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Biomedical subjects

L E Harrison

Publications and source records attributed to L E Harrison.

At least 19 recordsLinked to original sources
PubMed2001

Surgical implications of Helicobacter pylori infection.

Helicobacter pylori infection is the most common cause of peptic ulcer disease and is an etiologic factor in the development of gastric malignancies. Eradication of H. pylori heals most uncomplicated peptic ulcers, as well as preventing their relapse. In addition, H. pylori therapy has recently been used as a first line treatment for most low grade MALT lymphomas. Despite its efficacy, a small percentage of patients with peptic ulcer disease will require operative intervention and the indications for surgical intervention for the patient with peptic ulcer disease include; intractability, gastric outlet obstruction, acute perforation, and bleeding uncontrolled by endoscopic intervention. H. pylori has also been shown to be associated with an increased risk of gastric adenocarcinoma and surgical exploration may play a role in diagnosis, staging and treatment. Finally, the relationship between H. pylori infection and the development of gastric MALT lymphoma is well established. While treatment for H. pylori infection is indicated for low grade MALT lymphomas, surgical resection may be indicated for treatment failures, as well as for certain high grade lesions.

Adenocarcinoma↗
PubMed2001

Tributyrin, an oral butyrate analogue, induces apoptosis through the activation of caspase-3.

The purpose of this study was to investigate the anti-proliferative and pro-apoptotic effects of the butyrate analogues, tributyrin (TB) and phenylbutyrate (PB), in a colon cancer model. We demonstrate that HT-29 colon cancer cells exposed to PB and TB result in growth inhibition associated with an induction of apoptosis mediated through the activation of caspase-3 activity. A block in the G1/S cell cycle traverse associated with a decrease in CDK2 (cyclin dependent kinase) protein levels and retinoblastoma protein hypophosphorylation was also noted after PB and TB exposure. Importantly, TB proved to be the most potent agent in its ability to induce these phenotypic changes, and potentially may represent a novel therapy for patients with advanced colorectal cancer.

Adenocarcinoma↗
PubMed2001

Exploring the complex relationship between adolescent sexual offending and sex chromosome abnormality.

The nature and importance of the relationship between sex chromosome abnormalities (SCAs) and sexual maladaptive behaviour is uncertain. When considering the aetiology of sexual offending behaviour, the importance of sex chromosome disorder lies in its biopsychological manifestations and in its complex interactions with external influences. At the Adolescent Forensic Service, in keeping with previous research in institutional settings, we found a higher pick-up rate of SCAs among sexual offenders (5/121) than would be expected in an unbiased community sample (1.2/1000 male livebirths; Jacobs et al. (1992)). We present descriptive data on five patients with SCAs out of a total of 121 sexual offenders who presented to the Adolescent Forensic Service over a 6-year period. We discuss the biopsychosocial features of these five patients and compare them with the remainder of the sexual offenders in the series. We discuss the advantages of early diagnosis and the need for professional vigilance by adolescent forensic psychiatrists, child and adolescent psychiatrists, paediatricians and clinical geneticists.

Adolescent↗
PubMed2001

Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors.

