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T K Weber

Publications and source records attributed to T K Weber.

36 records · Page 2Linked to original sources
PubMed1996

A pilot study of cryochemotherapy for hepatic metastases from colorectal cancer.

Cryosurgery of hepatic metastases from colorectal carcinoma is a form of local therapy for unresectable disease. After curative resection, failures occur in the liver, and at extrahepatic sites. This pilot study evaluated the toxicity and tolerance to cryotherapy and intraoperative chemotherapy for unresectable hepatic metastases from colorectal cancer. If after exploratory celiotomy for potential curative resection of hepatic metastases the patient was deemed unresectable because of location and/or number of lesions, cryosurgery and intraoperative chemotherapy with systemic 5-fluorouracil 600 mg/m2 and leucovorin 500 mg/m2 was performed. Four patients were treated with cryochemotherapy. All patients developed toxicity. Two patients developed grade II leukopenia on Postoperative Days 2 and 12, and grades II and III diarrhea on Postoperative Days 5 and 7, respectively. Grade III hyperbilirubinemia and thrombocytopenia occurred in one patient on Postoperative Days 3 and 7. Acute respiratory distress syndrome, postoperative ileus, and grade II mucositis occurred in one patient each. All patients had delays and dose reductions on their subsequent chemotherapy treatments secondary to toxicity. Two patients had disease progression, one had stable disease. and one is "disease free." Combining the tumoricidal effects of chemotherapy and cryosurgery is in theory a good concept. However, the toxicity of 5-FU and leucovorin is enhanced by this approach.

Aged↗
PubMed1996

Adenosquamous carcinoma of the colon and rectum.

PURPOSE: Adenosquamous carcinomas of the colon and rectum are rare tumors. These tumors have malignant glandular and squamous components capable of metastasizing. We report seven patients with adenosquamous carcinoma of the colon and rectum and their clinical outcomes. METHODS: Retrospective review was undertaken of seven patients who were identified by the tumor registry at Roswell Park Cancer Institute between 1971 and 1994. RESULTS: These represent a 0.18 percent incidence of adenocarcinomas in our institution. There were five tumors located in the rectum and two in the colon. All patients were Stage III or IV on presentation. Median overall survival was 23 months. In three patients, the tumor was associated with ulcerative colitis; in one of these patients, hypercalcemia was present. All patients died of their disease or with the disease. CONCLUSIONS: Previously reported aggressive behavior of this cancer is confirmed in our series.

Adult↗
PubMed1996

Establishment of a hereditary nonpolyposis colorectal cancer registry.

INTRODUCTION: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition characterized by early age of onset colorectal cancer, right-sided predominance, excess of synchronous and metachronous colonic neoplasms, and extracolonic cancers. The purpose of this study is to report clinical characteristics of HNPCC families in our registry. METHODS: This is a retrospective review of medical records of patients with a significant history of colorectal cancer and interviews with their families. RESULTS: Three hundred one people with cancer in 40 HNPCC families were identified. In 284 of 301 (94 percent) people, 363 cancers were identified. Colorectal cancer only was identified in 182 people (64 percent) and, in conjunction with extracolonic tumors, in another 31 people (11 percent). Extracolonic cancer alone was noted in 71 people (25 percent). Median age at diagnosis of colorectal cancer was 48 (range, 17-92) years. In patients with documented pathology, right-sided tumors predominated (55 percent), synchronous and metachronous tumors were noted in 53 percent, and synchronous of metachronous adenomas were documented in 51 percent of people. Generational anticipation was also noted. CONCLUSION: This study demonstrates and confirms characteristics that have been described in HNPCC. Namely, early age of onset of colorectal cancer, right-sided predominance, multiple synchronous and metachronous neoplasms, increased extracolonic cancers, and generational anticipation.

Adolescent↗
PubMed1996

Clinical significance of colorectal cancer: metastases in lymph nodes < 5 mm in size.

