Search PubMed⌕ Search

Biomedical subjects

Vernon K Sondak

Publications and source records attributed to Vernon K Sondak.

At least 19 recordsLinked to original sources
PubMed2007

Chemotherapy for metastatic melanoma: time for a change?

Melanoma is a neoplasm with a rising incidence. Early-stage melanoma is curable, but advanced, metastatic melanoma almost uniformly is fatal, and patients with such advanced disease have a short median survival. Systemic therapy remains unsatisfactory, inducing complete durable responses in a small minority of patients. For the current review, the authors focused on the current role of cytotoxic chemotherapy in the treatment of metastatic melanoma and the future prospects for improvements for multiagent chemotherapy and chemotherapy combined with immunomodulatory and/or molecularly targeted agents. They discuss roles of single-agent chemotherapy, combination chemotherapy, combinations of chemotherapy with immunomodulatory or hormone agents, biochemotherapy, and combination chemotherapy with targeted therapies.

Antineoplastic Agents↗
PubMed2007

The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma.

BACKGROUND: In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS: The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS: The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS: Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma.

Adult↗
PubMed2006

Down-regulation of pro-apoptotic genes is an early event in the progression of malignant melanoma.

INTRODUCTION: Down-regulation of apoptosis genes has been implicated in the development and progression of malignant melanoma. We used cDNA microarray to evaluate pro-apoptotic gene expression comparing normal skin to melanoma (thin and thick), nodal disease and distant metastases. METHODS: Twenty-eight specimens including skin (n = 1), thin melanoma (n = 6), thick melanoma (n = 7), nodal disease (n = 6), and distant metastases (n = 8), were harvested at the time of resection from 16 individuals. RNA was isolated and microarray analysis utilizing the Affymetrix GeneChip (54,000 genetic elements, U133A+B... levels) was performed. Mean level of expression was calculated for each gene within a sample group. Expression profiles were then compared between tissue groups. Student's t-test was used to determine variance in expression between groups. RESULTS: We reviewed the expression of 54,000 genetic elements, of which 2,015 were found to have significantly altered expression. This represents 1,602 genes. Twenty-two pro-apoptotic genes were found to be down-regulated when compared to normal skin. Overall reduction was evaluated comparing normal skin to metastases with a range of 3.31-64.04-fold-decrease. When comparing the tissue types sequentially, the greatest fold-decrease in gene expression occurred when comparing skin to all melanomas (thin and thick) (p = 0.011). Subset analysis comparing normal skin to thin melanoma or thick melanoma, revealed the greatest component of overall reduction at the transition from thin to thick lesions (p = 0.003). CONCLUSION: Sequential down-regulation of pro-apoptotic genes is associated with the progression of malignant melanoma. The greatest fold-decrease occurs in the transformation from thin to thick lesions.

Apoptosis↗
PubMed2006

Markers and tissue resources for melanoma: meeting report.

The Markers and Tissue Resources for Melanoma meeting convened by the Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, Specialized Programs of Research Excellence at the Organ Systems Branch of the National Cancer Institute (NCI), and the Melanoma Research Foundation was held in Gaithersburg, MD on October 2005. The meeting reviewed the current status of biomarkers for early- and advanced-stage melanoma and addressed some of the challenges scientists and clinicians face as they unravel the biology of melanoma and try to apply these findings to patient care. Specifically, the participants focused on molecular changes associated with melanoma progression, potential diagnostic and prognostic markers emerging from molecular profiling studies, and new treatment targets for current and future clinical trials. They also highlighted the ongoing challenges about translational research in melanoma, including availability of tissue resources, and summarized the status of nevus and melanoma tissue microarrays, recently developed as a collaborative project between the melanoma research community and the NCI. The meeting report is intended to provide a perspective on emerging scientific approaches in translational research that can enhance the progress in discovery and validation of markers for melanoma. (Cancer Res 2006; 66(22): 10652-7).

