Biomedical subjects

M Posner

Publications and source records attributed to M Posner.

At least 19 recordsLinked to original sources

PubMed2006

Gene expression changes in peripheral blood cells provide insight into the biological mechanisms associated with regimen-related toxicities in patients being treated for head and neck cancers.

UNLABELLED: Patients treated with radiotherapy are prone to a constellation of local and systemic toxicities including mucositis, xerostomia, fatigue and anorexia. The biological complexities and similarities underlying the development of toxicities have recently been realized. Mucosal barrier injury is one of the best studied, and gene expression patterns, based on animal tissue samples, have added to its understanding. While investigations gene expression based on tissue samples was valuable, its use precludes more generalizable conclusions relative to common pathogenic mechanisms. Additionally, attempting to define the kinetics of changes in gene expression by sequential sampling is pragmatically unrealistic. Our objectives were: 1. to determine if changes in gene expression could be detected during toxicity development using PBM from patients receiving chemoradiation; 2. to characterize the relationship of expressed genes using graph theory and pathway analysis; and 3. to evaluate potential relationships between the expression of particular genes, canonical pathways, and functional networks in explaining the pathogenesis of regimen-related toxicities. DESIGN: Microarray analysis was performed using PBM-derived cRNA obtained before and 2 weeks after the initiation of chemoradiation in five patients with head and neck cancer who developed documented regimen-related toxicities. We created a database of those genes newly expressed at 2 weeks and evaluated their potential significance relative to toxicity, by canonical pathway analysis, compilation of regional networks around focus genes, and development of a model globalizing the individual functional networks. There was strong concordance between known pathogenic mechanisms of toxicity and the genes, pathways, and networks developed by our data. A role was elicited for unsuspected genes in toxicity development. Our results support the concept that radiation induced toxicities have common underlying mechanisms and demonstrate the utility of PBM as an RNA source for genetic studies. This methodology could be broadly applicable to the study of regimen-related toxicities.

Adult↗

PubMed2006

Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells.

INTRODUCTION: The hedgehog signaling pathway (Hh) is frequently over expressed in pancreatic adenocarcinomas. We studied the potential cytotoxic interactions between cyclopamine, a Hh pathway inhibitor and paclitaxel, cisplatin, gemcitabine and ionizing radiation (IR). METHODS: In vitro clonogenic survival analysis was performed with cyclopamine alone or cyclopamine in combination with paclitaxel, gemcitabine, cisplatin and IR in Hh expressing human pancreatic tumor cells and Hh non-expressing colon cancer cells. Relative cytotoxicity was assessed in combination treatment compared with exposure to single agents. Assays of apoptosis (annexin V) were performed in the presence of cyclopamine, chemotherapeutic agents, and IR. RESULTS: We report that cyclopamine increased the cytotoxic effects of paclitaxel and IR in Hh expressing pancreatic carcinoma cells. These effects were not observed in Hh non-expressing cells. Cyclopamine did not significantly increase killing by cisplatin or gemcitabine in Hh expressing pancreatic cancer cells. CONCLUSIONS: These data suggest strategies to combine Hh inhibitors with radiotherapy and chemotherapeutic agents, specifically paclitaxel and related compounds in the treatment of pancreatic cancer.

Antineoplastic Agents↗

PubMed2006

Salvage procedure for unexpected portal vein thrombosis in living donor liver transplantation.

Portal vein thrombosis (PVT) is considered a relative contraindication to living donor liver transplantation (LDLTx) due to technical difficulty and ethical considerations. So far, there have been a few reported cases of LDLTx with PVT, most of which were treated by thrombectomy with or without a venous conduit. We report a case of LDLTx in an unexpected recipient with grade 4 diffuse PVT, which was successfully managed using a variceal left gastric vein and a deceased donor iliac vein conduit to create a "de novo portal vein" for splanchnic inflow to the right lobe. The patient experienced an uneventful postoperative course with normal blood flow in the de novo portal vein at 1-year follow up. This report demonstrated that a variceal collateral vein can be used as appropriate alternative inflow for the right lobe in LDLTx cases in which an unexpected PVT is encountered.

