Matrix metalloproteinase inhibition of pancreatic cancer: matching mechanism of action to clinical trial design.
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Enzyme Inhibitors↗
Biomedical subjects
K R Hess
Publications and source records attributed to K R Hess.
Surgery for abdominal metastases of cutaneous melanoma.
The objective of this study was to support our hypothesis that surgical resection of abdominal metastases of melanoma, regardless of symptomatology, could provide prolonged palliation and improved survival. We performed a retrospective chart review at M.D. Anderson Cancer Center. A series of 251 melanoma patients (stages I, II, or III at registration) who developed intraabdominal metastases during follow-up were studied. Altogether, 96 patients underwent 119 laparotomies; 51 underwent endoscopic or percutaneous procedures; and 116 patients were treated medically. Surgery was associated with a median survival of 11 months, significantly longer than that with other treatment (p < 0.001). Tumor was extirpated during 37% of the first laparotomies, and in an additional 33% very good palliation was achieved with incomplete resection. Tumor extirpation was associated with 10-month symptom-free survival (SFS), significantly longer than that with any other approach (p < 0.0001). In the nonsurgically treated patients, good palliation was achieved in 8% to 17% of patients with no complete response. The median SFS after surgery was 5 months, but 23% of patients were symptom-free more than 12 months; 87 patients with minimal symptoms; and 72 severely symptomatic patients underwent surgery. Complete resection was feasible in 42% and 34%, respectively. Surgery was associated with 12 months median survival in both groups. There was a significant survival benefit from surgery in patients with gastrointestinal (GI) tract metastases in contrast to those who had non-GI metastases. For the 96 surgically treated patients, a time interval of more than 4 years between diagnosis of the primary lesion and the abdominal recurrence predicted decreased risk of death (p = 0.038). The 30-day postoperative complication and mortality rates were 19.0% and 3.3%, respectively. Complete surgical resection of melanoma metastases in the abdomen is associated with median and symptom-free survival benefits. Symptomatic and asymptomatic patients benefit equally, especially if abdominal metastases appear more than 4 years after the initial diagnosis and do not involve non-GI viscera. Less than complete resection can provide durable palliation.
Abdominal Neoplasms↗
Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration.
BACKGROUND: For patients with potentially resectable pancreatic cancer, the poor outcome associated with resection alone and the survival advantage demonstrated for combined-modality therapy have stimulated interest in preoperative chemoradiotherapy. The goal of this study was to analyze the effects of different preoperative chemoradiotherapy schedules, intraoperative radiation therapy, patient factors. and histopathologic variables on survival duration and patterns of treatment failure in patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head. METHODS: Data on 132 consecutive patients who received preoperative chemoradiation followed by pancreaticoduodenectomy for adenocarcinoma of the pancreatic head between June 1990 and June 1999 were retrieved from a prospective pancreatic tumor database. Patients received either 45.0 or 50.4 Gy radiation at 1.8 Gy per fraction in 28 fractions or 30.0 Gy at 3.0 Gy per fraction in 10 fractions with concomitant infusional chemotherapy (5-fluorouracil, paclitaxel, or gemcitabine). If restaging studies demonstrated no evidence of disease progression, patients underwent pancreaticoduodenectomy. All patients were evaluated with serial postoperative computed tomography scans to document first sites of tumor recurrence. RESULTS: The overall median survival from the time of tissue diagnosis was 21 months (range 19-26, 95%CI). At last follow-up, 41 patients (31%) were alive with no clinical or radiographic evidence of disease. The survival duration was superior for women (P = .04) and for patients with no evidence of lymph node metastasis (P = .03). There was no difference in survival duration associated with patient age, dose of preoperative radiation therapy, the delivery of intraoperative radiotherapy, tumor grade, tumor size, retroperitoneal margin status, or the histologic grade of chemoradiation treatment effect. CONCLUSION: This analysis supports prior studies which suggest that the survival duration of patients with potentially resectable pancreatic cancer is maximized by the combination of chemoradiation and pancreaticoduodenectomy. Furthermore, there was no difference in survival duration between patients who received the less toxic rapid-fractionation chemoradiotherapy schedule (30 Gy, 2 weeks) and those who received standard-fractionation chemoradiotherapy (50.4 Gy, 5.5 weeks). Short-course rapid-fractionation preoperative chemoradiotherapy combined with pancreaticoduodenectomy, when performed on accurately staged patients, maximizes survival duration and is associated with a low incidence of local tumor recurrence.