Biomarkers, Tumor↗
PubMed2006

Allogeneic and autologous melanoma vaccines: where have we been and where are we going?

The past three decades have seen substantial research on vaccines for the treatment of metastatic melanoma and the prevention of recurrence following resection. Despite their enormous promise, the actual results have been disappointing, with several high-profile vaccine clinical trials failing to show a benefit. Nonetheless, enthusiasm for melanoma vaccines remains and has increased with our expanding understanding of the immune response to tumor. Cellular vaccines can be divided into autologous, derived from the patient's own tumor and allogeneic vaccines. Autologous vaccines have the advantage of containing all potentially relevant tumor-associated antigens for that particular patient. However, autologous vaccines are difficult to obtain from most patients with advanced disease and impossible to obtain from patients who present after resection of all clinically evident disease. No consensus exists for how tumors should be processed, preserved, modified, and delivered to serve as an effective vaccine. The amount of autologous tumor available is rarely enough to produce more than two or three vaccination doses, and the time between initial tumor harvest and ultimate availability of the vaccine may result in interval tumor progression that diminishes the likelihood of vaccine efficacy. All these drawbacks of autologous tumor vaccination limit its applicability and also limit the ability to test autologous vaccines in prospective trials. Allogeneic vaccines avoid many of these problems, but may not contain all of the tumor-associated antigens present on the patient's own tumor. In particular, neoantigens created by mutations in the patient's tumor would be unlikely to be represented in an allogeneic vaccine. Although allogeneic vaccines can be manufactured in sufficient quantities to allow large-scale trials, there remain significant limiting issues in the manufacture and standardization of the vaccine product.

Animals↗
PubMed2006

Innovations and challenges in melanoma: summary statement from the first Cambridge conference.

Innovations and Challenges in Melanoma, chaired by Michael Atkins and cochaired by Ulrich Keilholz, John Kirkwood, and Jeffrey Sosman, was held July 15 to 16, 2005, in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, surgical oncology, anatomic pathology, dermatology, and immunotherapy who wished to advance the field of melanoma treatment by exchanging information and perspectives regarding recent advances and recommendations for further study. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on how genetics, biology, and data information can enhance our understanding of melanoma biology and help inform the use of therapies for this disease.

Humans↗
PubMed2006

Overall and progression-free survival in metastatic melanoma: analysis of a single-institution database.

BACKGROUND: Many new agents are currently in trial in melanoma. It remains unclear, however, what the benefit of a given therapy may be since information on progression-free and overall survival of untreated patients is limited. Since few trials in melanoma have had a non-treated cohort, it remains unclear what survival can be expected in patients who are not treated with chemotherapy. METHODS: To help develop parameters for future trials, we analyzed treatment history and survival in 212 patients with metastatic melanoma seen at our institution between January 1998 and September 2003. A retrospective analysis was done using a database created for melanoma patients at our center. Patient survival information was determined from this database, tumor registry, Social Security index, and direct patient calls. Patient staging information was determined according to the 2001 guidelines. Non-chemotherapy-treated patients with M1c disease were used as "controls." RESULTS: The median survival of stage M1c melanoma was 6.0 months. Survival was longer for stage M1a and M1b and shorter in older patients. No significant differences were found in survival based on gender. Among chemotherapy-treated patients, those with progressive disease on treatment or with increased lactate dehydrogenase (LDH) fared worse than those with a clinical response or normal LDH, respectively. Patients treated with either biochemotherapy or temozolomide and thalidomide survived longer than those who received no chemotherapy treatment. Dacarbazine (DTIC) treatment did not prolong survival. CONCLUSIONS: In this retrospective review of patients treated at a single institution, those treated with multiagent chemotherapy but not with single-agent DTIC appeared to have had a survival benefit.

Adult↗
PubMed2006

Targeting events in melanoma carcinogenesis for the prevention of melanoma.

