Biomedical subjects

Alex Smith

Publications and source records attributed to Alex Smith.

17 recordsLinked to original sources

PubMed2026

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans↗

PubMed2006

Childhood leukaemia and socioeconomic status: fact or artefact? A report from the United Kingdom childhood cancer study (UKCCS).

BACKGROUND: It is widely believed that children of high socioeconomic status (SES) are more likely than those of low SES to develop acute lymphoblastic leukaemia (ALL). Such observations have led to wide-ranging speculations about the potential aetiological role of factors associated with affluence and modernization. METHODS: Children (0-14 years) newly diagnosed with cancer in the UK between 1991 and 1996 were ascertained via a rapid hospital-based case finding system (n = 4430, of which 1578 were ALL). Children without cancer (controls) were randomly selected from primary care population registries for comparative purposes (n = 7763). Area-based deprivation scores were assigned as markers of SES at two time points - birth and diagnosis. An individual-based marker of SES - social class - was assigned using father's occupation as recorded on the child's birth certificate. RESULTS: No differences in area-based measures of deprivation were observed between cases and controls at time of diagnosis, either for all cancers combined [n = 4430, odds ratio (OR) = 1.00 (95% confidence intervals (CI) 0.98-1.01)] or for ALL alone (n = 1578 OR = 0.99, 95%CI 0.96-1.01). Findings were similar at time of birth (all cancers, OR = 0.99 95%CI 0.98-1.01, ALL OR = 0.98, 95%CI 0.96-1.00). In addition, no case-control differences were observed when an individual-based measure of SES - social class - based on father's occupation at time of birth was used. CONCLUSIONS: The comprehensive nature of the data, coupled with complete case-ascertainment and representative population-based controls suggests that SES in the UK is not a determinant of ALL in children. We believe the small effects reported for SES in some past studies may be artefactual.

Adolescent↗

PubMed2006

Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression.

OBJECTIVES: To analyze post-androgen depletion (AD) primary tumors to identify markers of treatment failure because AD does not reduce the probability of prostate-specific antigen (PSA) failure after prostatectomy. METHODS: Tumors removed by radical prostatectomy after 3 months of AD from 21 patients were analyzed for gene expression using oligonucleotide arrays. Differences between patients with and without relapse were identified using a conservative significance criteria of a threefold change and delta 0.68, ensuring a false discovery rate of less than 11%. RESULTS: At 50 months of follow-up, 7 of the 18 evaluable patients developed a biochemical recurrence. Gleason grade, pretherapy PSA level, T stage, and margin status were similar between the two groups. Patients with recurrence had greater post-AD PSA levels than those without recurrence (0.87 versus 0.19 ng/mL; P = 0.042). Gene expression analysis revealed 35 probe sets overexpressed in tumors from patients who relapsed. Among the highest ranked probe sets were PSA and other androgen-responsive genes. Serum PSA values during AD revealed similar findings. After 40 days of AD, the PSA level in those without recurrence was 1.21 ng/mL versus 4.5 ng/mL in those with recurrence (P = 0.0034). Immunohistochemistry of post-AD tumors also demonstrated a high PSA staining intensity in many tumors that recurred relative to those that didn't. CONCLUSIONS: The results of our study show that early recurrence is associated with expression of androgen-responsive genes. Surprisingly, these could be identified as early as 3 months after the initiation of AD therapy. Whether this represents a failure to abrogate androgen receptor mediated signaling with androgen depletion or early reactivation of signaling is under study.

Androgen Antagonists↗

PubMed2005

Integration of gene expression profiling and clinical variables to predict prostate carcinoma recurrence after radical prostatectomy.