BACKGROUND: The clinical significance of metastases in small lymph nodes is not known. Our objective was to evaluate possible relationships between the number and size of lymph node metastases and survival after potentially curative colorectal resection. METHODS: A retrospective chart review was performed in patients with Dukes'C (any T, N(1-3') M0) colorectal cancers from July 31, 1971 to December 31, 1987. All specimens underwent the lymph node clearing technique. Statistical analysis was performed with the log rank test and the Cox proportional hazards model. RESULTS: In 77 patients there were 253 (8%) of 3,087 cleared lymph nodes with metastases. One hundred seventy-five (69%) of these metastatic nodes were 5 mm or less in diameter. The distal margin of resection (p = 0.011) and number of positive lymph nodes (p = 0.036) were statistically significant factors influencing overall survival. There was no significant difference in overall survival (p = 0.73) or disease-free survival (p = 0.56) whether the involved lymph nodes were < or > 5 mm in size. CONCLUSION: Most metastatic lymph nodes were < 5 mm in diameter. Based on our results, the size of lymph node metastases do not affect disease-free or overall survival in colorectal carcinoma.

Adenocarcinoma↗
PubMed1996

Utility of mapping lymph nodes cleared from rectal adenocarcinoma specimens.

The lymph node clearing technique improves the detection of lymph nodes in colorectal cancer specimens. The purpose of this study was to determine the utility of mapping the lymph nodes cleared from rectal adenocarcinoma specimens by evaluating the possible relationship between the pattern of lymph node metastases to the site of the recurrent disease. A retrospective medical record review was performed in 40 patients with primary rectal adenocarcinoma. The specimens were analysed by lymph node clearing technique and mapped after surgery. The lymph nodes were mapped according to their location in the cleared specimens. Statistical analysis was performed using the chi 2-test. A total of 1290 lymph nodes were cleared in 40 specimens. Of these, 1126 (87%) lymph nodes were < or = 5 mm. One-hundred and ten (9%) lymph nodes were metastatic. Sixty-seven (61%) of these 110 lymph nodes were 5 mm or less in size. The majority of lymph nodes with or without metastases were in the pelvis, as opposed to an extrapelvic location (P = 0.0001). Eleven patients recurred. In nine of these patients the recurrence showed a direct relationship between the level of metastatic lymph node location (pelvic vs. extrapelvic) and the site of the recurrent disease (loco-regional or systemic, P = 0.05). The majority of lymph nodes, both normal and metastatic, cleared from specimens from rectal adenocarcinoma were < or = 5 mm in diameter. The lymph node mapping technique may help in predicting the site of recurrence.

Adenocarcinoma↗
PubMed1996

Colorectal cancer in patients aged 30 years or younger.

Colorectal cancer (CRC) is believed to carry a grim prognosis in young patients. A retrospective study of patients diagnosed with colorectal cancer at age 30 years or less between 1971 and 1994 was conducted. Statistical analyses were performed using non-parametric one way ANOVA tests and logistic regression models. Sixty-eight of the patients evaluated at our institution were suitable for this study. Risk factors were identified in 28% of patients. The median age at diagnosis was 27 years (range 14-30 years). Fifty-six patients (82%) were Stage III or IV at the time of diagnosis. Twenty-two of the 34 patients who underwent potentially curative surgery had recurring disease at a median of 12 months (range 1-43 months). At a median follow-up of 21.5 months, 54 patients had died from disease. At the time of death, abdominal carcinomatosis and distant disease were the most common patterns of failure. Stage of the primary tumour (P=0.0006) and recurrence (P=0.0001) were the only variables noted to be associated with survival. The stage of the primary tumour and whether the tumour recurred were each associated with survival in patients with colorectal cancer at age 30 years or less.

Adenocarcinoma↗
PubMed1996

Postoperative complications after splenectomy for hematologic malignancies.

