HCC cases in 1985-1986, 3319 cases in 1990-1991, and 5683 cases in 1994-1995 from hospital cancer registries across the U. S. These data represent approximately 4.3%, 11.2%, and 14.8% of the estimated cases of carcinomas of the liver and biliary tract diagnosed in the U.S. in each of the three respective time periods. RESULTS: The outcome for patients diagnosed with HCC remains poor, with only 10% of patients with American Joint Committee on Cancer Stage I disease surviving 5 years. Approximately 50% of patients received no therapy for their HCC, even those with early stage disease. Over these three time periods, the use of chemotherapy appears to have decreased. Among patients diagnosed with Stage II and III disease a difference in survival was noted between those treated with surgery only and those treated with chemotherapy only. Women appear to have a limited survival advantage over men. CONCLUSIONS: In spite of an overall poor prognosis, subsets of patients with HCC appear to benefit from surgical resection/ablation of their tumor. The decreasing use of chemotherapy and the early reports of newer ablative techniques (e.g., cryotherapy) suggest that other treatment modalities are emerging. These NCDB data provide a baseline for HCC treatment from which prospective studies are being developed to assess the newer treatments as well as the underlying causes.

Expression of focal adhesion kinase gene and invasive cancer.

The focal adhesion kinase (FAK) gene produces a tyrosine kinase that localises to contact points between cells and extracellular matrix. It is believed to be an important signal molecule in cell adhesion. We have isolated a human homologue of the FAK gene from primary sarcomas and looked for FAK mRNA in 49 human tissue samples, including paired normal and neoplastic samples. We found increased levels of FAK in 1 of 8 adenomatous tissues, in 17 of 20 invasive tumours, and in all 15 metastatic tumours. There was no detectable FAK mRNA in 6 normal tissue samples. These observations suggest that FAK overexpression may accompany changes in signal pathways involved in tumour cell invasion.

Novel protein kinases expressed in human breast cancer.

The family of protein kinases includes many oncogenes and growth-factor receptors, as well as genes that are involved in cell-cycle regulation. We have identified protein kinases expressed in a human breast-cancer cell line, 600PEI, and a primary human breast carcinoma, using PCR cloning techniques based on consensus sequences in the kinase domain. Twenty-five different protein kinases were isolated, including 3 novel putative tyrosine kinases (designated TK1, TK2, and TK5), and 2 novel putative cell-cycle-associated serine/threonine kinases (designated STK1 and STK2). TK1 is a new member of the src family of kinases that is expressed predominantly in epithelial cells. TK2 is homologous to the receptor kinase, HEK, and TK5 appears to be another member of the JAK family of kinases. The novel serine/threonine kinases, designated STK1 and STK2, were homologous to the human cdc2 and the Aspergillus nimA genes. We subsequently analyzed the levels of expression of all of these protein kinases in a panel of human breast carcinomas, using PCR-based methods. This analysis revealed different expression profiles in different primary breast carcinomas and, therefore, may determine new molecular sub-sets of human breast cancer.

Expression of growth factor receptors, the focal adhesion kinase, and other tyrosine kinases in human soft tissue tumors.

BACKGROUND: The tyrosine kinases are a family of genes that includes many growth factor receptors and protooncogenes. They appear to have a role in many cancers, but have not been systematically studied in the pathogenesis and progression of human sarcomas. METHODS: To characterize the protein tyrosine kinases that are expressed in human sarcomas, we used a polymerase chain reaction (PCR)-based method to construct kinase-specific cDNA libraries from low-grade and high-grade primary tumors. Thereafter, individual tyrosine kinase gene expression was assessed in a panel of sarcoma cell lines and primary tumors using Northern blotting and PCR. RESULTS: We identified 19 species of tyrosine kinase genes, including many growth factor receptors, the human homolog of the focal adhesion kinase (FAK) gene, and a novel trk-related kinase designated HGK2. Messenger RNA expression analyses showed relative overexpression of the two forms of the platelet-derived growth factor receptors (PDGFRs) with expression of the alpha form restricted to a subgroup of high-grad and metastatic sarcomas. We were unable to demonstrate coexpression of the PDGF isoforms in primary tumors that overexpressed the receptors, suggesting that a PDGF/PDGFR autocrine pathway may not be a central mechanism in the malignant transformation of sarcomas in vivo. FAK expression was observed in a variety of sarcomas, with increased levels in several high-grade and metastatic leiomyosarcomas. CONCLUSIONS: When grouped together by histologic cell type and grade, the expression data of the 19 kinases in primary tumors described a greater degree of heterogeneity than is generally appreciated by clinicopathologic classification schemes. This diversity suggests that sarcomas, even those that appear to be clinically similar, arise through a variety of molecular pathways involving tyrosine kinases.

Predictive value of a negative computed tomographic scan in 100 patients with rectal carcinoma.

The predictive value of a negative computed tomographic (CT) scan was assessed in a group of 100 patients with rectal carcinoma by correlating operative findings and pathologic stages in the patients who had no evidence of extrapelvic metastases on a preoperative CT scan. Sixty-four patients (64 percent) had stage T3 or T4 tumors. Ten patients had unsuspected distant metastases for an overall negative predictive value of 90 percent. Seven patients had small liver metastases, and three had periaortic nodal metastases. Six of the patients with liver metastases had them completely resected at the original laparotomy. The predictive value of the CT scan diminished in the patients who were selected to receive full-dose preoperative radiation therapy and had a mean delay of 12 weeks between CT scan and laparotomy. The preoperative carcinoembryonic antigen levels were of no value in predicting the presence of distant metastases. These results show that a negative CT scan will fail to detect 10 percent of patients with small liver metastases or positive periaortic nodes.

Liver metastases: comparison of current MR techniques and spiral CT during arterial portography for detection in 20 surgically staged cases.

PURPOSE: To compare spiral computed tomography during arterial portography (CTAP) with current magnetic resonance (MR) imaging, including hepatic arterial-dominant phase, gadolinium-enhanced, spoiled gradient-echo imaging, for the prospective detection of liver metastases in 20 patients who subsequently underwent surgery to confirm findings. MATERIALS AND METHODS: Twenty patients underwent spiral CTAP and MR imaging within 1 week. Spiral CTAP and MR images were interpreted separately in blinded fashion. All patients subsequently had intraoperative confirmation. Sensitivity, specificity, and positive and negative predictive values were determined for lesion detection and segmental distribution. RESULTS: CTAP and MR images demonstrated, respectively, 54 and 60 true-positive lesions, six and one false-positive lesions, 15 and 22 true-negative (i.e., benign) lesions, and eight and two false-negative lesions. CTAP and MR images demonstrated, respectively, 57 and 62 true-positive segmental involvements, six and one false-positive segmental involvements, 89 and 95 true-negative segmental involvements, and eight and two false-negative segmental involvements. No significant difference in lesion detection was observed. CONCLUSION: Spiral CTAP and MR imaging were approximately equivalent for lesion detection in patients who were evaluated preoperatively for resection of liver metastases. The lower cost and fewer problems with artifacts may suggest that MR imaging is the preferred modality for preoperative assessment of patients for surgical treatment of liver metastases.