BACKGROUND: Gene expression profiling of prostate carcinoma offers an alternative means to distinguish aggressive tumor biology and may improve the accuracy of outcome prediction for patients with prostate carcinoma treated by radical prostatectomy. METHODS: Gene expression differences between 37 recurrent and 42 nonrecurrent primary prostate tumor specimens were analyzed by oligonucleotide microarrays. Two logistic regression modeling approaches were used to predict prostate carcinoma recurrence after radical prostatectomy. One approach was based exclusively on gene expression differences between the two classes. The second approach integrated prognostic gene variables with a validated postoperative predictive model based on standard variables (nomogram). The predictive accuracy of these modeling approaches was evaluated by leave-one-out cross-validation (LOOCV) and compared with the nomogram. RESULTS: The modeling approach using gene variables alone accurately classified 59 (75%) tissue samples in LOOCV, a classification rate substantially higher than expected by chance. However, this predictive accuracy was inferior to the nomogram (concordance index, 0.75 vs. 0.84, P = 0.01). Models combining clinical and gene variables accurately classified 70 (89%) tissue samples and the predictive accuracy using this approach (concordance index, 0.89) was superior to the nomogram (P = 0.009) and models based on gene variables alone (P < 0.001). Importantly, the combined approach provided a marked improvement for patients whose nomogram-predicted likelihood of disease recurrence was in the indeterminate range (7-year disease progression-free probability, 30-70%; concordance index, 0.83 vs. 0.59, P = 0.01). CONCLUSIONS: Integration of gene expression signatures and clinical variables produced predictive models for prostate carcinoma recurrence that perform significantly better than those based on either clinical variables or gene expression information alone.

Aged↗

PubMed2005

A theoretical approach to choosing the minimum number of multiple tumors required for assessing treatment response.

BACKGROUND AND OBJECTIVE: Most advanced cancer patients have multiple tumors. Because the multiple tumors are from the same patient, the tumor sizes are expected to be correlated and the information contained in each additional tumor might not always have significant 'added value' toward the response assessment. Needing to measure only a subset of tumors would reduce workload for the study radiologist but is expected to increase the variability in response outcome. We compute this increment in variability and find a procedure for choosing the minimum number (m) of tumors among some fixed maximum number (M) of correlated tumors that must be considered to ensure precision of at least as high as a specified proportion of the precision obtained if one were to measure all M tumors. METHOD: The ratio V(m)(R)/V(M)(R) = M2[m + (m2 - m)rho(ICC)]/m2[M + (M2 - M)rho(ICC)] quantifies the percentage increment in variance of the response R, where rho(ICC) is the intra-class between tumors within patient correlation coefficient. The procedure for choosing the minimum number of tumors is demonstrated using data for 42 cancer patients with 10 or more tumors. RESULTS: Using the criterion that >20% increase in variability due to selection of a subset out of M of 10 tumors is unacceptable, we find that m of 9, 6, 5, 3, and 2 tumors are needed when rho(ICC)=0.0 (no correlation), 0.2, 0.4, 0.6, and 0.8, respectively. If the criterion is made stricter to >10%, the number of tumors needed rise to 10, 8, 6, 4, and 3, respectively. For the example, 6 tumors out of 10 are found to provide sufficiently stable response categorization confirming the theoretical result. CONCLUSION: If cancer research community can agree on a percentage of variability in response outcome that is unacceptable, it is mathematically possible to recommend a minimum number of tumors that should be used for response assessment.

Data Collection↗

PubMed2005

Polymorphisms in cytochrome P450 17A1 and risk of non-Hodgkin lymphoma.

Broad cross-talk exists between the endocrine and immune systems. Estrogen receptor expression in lymphocytes suggests that hormonal modulation may influence lymphoma risk. Analysis of genetic polymorphisms that affect oestrogen production, such as cytochrome P450 17A1 (CYP17A1) -34T>C, may provide insight into oestrogen's role in lymphomagenesis. CYP17A1-34T>C and CYP17A1 IVS2 105A>C polymorphisms were analyzed in a non-Hodgkin lymphoma (NHL) population-based case-control study. The CYP17A1-34CC genotype was positively associated with NHL [odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.02-2.03], particularly diffuse large B-cell lymphoma (OR = 1.76, CI 1.14-2.71). Associations of CYP17A1 polymorphisms with increased risk of NHL suggest a role for oestrogen in lymphomagenesis.