OBJECTIVE: The authors analyzed the frequency and character of postoperative complications after splenectomy in patients with hematologic malignancies, and correlated these findings with preoperative conditions that could have predicted their outcome. SUMMARY BACKGROUND DATA: Splenectomy is performed for hematologic malignancies for diagnostic and therapeutic indications. The role of splenectomy for lymphoproliferative and myeloproliferative malignancies is complex and sometimes controversial. METHODS: The medical records of 135 patients undergoing splenectomies for hematologic malignancies at Roswell Park Cancer Institute from January 1, 1984 to December 31, 1993 were reviewed retrospectively. These included Hodgkin's disease (HD), hairy cell leukemia (HCL), non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and a miscellaneous group. RESULTS: The overall postoperative complication and mortality rates for all patients were 52% and 9%, respectively. The complication rate was 63% for patients whose spleens weighed greater than 2000 g, and 29% for patients whose spleens weighed less than 2000 g (p = 0.001). Seventy-three percent of the postoperative deaths were due to septic complications, only one of which was caused by an encapsulated organism. Complications occurred in less than 20% of patients with the diagnosis of HD and HCL; more than 50% of patients with NHL, CLL, and CML suffered postoperative complications. CONCLUSIONS: Splenectomy performed in patients with hematologic malignancies is a potentially morbid procedure. Splenic size was the only preoperative factor found to be predictive of postoperative complications. The complication rate differed significantly between the different diagnostic subgroups.

Adolescent↗
PubMed1996

Desmoid tumors.

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Diagnosis, Differential↗
PubMed1996

The management of infectious and noninfectious anorectal complications in patients with leukemia.

BACKGROUND: Infectious and noninfectious anorectal complications may occur in patients undergoing therapy for leukemia. Controversy surrounds the treatment of this problem in immunocompromised patients. STUDY DESIGN: A retrospective review of the medical records of 83 patients with acute or chronic leukemia in whom anorectal disease developed during inpatient therapy for leukemia was performed to determine the initial signs and symptoms, treatment, and outcomes. RESULTS: During a 12-year period, 92 patients with anorectal complications were treated. This series included 25 patients with perirectal abscesses, 22 patients with anal fissures, 18 patients with symptomatic external hemorrhoids, 12 patients with perianal ulcerations, 12 patients with symptomatic internal hemorrhoids, and three patients with fistulas in ano. Overall, 79 (86 percent) of the 92 anorectal complications resolved in 68 of the 83 patients. Increasing periods of neutropenia did not adversely affect the resolution of anorectal disease. Thirteen patients (16 percent) required surgical intervention, most commonly secondary to a perirectal abscess. Incision and drainage was necessary in ten (40 percent) of 25 patients with perirectal abscess, which included five patients with fluctuation and five patients in whom infection failed to respond to medical therapy. CONCLUSIONS: Noninfectious anorectal complications in patients with leukemia respond to nonoperative intervention and rarely progress to a life-threatening infection. Nonoperative intervention in the form of systemic antibiotics and sitz baths is successful in the treatment of infectious anorectal complications. Incision and drainage should be performed when fluctuation is present and in patients whose complications fail to respond to medical therapy.

Abscess↗
PubMed1995

An anoxia inducible endonuclease and enhanced DNA breakage as contributors to genomic instability in cancer.

Fischer rat embryo fibroblasts subjected to temporary anoxia followed by an aerobic recovery period show genomic instability in the form of highly elevated CAD gene amplification rates. As revealed by flow cytometric analysis this is associated with DNA breakage in vivo, followed by repair during the recovery period. Such genomic instability parallels expression of a M(r) 29,000/31,000 endonuclease; this enzyme requires no added divalent metal ion and has a pH optimum of about 6.5. The same endonuclease was found to be expressed within healing wounds and in four of ten human colorectal cancers but was not seen in eight normal colorectal tissue samples. Our results indicate that DNA breakage resulting from endogenous endonuclease activity can have a substantial effect in modulating genomic instability.

Animals↗
PubMed1995

Inhibition of N-linked glycosylation of P-glycoprotein by tunicamycin results in a reduced multidrug resistance phenotype.