Melanoma is one of the few tumors that have increased in incidence over the last few decades. Strategies devoted solely to protecting against ultraviolet radiation have, at best, had a modest impact on the development of melanoma. Chemoprevention is an under-explored approach that could significantly decrease the morbidity and mortality from this deadly cancer. However, the scientific and logistical challenges of performing clinical studies in chemoprevention require innovative approaches to prove the effectiveness of putative preventive agents. There are several pharmacological and nutriceutical agents that are mechanistically linked to events in melanoma carcinogenesis that are candidates for advanced human studies. We will review the data for several promising agents, including statins, curcumin, resveratrol, silymarin and green tea, and discuss some importance issues and concepts that should be considered in any melanoma chemoprevention strategy.

Apoptosis↗
PubMed2006

Current status of biomarkers for melanoma metastasis.

There is a critical unmet need for new predictive and prognostic biomarkers for melanoma. This feature presents a brief overview of the opportunities and challenges facing investigators who are seeking biomarkers that can predict those melanomas that are likely to result in progression (metastasis) and death. Melanoma metastasis to the regional lymph nodes is now readily identified by sentinel node biopsy. However, currently available prognostic factors, which are based on clinical parameters and histological findings in the primary tumor, are limited in their ability to reliably discriminate which patients will manifest sentinel node metastasis and/or disseminated disease. To date, even those biomarkers for which substantial clinical correlation has been obtained have suffered from both conflicting data in clinical trials involving different patient populations and poorly understood interactions between the biomarkers and other established prognostic factors. An understanding of whether biomarker data should be viewed as a continuum or be categorized based on discrete breakpoints is also frequently lacking. In many cases, biomarkers are initially developed based on unequivocal index cases, such as clearly benign or clearly malignant melanocytic lesions, but then fail as predictive tools when applied to the more difficult cases that arise in clinical practice; such cases occupy a 'gray' zone that is filled with uncertainty and lacks an established 'gold standard' against which a biomarker prediction can be validated.

Animals↗
PubMed2005

Retroperitoneal sarcomas.

Retroperitoneal sarcomas are rare neoplasms. CT or MR imaging is performed in patients with these tumors to detect local extent and distant metastases of the tumor and for preoperative surgical planning. Most sarcomas cannot be characterized as to cell type with CT or MR, with the exceptions being liposarcomas and intracaval leiomyosarcomas. Similarly histological grading cannot be made definitively with imaging alone, the exception being liposarcoma since well differentiated liposarcomas contain more macroscopic fat than do less differentiated liposarcomas. After surgery, follow up imaging with CT or MR and careful scrutiny of the tumor bed and resection site are essential to detect early recurrences, which can often be managed with re-resection.

Diagnostic Imaging↗
PubMed2005

Phase II study of 9-nitro-camptothecin in patients with advanced chordoma or soft tissue sarcoma.

PURPOSE: The purpose of this trial was to assess the objective clinical response, toxicity, and time to progression of treatment with 9-Nitro-Camptothecin (9-NC) in patients with advanced chordoma, soft tissue sarcoma (STS), and gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Patients with locally advanced and/or metastatic chordoma, STS, or GIST received 9-NC 1.25 mg/m2 orally for 5 consecutive days followed by 2 days of rest. Patients continued on therapy until disease progression, uncontrollable toxicity, or withdrawal of consent. RESULTS: From January 2000 to May 2003, 51 patients (15 chordoma, 23 STS, 13 GIST patients) enrolled. One patient (7%) with chordoma and one patient (4%) with STS had an objective response. Median time to progression was 9.9, 8.0, and 8.3 weeks for chordoma, STS, and GIST patients, respectively. Three- and 6-month progression-free survival rates were 47% and 33% for chordoma patients, 26% and 22% for STS patients, and 31% and 23% for GIST patients, respectively. Ten patients (10%) stopped study drug before disease progression secondary to toxicity. Common adverse events included anemia (42 patients, seven with grade 3/4 toxicity), leukopenia (33 patients, nine with grade 3/4 toxicity), fatigue (30 patients, three with grade 3/4 toxicity), nausea (34 patients, six with grade 3/4 toxicity), and diarrhea (28 patients, five with grade 3/4 toxicity). CONCLUSION: 9-NC has modest activity in delaying progression in patients with unresectable or metastatic chordoma. 9-NC is associated with moderate toxicity and shows little benefit in patients with advanced STS and GIST.

