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Biomedical subjects

Timothy M Pawlik

Publications and source records attributed to Timothy M Pawlik.

At least 37 records · Page 2Linked to original sources
PubMed2005

Catalytic subunit of human telomerase reverse transcriptase is an independent predictor of survival in patients undergoing curative resection of hepatic colorectal metastases: a multicenter analysis.

PURPOSE: To determine the role of the catalytic subunit of human telomerase reverse transcriptase (hTERT) in predicting survival after resection of hepatic colorectal metastases (CRM). PATIENTS AND METHODS: Two hundred one patients who underwent curative resection of hepatic CRM between 1990 and 2000 were identified from a multicenter database. The CRM were analyzed for hTERT nucleolar expression by standard immunohistochemical techniques. hTERT expression and known clinicopathologic factors of survival were examined. RESULTS: With a median follow-up of 80 months, 152 patients (75.6%) had died; the 5-year overall survival was 30.7%. On univariate analysis, number of metastases greater than two (P = .0005), extrahepatic disease (P = .0054), disease-free interval less than 12 months (P = .006), carcinoembryonic antigen level greater than 200 ng/mL (P = .0071), and positive hTERT nucleolar staining (P < .0001) were associated with decreased survival. On multivariate analysis, three factors independently predicted survival: number of metastases (relative risk [RR] = 1.74; P = .0011); disease-free interval (RR = 1.70; P = .0035); and positive hTERT nucleolar staining (RR = 2.03; P < .0001). Patients with none or one of these factors had a 5-year survival rate of 48%, whereas those with two or three of these factors had a 5-year survival of 15% (P < .0001). CONCLUSION: hTERT nucleolar expression is associated with worse survival after resection of hepatic CRM. hTERT expression in conjunction with number of hepatic metastases and disease-free interval may permit more accurate prediction of survival after resection of hepatic CRM.

Adult↗
PubMed2005

Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database.

BACKGROUND: The role of surgical resection in patients with large or multinodular hepatocellular carcinoma (HCC) remains unclear. This study evaluated the long-term outcome of patients with hepatic resection for large (>5 cm in diameter) or multinodular (more than three nodules) HCC by using a multi-institutional database. METHODS: The perioperative and long-term outcomes of 404 patients with small HCC (<5 cm in diameter; group 1) were compared with those of 380 patients with large or multinodular HCC (group 2). The prognostic factors in the latter group were analyzed. RESULTS: The postoperative complication rate (27% vs. 23%; P = .16) and hospital mortality rate (2.4% vs. 2.7%; P = .82) were similar between groups. The overall survival rates were significantly higher in group 1 than group 2 (1 year, 88% vs. 74%; 3 years, 76% vs. 50%; 5 years, 58% vs. 39%; P < .001). Among patients in group 2, five independent prognostic factors were identified to be associated with a worse overall survival: namely, symptomatic disease, presence of cirrhosis, multinodular tumor, microvascular tumor invasion, and positive histological margin. CONCLUSIONS: Hepatic resection can be safely performed in patients with large or multinodular HCC, with an overall 5-year survival rate of 39%. Symptomatic disease, the presence of cirrhosis, a multinodular tumor, microvascular invasion, and a positive histological margin are independently associated with a less favorable survival outcome.

Aged↗
PubMed2005

Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma.

HYPOTHESIS: A subset of patients with hepatocellular carcinoma (HCC) with a diameter of 10 cm or larger may benefit from hepatic resection. DESIGN: Retrospective study of a multi-institutional database. SETTING: Five major hepatobiliary centers. PATIENTS: We identified 300 patients who underwent hepatic resection for HCC 10 cm or larger. MAIN OUTCOME MEASURES: Clinical and pathologic data were collected, and prognostic factors were evaluated by univariate and multivariate analyses. Patient survival was stratified according to a clinical scoring system and pathologic T classification. RESULTS: The perioperative mortality rate was 5%. At a median follow-up of 32 months, the median survival was 20.3 months, and the 5-year actuarial survival rate was 27%. Four clinical factors-alpha-fetoprotein of 1000 ng/mL or higher, multiple tumor nodules, the presence of major vascular invasion, and the presence of severe fibrosis-were significant predictors of poor survival (all P<.05). Patients were assigned a clinical score according to the following risk factors: 1, no factor; 2, one or two factors; or 3, three or four factors. On the basis of the clinical score, patients could be stratified into only 2 distinct prognostic groups: no factor (score of 1) vs 1 or more factors (score of 2 or 3) (P<.001). In contrast, when patients were stratified according to pathologic T classification, 3 distinct groups were identified: T1 vs T2 vs T3 and T4 combined (P<.001). Fifty-six percent of the patients with a clinical score of 2 and 20% of patients with a clinical score of 3 actually had T1 or T2 disease on pathologic examination. CONCLUSIONS: Patients with large HCCs should be considered for liver resection as this treatment is associated with a 5-year survival rate exceeding 25%. Clinical predictors should not be used to exclude patients from surgical resection because these factors do not reliably predict outcome.