Cyclin-dependent kinases (cdk's) have recently been suggested to regulate human immunodeficiency virus type 1 (HIV-1) transcription. Previously, we have shown that expression of one cdk inhibitor, p21/Waf1, is abrogated in HIV-1 latently infected cells. Based on this result, we investigated the transcription of HIV-1 in the presence of chemical drugs that specifically inhibited cdk activity and functionally mimicked p21/Waf1 activity. HIV-1 production in virally integrated lymphocytic and monocytic cell lines, such as ACH(2), 8E5, and U1, as well as activated peripheral blood mononuclear cells infected with syncytium-inducing (SI) or non-syncytium-inducing (NSI) HIV-1 strains, were all inhibited by Roscovitine, a purine derivative that reversibly competes for the ATP binding site present in cdk's. The decrease in viral progeny in the HIV-1-infected cells was correlated with a decrease in the transcription of HIV-1 RNAs in cells treated with Roscovitine and not with the non-cdk general cell cycle inhibitors, such as hydroxyurea (G(1)/S blocker) or nocodazole (M-phase blocker). Cyclin A- and E-associated histone H1 kinases, as well as cdk 7 and 9 activities, were all inhibited in the presence of Roscovitine. The 50% inhibitory concentration of Roscovitine on cdk's 9 and 7 was determined to be approximately 0.6 microM. Roscovitine could selectively sensitize HIV-1-infected cells to apoptosis at concentrations that did not impede the growth and proliferation of uninfected cells. Apoptosis induced by Roscovitine was found in both latent and activated infected cells, as evident by Annexin V staining and the cleavage of the PARP protein by caspase-3. More importantly, contrary to many apoptosis-inducing agents, where the apoptosis of HIV-1-infected cells accompanies production and release of infectious HIV-1 viral particles, Roscovitine treatment selectively killed HIV-1-infected cells without virion release. Collectively, our data suggest that cdk's are required for efficient HIV-1 transcription and, therefore, we propose specific cdk inhibitors as potential antiviral agents in the treatment of AIDS.

Cell Line↗
PubMed2000

Prognostic significance of immunohistochemical micrometastases in node negative gastric cancer patients.

BACKGROUND AND OBJECTIVES: The purpose of this study is to examine the prognostic significance of immunohistochemical (IHC) evidence of lymph node (LN) metastases in histologic node negative gastric cancer patients. METHODS: Retrospective review from 1981 to 1998 revealed 25 patients resected for T1-4N0M0 gastric and gastroesophageal (GE) junction adenocarcinoma. All cases were reviewed and histopathologic parameters were defined for each primary tumor. All LNs underwent IHC analysis with the epithelial marker CAM 5.2. Data are reported as median (range). RESULTS: The median number of LN resected was 7 (range 1-33). The median follow-up time was 25 months (range 4-195) with an overall 5-year survival rate of 55%. For patients with IHC evidence of LN micrometastasis (n = 9), the 5-year survival rate was significantly decreased (35%) compared to a 66% 5-year survival rate for IHC negative patients (n = 16, P = 0.05). CONCLUSIONS: The presence of IHC-detected LN micrometastases correlates with worse prognosis for patients with histologic node negative gastric cancer. IHC may be a useful additional staging modality in this subset of patients.

Adult↗
PubMed2000

p53/56(lyn) antisense shifts the 1,25-dihydroxyvitamin D3-induced G1/S block in HL60 cells to S phase.

p53/56(lyn) is a member of the src family that is predominantly expressed in hematopoietic cells and is thought to play a role in cellular proliferation. In this study, we demonstrate the participation of p53/56(lyn) in 1,25-dihydroxyvitamin D(3) (1, 25D(3))-induced growth arrest in HL60 cells. We show that the mRNA and protein levels of p53/56(lyn) are markedly elevated after 1, 25D(3) treatment, which is accompanied by an increase of p53/56(lyn) kinase activity. We also demonstrate that treatment with p53/56(lyn) antisense oligodeoxynucleotides reverses the 1,25D(3)-induced G1/S block, and results in an accumulation of cells with S-phase DNA content. BrdU pulse-chase experiments reveal that this accumulation results from an increased proportion of cells actively synthesizing DNA, which are inhibited from exiting the S-phase compartment. These results indicate that upregulation of p53/56(lyn) contributes significantly to the G1/S growth arrest induced by 1,25D(3) in HL60 cells and thus its activation may be a desirable outcome of chemotherapeutic regimens.

Base Sequence↗
PubMed2000

Changes in E2F binding after phenylbutyrate-induced differentiation of Caco-2 colon cancer cells.