Adult↗
PubMed2005

Expression of receptor tyrosine kinases epidermal growth factor receptor and HER-2/neu in synovial sarcoma.

BACKGROUND: Synovial sarcomas are high-grade soft tissue neoplasms often characterized by a biphasic spindle and epithelioid cell morphology. The majority of synovial sarcomas harbor a specific chromosomal translocation in which the proximal portion of the SYT gene at chromosome 18q11 is fused to the distal portion of one of several duplicated SSX genes (most notably SSX1 and SSX2) at chromosome Xp11. SYT/SSX1 translocations are seen in nearly three times as many synovial sarcomas as SYT/SSX2 translocations. Although the SYT/SSX2 fusion is usually associated with the monophasic disease pattern, the SYT/SSX1 fusion is present in tumors with biphasic or monophasic patterns. The SYT/SSX1 fusion gene is associated with more aggressive tumor growth and poor outcome. Despite advances in the therapy of local disease, distant metastasis remains the predominant cause of death. Accordingly, there is a need for alternate therapies, such as those recently developed against the receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and HER-2/neu. METHODS: Archival specimens of synovial sarcoma (n=38) representing 30 patients were assessed for EGFR and HER-2/neu protein expression by standard immunohistochemical techniques. To validate the immunohistochemistry results, quantitative real-time polymerase chain reaction (Q-PCR) assays using either fresh and/or archival material was performed. The presence of gene amplification was determined by chromogenic in-situ hybridization. RESULTS: EGFR and HER-2/neu protein were detected by immunohistochemistry in 21 of 38 (55.3%) and 20 of 38 (52.6%) synovial specimens, respectively. EGFR immunoreactivity showed a granular and membranous pattern, whereas HER-2/neu immunoreactivity demonstrated only a membrane pattern. Coexpression was observed in 13 of 38 specimens (34.2%). HER-2/neu expression by immunohistochemistry in synovial sarcomas was restricted to tumors with the SYT/SSX1 translocations. Of 6 specimens with SSX2 translocation, none (0%) showed HER-2/neu immunoreactivity and 1 (17%) demonstrated EGFR expression. Q-PCR demonstrated the presence of mRNA for EGFR and HER-2/neu in 19 of 30 specimens (63.3%) and 22 of 30 specimens (73.3%), respectively. EGFR and HER-2/neu were expressed at low concentrations compared with the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No evidence of gene amplification was observed. CONCLUSIONS: EGFR and HER-2/neu are expressed in the majority of patients with SYT/SSX1 synovial sarcomas, albeit at low levels. Treatment with tyrosine kinase inhibitors may represent appropriate alternate therapy for these patients.

Adolescent↗
PubMed2005

Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (G-CSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma.

PURPOSE: The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS. PATIENTS AND METHODS: Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m(2) and either SD ifosfamide (1.5 g/m(2)/d, days 1 through 4) or HD ifosfamide (3.0 g/m(2), days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity. RESULTS: The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm. CONCLUSION: When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.

Adolescent↗
PubMed2005

Cutaneous melanoma: pathogenesis and rationale for chemoprevention.

