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Axel Hoos

Publications and source records attributed to Axel Hoos.

At least 19 recordsLinked to original sources
PubMed2007

A clinical development paradigm for cancer vaccines and related biologics.

Therapeutic cancer vaccines are a heterogeneous group of complex biologics with distinctly different clinical characteristics than cytotoxic agents. The current clinical development paradigm used for oncology drug development is based on criteria developed for cytotoxic agents. More flexible and focused developmental guidelines are needed to address the unique characteristics of therapeutic cancer vaccines. Over the course of 1 year, the Cancer Vaccine Clinical Trial Working Group, representing academia and the pharmaceutical and biotechnology industries with participation from the US Food and Drug Administration, defined in a consensus process the cornerstones of a new clinical development paradigm for cancer vaccines and related biologics. Four major topics were addressed: (1) end points for clinical trials, (2) trial designs and statistical methods, (3) technical and developmental challenges, and (4) combination therapy. The proposed paradigm suggests therapeutic cancer vaccines to be investigated in 2 general types of clinical studies: proof-of-principle trials and efficacy trials. Proof-of-principle trials, which introduce a novel cancer vaccine into humans, should include a minimum of 20 or more patients in a homogenous, well-defined population in an adjuvant setting or without rapidly progressive disease in a metastatic setting to allow vaccines adequate time to induce biologic activity and should incorporate immune and molecular markers. Objectives should include initiation of a safety database, determination of dose and schedule, and demonstration of biologic activity as proof-of-principle. Biologic activity is defined as any effect of the vaccine on the target disease or host immune system using biologic markers as study end points, for example, clinical, molecular, or immune response. Immune response is demonstrated if determined in 2 separate, established and reproducible assays at 2 consecutive follow-up time points after the baseline assessment. If proof-of-principle trials show such immune response, or other biologic or clinical activity, efficacy trials may be initiated. If none of these end points is met, the clinical development plan should be reevaluated to decide if further development is warranted. Efficacy trials formally establish clinical benefit either directly or through a surrogate and are encouraged to be randomized studies. This is in contrast to single-arm phase 2 trials used for cytotoxic agents, which often use tumor response rate as the primary end point and historical controls as a comparator. Efficacy trials may use prospectively planned adaptive designs to expand from randomized phase 2 into phase 3 studies if well-defined trigger-point criteria are met, but the cost of incorporating such design elements should be carefully evaluated. Efficacy trials can also be exploratory randomized phase 2 trials or conventional phase 3 trials. In addition, conventional clinical end points can be adjusted to account for biologic features of cancer vaccines. The concept of efficacy trials allows for an early assessment of vaccine efficacy based on credible prospective data. This 2-phase developmental paradigm supports a more flexible, expeditious, and focused clinical developmental process with early and informed decision making. In addition, this report addresses clinical development challenges and issues for combination therapies.

Cancer Vaccines↗
PubMed2006

Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone.

PURPOSE: Treatment of rectal cancer with neoadjuvant radiotherapy has been shown to reduce local recurrence and improve overall survival. The role of chemoradiotherapy in patients with T2, N0 and early T3, N0 rectal cancer, treated by radical surgery with total mesorectal excision, remains controversial. The aim of this study was to identify predictors of recurrence in this group of patients to enhance treatment selection. PATIENTS AND METHODS: One hundred patients with primary T2-3, N0 adenocarcinoma of the rectum, uniformly treated by surgery alone, were studied. The pathology slides available for 97 patients were rereviewed. Three patients with incomplete data sets were excluded. Clinical and survival data were obtained from a prospective computerized database and updated from hospital and office charts. The study end points were disease-free survival, disease-specific survival (DSS), time to pelvic recurrence (PR), and distant recurrence. RESULTS: Complete follow-up was available for all study patients. Median follow-up was 79.5 months (range, 57.7 to 105.9 months). During this time period 30 patients (31.9%) died as a result of disease and 64 patients (68.1%) remained alive and disease free. Five-year DSS was 73%. The cumulative risk for PR was 8% at 5 years and 10% at 8 years. Lymphovascular invasion, preoperative serum carcinoembryonic antigen (CEA > 5 ng/mL) level, and age older than 70 years were all associated with adverse outcome. CONCLUSION Patients with T2-3, N0 rectal cancers and either lymphovascular invasion or elevated CEA levels have reduced survival and a higher incidence of PR, and should be considered for future randomized trials.