Adolescent↗

PubMed2004

Localization of cancer susceptibility genes by genome-wide single-nucleotide polymorphism linkage-disequilibrium mapping.

With the large numbers of single nucleotide polymorphisms (SNPs) available and new technologies that permit high throughput genotyping, we have investigated the possibility of the localization of disease genes with genome-wide panels of SNP markers and taking advantage of the linkage-disequilibrium (LD) between the disease gene and closely linked markers. For this purpose, we selected cases from the Ashkenazi Jewish population, in which the mutant alleles are expected to be identical by descent from a common founder and the regions of LD encompassing these mutant alleles are large. As a validation of this approach for localization, we performed two trials: one in autosomal recessive Bloom syndrome, in which a unique mutation of the BLM gene is present at elevated frequencies in cases, and the other in autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC), in which a unique mutation of MSH2 is present at elevated frequencies. In the Bloom syndrome trial, we genotyped 3,258 SNPs in 10 Jewish Bloom syndrome cases and 31 non-Bloom syndrome Jewish persons as a comparison group. In the HNPCC trial, we genotyped 8,549 SNPS in 13 Jewish HNPCC cases whose colon cancers exhibited microsatellite instability and in 63 healthy Jews as a comparison group. To identify significant associations, we performed (a) Fisher's exact test comparing genotypes at each locus in cases versus controls and (b) a haplotype analysis by estimating the frequency of haplotypes with the expectation-maximization algorithm and comparing haplotype frequencies in cases versus controls by logistic regression and a maximum likelihood ratio method. In the Bloom syndrome trial, by Fisher's exact test, statistically significant association was detected at a single locus, TSC0754862, which is a locus 1.7 million bp from BLM. Two-locus, three-locus, and four-locus haplotypes that included TSC0754862 and flanked BLM were also statistically more frequent in cases versus controls. In the HNPCC trial, although a significant P value was not obtained by the single SNP genotype analysis, significant associations were detected for several multilocus haplotypes in an 11-million-bp region that contained the MSH2 gene. This work demonstrates the power of the LD mapping approach in an isolated population and its general applicability to the identification of novel cancer-causing genes.

Adenosine Triphosphatases↗

PubMed2004

A statistical simulation study finds discordance between WHO criteria and RECIST guideline.

OBJECTIVE: Tumor shrinkage has been adopted as an end point for evaluating the effectiveness of new anticancer agents. The WHO (World Health Organization) criterion suggested measuring the tumor shrinkage by the change in the product of maximal diameter (MD) and the corresponding largest perpendicular diameter (LPD). The RECIST (Response Evaluation Criteria In Solid Tumor) guideline proposed using the change in MD only, based on the observation that this measure is more linearly related to tumor cell kill than the cross product (MD*LPD). Both criteria classify patients into four categories of response: complete response (CR: total disappearance), partial response (PR), stable disease (SD), and progressive disease (PD) but the criteria used in the definition of PD vary. It was anticipated that patients' actual response categorization would not be considerably affected by utilizing the RECIST criteria instead of WHO. Empirical evidence supporting this fact was provided by retrospective analysis of several large datasets. STUDY DESIGN AND SETTING: A statistical simulation is performed to generate tumor measurements and patient response data under meaningful probability distributions with parameters based on data from 130 patients on clinical trials at a cancer center. Concordance measures between the two response criteria (Kappa coefficient and percentage disagreement per response category) are assessed systematically over various combinations of the percentage of elliptical tumors at baseline and the percentage of tumors changing shape from baseline to follow-up. RESULTS: The overall percentage of disagreement between the two methods of response assessment is found to be in the range of 14-20%. The patients categorized by WHO in the PR, SD, and PD groups fall into a different category when assessed by RECIST between 8-16%, 3-12%, and 32-35% of the times, respectively. The kappa coefficient ranges between 0.68-0.77. The proportion of elliptical tumors at baseline does not greatly impact the concordance, but the magnitude of the change in the aspect ratio has a large impact. CONCLUSION: Response assessment as measured by RECIST, with both a change in the underlying metric and change in definition of progression, often results in different categorization of response compared to WHO. The difference in response categorization may be problematic when new experimental therapies are compared to conventional agents whose response rates have been established in historical trials. The apparent lower rate of disease progression with RECIST may mean that more patients remain on therapy. Higher percentages of patients with SD need to be interpreted cautiously by distinguishing those due to the change in the response criterion as opposed to those induced by drugs using pathways such as angiogenesis where disease stabilization is expected rather than shrinkage of tumor.