Humans↗

PubMed2004

Non-resective ablation therapy for hepatocellular carcinoma: effectiveness measured by intention-to-treat and dropout from liver transplant waiting list.

BACKGROUND: Orthotopic liver transplantation (OLT) for patients with small hepatocellular carcinoma (HCC) is widely accepted, and the usefulness of local ablation techniques as a bridge for liver transplantation is still under investigation. METHODS: From December 1997 to February 2003, patients with cirrhosis and T0-T1-T2-T3 stage HCC received multi-modality ablative therapy (MMT) for the treatment of their HCC and were evaluated for OLT; listed, and transplanted when an allograft became available. MMT included radiofrequency ablation (RFA), and/or Trans-Arterial Chemo-Embolization (TACE), and alcohol (EtOH) ablation, followed by Trans-Arterial Chemo-Infusion (TACI), with repeated treatments based on follow up hepatic magnetic resonance imaging (MRI) during the waiting period for OLT. RESULTS: A total of 135 HCC patients were seen at our center within this time frame. The intention-to-treat group included 33 (24.4%) patients with T0, T1, T2, T3 HCC and cirrhosis. There were 31 men and two women. The mean age was 53.6 +/- 7.2 yr. All patients received MMT with a mean of 2.90 +/- 1.5 procedures per patient. Tumor-node-metastasis (TNM) stages at time of listing were: T0 in one patient, T1 in nine patients, T2 in 17 patients, and T3 in six patients. Twenty-eight (85%) patients have received OLT. Five (12.19%) patients were listed and removed (dropout) from the transplant waiting list after waiting 5, 5, 5, 8, and 14 months respectively. The waiting time of the HCC listed group was 9.1 +/- 14.8 months with a mean follow up of 32 months. OLT patient survival and cancer-free survival are 92.9% and 95.24%, respectively; the overall survival of intention-to-treat group was 79% at 32 months follow up. Predictors of dropout included an alpha-fetoprotein (AFP, >400 ng/mL) and T3 HCC stage. CONCLUSION: Aggressive ablation therapy with a short transplant waiting time optimizes the use of OLT for curative intent in selective cirrhotic HCC patients.

Antineoplastic Agents↗

PubMed2003

Non-resective ablation and liver transplantation in patients with cirrhosis and hepatocellular carcinoma (HCC): safety and efficacy.

We investigated the efficacy of nonresective ablation techniques and the tumor-free survival of cirrhotic patients undergoing liver transplantation for hepatocellular carcinoma (HCC). In group 1, 11 HCC patients were treated with these techniques and transplanted. On the waiting list, patients were treated to complete ablation, judged by gadolinium-enhanced MRI and alpha-fetoprotein (AFP) levels. Group 1 was compared with a concurrent group of 10 liver transplant patients (group 2) with incidental HCC (stages T1 three patients, T2 seven patients). The group 1 patients received 36 procedures (4 alcohol ablations, 14 trans -hepatic artery chemo-embolizations, 15 trans -hepatic chemo-infusions, and 3 radio frequency ablations) for treatment of 13 liver masses. Tumor-node-metastasis (TNM) stage was reduced in eight patients (72.7%), unchanged in two patients and increased in one patient before transplantation. The mean waiting time for transplantation was 12.9 7.6 months. Both groups had a tumor-free survival of 100%, at 30 12 months post transplant. On pathology, 54.5% of explanted livers had residual viable HCC after tumor treatment, and 36.4% (4/11) explants had synchronous lesions. Non-resective ablation therapy is safe and effective in reducing the HCC progression in cirrhotic patients awaiting liver transplantation. The cancer-free survival rate in this treatment group is equal to that for incidental T1-T2 HCCs.