Differentiation agents use existing cellular systems to induce neoplastic cells to regain a normal phenotype and/or to cause growth arrest and therefore may offer novel chemotherapeutic approaches to treating solid tumors. In this study, we demonstrate in Caco-2 colon cancer cells that the differentiation agent phenylbutyrate (PB) causes a decrease in viable cells, an increase in cell differentiation, and a G1-S-phase block. The mechanism of this last effect is related to a PB-induced increase in p27Kip1, leading to a decrease in the activity of cyclin-dependent kinase 2 (CDK2), a positive regulator of the G1-S-phase cell cycle transition. Consistent with the decreased CDK2 kinase activity, we also observed a decrease in the phosphorylation state of the retinoblastoma protein after PB treatment. This was associated with increased binding and consequent inactivation of E2F, a transactivator of genes that regulate the G1 to S phase cell cycle transition. These data suggest that the differentiation agent PB inhibits tumor growth by limiting the availability of active E2F, with a subsequent G1-S-phase block. Additional studies should show whether PB is a clinically effective therapeutic agent against colorectal cancer.

Alkaline Phosphatase↗
PubMed1999

1,25-dihydroxyvitamin D(3)-induced retardation of the G(2)/M traverse is associated with decreased levels of p34(cdc2) in HL60 cells.

Cellular differentiation of neoplastic cells after exposure to 1, 25-dihydroxyvitamin D(3) (1,25 D(3)) is accompanied by altered cell cycle regulation. In previous studies, blocks in both G(1)/S and G(2)/M checkpoints have been observed in 1,25D(3)-treated HL60 cells, but the mechanism of the 1,25D(3)-induced G(2)/M block has not been previously reported. In this study, we show by cell cycle analysis, using bromodeoxyuridine pulse-chase labeling, that the G(2)/M block in 1,25D(3)-treated HL60 cells is incomplete. We also demonstrate that although the 1,25D(3)-treated cells exhibit elevated levels of cyclin B1, Cdc25C, and Cdk7, which are positive regulators of the G(2)/M traverse, these cells have decreased protein levels of p34(cdc2) and decreased p34(cdc2) kinase activity. This provides potential mechanisms for the observed accumulation of cells in the G(2) cell cycle compartment and occasional polyploidization following treatment of HL60 cells with 1,25D(3). The data also suggest that the ability of some cells to traverse this block may be the result of cellular compensatory mechanisms responding to decreased p34(cdc2) activity by increasing the levels of other regulators of the G(2) traverse, such as cyclin B1, Cdc25C, and Cdk7.

Bromodeoxyuridine↗
PubMed1999

Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection.

OBJECTIVE: To identify the pathologic features of prognostic significance in patients with resectable adrenocortical carcinomas. DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Review of the Memorial Sloan-Kettering Cancer Center prospective adrenocortical carcinoma database from 1986 through 1996 identified 46 patients who underwent curative adrenalectomy for primary disease. All cases were reviewed by a single pathologist and each primary tumor was characterized by 16 separate pathologic parameters. MAIN OUTCOME MEASURE: Overall survival rates in the patient population. RESULTS: The 5-year overall survival rate for the entire cohort was 36% (median survival rate, 28 months). Of the pathologic factors analyzed, tumor size, number of mitotic figures, and the presence of intratumoral hemorrhage were independent prognostic factors. Patients presenting with primary tumors larger than 12 cm (n = 30) had a worse outcome compared with those with smaller tumors (n = 16) (5-year survival rate: 53% vs. 22%, P<.05). Mitotic count (> or =6 per 10 high-power fields) was a negative prognostic feature (n = 15) with a 5-year survival rate of 13% vs. 51% for 0 to 6 mitotic figures per 10 highpower fields (n = 31, P<.05). Intratumoral hemorrhage (n = 23) was also a negative prognostic factor compared with no evidence of intratumoral hemorrhage (n = 23) (5-year survival rate, 53% vs. 22%, P<.05). Overall survival rates were also calculated based on the number of pathologic risk factors. Patients with no risk factors had an 83% 5-year survival rate, which decreased to 42% with 1 factor, 33% with 2 factors, and 0% with all 3 risk factors. CONCLUSIONS: Tumor size, hemorrhage, and mitotic count correlate with survival rates for patients undergoing curative resection. Based on these pathologic factors, adrenocortical carcinomas may be divided into low- and high-risk groups.