Antineoplastic Agents↗

PubMed2004

Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance.

The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.

Algorithms↗

PubMed2003

Response assessment classification in patients with advanced renal cell carcinoma treated on clinical trials.

BACKGROUND: The objective of the current study was to evaluate the effect on response assessment classification in patients with metastatic renal cell carcinoma (RCC) using unidimensional (Response Evaluation Criteria in Solid Tumors) and bidimensional (World Health Organization) criteria, including or excluding measurements of the primary renal tumor and using a new index to compensate for the disproportionate effect of large renal tumors relative to their metastases. METHODS: Fifty-three imaging studies involving a total of 44 patients with metastatic RCC who were treated on clinical trials of interferon-alpha analogue and/or thalidomide were reviewed retrospectively. The best overall response assessment and progression free survival were calculated with both unidimensional and bidimensional tumor measurements. Patients were then stratified into two groups: patients with primary renal tumors in situ and patients who underwent resection of their primary renal tumors. The best overall response and the time to disease progression were calculated based on the sum of measurements (conventional methodology), both including and excluding the primary tumor. A new method of response assessment, the 'normalized lesion index', which equalizes the differences in tumor size for an individual patient, was evaluated and compared with the conventional response assessment. RESULTS: There was an 11% disagreement rate in the best overall response assessment between unidimensional and bidimensional measurements. The time to progression was 9.2 months measured unidimensionally, compared with 6.4 months assessed bidimensionally. In the group of patients who had primary renal tumors in situ, using the conventional sum of measurements method, the apparent time to progression was an average of 4.2 months longer compared with measurements that did not include the primary renal tumor. The use of the normalized lesion index method resulted in an improved concordance in best overall response assessments and similar time to progression assessments when the primary renal tumor was included compared with patients who did not have primary renal tumors in situ. CONCLUSIONS: The use of unidimensional measurements in RCC therapy assessment results in significantly different time to progression classification compared with the use of bidimensional measurements. Response assessment classification in patients with RCC is affected by the exclusion or inclusion of measurements of the primary renal tumor. The normalized lesion index warrants further study in assessing response in patients with metastatic RCC and other solid tumor malignancies that often show substantial differences in sizes of measurable lesions.

Adult↗

PubMed2003

Variability in response assessment in solid tumors: effect of number of lesions chosen for measurement.

PURPOSE: This study was performed to systematically evaluate the variability in tumor response assessments that occurs depending on how many tumor deposits are selected for measurement at imaging. EXPERIMENTAL DESIGN: The two largest perpendicular diameters of all tumor deposits in 36 patients were measured on computed tomography scans obtained at baseline and first posttherapy follow-up. A computerized modeling analysis of those data was performed to determine each patient's therapeutic response category assignment for every possible number of lesions in a grouping. The variance in the sum of measurements of these lesion groupings was calculated, and the frequency of response assessment categories was plotted against the number of lesions. RESULTS: The computerized analysis of the resultant 1,833,821 possible combinations of tumor deposits showed that when six lesions were measured bidimensionally and four lesions were measured undimensionally, the average variance decreased by 90%. The number of different response assessment categories into which a patient was assigned decreased with increasing lesion grouping size. When six or more lesions were measured bidimensionally, 9% of all possible lesion groupings still fell into a second response category, reflecting the effect of which particular lesions are chosen for measurement. CONCLUSIONS: Measuring larger numbers of lesions will decrease the variance. In this population, the variance decreased by at least 90% when six or more lesions were measured bidimensionally. Further confirmatory studies with larger series of patients are warranted before adopting this number as a criterion in clinical trials for assessing the activity of antineoplastic therapies.