Actuarial Analysis↗
PubMed2005

Feasibility of a randomized trial of extended lymphadenectomy for pancreatic cancer.

HYPOTHESIS: The required sample size of a prospective randomized trial comparing standard pancreaticoduodenectomy with pancreaticoduodenectomy plus extended lymphadenectomy for pancreatic adenocarcinoma is prohibitively large, making such a trial infeasible. DESIGN: Retrospective cohort study. SETTING: Comprehensive cancer center. PATIENTS: We identified 158 patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma with separate pathologic analysis of second-echelon lymph nodes, defined as lymph nodes along the proximal hepatic artery and/or the great vessels. MAIN OUTCOME MEASURES: To estimate the sample size required for a randomized trial, we devised a biostatistical model with the following assumptions: extended lymphadenectomy can benefit only patients who (1) actually have disease removed from second-echelon nodes, (2) have microscopically negative (R0) primary tumor resection margins, and (3) do not have visceral metastatic (M0) disease. RESULTS: Seventy-six patients (48.1%) had negative first- and second-echelon lymph nodes, 65 (41.1%) had positive first-echelon and negative second-echelon lymph nodes, and 17 (10.8%) had positive first- and second-echelon lymph nodes. Patients with positive second-echelon lymph nodes had an R0 resection rate of 47.1%. At a median follow-up of 65.1 months, 4 patients with positive second-echelon lymph nodes were alive, but 3 had recurrent disease. This implies that only 1 patient (5.9%) with positive second-echelon lymph nodes may have had true M0 disease. Therefore, only 0.3% of patients (10.8% with positive second-echelon lymph nodes x 47.1% with R0 resection x 5.9% with M0 disease) may achieve a survival benefit from extended lymphadenectomy. A randomized trial of standard pancreaticoduodenectomy vs pancreaticoduodenectomy with extended lymphadenectomy would require 202 000 patients in each study arm to detect such a small difference. CONCLUSIONS: Definitive evaluation of the potential benefits of extended lymphadenectomy would require a prohibitively large sample size. Adequately powered randomized trials to address the potential benefit of extended lymphadenectomy are infeasible.

Adenocarcinoma↗
PubMed2005

Tumor size predicts vascular invasion and histologic grade: Implications for selection of surgical treatment for hepatocellular carcinoma.

Vascular invasion and high histologic grade predict poor outcome after surgical resection or liver transplantation for hepatocellular carcinoma (HCC). Despite the known association between tumor size and vascular invasion, a proportion of patients with large tumors can be treated surgically with excellent outcomes. Clarification of the association between tumor size, histologic grade, and vascular invasion has implications for patient selection for resection and transplantation. The objective of this study was to examine the relationship between HCC tumor size and microscopic (occult) vascular invasion and histologic grade in a multicenter international database of 1,073 patients who underwent resection of HCC. The incidence of microscopic vascular invasion increased with tumor size (< or =3 cm, 25%; 3.1-5 cm, 40%; 5.1-6.5 cm, 55%; >6.5 cm, 63%) (P < 0.005). Both size and number of tumors were important factors predicting vascular invasion. Among all patients with tumors 5.1 to 6.5 cm, microscopic vascular invasion was present in 55% compared with 31% for all patients with tumors 5 cm or smaller (P < 0.001). Among patients with solitary tumors only, microscopic vascular invasion was significantly more common in tumors measuring 5.1 to 6.5 cm (41%) compared with 27% of tumors 5 cm or smaller (P < 0.003). Tumor size also predicted histologic grade: 36% of tumors 5 cm or smaller were high grade, compared with 54% of lesions 5.1 to 6.5 cm (P = 0.01). High histologic grade, an alpha-fetoprotein level of at least 1000 ng/mL, and multiple tumor nodules each predicted occult vascular invasion in tumors larger than 5 cm. The high incidence of occult vascular invasion and advanced histologic grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients.

Adolescent↗
PubMed2005

Significant differences in nipple aspirate fluid protein expression between healthy women and those with breast cancer demonstrated by time-of-flight mass spectrometry.