Adrenal Gland Neoplasms↗
PubMed1999

Differentiation-related changes in the cell cycle traverse.

This review examines recent developments relating to the interface between cell proliferation and differentiation. It is suggested that the mechanism responsible for this transition is more akin to a "dimmer" than to a "switch," that it is more useful to refer to early and late stages of differentiation rather than to "terminal" differentiation, and examples of the reversibility of differentiation are provided. An outline of the established paradigm of cell cycle regulation is followed by summaries of recent studies that suggest that this paradigm is overly simplified and should be interpreted in the context of different cell types. The role of inhibitors of cyclin-dependent kinases in differentiation is discussed, but the data are still inconclusive. An increasing interest in the changes in G2/M transition during differentiation is illustrated by examples of polyploidization during differentiation, such as megakaryocyte maturation. Although the retinoblastoma protein is currently maintaining its prominent role in control of proliferation and differentiation, it is anticipated that equally important regulators will be discovered and provide an explanation at the molecular level for the gradual transition from proliferation to differentiation.

Animals↗
PubMed1999

The impact of splenectomy on outcomes after resection of pancreatic adenocarcinoma.

BACKGROUND: Splenectomy at the time of resection of esophageal, gastric, or colon cancer has been correlated with inferior longterm survival. No such effect has yet been demonstrated for pancreatic cancer. STUDY DESIGN: Patients undergoing resection of pancreatic adenocarcinoma with curative intent at Memorial Sloan-Kettering Cancer Center between October 1983 and October 1995 were identified from a prospective clinical database. The impact of splenectomy on hospital stay and survival was calculated with univariate and multivariate nonparametric methods. RESULTS: Of 332 patients undergoing pancreatectomy, 326 with confirmed local or regional disease only formed the study cohort. Of these, 37 underwent concomitant splenectomy (11.4%). Splenectomy was significantly correlated with distal or total pancreatectomy, primary location in tail or body, portal vein invasion or resection, a larger maximal tumor diameter, and an operative blood loss of greater than 2,000 mL. Death or need for reoperation was not affected by splenectomy. Patients undergoing splenectomy had a higher median transfusion requirement (3 versus 1; p = 0.002). The median postoperative length of stay was 15 days regardless of splenectomy. At a median followup of 16.3 months (36.4 months for surviving patients), the median actuarial survival was 12.2 months with splenectomy versus 17.8 months without splenectomy (p<0.005). On multivariate analysis, splenectomy emerged as an independent factor predictive of decreased postoperative survival (p = 0.02), in addition to pathologic lymph node status (p = 0.0002), tumor diameter (p = 0.0004), and tumor differentiation (p = 0.007). Tumor location within the pancreas and the type of pancreatectomy were not independent prognostic factors influencing survival. CONCLUSIONS: After pancreatectomy for pancreatic cancer, splenectomy has no significant measurable impact on postoperative recovery, but has a negative influence on longterm survival independent of disease-related factors. Unless required because of tumor proximity or invasion, splenectomy should be avoided in the operative treatment of exocrine pancreatic cancer at any location.

Adenocarcinoma↗
PubMed1999

Butyrate-induced G2/M block in Caco-2 colon cancer cells is associated with decreased p34cdc2 activity.

Butyrate, a short-chain fatty acid, has been reported to inhibit proliferation and stimulate differentiation in multiple cancer cell lines. Whereas the effects of butyrate on cellular differentiation are well documented, the relationship between butyrate-induced differentiation and its effect on cell cycle traverse is less well understood. The purpose of this study was to investigate the effects of butyrate on the regulatory proteins of the G2/M traverse in the Caco-2 colon cancer cell model. We demonstrated that the inhibition of proliferation and increased cellular differentiation after treatment of Caco-2 cells with butyrate were associated with a significant G2/M cell cycle block. Although protein levels of the major G2/M regulatory protein, p34cdc2, were unchanged, a decrease in p34cdc2 activity was noted. Despite this decrease in activity, the inhibitory tyrosine phosphorylation of p34cdc2 was decreased, suggesting that other factors are responsible for the decreased kinase activity. The reduced activity of p34cdc2 provides a possible mechanism for the accumulation of Caco-2 cells in the G2/M cell cycle compartment following exposure to butyrate. This cell system provides a new model for studies of G2/M cell cycle perturbations.