Adenocarcinoma↗
PubMed2006

A Phase 2 trial of the liposomal DACH platinum L-NDDP in patients with therapy-refractory advanced colorectal cancer.

PURPOSE: L-NDDP (Aroplatin) is a liposomal formulation of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II), a structural analogue of oxaliplatin. In a Phase 1 trial, the maximum tolerated dose (MTD) of L-NDDP was 312.5 mg/m2 with myelosuppression as dose limiting toxicity (DLT). We conducted a Phase 2 trial of L-NDDP in patients (pts) with advanced colorectal cancer (CRC) refractory to 5-fluorouracil/leucovorin or capecitabine and irinotecan to investigate the anti-tumor response of L-NDDP and to further characterize its toxicity profile in this population. METHODS: L-NDDP was administered intravenously, once every 28 days. The starting dose was 300 mg/m2, with possible intra-patient dose escalation in the absence of grade 2 or higher drug-related toxicity. Patients were treated until disease progression or unacceptable toxicity. Of 20 eligible patients all were evaluable for toxicity and 18 were evaluable for response. Hematologic toxicities included anemia (grades 1-4) in 20% of pts and leucopenia, neutropenia and thrombocytopenia (grade 1/2) in 5% of patients each. Common non-hematologic toxicities included nausea (75%), vomiting (60%), and fatigue (70%), reversible infusion reactions (chest/back pain or shortness of breath; 40%), transient transaminase elevations (35%) and hyperbilirubinemia (20%). Grade 3-4 toxicities included infusion reaction (20%), vomiting (15%), fatigue (15%), anemia (10%) and ALT/AST elevation (5/15%). Peripheral neuropathy (grade 1/2) was seen in 15% of pts. One of 18 pts had a confirmed PR (5.6%), three (16.7%) had stable disease (> or =3 months) and 14 pts progressed. L-NDDP was well tolerated in this group of refractory patients and demonstrated evidence of anti-tumor activity. CONCLUSION: Further studies of L-NDDP, preferably in combination with other agents such as fluoropyrimidines, are warranted.

Aged↗
PubMed2005

A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients.

The aim of this study was to determine the immunogenicity and antitumor activity of autologous, tumor-derived heat shock protein gp96-peptide complex vaccine (HSPPC-96; Oncophage given with GM-CSF and IFN-alpha in pre-treated metastatic (AJCC stage IV) melanoma patients. Patients underwent surgical resection of metastatic lesions for HSPPC-96 production. HSPPC-96 was administered subcutaneously (s.c.) in four weekly intervals (first cycle). Patients with more available vaccine and absence of progressive disease received four additional injections in 2-week intervals (second cycle) or more. GM-CSF was given s.c. at the same site at days -1, 0 and +1, while IFN-alpha (3 MU) was administered s.c. at a different site at days +4 and +6. Antigen-specific anti-melanoma T and NK lymphocyte response was assessed by enzyme-linked immunospot assay on peripheral blood mononuclear cells obtained before and after vaccination. Thirty-eight patients were enrolled, 20 received at least four injections (one cycle) of HSPPC-96 and were considered assessable. Toxicity was mild and most treatment-related adverse events were local erythema and induration at the injection site. Patients receiving at least four injections of HSPPC-96 were considered evaluable for clinical response: of the 18 patients with measurable disease post surgery, 11 showed stable disease (SD). The ELISPOT assay revealed an increased class I HLA-restricted T and NK cell-mediated post-vaccination response in 5 out of 17 and 12 out of the 18 patients tested, respectively. Four of the five class I HLA-restricted T cell responses fall in the group of SD patients. Vaccination with autologous HSPPC-96 together with GM-CSF and IFN-alpha is feasible and accompanied by mild local and systemic toxicity. Both tumor-specific T cell-mediated and NK cell responses were generated in a proportion of patients. Clinical activity was limited to SD. However, both immunological and clinical responses were not improved as compared with those recorded in a previous study investigating HSPPC-96 monotherapy.

Adjuvants, Immunologic↗
PubMed2004

Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma.