Adult↗

PubMed2002

Immunobiology and long-term graft function in a transplant heterotopic renal rat model.

BACKGROUND: The Th1-Th2 paradigm proposes clonal expansion of Th2 lymphocytes as the basis of allograft tolerance. The Th2 cells have been found to be present in recipients with long-term allograft survival. However, the presence of Th2 cells and tolerance is not a uniform finding. Previously we have shown that pre-engraftment single dose rapamycin and a 7-d course of cyclosporin induce transplantation tolerance to 120 d. In the present study, we investigated the immunobiology of grafts in a long-term follow-up (>350 d). METHODS: Kidney allografts (n = 7), isografts (n = 5) and single nephrectomy (n = 3) groups were followed for 350 +/- 87 d. Heterotopic kidney transplant was performed by the same surgeon in the allograft group (ACI-Lewis) and the isograft group (Lewis-Lewis). The left kidney was removed in the single nephrectomy group. The allograft group was treated with pre-engraftment single dose rapamycin and a 7-d course of cyclosporin. A kidney biopsy was performed at midpoint time for histological study and tissue was frozen for measuring intragraft cytokine expression (IL-4, IL-10) in all animals. Prior to biopsy, serum blood urea nitrogen (BUN) and creatinine (Cr) levels were studied. Serum BUN, Cr levels, plus 24-h urinary protein (PRO) were measured prior to sacrifice. Randomly, four allograft rats received skin grafts (ACI, Lewis and Buffalo skin donors) after kidney biopsy. Skin grafts were studied for a mean of 6 weeks for signs of acceptance or rejection. Analysis of variance (ANOVA) with Tukey's test was used; p < 0.05 was considered statistically significant. RESULTS: The mean follow up was 352 +/- 87 d. BUN and Cr levels at biopsy time (mean 214 d) were not statistically different between the three groups (p = 0.19 and p = 0.66). At sacrifice (mean 352 d), BUN, Cr and PRO were statistically different between allograft and isograft groups (p = 0.013), and between allograft and single nephrectomy groups (p = 0.027). Functional and histological signs of graft loss occurred in three of seven (42.8%) of the allografts at 352 d. Using BANFF criteria, three allografts at biopsy time and seven allografts (100%) and four isografts (80%) at sacrifice time developed chronic histologic changes. Intragraft overexpression of IL-4 and IL-10 was seen at biopsy and sacrifice time in six of seven allografts and one of five isografts. All donor specific skin grafts (ACI-Lewis) on allografts were accepted and third party (Buffalo) donor skin grafts were rejected in all animals (>95% skin necrosis). CONCLUSIONS: This highly stringent, functional, renal transplant model yields 100% normal renal function as compared with isografts at 120 d follow-up. With the follow-up extended to 350 d, 43% of the allografts loose function and develop a chronic allograft histology despite a demonstrated intragraft Th2 cytokine dominance and donor specific skin graft acceptance.

Animals↗

PubMed2001

Hypothyroidism incidence after multimodality treatment for stage III and IV squamous cell carcinomas of the head and neck.

PURPOSE: Treatment of head-and-neck cancer patients with surgery, radiotherapy (RT), and chemotherapy has been associated with posttherapy hypothyroidism (HT). We evaluated the rate of posttherapy HT in patients with locally advanced squamous cell carcinoma of the head and neck, treated with multimodality therapy to determine which factors might predict this condition and at what interval the condition developed. METHODS: We reviewed the prospectively collected thyroid function data of patients treated with sequential chemotherapy, RT, and neck dissection. The incidence of posttherapy HT was estimated. The patient, tumor, and treatment factors possibly associated with HT were evaluated. RESULTS: Of 203 patients, 118 had data adequate for evaluation. HT developed in 45% at a median of 24.4 months after therapy. HT occurred in 14% and 27% of patients at 6 months and 1 year after treatment, respectively. Univariate and multivariate analyses of sex, age, RT dose, RT fractionation, T and N stage, tumor site, and neck dissection failed to identify a clinically relevant risk factor. CONCLUSIONS: A high number of patients undergoing aggressive organ-sparing multimodality therapy for advanced squamous cell carcinoma of the head and neck are at risk for subsequent HT. We recommend that all patients definitively irradiated to the head and neck region undergo frequent serum thyroid-stimulating hormone screening for HT, beginning 6 months after RT.