Alkaline Phosphatase↗
PubMed1999

Growth hormone, alone and in combination with insulin, increases whole body and skeletal muscle protein kinetics in cancer patients after surgery.

OBJECTIVE: To investigate the impact of growth hormone, alone and in combination with insulin, on the protein kinetics of patients with upper gastrointestinal (GI) tract cancer who have undergone surgery and are receiving total parenteral nutrition (TPN). SUMMARY BACKGROUND DATA: Patients with malignancies of the upper GI tract are at increased risk for malnutrition and perioperative death and complications. Standard nutritional support has not significantly altered outcome. Growth hormone (GH) and insulin have been shown to have some benefit in patients with cancer; however, their action in patients undergoing resection has not previously been studied. METHODS: Thirty patients undergoing surgery for upper GI tract malignancies were prospectively randomized into one of three nutritional support groups after surgery: 10 patients received standard TPN, 10 received TPN plus daily injections of GH, and 10 received daily GH, systemic insulin, and TPN. The patients underwent a protein kinetic radiotracer study on the fifth day after surgery to determine whole body and skeletal muscle protein kinetics. RESULTS: Patients who received standard TPN only were in a state of negative skeletal muscle protein net balance. Those who received GH and insulin had improved skeletal muscle protein net balance compared with the TPN only group. Whole body protein net balance was improved in the GH and the GH and insulin groups compared with the TPN only group. GH and insulin combined did not improve whole body net balance more than GH alone. GH administration significantly increased serum IGF-1 and GH levels. Insulin infusion significantly increased serum insulin levels and the insulin/glucagon ratio. CONCLUSION: Growth hormone and GH plus insulin regimens improve protein kinetic parameters in patients with upper GI tract cancer who are receiving TPN after undergoing surgery.

Aged↗
PubMed1998

A preoperative biliary stent is associated with increased complications after pancreatoduodenectomy.

BACKGROUND: A preoperative biliary stent is commonly used after the initial evaluation of the patient with a periampullary mass. OBJECTIVE: To evaluate the effect of a preoperative biliary stent on operative difficulty, postoperative complications, and length of hospital stay after a pancreatoduodenectomy. DESIGN: A retrospective review of a prospectively collected consecutive series. SETTING: The Memorial Sloan-Kettering Cancer Center's Surgical Service, New York, NY. PATIENTS AND METHODS: Seventy-four patients underwent pancreatoduodenectomy between March 1, 1994, and February 15, 1996. Thirty-five did not receive a biliary stent, and 39 received a biliary stent prior to medical evaluation. We analyzed patient, nutritional, laboratory, and operating room factors. Univariate analysis was by Student t test, chi2 test, and Fisher exact test; multivariate analysis was by logistic regression. Significance was defined at P<.05. MAIN OUTCOME MEASURES: Operative time, amount of blood loss, complications, and length of hospital stay. Wound complications were defined as cellulitis, superficial infections, and deep infections. Intra-abdominal complications were defined as intra-abdominal abscesses and pancreatic or biliary fistula. RESULTS: Groups were equivalent for tumor size, risk of comorbidity, time spent in the operating room, and amount of blood loss. There was 1 perioperative death. Patients with a stent had significantly lower bilirubin (P<.03) and aspartate aminotransferase (P<.04) levels and a significantly increased risk of nodal positivity (P<.05). The patients with a biliary stent had an increased risk of wound or abdominal complications on univariate (P<.003) and multivariate (P<.02) analysis and tended toward a prolonged hospital stay (P<.04, Wilcoxon signed rank test). CONCLUSIONS: A preoperative biliary stent was associated with an increased risk of wound or intra-abdominal complications; a stent may prolong the length of hospital stay. However, length of time under anesthesia, amount of blood loss, and transfusion requirements were not altered. A biliary stent should be used with a high degree of selectivity in the management of patients with resectable periampullary masses.