Characterisation of altered glycosylation of P-glycoprotein (P-gp) found associated with the absence of a multidrug resistance (MDR) phenotype in cell lines prompted an investigation to assess the role of post-translational processing in establishing P-gp efflux pump functionally. The clone A cell line used in this study displays a strong MDR phenotype mediated by high constitutive levels of expression of P-gp. Incubation of clone A cells with tunicamycin for different periods resulted in a time-dependent increase in daunorubicin accumulation, reflecting a reduction in P-gp function. Parallel experiments conducted with verapamil resulted in no loss of P-gp functionality in clone A cells. Reduction in surface-associated P-gp following exposure to tunicamycin was established by FACS analysis, Western blot analysis and immunoprecipitation of surface-iodinated P-gp. In addition, immunoprecipitation of P-gp from 32P-orthophosphate-labelled cells demonstrated reduced phosphorylation of P-gp associated with tunicamycin exposure. From these studies we conclude that glycosylation of P-gp is required to establish the cellular MDR phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Modulation of mdr-1 expression by a H-ras oncogene in a human colon carcinoma cell line.

In an established colon differentiation model, introduction of a c-H-ras-1 oncogene into a poorly differentiated human colon carcinoma cell line (Clone A) results in changes associated with the acquisition of a more differentiated phenotype. Down-regulation of mdr-1 mRNA was shown to accompany ras-related differentiation events resulting in decreased Pgp synthesis and a significant reduction in membrane Pgp as detected by immunoprecipitation, Western-blot and FACS analysis. Consistent with these observations was a reduction in Pgp-mediated drug resistance associated with Clone-A ras transfectants, with no alteration in drug sensitivity being observed with non-MDR drugs in these cells. An alternative differentiation model involves exposure of Clone-A cells to sodium butyrate. Under these conditions, differentiation-related changes resulted in up-regulation of mdr-1 mRNA and Pgp synthesis, although no alteration in drug sensitivity was recorded. In agreement with this observation, the levels of membrane-associated Pgp remained unchanged throughout the period of exposure to sodium butyrate. This study shows that modulation of Pgp expression in colon differentiation is dependent upon the differentiation induction agent used.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Immortalization and neoplastic transformation of normal rat colon epithelium: an in vitro model of colonic neoplastic progression.

BACKGROUND: Because of the refractory nature of colon epithelium to growth and maintenance in vitro, the cell lines currently available for study are derived from tumors. Unlike most epithelial model systems, there exist no preneoplastic, nontumorigenic colon cell lines for manipulation and study. METHODS: Intact fetal rat colon was cultured in the presence of a feeder layer of cells producing a retrovirus that harbors the SV40 LT gene resulting in the establishment of immortalized colon cell lines. RESULTS: The epithelial and intestinal origin of cell lines was established from the constitutive expression of keratin and villin, respectively. All cell lines displayed an absence of anchorage independent growth and failed to produce tumors in vivo. Neoplastic transformation of immortalized rat colon epithelial cell lines was achieved following introduction of individual oncogenic ras gene members or the v-src oncogene. Probing of cell lysates with phosphotyrosine antibodies revealed altered phosphotyrosyl protein profiles associated with different stages of colonic neoplastic progression. CONCLUSIONS: The establishment of immortalized nontumorigenic colon epithelial cell lines facilitates the biochemical analysis of events associated with different stages of colonic neoplastic progression. In addition, this simple culture technique lends itself to studies involving alternative genetic elements implicated in the genesis of colon tumors.

Animals↗
PubMed1993

Constitutive expression of multidrug resistance in human colorectal tumours and cell lines.