New approaches are needed for the early detection of breast cancer. Proteomic profiling technologies, such as surface-enhanced laser desorption ionization mass spectrometry (SELDI-MS), may be able to identify tumor markers in biological fluids. The objective of this study was to determine whether there are differences in protein expression patterns in nipple aspirate fluid (NAF) from the cancerous and noncancerous breasts of patients with unilateral breast cancer and the breasts of healthy volunteers. Paired NAF samples were obtained from 23 women with stage I or II unilateral invasive breast carcinoma and five healthy female volunteers. Aliquots of the samples were applied to SELDI Protein-chip arrays (WCX2 and IMAC3-Cu++), and protein expression was analyzed using time-of-flight MS. A total of 463 distinct peaks were detected and analyzed. In breast cancer patients, no differences in protein expression were identified between the breast with the intact primary carcinoma and the contralateral noncancerous breast. Seventeen peaks were overexpressed in cancer-bearing breasts compared to breasts of healthy volunteers (p < 0.0005). When spectra from the nontumor-bearing breasts of breast cancer patients were compared with spectra from breasts of healthy volunteers, two peaks that were overexpressed in breast cancer patients and one peak that was underexpressed in breast cancer patients were detected (p < 0.0027). SELDI-MS was able to identify differences in the phenotypic proteomic profile of NAF samples obtained from patients with early-stage breast cancer and healthy women. Proteomic screening techniques such as SELDI-MS analysis of NAF may be useful for breast cancer screening and diagnosis.

Biopsy, Needle↗
PubMed2005

Ethical issues in surgical palliative care: am I killing the patient by "letting him go"?

Recent medical advances have complicated decisions regarding terminal care. Surgeons should be familiar with the ethical issues that contribute to end-of-life decision-making. Four clusters of ethical principles (autonomy, nonmaleficence, beneficence, and justice)are used commonly in ethical deliberations. Artificial ethical distinctions between withholding versus withdrawing care or ordinary versus extraordinary treatments can confuse clinical decision-making at the end of life. An ethics of death and dying requires that the intent and the action of the moral agent be considered.

Advance Directives↗
PubMed2005

Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study.

BACKGROUND: The role of hepatic resection in patients with hepatocellular carcinoma (HCC) and invasion of a main portal or hepatic vein branch is controversial. We evaluated the efficacy of hepatic resection and the factors affecting survival after resection in such patients. METHODS: The records of 102 patients who underwent resection for HCC with major vascular invasion between 1984 and 1999 were reviewed. Prognostic factors were evaluated by univariate and multivariate analysis. RESULTS: The study included 87 men and 15 women. The median age was 59 years. The perioperative mortality rate was 5.9%. Median survival was 11 months (median follow-up, 93 months). The 1-, 3-, and 5-year survival rates were 45%, 17%, and 10%; the longest-living survivor was still alive at 14.8 years. Absence of moderate to severe fibrosis and absence of high nuclear grade were associated with a better 5-year survival rate (23% vs 5%; P = .001 and 21% vs 9%; P = .04, respectively). On multivariate analysis, moderate to severe fibrosis remained a significant predictor of both short-term (< or = 6 months) and long-term (>6 months) survival ( P < .03 and P < .01, respectively). CONCLUSIONS: Hepatic resection for HCC with major vascular invasion is associated with median survival exceeding historical survival in patients not treated surgically. Patients with HCC and major vascular invasion who derive long-term benefit from resection have no or minimal underlying fibrosis.

Adolescent↗
PubMed2005

Making unresectable hepatic colorectal metastases resectable--does it work?

In patients with colorectal liver metastases, surgical resection is the treatment of choice. Reported 5-year survival rates with surgical resection range from 40% to 58%. The definition of resectability has changed over the past decade from a limited number of metastases (three to four) to any number of metastases as long as resection can be completed with anticipated negative surgical margins. In patients with bilobar hepatic colorectal metastases, potentially curative resection after preoperative chemotherapy may be possible only with an extended hepatectomy (bilobar hepatic resection of five or more hepatic segments). Extended hepatic resection should be considered because it is associated with a near-zero mortality rate with modern surgical techniques. If the estimated volume of liver that remains after resection is too small to permit safe extended hepatectomy (ie, 20% or less of the total estimated liver volume), preoperative portal vein embolization can be safely used to increase the volume of the future liver remnant and improve postoperative liver function. Other approaches for patients with bilobar metastases include two-stage hepatic resection and the combined use of resection with radiofrequency ablation.