Aged↗
PubMed1998

Surgical treatment of 32 patients with peripheral intrahepatic cholangiocarcinoma.

BACKGROUND: Peripheral intrahepatic cholangiocarcinoma (PIC) is an intrahepatic primary liver neoplasm which is clinicopathologically distinct from hepatocellular carcinoma and major duct cholangiocarcinoma. The clinical outcome after resection of these rare tumours is not well documented. METHODS: Review of the hepatic database and tumour registry at Memorial Sloan-Kettering Cancer Center identified 32 cases of PIC resected for cure over a 23-year period. Intrahepatic cholangiocarcinomas with major bile duct involvement were excluded from this analysis. Demographics, pathological features, biochemical markers, operative results and survival were analysed. RESULTS: The majority of patients presented with abdominal pain (n=19). Only two patients had pathological evidence of hepatic cirrhosis. Serum marker levels included 7-fetoprotein (AFP; median 3.7 (range 0-225) ng/ml) and carcinoembryonic antigen (CEA; median 1-6 (range 0-30) ng/ ml). Type of hepatic resection included: wedge (n=2), lobectomy (n=14) and extended lobectomy (n=16). There was one postoperative death. Median follow-up time was 27 months. Median survival was 59 months with an actuarial 5-year survival of 42 per cent. Vascular invasion and intrahepatic satellite lesions were predictors of worse survival (P < 0.05). CONCLUSION: PIC is a rare hepatic primary tumour, which usually presents in non-cirrhotic livers with a normal serum AFP and CEA level. In selected patients, complete surgical resection can be performed safely and is associated with long-term survival.

Aged↗
PubMed1998

Portal vein resection for pancreatic adenocarcinoma.

Although isolated portal vein involvement has classically been a contraindication for resection, portal vein resection can be performed safely with a low perioperative mortality rate. Importantly, overall survival is similar between patients undergoing pancreatectomy with portal vein resection and those undergoing standard pancreatic resection. Suspected isolated portal vein involvement, therefore, frequently does not preclude operability and, by itself, should not be a contraindication for pancreatic resection.

Adenocarcinoma↗
PubMed1998

Total gastrectomy is not necessary for proximal gastric cancer.

BACKGROUND: Although there is an increasing incidence of proximal gastric cancers in the United States, the appropriate extent of resection for proximal gastric cancer is not known. This study addresses whether the type of operation (total gastrectomy [TG] vs proximal gastrectomy [PG]) affects outcome for proximal gastric adenocarcinoma. METHODS: Review of the prospective gastric database at Memorial Sloan-Kettering Cancer Center from July 1985 to August 1995 identified 391 patients with proximal gastric cancer. Of those patients, 98 underwent curative TG or PG through an exclusively abdominal approach. Patients undergoing esophagogastrectomy (n = 293) were excluded from analysis. Data are expressed as medians and ranges. RESULTS: The length of hospital stay was the same for patients undergoing resection for PG (16.5 days [range 8 to 55]) and for TG (18 days [range 8 to 48]). In addition, hospital mortality rates for PG (6.0%) were similar to those for TG (3.0%). There was no significant difference in tumor differentiation and overall stage between the groups that underwent TG and those that underwent PG. There was no significant difference in time to recurrence between the two operative groups (PG, 15.7 months, versus TG, 18 months). In addition, there was no association between first site of recurrence and type of procedure. The overall 5-year survival rate for proximal gastric cancer was 43% (median survival 46 months), whereas the 5-year survival rate for TG was 41% (median survival 51 months; difference not significant). CONCLUSIONS: The extent of resection for proximal gastric cancer does not affect long-term outcome. TG and PG have similar overall survival rates and time and rate of recurrence, and both procedures can be accomplished safely.

Adenocarcinoma↗