Analysis of Variance↗

PubMed2001

Oral cancer in vivo gene expression profiling assisted by laser capture microdissection and microarray analysis.

Large scale gene expression profiling was carried out on laser capture microdissected (LCM) tumor and normal oral epithelial cells and analysed on high-density oligonucleotide microarrays. About 600 genes were found to be oral cancer associated. These oral cancer associated genes include oncogenes, tumor suppressors, transcription factors, xenobiotic enzymes, metastatic proteins, differentiation markers, and genes that have not been implicated in oral cancer. The database created provides a verifiable global profile of gene expression during oral carcinogenesis, revealing the potential role of known genes as well as genes that have not been previously implicated in oral cancer.

Aged↗

PubMed2001

Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer.

PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 10(11) particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication > or = 22 days after injection. CONCLUSION: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.

Adenovirus E1B Proteins↗

PubMed2001

Genes and attention deficit hyperactivity disorder.

The initial molecular genetic studies of attention deficit hyperactivity disorder (ADHD) evaluated two candidate genes (DAT and DRD4) suggested by dopamine theories of this common disorder and its treatment with stimulant medication. The initial reports of weak associations with ADHD have been replicated by many (but not all) investigators, as is expected for genes with small effects. This literature is reviewed, along with emerging literature generated by active research groups investigating additional genes that might contribute to the genetic basis of this complex disorder.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

Defining hepatocellular chimerism in a liver failure patient bridged with hepatocyte infusion.

BACKGROUND: A practical method of monitoring engraftment by transplanted hepatocytes for the purpose of bridging human liver failure to native regeneration is described. METHODS: A previously healthy 37-year-old female with a 2-week history of a febrile illness presented with fulminant liver failure. Findings on admission included the following: illicit drug use, serum hepatitis B surface antigen positive, grade 1 encephalopathy, prothrombin time (pt) >100 sec, F7<1%, NH3 150 micromol/L, alanine aminotransferase 4079 U/L, total bilirubin level 11.4 mg/dl, and glucose 70 mg/dl (on IV D10). With immunosuppression, 8.8x10(8), 96% viable human hepatocytes were intraportally infused. Clinical chemistries, total sHLA class I, and ELISA to measure donor-specific sHLA-A1 and -B8 were recorded. Serial transjugular liver biopsies were performed and pooled for histological examination, DNA extraction, and HLA DNA typing. RESULTS: The patient fully recovered. At months 3 and 4 with donor biopsy specimen class I HLA DNA no longer detectable, immunosuppression was tapered off. The patient is clinically normal, serum hepatitis B surface antigen negative at 10 months of follow-up. CONCLUSIONS: Bridging liver failure with donor hepatocytes with HLA class I antigen disparate from recipients is clinically feasible, and allows for a marker, combined with serial graft histology, to safely wean immunosuppression when native liver regeneration succeeds.

Adult↗

PubMed2000

Dopamine genes and ADHD.

Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993-998, Gill et al., Molecular Psychiatry 1997;2:311-313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121-124: Smalley et al., 1998;3:427-430; Swanson et al., Molecular Psychiatry 1998;3:38-41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37-42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.

Alleles↗

PubMed2000

The N-terminal V3 loop glycan modulates the interaction of clade A and B human immunodeficiency virus type 1 envelopes with CD4 and chemokine receptors.