Adult↗

PubMed2003

Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma.

Molecular mechanisms through which MYCN expression contributes to the malignant phenotype of neuroblastoma are unknown. We performed a genome-widegene expression analysis of 40 well-characterized neuroblastic tumors and 12 cell lines to identify genes and biological pathways associated with MYCN expression. Gene expression was validated by reverse transcription-PCR and immunohistochemistry using tissue arrays. Two hundred twenty-two of 62,839 oligonucleotide probe sets detected expression of genes that were strongly associated with MYCN expression. Differentially expressed genes included examples of known oncogenes, genes associated with neural differentiation, and genes related to cell proliferation. Expression of a subset of these genes was altered after transfection of a neuroblastoma cell line, SK-N-ER, with a MYCN expressing gene construct when protein synthesis was inhibited and have consensus MYCN binding E-box sequences in their promotor regions, suggesting they represent direct targets. Several novel genes/expressed sequences were identified as overexpressed and most likely coamplified with MYCN in a subset of cases. A classification model to identify neuroblastomas with high levels of MYCN expression was developed based on expression profiles. The identification of coexpressed and coamplified genes associated with MYCN overexpression in neuroblastoma suggests biochemical pathways that contribute to the malignant behavior of these tumors and forms a basis for molecular classification.

Cell Nucleus↗

PubMed2003

Methods for categorizing a prognostic variable in a multivariable setting.

The literature is filled with examples of categorization of a continuous prognostic variable in a univariable setting followed by the addition of this categorical variable to an existing multivariable model. Typically, an "optimal" cutpoint for a new prognostic variable is obtained through a systematic search relating the variable to the outcome in an univariable manner. The corresponding categorical variable is then fitted in a multivariable model along with other already established prognostic covariates to assess the additional value of the new variable. This prompts the question whether the cutpoint search should have been performed in the same multivariable setting where it will ultimately be used. In this paper, we extend the univariable cutpoint search methods (split-sample approach and two-fold cross-validation approach) to the multivariable setting using -2 x log-likelihood statistic as the correlative measure. A Monte Carlo simulation study demonstrates that both methods are more efficient in detecting the true cutpoint and in estimating the effect size under the multivariable setting as opposed to the univariable setting. The cross-validation method performs better than the split-sample method in univariable as well as multivariable scenarios. For the cross-validation method in the multivariable setting, there is still a substantial loss of power when a cutpoint model is used in cases where there is a continuous relationship between the covariate and the outcome. An example is provided to illustrate the value of the multivariable cross-validation approach.

Humans↗

PubMed2002

Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease.

The identification of genes that contribute to the biological basis for clinical heterogeneity and progression of prostate cancer is critical to accurate classification and appropriate therapy. We performed a comprehensive gene expression analysis of prostate cancer using oligonucleotide arrays with 63,175 probe sets to identify genes and expressed sequences with strong and uniform differential expression between nonrecurrent primary prostate cancers and metastatic prostate cancers. The mean expression value for >3,000 tumor-intrinsic genes differed by at least 3-fold between the two groups. This includes many novel ESTs not previously implicated in prostate cancer progression. Many differentially expressed genes participate in biological processes that may contribute to the clinical phenotype. One example was a strong correlation between high proliferation rates in metastatic cancers and overexpression of genes that participate in cell cycle regulation, DNA replication, and DNA repair. Other functional categories of differentially expressed genes included transcriptional regulation, signaling, signal transduction, cell structure, and motility. These differentially expressed genes reflect critical cellular activities that contribute to clinical heterogeneity and provide diagnostic and therapeutic targets.

Adult↗

PubMed2002

Intraperitoneal chemotherapy for ovarian carcinoma: results of long-term follow-up.