PURPOSE: Maintenance of telomeres through reactivation of telomerase is a prerequisite for tumors to preserve their ability to proliferate. The purpose of this study was to evaluate telomere length and human telomerase reverse transcriptase (hTERT) expression as markers for progression and prognosis of colorectal carcinoma. PATIENTS AND METHODS: Telomere length and hTERT expression were analyzed in matched cancer and adjacent noncancer mucosa samples from 57 patients with R0-resected colorectal carcinoma. The median follow-up time was 76 months. RESULTS: Telomere length and hTERT expression correlated significantly in cancer tissues and adjacent mucosa samples (r = 0.52, P <.001; and r = 0.54, P <.001, respectively). Overall, cancer tissue had shorter telomeres than adjacent mucosa (P <.001). Only in noncancer tissue did telomere length decrease with age (r = 0.36; P <.01). Telomere length in cancer tissue was significantly correlated with tumor stage (P <.01), with longer telomeres in advanced tumors. Patients with ratios of telomere length in cancer to noncancer tissue greater than 0.90 had a significantly poorer overall survival compared with patients with smaller telomere length ratios (P <.002). In multivariate analysis, the telomere length ratio proved to be of independent prognostic value (P <.03). CONCLUSION: Telomeres in colorectal carcinoma tissue were significantly shorter compared with adjacent normal mucosa as an indication for extensive cell proliferation. The correlation with tumor stage and patient survival suggest that hTERT-mediated telomere stabilization may be critical for progression and prognosis of colorectal carcinoma.

Adult↗
PubMed2004

Prognostic evaluation and review of immunohistochemically detected disseminated tumor cells in peritumoral lymph nodes of patients with pN0 colorectal cancer.

BACKGROUND: The value of immunohistochemical detection of disseminated tumor cells in histopathologically tumor-free lymph nodes (pN0) of patients with colorectal cancer is still of uncertain prognostic value. We therefore evaluated the immunohistochemical detection rates and their prognostic value comparing three different monoclonal antibodies. METHODS: A total of 170 lymph nodes of 85 patients with curatively resected colorectal carcinoma at UICC stage I or II were evaluated for disseminated tumor cells. Frozen sections of each lymph node were immunohistochemically stained using three antibodies directed against CEA, CK20, and Ber-EP4. The detection rates were compared with histopathological tumor parameters and with the patient's survival. The median follow-up time was 86 months. RESULTS: CEA-, CK20-, and Ber-EP4-positive disseminated tumor cells were identified microscopically in lymph nodes of 23 patients (27%), 24 patients (28%), and 23 patients (27%), respectively. In 18 patients (21%) disseminated tumor cells were found in consecutive sections and stained positive for all three monoclonal antibodies. The lymph nodes of 10 of 18 patients (56%), which developed tumor recurrence, contained CEA- and CK20-positive disseminated tumor cells. Ber-EP4-positive cells were present in lymph nodes of 9 of 18 patients (50%) with tumor recurrence. The 5-year overall survival of the 23 patients with CEA-positive disseminated tumor cells was 72% compared to 91% of the patients without immunohistochemical evidence of tumor cells (p<0.01). While the identification of CK20-positive tumor cells was also correlated significantly with a worse overall patient survival (p<0.01), the application of Ber-EP4 failed to reach significance (p=0.057). Multivariate analysis identified the tumor site (colon versus rectal cancer) (p<0.006) and the presence of CEA-positive disseminated tumor cells (p<0.03) as independent prognostic factors. CONCLUSION: In colorectal carcinoma, the immunohistochemical detection of disseminated tumor cells in histopathologically pN0 peritumoral lymph nodes allows the identification of a subgroup with a significantly worse prognosis. Nevertheless, the prognostic value of immunohistochemically detected disseminated tumor cells remains controversial due to the nonuniform data in the literature.

Adult↗
PubMed2004

Squamous cell carcinoma-related oncogene is highly expressed in developing, normal, and adenomatous adrenal tissue but not in aggressive adrenocortical carcinomas.

BACKGROUND: Our previous work has demonstrated squamous cell carcinoma-related oncogene (SCCRO) expression in adult murine adrenocortical tissue. The aim of this study was to assess patterns of SCCRO expression in the embryonic murine adrenal gland, and in normal and neoplastic human adrenocortical tissues in order to determine its role as a marker of differentiation in adrenocortical development and neoplastic progression. METHODS: Murine embryos were procured at developmental stages E8 to E18. A tissue microarray was constructed containing 38 normal, 39 adenomatous, and 87 carcinomatous human adrenocortical specimens. Immunohistochemistry for SCCRO was performed and its expression was graded in suitable tissues. RESULTS: SCCRO expression was detected in the murine adrenal cortex as early as E15 and persisted into the postnatal period. High-level SCCRO expression was identified in 94% of normal (32/34) and adenomatous (29/31) adrenocortical specimens but in only 63% (45/72) of adrenocortical carcinoma (ACC) specimens ( P = .001). Loss of SCCRO expression in primary ACC (13/34 (34%)) correlated with advanced stage ( P = .06), presence of M1 disease at presentation ( P = .03), and worse overall survival ( P = .006). CONCLUSIONS: SCCRO appears to be a marker of adrenocortical differentiation in both murine and human systems. SCCRO expression may be useful in distinguishing adrenocortical adenomas from ACC. Moreover, loss of SCCRO expression in primary ACC is associated with worse outcome and may be a marker of progressive dedifferentiation in these tumors.