Adenocarcinoma↗
Microarrays: handling the deluge of data and extracting reliable information.
Application of powerful, high-throughput genomics technologies is becoming more common and these technologies are evolving at a rapid pace. Genomics facilities are being established in major research institutions to produce inexpensive, customized cDNA microarrays that are accessible to researchers in a broad range of fields. These high-throughput platforms have generated a massive onslaught of data, which threatens to overwhelm researchers. Although microarrays show great promise, the technology has not matured to the point of consistently generating robust and reliable data when used in the average laboratory. This article addresses several aspects related to the handling of the deluge of microarray data and extracting reliable information from these data. We review the essential elements of data acquisition, data processing and data analysis, and briefly discuss issues related to the quality, validation and storage of data. Our goal is to point out some of the problems that must be overcome before this promising technology can achieve its full potential.
DNA, Complementary↗
Identifying differentially expressed genes in cDNA microarray experiments.
A major goal of microarray experiments is to determine which genes are differentially expressed between samples. Differential expression has been assessed by taking ratios of expression levels of different samples at a spot on the array and flagging spots (genes) where the magnitude of the fold difference exceeds some threshold. More recent work has attempted to incorporate the fact that the variability of these ratios is not constant. Most methods are variants of Student's t-test. These variants standardize the ratios by dividing by an estimate of the standard deviation of that ratio; spots with large standardized values are flagged. Estimating these standard deviations requires replication of the measurements, either within a slide or between slides, or the use of a model describing what the standard deviation should be. Starting from considerations of the kinetics driving microarray hybridization, we derive models for the intensity of a replicated spot, when replication is performed within and between arrays. Replication within slides leads to a beta-binomial model, and replication between slides leads to a gamma-Poisson model. These models predict how the variance of a log ratio changes with the total intensity of the signal at the spot, independent of the identity of the gene. Ratios for genes with a small amount of total signal are highly variable, whereas ratios for genes with a large amount of total signal are fairly stable. Log ratios are scaled by the standard deviations given by these functions, giving model-based versions of Studentization. An example is given.
Analysis of Variance↗
Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients.
OBJECTIVE: To examine the relationship between preoperative biliary drainage and the morbidity and mortality associated with pancreaticoduodenectomy. SUMMARY BACKGROUND DATA: Recent reports have suggested that preoperative biliary drainage increases the perioperative morbidity and mortality rates of pancreaticoduodenectomy. METHODS: Peri-operative morbidity and mortality were evaluated in 300 consecutive patients who underwent pancreaticoduodenectomy. Univariate and multivariate logistic regression analyses were done to evaluate the relationship between preoperative biliary decompression and the following end points: any complication, any major complication, infectious complications, intraabdominal abscess, pancreaticojejunal anastomotic leak, wound infection, and postoperative death. RESULTS: Preoperative prosthetic biliary drainage was performed in 172 patients (57%) (stent group), 35 patients (12%) underwent surgical biliary bypass performed during prereferral laparotomy, and the remaining 93 patients (31%) (no-stent group) did not undergo any form of preoperative biliary decompression. The overall surgical death rate was 1% (four patients); the number of deaths was too small for multivariate analysis. By multivariate logistic regression, no differences were found between the stent and no-stent groups in the incidence of all complications, major complications, infectious complications, intraabdominal abscess, or pancreaticojejunal anastomotic leak. Wound infections were more common in the stent group than the no-stent group. CONCLUSIONS: Preoperative biliary decompression increases the risk for postoperative wound infections after pancreaticoduodenectomy. However, there was no increase in the risk of major postoperative complications or death associated with preoperative stent placement. Patients with extrahepatic biliary obstruction do not necessarily require immediate laparotomy to undergo pancreaticoduodenectomy with acceptable morbidity and mortality rates; such patients can be treated by endoscopic biliary drainage without concern for increased major complications and death associated with subsequent pancreaticoduodenectomy.
Adolescent↗
Correlation of kidney weight and volume and selected skeletal parameters to sex in the adult rhesus monkey (Macaca mulatta).
This report outlines a comparison of renal weight and volume and selected skeletal parameters to sex in 22 adult male and 156 adult female rhesus macaques. Means and standard deviations for kidney weight and volume, body weight, and radiographic measurements for both males and females are reported. Ninety-five percent confidence intervals and P-values for the mean differences between the sexes for these parameters were also compiled. Male monkeys were larger, but had kidneys of similar size to those of the females. Joint distributions of the radiographic measurements of the first lumbar vertebra and the skull showed that males were larger in both measurements. The distributions of these parameters were clearly separate in males and females, while joint distributions of kidney weight and volume for males and females overlapped almost completely. We found that, regardless of age, sex, weight, or skeletal size, all normal adult rhesus monkeys generally have similar-sized kidneys.