PURPOSE: To determine long-term survival and predictors of recurrence in a retrospective cohort of patients with epithelial ovarian cancer treated with intraperitoneal (IP) chemotherapy. PATIENTS AND METHODS: Records were reviewed of 433 patients who received IP therapy for ovarian cancer between 1984 and 1998; follow-up data were available for 411 patients. IP therapy was provided as consolidation therapy (n = 89), or for treatment of persistent (n = 310) or recurrent (n = 12) disease after surgery and initial systemic therapy; therapy usually consisted of platinum-based combination therapy. Statistical analysis included tests for associations between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox proportional hazard model. RESULTS: The mean age of patients was 52 years (range, 25 to 76 years). Distribution by stage and grade was as follows: stage I, 7; II, 24; III, 342; IV, 52; not available (NA), 8; and grade 1, 30; 2, 99; and 3, 289; NA, 15. The median survival from initiation of IP therapy by residual disease was none, 8.7 years; microscopic, 4.8 years; less than 1 cm, 3.3 years; more than 1 cm, 1.2 years. In a multivariate analysis, the only significant predictors of long-term survival were grade and size of residual disease at initiation of IP therapy. CONCLUSION: Prolonged survival was observed in selected patients receiving IP platinum-based therapy. It is not possible to determine the contribution of IP therapy to survival in this study. A relationship between size of disease at the initiation of IP therapy and long-term survival was demonstrated.

Adenocarcinoma↗

PubMed2002

An optimal two-stage phase II design utilizing complete and partial response information separately.

Phase II clinical trials in oncology are performed to evaluate the therapeutic efficacy of a new treatment regimen. A common measure of efficacy for these trials is the proportion of patients who obtain a response measured by tumor shrinkage. It is standard practice to classify this response into the following categories: (1) complete response (CR); (2) partial response (PR); (3) stable disease; and (4) progression of disease. Tumor response is then treated as a binary variable whereby patients who achieve either a CR or a PR are considered responders and all others nonresponders. A two-stage design that allows for early termination of the trial if the treatment shows little efficacy such as Gehan or Simon gives equal weight to a CR and a PR. However, a CR, defined as complete disappearance of the tumor, is more likely than a PR to signal an important antitumor effect and result in a survival advantage. We argue that CRs and PRs should be considered separately, and hence we propose a two-stage design with a multilevel endpoint (i.e., CR, PR, and nonresponders). This design is an extension of Simon's optimal two-stage design and is based on a trinomial model. For most scenarios the proposed design results in an improvement in expected sample size compared to Simon's optimal design. Design optimization was performed by a direct search based on enumerating exact trinomial probabilities. Sample size tables are provided for parameter sets commonly used in the oncologic setting. Software is available by contacting the authors.

Clinical Trials, Phase II as Topic↗

PubMedDate not supplied

Clinical value of combined positron emission tomography/computed tomography imaging in the interpretation of 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography studies in cancer patients.

BACKGROUND: Positron emission tomography (PET)/computed tomography (CT) is a new imaging modality that provides exact coregistration of anatomic and metabolic data. We have investigated to what degree this new technique might affect the interpretation of PET images in a nonselected group of consecutive cancer patients, reflecting routine condition in a busy cancer center. METHODS: Whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET and PET/CT fusion image sets were compared in 100 consecutive, nonselected patients: 21 with head and neck cancer, 39 with chest malignancies, and 40 with malignancies of the abdomen and pelvis. All studies were performed for primary staging or evaluation of therapy and were interpreted by two nuclear medicine physicians also trained in radiology. Areas of abnormal FDG uptake were identified on PET and graded as likely benign, equivocal, or likely malignant. Positron emission tomography/computed tomography fusion images were then made available, and the initial findings were amended if necessary. RESULTS: One hundred sixty-six areas with abnormal FDG uptake were identified. Based on PET alone, 51 sites were considered equivocal for malignancy. With PET/CT, the number of equivocal lesions decreased to 24. This difference is more marked in the head and neck as well as the abdomen and pelvis. When the equivocal sites were included in the analysis and grouped with the malignant sites, positive predictive value (PPV) of PET/CT was 89% compared with 75% for PET (p = 0.04). CONCLUSION: Combined PET/CT results in increased reader confidence and 53% fewer equivocal readings, as well as improved PPV compared with PET alone.

Adolescent↗