Adrenal Cortex Neoplasms↗
PubMed2003

An evidence-based approach to the surgical management of resectable pancreatic adenocarcinoma.

BACKGROUND: Randomized prospective trials have addressed various treatment approaches to pancreatic adenocarcinoma in order to improve on the dismal prognosis associated with this disease. We conducted a comprehensive review of prospective randomized clinical trials and summarized the contemporary treatment of resectable pancreatic carcinoma. STUDY DESIGN: A literature search strategy identified prospective randomized clinical trials for pancreatic carcinoma using standard medical subject heading terms. The articles were critically reviewed and ranked according to a standardized three-tiered system (Ia, Ib, Ic) by a panel of experts. RESULTS: Surgical studies have demonstrated that morbidity and mortality are similar for pylorus-preserving and classic pancreaticoduodenectomy. Extended retroperitoneal lymphadenectomy can be performed with similar mortality but increased morbidity compared with standard pancreaticoduodenectomy but does not prolong survival. Pancreaticogastrostomy and pancreaticojejunostomy appear to be comparable techniques for pancreatic duct reconstruction. Pancreatic-enteric anastomosis is associated with lower rates of pancreatic fistula and endocrine insufficiency than duct occlusion without anastomosis. Intraperitoneal drainage after pancreatic resection is unwarranted and may contribute to intraabdominal complications. Routine use of prophylactic octreotide does not lower the rate of pancreatic fistula; it should be considered for reoperative pancreatic resection or for a soft gland. Early trials found that adjuvant chemoradiation therapy prolongs survival. But in more recent studies chemoradiation after resection has failed to show a survival advantage over surgery alone. CONCLUSIONS: Surgical resection remains the only potentially curative therapy for adenocarcinoma of the pancreas. There is no clear indication as to a single preferable resection approach.

Adenocarcinoma↗
PubMed2003

Parathyroid neoplasms: clinical, histopathological, and tissue microarray-based molecular analysis.

We studied 45 patients with typical and 8 with atypical parathyroid adenomas as well as 20 with parathyroid carcinomas. Clinical, pathological, and molecular analyses were conducted on all adenomas. Clinical data were analyzed for 20, histopathologic slides for 16, and tissue specimens for 8 patients with carcinoma. Molecular expression profiles were investigated by immunohistochemistry (IHC) for Ki-67, p53, mdm2, p21, Bcl-2, cyclin D1, and p27 on paraffin-embedded tissues arrayed on tissue microarrays. Trabecular growth and vascular, capsular, and soft-tissue invasion were characteristic of parathyroid carcinomas but not of typical adenomas. No adenomas recurred. Seventy-four percent of carcinomas recurred, most in the neck. Seventy-nine percent of patients with such illness died of disease after an indolent, multiply recurrent course responsive to repeated resections; the 5-year survival rate was 50%. High Ki-67 proliferative index was seen in 2% of adenomas and 25% of carcinomas, whereas p27 expression was present in 80% of adenomas and 18% of carcinomas. The molecular phenotype, p27(+)Bcl-2(+)Ki-67(-)mdm2(+), was observed in 76%, 29%, and 0% of typical and atypical adenomas and carcinomas, respectively. The complexity of molecular phenotypes increased with tumor aggressiveness. Parathyroid carcinoma is an aggressive disease with a propensity for multiple recurrences. It is characterized by capsular, vascular, and soft-tissue invasion. Recurrence portends poor outcome. Molecular markers, Ki-67 and p27, may distinguish parathyroid carcinoma from adenoma. The molecular phenotype, p27(+)Bcl-2(+)Ki-67(-)mdm2(+), appears to be unique to nonmalignant parathyroid tumors, and multimarker phenotypes are more complex in carcinomas.

Adenoma↗
PubMed2003

Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.

Adolescent↗
PubMed2003

Vaccination with heat shock protein-peptide complexes: from basic science to clinical applications.