In this study we report detection of mdr1 gene expression in the liver metastases of 7/11 patients with colon carcinoma and characterise the MDR phenotype associated with a panel of 19 human colon carcinoma cell lines. Within this panel, mdr1 mRNA biosynthesis and surface localisation of Pgp were assessed with respect to MDR functionality where the cell lines are representative of different clinical stages of tumour progression, metastatic potential and differentiation. The data indicates that constitutive levels of mdr1 mRNA/Pgp expression may not necessarily result in the functional expression of the MDR phenotype. While low levels of mdr1 mRNA/Pgp were detected in 5/8 well differentiated colon cell lines, only 2/8 were functionally MDR. In contrast, 10/11 moderate and poorly differentiated lines expressed mdr1 mRNA/Pgp and of these, 9/11 were functionally MDR. The phosphorylation status of the mature 170 kD P-glycoprotein and the surface localisation of this glycoprotein showed the strongest correlation with functionality. Analysis of cell lines for cross-resistance and chemosensitivity profiles against a battery of chemotherapeutic drugs suggests multiple mechanisms, in addition to Pgp, contribute to the overall resistance of colorectal cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Differential pp60c-src activity in well and poorly differentiated human colon carcinomas and cell lines.

The results presented in this report demonstrate increased pp60c-src kinase activity associated with moderate to well differentiated colon tumors, corroborating previous observations by other groups. Extension of this analysis to include a small number of poorly differentiated colon carcinomas revealed src kinase activity comparable to that observed in normal colonic mucosa, considerably less than that observed in moderate/well differentiated lesions. Correlations of src kinase activity with differentiation was confirmed within a panel of colon cell lines where increased activity, associated with moderate/well differentiated lines, was accompanied by increased expression of pp60c-src protein. Use of an antiphosphotyrosine antibody in immunoprecipitation revealed the presence of novel phosphotyrosyl cellular substrates in human colon cell lines displaying elevated pp60c-src kinase activity. These observations suggest a role for the src protooncogene in colonic differentiation pathways.

Cell Differentiation↗
PubMedDate not supplied

Novel hMLH1 and hMSH2 germline mutations in African Americans with colorectal cancer.

CONTEXT: Germline mutations of the DNA mismatch repair (MMR) genes hMLH1 and hMSH2 have been shown to cosegregate with the colorectal cancer phenotype in multiple hereditary nonpolyposis colorectal cancer (HNPCC) pedigrees. However, the frequency of these mutations among African American patients with colorectal cancer is unknown. OBJECTIVE: To investigate the frequency of germline alterations of the DNA MMR genes hMLH1 and hMSH2 among African Americans affected by HNPCC and early-age onset colorectal cancer. DESIGN, SETTING, AND PATIENTS: Forty unrelated African American HNPCC and early-age onset colorectal cancer patients (8 women, 3 men) were identified from the cancer registry at a National Cancer Institute-designated referral center, 11 of whom were available for and agreed to study participation from January 1997 to February 1998. The mean age of the subjects was 44 years. An additional 50 age- and sex-matched African Americans without personal or family history of colorectal, endometrial, ovarian, urinary tract, or upper gastrointestinal tract malignancy were also studied as a polymorphism control population. In all subjects, genomic DNA was amplified by polymerase chain reaction for all hMLH1 and hMSH2 exons and screened using single-strand conformation polymorphism (SSCP) analysis. Samples demonstrating significant SSCP shifts underwent automated nucleotide sequencing analysis. MAIN OUTCOME MEASURE: Frequency of hMLH1 and hMSH2 germline alterations in the affected and control subjects. RESULTS: Germline hMLH1 and hMSH2 mutations were detected in 3 (27%) of the African American colorectal cancer probands studied. Each mutation was novel. Two hMLH1 (an A-->T transversion at codon 26 and a GG-->AT substitution across codons 177 and 178) mutations and 1 hMSH2 mutation (a C-->T transition at codon 389) were identified in 3 female study subjects. Six other hMLH1 and hMSH2 alterations were detected but were presumed to be polymorphisms. Neither missense mutation (at codons 26 and 389) was detected in the control population. CONCLUSIONS: The results of our analysis support an association between the 3 mutations reported and predisposition to colorectal cancer. Further studies are needed to define DNA MMR gene-associated colorectal cancer in African Americans, an understudied population at increased risk of fatal colorectal cancer.

Adaptor Proteins, Signal Transducing↗