We investigated the underlying mechanism by which the highly conserved N-terminal V3 loop glycan of gp120 conferred resistance to neutralization of human immunodeficiency virus type 1 (HIV-1). We find that the presence or absence of this V3 glycan on clade A and B viruses accorded various degrees of susceptibility to neutralization by antibodies to the CD4 binding site, CD4-induced epitopes, and chemokine receptors. Our data suggest that this carbohydrate moiety on gp120 blocks access to the binding site for CD4 and modulates the chemokine receptor binding site of phenotypically diverse clade A and clade B isolates. Its presence also contributes to the masking of CD4-induced epitopes on clade B envelopes. These findings reveal a common mechanism by which diverse HIV-1 isolates escape immune recognition. Furthermore, the observation that conserved functional epitopes of HIV-1 are more exposed on V3 glycan-deficient envelope glycoproteins provides a basis for exploring the use of these envelopes as vaccine components.

Binding Sites↗

PubMed2000

Laser capture microdissection-generated target sample for high-density oligonucleotide array hybridization.

Current advances in biomolecular technology allow precise genetic fingerprinting of specific cells responsible for the pathogenesis of human diseases. This study demonstrates the feasibility of generating target samples from laser capture microdissection (LCM) tissues suitable for hybridization of high-density oligonucleotide arrays for gene expression profiling. RNA was successfully isolated by LCM from three paired specimens of oral cancer and linearly amplified using T7 RNA polymerase. Evaluation of the cDNA revealed that five of five cellular maintenance transcripts are detected. Biotinylated cRNA was generated and hybridized to the human Test 1 GeneChip probe arrays, which demonstrated that the RNA is of sufficient quality and integrity to warrant further analysis. Subsequent hybridization of the samples to the HuGenFL GeneChip probe arrays revealed that 26.5%-33.0% of the approximately 7000 represented genes are expressed in each of the six samples. These results demonstrate that LCM-generated tissues can generate sufficient quality cRNA for high-density oligonucleotide microarray analysis, an important step in determining comprehensive gene expression profiling using this high-throughput technology.

Biotinylation↗

PubMed1999

Cloning, sequencing and differential expression of alphaB-crystallin in the zebrafish, Danio rerio.

Here we report the cloning and expression of alphaB-crystallin from the zebrafish. 5'- and 3'-RACE was used to isolate a 900-bp transcript that contained insertions and deletions that differentiate it from both alphaA-crystallin and HSP-27. The deduced amino acid sequence of zebrafish alphaB-crystallin revealed that it lacked four residues in the C-terminus implicated in protein-protein interactions in other vertebrate species. In addition, the sequence contained two substitutions at sites implicated in phosphorylation in other vertebrate species. Northern analysis and semi-quantitative RT-PCR indicate that zebrafish alphaB-crystallin is expressed at extremely low levels outside of the lens.

Amino Acid Sequence↗

PubMed1999

Intragenic mutation analysis of the human epidermal growth factor receptor (EGFR) gene in malignant human oral keratinocytes.

Alteration in epidermal growth factor receptor (EGFR) expression is frequently associated with malignant transformation of epithelial tissues, including oral mucosa. This study examines the mutations in the coding region of the human EGFR gene in normal and malignant human oral keratinocytes. To examine the intragenic mutations in the human EGFR gene, a panel of normal and malignant human oral keratinocytes were examined by a nonisotopic RNase cleavage assay. Two consistent alterations were detected. First, a polymorphism, which generates a unique BsrI restriction site, was detected at position 2073. This BsrI polymorphism was present only in malignant keratinocytes. Second, Southern blot hybridization of PCR products revealed that there is a truncated EGFR mRNA (approximately 1.5-kb) in oral squamous cell carcinoma cell lines. Similar analysis in normal cell lines revealed that this truncated EGFR transcript is also present. Immunoblotting revealed the presence of this truncated form of EGFR in all keratinocyte cell lines. These data permit us to conclude that there exists a novel truncated form of EGFR in human oral keratinocytes. Furthermore, there exists a tumor-associated BsrI polymorphic site at position 2073. The potential biological relevance of the truncated receptor and the utility of the BsrI polymorphic site for diagnostic applications are currently being explored.