There are currently over 150 medical centers worldwide enrolling patients in randomized, controlled Phase III clinical trials testing autologous cancer-derived heat-shock protein (HSP)-peptide complexes for the treatment of renal cell carcinoma and melanoma. In addition, autologous HSP-peptide complexes have been or are being tested in Phase I and II trials of chronic myelogenous leukemia, lymphoma and pancreatic, gastric and colorectal cancers. The door has more recently opened to clinical testing of off-the-shelf HSP-based treatments for infectious diseases. This review recounts the long history of basic research on HSPs in immune response. A keen understanding of how these ancient molecules orchestrate the immune response to cancer and infections has been gained, providing a clear rationale for translating this knowledge into clinical medicine.

Animals↗
PubMed2002

Prognostic significance of cytokeratin-20 reverse transcriptase polymerase chain reaction in lymph nodes of node-negative colorectal cancer patients.

PURPOSE: Approximately 20% to 30% of patients with curatively resected, node-negative (pN0) colorectal cancer die of tumor recurrence, which can be caused by minimal residual disease. To identify patients with an increased risk of tumor recurrence and evaluate the prognostic value of cytokeratin-20 (CK-20), we detected CK-20-positive cells in histopathologically tumor-free lymph nodes (pN0) of patients with colorectal cancer. PATIENTS AND METHODS: Two peritumoral lymph nodes each from 85 patients with completely resected (R0) colorectal cancer without lymph node metastases (pN0) by routine examination were analyzed using a CK-20-specific reverse transcriptase polymerase chain reaction (RT-PCR) and compared with CK-20-specific immunohistochemistry (IHC). The results were correlated with histopathologic findings and with survival. RESULTS: CK-20 RT-PCR was positive in 44 patients (52%) and detected 83% of cancer-related death. Positive RT-PCR was significantly correlated with poorer overall survival (P <.009). Comparing RT-PCR with IHC, 13 patients with positive RT-PCR were identified, where the CK-20 expression was caused by tumor cell contamination located exclusively outside the lymph node capsule and had no prognostic impact. Defining these 13 patients as RT-PCR negative improved specificity of the RT-PCR assay from 57% to 75%. The 5-year overall survival of the 31 RT-PCR-positive patients was 71%, compared with 96% in the 54 negative patients (P <.001). Multivariate analysis showed expression of CK-20 mRNA to be an independent prognostic factor with a relative risk of cancer-related death of 6.1. CONCLUSION: CK-20 RT-PCR in peritumoral histopathologic tumor-free (pN0) lymph nodes of colorectal cancer is an independent prognostic factor for overall survival. Additional CK-20 IHC improves the specificity and prognostic value of RT-PCR for cancer-related death.

Aged↗
PubMed2002

Adrenocortical carcinoma: clinical, morphologic, and molecular characterization.

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P =.005). The phenotype Ki-67(-)p53(-)mdm-2(+)cyclinD1(-)Bcl-2(-)p21(-)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P =.01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.

Adolescent↗
PubMed2002

Xenogeneic DNA immunization in melanoma models for minimal residual disease.

INTRODUCTION: DNA immunization with xenogeneic genes encoding homologous antigens protects mice against tumor challenge with syngeneic melanoma in a lung metastasis model. The effect of xenogeneic human TRP-2 (hTRP2) DNA immunization on disease confined to an orthotopic site, the skin, and in a model of minimal residual disease that is relevant to a setting of adjuvant therapy for micrometastatic cancer is reported. METHODS: Immunization and tumor challenge with B16F10LM3 melanoma were performed in C57BL/6 mice and in mice genetically deficient in MHC class I or II molecules. A melanoma variant of B16 with a predilection for lung metastasis was selected and used to challenge C57BL/6 mice. Tumor challenge in the footpad with the B16 variant was followed by local tumor growth and lung metastasis. The tumor-bearing distal extremities were surgically resected and mice were randomized to receive hTRP2 DNA immunization or no treatment. Approximately 3-5 weeks after surgical resection, lungs were harvested and metastases counted. RESULTS: Xenogeneic DNA immunization with hTRP2 prevented tumor growth in the skin by a mechanism requiring CD4(+) and CD8(+) T cells but did not inhibit the growth of established tumors. Adjuvant immunization with hTRP2 DNA after resection significantly reduced lung metastases and decreased local recurrence rates after surgical resection. CONCLUSIONS: Xenogeneic DNA immunization with hTRP2 was effective in protecting mice from intradermal tumor challenge. Immunization prevented local recurrence and the development of metastases in a mouse model of minimal residual disease, supporting a role for DNA immunization against melanosomal antigens as an adjuvant to surgery in high-risk primary melanomas.