Adenocarcinoma↗
PubMed2005

Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases.

OBJECTIVE: To evaluate the influence of surgical margin status on survival and site of recurrence in patients treated with hepatic resection for colorectal metastases. METHODS: Using a multicenter database, 557 patients who underwent hepatic resection for colorectal metastases were identified. Demographics, operative data, pathologic margin status, site of recurrence (margin, other intrahepatic site, extrahepatic), and long-term survival data were collected and analyzed. RESULTS: On final pathologic analysis, margin status was positive in 45 patients, and negative by 1 to 4 mm in 129, 5 to 9 mm in 85, and > or =1 cm in 298. At a median follow-up of 29 months, the 1-, 3-, and 5-year actuarial survival rates were 97%, 74%, and 58%; median survival was 74 months. Tumor size > or =5 cm, >3 tumor nodules, and carcinoembryonic antigen level >200 ng/mL predicted poor survival (all P < 0.05). Median survival was 49 months in patients with positive margins and not yet reached in patients with negative margins (P = 0.01). After hepatic resection, 225 (40.4%) patients had recurrence: 21 at the surgical margin, 56 at another intrahepatic site, 82 at an extrahepatic site, and 66 at both intrahepatic and extrahepatic sites. Patients with negative margins of 1 to 4 mm, 5 to 9 mm, and > or =1 cm had similar overall recurrence rates (P > 0.05). Patients with positive margins were more likely to have surgical margin recurrence (P = 0.003). Adverse preoperative biologic factors including tumor number greater than 3 (P = 0.01) and a preoperative CEA level greater than 200 ng/mL (P = 0.04) were associated with an increased risk of positive surgical margin. CONCLUSIONS: A positive margin after resection of hepatic colorectal metastases is associated with adverse biologic factors and increased risk of surgical-margin recurrence. The width of a negative surgical margin does not affect survival, recurrence risk, or site of recurrence. A predicted margin of <1 cm after resection of hepatic colorectal metastases should not be used as an exclusion criterion for resection.

Colorectal Neoplasms↗
PubMed2004

Clinicopathologic features in colorectal cancer patients with microsatellite instability.

The microsatellite instability (MSI) mutational pathway is critical to carcinogenesis in a small but significant proportion of colorectal cancers. While MSI is identified in most cancers in individuals with hereditary non-polyposis colorectal cancer, the majority of MSI tumors are found in individuals with sporadic disease. Colorectal cancers arising as a result of MSI have distinct clinicopathologic features distinguishing them from those with microsatellite stability. MSI colorectal cancers affect a larger percentage of women, are usually localized proximal to the splenic flexure, and have a higher incidence of synchronous and metachronous tumors. They are associated with a mucinous histology, tumor-infiltrating lymphocytes, a Crohn's-like inflammatory response, and a higher grade but lower stage. Overall survival is better in individuals with MSI. The benefit of chemotherapy in MSI colorectal cancers, with and without lymph node metastases, remains unclear.

Base Pair Mismatch↗
PubMed2004

Oncolysis by viral replication and inhibition of angiogenesis by a replication-conditional herpes simplex virus that expresses mouse endostatin.

BACKGROUND: In preclinical models, infection of tumors by oncolytic strains of herpes simplex virus 1 (HSV-1) resulted in the destruction of tumor cells by viral replication and release of progeny virion that infected and destroyed adjacent tumor cells. However, complete tumor regression was rarely observed. METHODS: To augment the antitumor effect of viral oncolysis, a replication conditional HSV-1 mutant (HSV-Endo) was constructed in which the murine endostatin gene was incorporated into the HSV-1 genome. RESULTS: Replication of HSV-Endo effectively destroyed several colon carcinoma cell lines in vitro. Secretion of endostatin by HSV-Endo-infected HT29 human colon carcinoma cells was confirmed by Western blot analysis. The secreted endostatin was biologically active as assessed in a chick chorioallantoic membrane assay. Importantly, endostatin production at the site of viral replication did not inhibit viral replication. Direct injection of HSV-Endo into flank tumors caused tumor destruction, and some of the HSV-Endo-treated flank tumors completely sloughed. Immunohistochemical staining of the tumors revealed a decreased number of blood vessels in the HSV-Endo-treated group versus the control group. CONCLUSIONS: The oncolytic HSV-1 mutant HSV-Endo provided a two-pronged therapy; namely, inhibition of angiogenesis and direct tumor cell destruction by viral replication.

Allantois↗
PubMed2004

Role of cell cycle in mediating sensitivity to radiotherapy.