Animals↗
"Ditzels" on chest CT: survey of members of the Society of Thoracic Radiology.
OBJECTIVE: We surveyed the members of the Society of Thoracic Radiology regarding their interpretation of and management decisions for very small (3-5 mm) pulmonary nodules-"ditzels"-noted on CT. SUBJECTS AND METHODS: A survey consisting of 13 case scenarios in which ditzels were encountered on CT examinations was mailed to the 406 members of the Society of Thoracic Radiology. Statistical analysis was performed to determine associations between responses, years of experience, location in an endemic region of granulomatous disease, and location at a lung or a general cancer center. RESULTS: One hundred fifty-one surveys (37%) could be included in the analysis. The most common response was "short-term follow-up." As the likelihood of malignancy increased, the response of "recommend biopsy" or "considered malignant or metastatic" increased. Those radiologists located in an area considered endemic for granulomatous disease were more likely to consider an incidental ditzel benign and to recommend follow-up, whereas those in a nonendemic area were more likely to recommend biopsy. In the cases in which years of experience had an influence, the less experienced respondents were more likely to choose "nothing, considered benign" or short-term follow-up than biopsy. CONCLUSION: The most common response was short-term follow-up, with less aggressive recommendations in cases with a lower likelihood of malignancy and more aggressive recommendations in cases with a higher likelihood of malignancy. Location in an area considered endemic for granulomatous disease and years of experience influenced decisions.
Biopsy↗
Statistical pattern analysis of gene expression profiles for glioblastoma tissues and cell lines.
The recent development and refinement of cDNA array and genechip techniques allows for large-scale parallel screening of gene expression and thereby provides a global assessment of molecular events transpiring in cell populations. We hypothesized that such an approach might help illuminate current issues in glioma research. To what degree are glioblastoma multiforme (GBM) cell lines representative of primary GBM tumors? We carried out a gene expression profiling study using cDNA array technology on 10 GBM primary tissues and 3 GBM cell lines. The gene expression levels were quantified, and the within-subject ranks of the gene expression levels were subsequently evaluated by hierarchical clustering analysis, multidimensional scaling analysis, and principal component analysis. Hierarchical cluster analysis shows that the 3 cell lines form one main cluster and the 10 tissue samples form a separate cluster. Multidimensional scaling and principal components analysis provided further graphical demonstration that the cell lines are clearly different from the tissue samples and that the cell lines are more different between themselves than are the tissues.
Central Nervous System Neoplasms↗
Impact of neoadjuvant chemotherapy on postoperative morbidity in soft tissue sarcomas.
PURPOSE: The purpose of this study was to test the hypothesis that neoadjuvant chemotherapy (NeoCT) does not increase morbidity in patients undergoing radical surgery for soft tissue sarcomas. PATIENTS AND METHODS: The records of 309 patients who presented to The University of Texas M.D. Anderson Cancer Center for definitive surgical management of primary soft tissue sarcomas were retrospectively reviewed. One hundred five patients who received NeoCT were compared with 204 patients who had surgery first (Surg). Patients had extremity sarcomas (71 NeoCT patients and 130 Surg patients) or retroperitoneal/visceral sarcomas (34 NeoCT and 74 Surg). RESULTS: NeoCT patients had larger tumors (median, 12 v 8 cm), more frequently had high-grade tumors (90% v 64%), and were younger (median age 47 v 55 years). The incidence of surgical complications was not different for NeoCT patients than for Surg patients, both in those with extremity sarcomas (34% v 41%) and in those with retroperitoneal/visceral sarcomas (29% v 34%). The most common complications were wound infections and other wound complications. Preoperative radiation therapy, autologous flap coverage, and extremity tumors were associated with increased wound complications. No significant differences in length of hospital stay, rate of readmission, or rate of reoperation for complications were found between the NeoCT and Surg groups. One of the three postoperative deaths in our series occurred in the NeoCT group. CONCLUSION: In this retrospective review, there was no evidence that NeoCT increased postoperative morbidity in patients with soft tissue sarcomas. Prospective, randomized studies are needed to confirm these results.
Antibiotics, Antineoplastic↗
Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region.
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Adenocarcinoma↗
Cognitive function as a predictor of survival in patients with recurrent malignant glioma.