Carcinoma, Squamous Cell↗

PubMed1998

Flow cross-matching identifies patients at risk for postoperative elaboration of cytotoxic antibodies.

BACKGROUND: Cytotoxic IgG against class I antigens can contribute to renal dysfunction or failure after transplantation. However, the clinical relevance of IgG measured by flow cytometric cross-matching is controversial. This study correlated pre- and postoperative flow reactivity with clinical outcome among renal transplant patients with negative preoperative cytotoxic cross-matches. METHODS: Nonsensitized primary renal allograft patients (n = 157) with negative preoperative cytotoxic cross-matches (complement-dependent lymphocytotoxicity assays) were stratified on the basis of IgG reactivity measured by flow cytometric cross-matching (FCXM) as FCXM negative (Neg) or positive against class I (T-pos FCXM) or class II (B-pos FCXM) antigens. The groups were compared in terms of frequency of early rejection and 1-year graft survival. RESULTS: Patient distribution was 67% Neg, 14% T-pos FCXM, 14% B-pos FCXM, and 5% IgM FCXM. The incidence of early rejection was 25+/-3% for Neg and 51+/-3% for T- and B-pos FCXM (P < 0.05). One-year graft survival for Neg versus T-pos and B-pos FCXM was 97+/-3% versus 44+/-10% (P < 0.05) and 77+/-5% (P = 0.06), respectively. Rejections requiring plasmapheresis were found only among patients with T-pos FCXM. Among 29 patients, FCXM and complement-dependent lymphocytotoxicity assays were performed 10+/-2 and 28+/-4 days after transplantation. Pre- and posttransplant antibody levels were relatively unchanged among Neg and B-pos FCXM patient groups. In contrast, patients with T-pos FCXM produced cytotoxic IgG against class I after transplantation, which may have contributed to the severe graft dysfunction experienced by this group. CONCLUSIONS: FCXM is a useful tool to stratify primary renal transplant candidates in terms of potential risk for severe rejection. Furthermore, demonstration of preoperative flow reactivity against class I may identify a subgroup of patients at risk for early elaboration of cytotoxic alloantibody.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1998

Apoptosis in esophageal cancer following induction chemoradiotherapy.

BACKGROUND: The poor survival of patients with esophageal cancer following esophagectomy has led to intense investigation into combined modality therapy. Based on results from clinical trials examining chemoradiotherapy alone without surgery, resection has come under increased scrutiny and its necessity as a component of a multimodal approach has been questioned. In this study, we examined whether residual tumor cells in esophagectomy specimens following induction chemoradiotherapy are viable and, therefore, provide putative evidence for the appropriateness of esophagectomy. MATERIALS AND METHODS: Between August 1991 and January 1995, 46 patients were entered into an induction chemoradiotherapy trial consisting of 5-fluorouracil, cisplatin, alpha-interferon, and concurrent external beam radiotherapy followed by esophagectomy. Response was determined histologically and apoptosis assessed with a terminal deoxytransferase assay system. p53 status was determined by immunohistochemistry and mutational analysis. RESULTS: Thirty-eight patients underwent esophagectomy, 33 of whom had either a complete (n = 10) or partial (n = 23) response. None of the 28 patients with residual tumor in the resected specimen had 100% apoptotic cells and the vast majority of specimens had less than a 10% apoptotic rate. The percentage of apoptotic cells did correlate with tumor differentiation but not with histologic type nor presence of p53 mutations. CONCLUSIONS: These data suggest that resection following upfront chemoradiotherapy is a necessary component of a multimodality approach to esophageal cancer and will ultimately provide superior local-regional control to a nonsurgical approach.

Adult↗