OBJECTIVE: To critically review aspects of melanoma pathogenesis that lend themselves to a chemoprevention strategy. To discuss potential candidate chemoprevention agents with an emphasis on the lipid lowering drugs, the statins, currently, the most promising agents. DATA SOURCES: A retrospective review of the literature. STUDY SELECTION: Studies included those relevant to melanoma pathogenesis, to the scientific rationale of chemoprevention, and pertinent epidemiologic, pre-clinical, and clinical studies. The referenced study designs and methodologies varied. DATA EXTRACTION AND SYNTHESIS: Data were extracted by two reviewers, and the main results are presented in a quantitative descriptive manner. CONCLUSION: Melanoma is a preventable disease by altering behavior (sun exposure) among at-risk individuals. There is also considerable evidence to suggest that melanoma development may be prevented or delayed by drugs of sufficiently low toxicity to make clinical trials of chemoprevention feasible and potentially successful. Among potential candidate agents, statins have compelling data for long-term safety and sufficient pre-clinical and clinical evidence for efficacy to justify their evaluation in well-designed trials in high-risk individuals, incorporating intermediate biologic endpoints.

Chemoprevention↗
PubMed2005

Predictors of nonsentinel lymph node positivity in patients with a positive sentinel node for melanoma.

BACKGROUND: Patients found to harbor melanoma micrometastases in the sentinel lymph node (SLN) are recommended to proceed to complete lymph node dissection (CLND), although the majority of patients will have no additional disease identified in the nonsentinel lymph nodes (NSLNs). We sought to assess predictive factors associated with finding positive NSLNs, and identify a subset of patients with low likelihood of finding additional disease on CLND. STUDY DESIGN: We queried our prospective melanoma database for patients from January 1996 to August 2003 with a positive SLN. Univariable logistic regression models were fit for multiple factors and a positive NSLN. To derive a probabilistic model for occurrence of one or more positive NSLN(s), a multivariable logistic model was fit using a stepwise variable selection method. RESULTS: Of 980 patients who underwent SLN biopsy for cutaneous melanoma, 232 (24%) had a positive SLN; 221 (23%) followed by CLND. Of these patients, 34 (15%) had one or more positive NSLN(s). In multivariable analysis, male gender (odds ratio [OR] 3.6 [95% CI 1.33, 9.71]; p = 0.01), Breslow thickness (OR 4.58 [95% CI 1.28, 16.36]; p = 0.019), extranodal extension (OR 3.2 [95% CI 1.0, 10.5]; p = 0.05), and three or more positive sentinel nodes (OR 65.81 [95% CI 5.2, 825.7]; p = 0.001) were all associated with the likelihood of finding additional positive nodes on CLND. Of 47 patients with minimal tumor burden in the SLN, only 1 (2%) had additional disease in the NSLN. CONCLUSIONS: These results provide additional data to plan clinical trials to answer the question of who can safely avoid CLND after a positive SLN. Patients with minimal tumor burden in the SLN might be the most likely group, although defining "minimal tumor burden" must be standardized. Serial sectioning and immunohistochemistry on the NSLN in any "low-risk" group must be performed in a clinical trial to confirm that residual disease is unlikely before avoiding CLND can be recommended.

Adolescent↗
PubMed2005

Chemoprevention of melanoma: theoretical and practical considerations.

BACKGROUND: Chemoprevention refers to the use of agents to reverse, suppress, or prevent carcinogenic progression of cancer. The use of chemoprevention is an unexplored strategy in melanoma prevention. METHODS: A retrospective review of the literature was undertaken regarding the important elements in evaluating chemoprevention as a strategy in melanoma. RESULTS: Several considerations need to be addressed before a chemoprevention agent can be moved to a large randomized trial. Statins have both experimental and epidemiologic evidence to support their further development as candidate chemopreventive agents, but the evidence is insufficient to justify large-scale phase III studies. A strong scientific rationale, a systematic approach to chemoprevention agent development with rigorous chemoprevention designs, and careful selection of surrogate endpoint biomarkers are critical issues in developing a chemoprevention strategy. CONCLUSIONS: Addressing these relevant considerations will allow for the development of chemoprevention in melanoma.

Chemoprevention↗