Multiple pathways are involved in maintaining the genetic integrity of a cell after its exposure to ionizing radiation. Although repair mechanisms such as homologous recombination and nonhomologous end-joining are important mammalian responses to double-strand DNA damage, cell cycle regulation is perhaps the most important determinant of ionizing radiation sensitivity. A common cellular response to DNA-damaging agents is the activation of cell cycle checkpoints. The DNA damage induced by ionizing radiation initiates signals that can ultimately activate either temporary checkpoints that permit time for genetic repair or irreversible growth arrest that results in cell death (necrosis or apoptosis). Such checkpoint activation constitutes an integrated response that involves sensor (RAD, BRCA, NBS1), transducer (ATM, CHK), and effector (p53, p21, CDK) genes. One of the key proteins in the checkpoint pathways is the tumor suppressor gene p53, which coordinates DNA repair with cell cycle progression and apoptosis. Specifically, in addition to other mediators of the checkpoint response (CHK kinases, p21), p53 mediates the two major DNA damage-dependent cellular checkpoints, one at the G(1)-S transition and the other at the G(2)-M transition, although the influence on the former process is more direct and significant. The cell cycle phase also determines a cell's relative radiosensitivity, with cells being most radiosensitive in the G(2)-M phase, less sensitive in the G(1) phase, and least sensitive during the latter part of the S phase. This understanding has, therefore, led to the realization that one way in which chemotherapy and fractionated radiotherapy may work better is by partial synchronization of cells in the most radiosensitive phase of the cell cycle. We describe how cell cycle and DNA damage checkpoint control relates to exposure to ionizing radiation.

Antineoplastic Agents↗
PubMed2004

Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen.

Replication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of gamma(1)34.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3gamma34.5) preferentially in DF3/MUC1-positive cells. HSV-1 gamma(1)34.5 functions to dephosphorylate elongation initiation factor 2alpha, which is an important step for robust HSV-1 replication. After DF3gamma34.5 infection of cells, elongation initiation factor 2alpha phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of gamma(1)34.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD(50). Preferential replication of DF3gamma34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3gamma34.5 was effective against carcinoma xenografts in nude mice. Regulation of gamma(1)34.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.

Animals↗
PubMed2004

Potential applicability of balloon catheter-based accelerated partial breast irradiation after conservative surgery for breast carcinoma.

BACKGROUND: Balloon catheter-based accelerated partial breast irradiation (APBI) is an alternative to whole-breast external-beam irradiation during breast-conserving therapy (BCT) for breast carcinoma, but it is limited by the size of the segmental mastectomy cavity. There are scant data on the average or optimal volume of resection (VR) in BCT. The objective of the current study was to evaluate the percentage of patients who would be eligible for balloon catheter-based APBI based on the selection criteria of the American Society of Breast Surgeons and the surgical VR. METHODS: The authors reviewed the medical records of 443 patients with ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCT. Patient treatment and pathologic data were analyzed to assess VR and eligibility for APBI. RESULTS: BCT was performed for 178 patients with DCIS and 267 patients with invasive breast carcinoma. The majority of invasive carcinomas (63.3%) were infiltrating ductal carcinomas. The median overall lumpectomy volume was 67.61 cm3, with no significant difference between DCIS and invasive carcinoma (P>0.05). Although the majority (62.9-82.0%) of patients met the individual selection criteria for APBI, only 27.4% of the cohort was found to be eligible for any type of APBI when the selection criteria were considered together. Based on VR, only approximately one-half of the patients initially eligible for APBI would be candidates for immediate balloon catheter-based APBI using the 70 cm3 balloon device (13.3%). However, with the new, larger 125 cm3 balloon device, approximately three-fourths of patients initially eligible for APBI would be eligible for balloon catheter-based APBI at the time of the initial surgical procedure (20.7%). Although not evaluated in the current study, shrinkage of the lumpectomy cavity with time may increase the number of patients eligible based strictly on VR criteria. Patients with a very large VR (> or =125 cm3) were more likely to have invasive carcinoma (P=0.02; hazard ratio [HR], 7.4) and tumors > or =5 cm on final pathology (P<0.01; HR, 22.0). CONCLUSIONS: Approximately one-fifth to one-fourth of patients presenting for BCT may be eligible for balloon catheter-based APBI according to accepted national guidelines and VR. VR must be considered when selecting patients for balloon catheter-based APBI, because a minority of patients will have a lumpectomy cavity that exceeds the size limit of the current balloon device.

Adult↗