Animals↗
PubMed2002

Hürthle cell carcinoma: a 60-year experience.

BACKGROUND: The aim of this study was to define the clinical behavior and prognostic indicators of outcome in Hürthle cell cancer (HCC). METHODS: Diagnosis was confirmed for 56 patients with HCC treated between 1940 and 2000, who form the basis of this study. Primary end points were relapse-free survival (RFS) and disease-specific survival (DSS). Data were analyzed with the Kaplan-Meier method and by log-rank test. RESULTS: The extent of thyroid resection did not predict outcome. Recurrence was a significant predictor of tumor-related mortality. Significant adverse predictors of RFS and DSS were degree of invasion, size >4 cm, extrathyroidal extension, and initial nodal or distant metastases. The most significant predictor of outcome was extent of invasion. Eight-year RFS values for low- and high-risk groups were 100% and 24%. Corresponding rates of 8-year DSS were 100% and 58%. CONCLUSIONS: Widely invasive HCC is an aggressive malignancy that identifies patients who are at high risk for recurrence and tumor-related death. Patients with HCC have a prognosis that is reliably predicted by degree of invasion, tumor size, extrathyroidal disease extension, and initial nodal or distant metastasis. Recurrence portends a poor outcome. High-risk patients and those with recurrence should be considered for adjuvant therapy.

Adenoma, Oxyphilic↗
PubMed2002

Clinical significance of molecular expression profiles of Hürthle cell tumors of the thyroid gland analyzed via tissue microarrays.

Hürthle cell tumors are rare thyroid neoplasms for which disease biology is poorly understood and diagnosis of carcinoma can be challenging. The aim of the study was to characterize molecular expression profiles of Hürthle cell tumors and to determine the clinical significance of identified phenotypes. Paraffin-embedded tissue cores of normal thyroid (n = 18), and histopathologically well-defined Hürthle cell adenomas (n = 27), Hürthle cell tumors of unknown malignant behavior (n = 7), and minimally (n = 14) and widely (n = 21) invasive Hürthle cell carcinomas were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, and Ki-67 were detected by immunohistochemistry and correlated with clinicopathological data and patient outcome using standard statistical methodology. Median follow-up time was 8 years. High Ki-67 proliferative index was evident only in the clinically aggressive widely invasive Hürthle cell carcinomas and was associated with significantly reduced relapse-free (P = 0.001) and disease-specific (P < 0.001) survival. The molecular phenotype of Hürthle cell tumors, independent of histopathological subtype diagnosis, was characterized by p53(-), mdm-2(+), p21(+/-), cyclin D1(-), and Bcl-2(+/-). Normal thyroid tissue demonstrated a p53(-), mdm-2(-), p21(-), cyclin D1(-), and Bcl-2(+) phenotype. The Bcl-2(+) phenotype was associated with improved relapse-free survival (P = 0.04) and disease-specific survival (P = 0.01) in widely invasive carcinomas and the Ki-67(+)/Bcl-2(-) phenotype was associated with the diagnosis of widely invasive Hürthle cell carcinoma (P < 0.001). This study demonstrates that tissue microarray-based profiling allows identification of molecular markers that are associated with patient prognosis. High Ki-67 proliferative index was associated with adverse outcome in Hürthle cell neoplasms. Together with down-regulation of Bcl-2, high Ki-67 proliferative index may be useful for diagnosing widely invasive Hürthle cell carcinomas. Molecular alterations in the p53 pathway play a role in Hürthle cell tumorigenesis, but other unidentified molecular changes seem to be required to induce the malignant phenotype.

Adenoma, Oxyphilic↗
PubMed2002

Randomized clinical trials in pancreatic cancer.

The authors reviewed 59 prospective, randomized, controlled trials for pancreatic carcinoma that were published between 1977 and 2000. Of the 11 surgical trials, two each studied extent of resection (standard versus pylorus-preserving pancreaticoduodenectomy) and lymphadenectomy (standard versus extended lymph node dissection), five trials compared different types of pancreaticenteric reconstruction, and one each evaluated the role of prophylactic gastrojejunostomy and chemical splanchnicectomy in the setting of advanced disease.

Evidence-Based Medicine↗