PURPOSE: To determine the contribution of cognitive function in predicting the survival of patients with recurrent malignant brain tumors. PATIENTS AND METHODS: A total of 80 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma were seen for baseline evaluations before beginning a phase I or phase II clinical trial. Each patient received a battery of nine brief tests measuring cognitive function, ability to perform activities of daily living (ADLs), and quality of life (QOL). Tests were given monthly after treatment was begun. RESULTS: Performance on a test of verbal memory was independently and strongly related to survival after accounting for age, Karnofsky performance status score, histology, and time since diagnosis. Models incorporating three of nine and all nine tests in the battery accounted for significantly more variance in survival than did the clinical variables alone. Measures of QOL and ADLs (bathing, feeding, and so on) were not independently related to survival, although they provide clinical information that is important for patient care. CONCLUSION: These results indicate that a multifaceted assessment of cognition, QOL, and patient function is practical for brain tumor patients in clinical trials and can provide information regarding the relative risks versus benefits of new treatment regimens that supplements the information from the usual clinical variables.
Activities of Daily Living↗
Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival.
The retinoblastoma pathway is a key cell cycle regulatory complex that controls the passage of cells through the G1 checkpoint and is a frequent target of genetic alterations in gliomas. In this study, we examined the expression of Rb and p16 in 170 primary astrocytic gliomas by immunohistochemical techniques, and correlated the expression with overall survival to determine their prognostic value as immunomarkers. There were 130 patients with glioblastoma multiforme (GBM) and 40 with anaplastic astrocytoma (AA). Alterations in the levels of Rb or p16 expression were seen in the majority (>90%) of the gliomas studied. The expression of Rb was completely absent or low in 47.5% of the GBM and 67.5% of the AA. The remainder of the tumors was immunopositive for Rb to varying degrees. Immunoreactivity for p16 was absent in 56% of the GBM and 77.5% of the AA. Kaplan-Meier survival plots (log-rank test) and Cox proportional hazards regression analysis, adjusted for age and histology, showed that neither Rb nor p16 expression independently predicted survival. The results of our study suggest that although genetic alterations of Rb and p16 are common in gliomas, immunohistochemical analysis of these markers correlates poorly with prognosis.
Adolescent↗
Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.
Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
Adolescent↗
Revisiting the truth-telling debate: a study of disclosure practices at a major cancer center.
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Cancer Care Facilities↗
Hazard function estimators: a simulation study.
Kernel-based methods for the smooth, non-parametric estimation of the hazard function have received considerable attention in the statistical literature. Although the mathematical properties of the kernel-based hazard estimators have been carefully studied, their statistical properties have not. We reviewed various kernel-based methods for hazard function estimation from right-censored data and compared the statistical properties of these estimators through computer simulations. Our simulations covered seven distributions, three levels of random censoring, four types of bandwidth functions, two sample sizes and three types of boundary correction. We conducted a total of 504 simulation experiments with 500 independent samples each. Our results confirmed the advantages of two recent innovations in kernel estimation - boundary correction and locally optimal bandwidths. The median relative improvement (decrease) in mean square error over fixed-bandwidth estimators without boundary correction was 3 per cent for fixed-bandwidth estimators with left boundary correction, 52 per cent locally optimal bandwidths without boundary correction, and 66 per cent for locally optimal bandwidths with left boundary correction. The locally optimal bandwidth estimators with left boundary correction also outperformed three previously published and publicly available algorithms, with median relative improvements in mean square error of 31 per cent, 77 per cent and 80 per cent.
Computer Simulation↗
Informed consent for tissue research.
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Informed Consent↗
Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme: a revelation by parallel gene expression profiling.
We carried out a gene expression profiling study using cDNA array technology with 24 primary glioma tissues of low-grade (oligodendroglioma), intermediate-grade (anaplastic oligodendroglioma and anaplastic astrocytoma), and high-grade (glioblastomas multiforme) tumors and found that insulin-like growth factor binding protein 2 (IGFBP2) was consistently overexpressed only in glioblastoma multiforme. The cDNA array results were confirmed by Northern and Western blotting. The fact that the IGFBP2 gene, which is normally expressed in fetal cells and turned off in adult cells, becomes reactivated in the most advanced stage of glioma suggests that glioma progression is a result of dedifferentiation or results from a block of differentiation. Identification of IGFBP2 as a gene associated with glioma progression demonstrates the power and utility of high-throughput gene expression profiling in cancer gene discovery.
Gene Expression Regulation, Enzymologic↗