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Biomedical subjects

Kelly M McMasters

Publications and source records attributed to Kelly M McMasters.

At least 19 recordsLinked to original sources

Vaccination with an adenoviral vector expressing calreticulin-human papillomavirus 16 E7 fusion protein eradicates E7 expressing established tumors in mice.

BACKGROUND: Cervical cancer remains a leading cause of cancer-related mortality in women, particularly in developing countries. The causal association between genital human papilloma virus (HPV) infection and cervical cancer has been firmly established, and the oncogenic potential of certain HPV types has been clearly demonstrated. Vaccines targeting the oncogenic proteins, E6 and E7 of HPV-16 and -18 are the focus of current vaccine development. Previous studies have shown that calreticulin (CRT) enhances the MHC class I presentation of linked peptide/protein and may serve as an effective vaccination strategy for antigen-specific cancer treatment. METHODS: Two replication-deficient adenoviruses, one expressing HPV-16 E7 (Ad-E7) and the other expressing CRT linked to E7 (Ad-CRT/E7), were assessed for their ability to induce cellular immune response and tested for prophylactic and therapeutic effects in an E7-expressing mouse tumor model. RESULTS: Vaccination with Ad-CRT/E7 led to a dramatic increase in E7-specific T cell proliferation, interferon (IFN)-gamma-secretion, and cytotoxic activity. Immunization of mice with Ad-CRT/E7 was effective in preventing E7-expressing tumor growth, as well as eradicating established tumors with long-term immunological memory. CONCLUSION: Vaccination with an adenoviral vector expressing CRT-E7 fusion protein represents an effective strategy for immunotherapy of cervical cancer in rodents, with possible therapeutic potential in clinical settings.

Adenoviridae↗

Assessment of symptom experience in patients undergoing hepatic resection or ablation.

BACKGROUND: Quality of life (QOL) currently is considered both clinically meaningful and biologically important for patient outcome and is considered as important as disease-free and overall survival. Thus, the objective of the current study was to evaluate the QOL symptoms of patients who underwent major hepatic resection, minor hepatic resection, and ablation for primary or metastatic cancer to the liver. METHODS: From October 2002 to June 2004, 40 patients who underwent either hepatic ablation or resection were enrolled. Patients were assessed at 5 time points (the initial visit, the initial postoperative visit, and visits at 6 weeks, 3 months, and 6 months) by questionnaires of the Functional Assessment in Cancer Therapy (FACT) core instrument with the Hepatobiliary subscale (FACT-Hep), the FACT Hepatobiliary Symptom Index (FHSI-8), the Profile of Mood States (POMS), the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire (QLQ) for patients with pancreatic cancer (QLQ-PAN), and the general core EORTC QLQ. RESULTS: The patients enrolled included 20 men and 20 women with a median age of 62 years (range, 41-77 years), including 24 patients who underwent major hepatectomy, 8 patients who underwent minor hepatectomy, and 8 patients who underwent ablation. An evaluation of the FACT Physical, Social, Emotional, and Functional subscales demonstrated no differences at the initial or first postoperative visits. However, at 6 weeks, both the Physical (P = .0455) and Functional (P = .0372) scores were significantly worse for the major hepatectomy group. At 3 months, all QOL parameters were similar. Similar differences were observed at 6 weeks for the FHSI-8 (P = .02), POMS (P = .007), QLQ-PAN (P = .04), and EORTC (P = .003) with the resolution of this difference at 3 months. CONCLUSIONS: There was little difference in QOL between patients who underwent major hepatic resection, minor hepatic resection, and hepatic ablation. Patients who underwent major hepatectomy demonstrated a worse QOL at 6 weeks compared with patients who underwent minor hepatic resection and hepatic ablation, with the resolution of this difference and significant improvements observed in all 3 groups at 3 months.

Adult↗

Predicting patients at low probability of requiring postmastectomy radiation therapy.

BACKGROUND: Postmastectomy radiation therapy (PMRT) is recommended for patients with four or more positive lymph nodes (LN+). Given the ramifications of PMRT for immediate reconstruction, we sought to create a model using preoperative and intraoperative factors to predict which patients with a positive sentinel lymph node will have less than four LN+. METHODS: The database from a prospective multicenter study of 4,131 patients was used for this analysis. Patients with one to three positive sentinel lymph nodes (SLN) and tumors < 5 cm (n = 1,133) in size were randomly divided into a training set (n = 580) and a test set (n = 553). Multivariate logistic regression was used on the training set to create a prediction rule that was subsequently validated in the test set. RESULTS: Median patient age was 57 (range, 27-100) years, and median tumor size was 2.0 (range, 0.2-4.8) cm. In the training set, factors associated with having four or more LN+ on multivariate analysis were: tumor size [odds ratio (OR) = 2.087; 95% confidence interval (CI): 1.307-3.333, P = 0.002), number of positive SLN (P < 0.0005), and proportion of positive SLN (OR = 3.602; 95% CI: 2.100-6.179, P < 0.005). A predictive model was established with a point assigned to each positive SLN, T2 (vs. T1), and if proportion of positive SLN was > 50%, for a maximum of five points. In both the training and test sets, patients with one point had a low probability of having four or more LN+ (3.8% and 3.3%, respectively). CONCLUSION: Tumor size, number of positive SLN, and the proportion of positive SLN influence whether patients will have four or more LN+. A simple model can predict the probability of requiring PMRT.

Adult↗

Adenovirus-mediated gene transfer of FKHRL1 triple mutant efficiently induces apoptosis in melanoma cells.

The PTEN/Akt signal pathway plays an important role in tumorigenesis. Mutations or deletions of PTEN have been observed in up to 60% of melanoma cell lines, resulting in PI3K/Akt activation. The Forkhead family of transcription factors induce apoptosis in their unphosphorylated forms and were recently reported to be a substrate of Akt kinase. In the present study, an adenovirus expressing a triple mutant (TM) of FKHRL1, which cannot be phosphorylated by Akt, was assessed for its ability to induce apoptosis in melanoma cells. Marked overexpression of FKHRL1/TM was evident in the SK-MEL-2 cell line 24 hours after infection with Ad-FKHRL1/TM by Western blot analysis. The expression of FKHRL1/ TM was moderately delayed in SK-MEL-28 cells. Overexpression of FKHRL1/TM can efficiently inhibit melanoma cell growth and result in rapid loss of cell viability. Cell cycle analysis showed overexpression of FKHRL1/TM in both melanoma cell lines resulted in development of a Sub-G1 population, indicating apoptosis by Ad-FKHRL1/TM infection. Apoptosis was confirmed by morphologic inspection, poly-ADP-ribosepolymerase (PARP) cleavage assay, and annexin V-PE analysis. After Ad-FKHRL1/TM infection, the expression of Bax and Bak did not differ markedly, whereas Mcl-1 and Bcl-x(L) levels decreased markedly. Involvement of caspase 3 and 6 in FKHRL1/TM-mediated apoptosis was demonstrated by cleavage of caspase 3/CPP32 and PARP as well as fragmentation of the caspase 6 substrate lamin B in SK-MEL-2 cells as early as 24 hours after Ad-FKHRL1/ TM infection, but those events were delayed 72 hours in SK-MEL-28. In addition, we found that p27(kip1) was cleaved in SK-MEL-2 cells at 24 hours after treatment with Ad-FKHRL1/TM. This cleavage was observed in SK-MEL-28 cells until 72 hours after infection with Ad-FKHRL1/TM. Our data suggest that adenovirus expressing a FKHRL1 triple mutant could be a useful vector for gene therapy of cancers resistant to chemotherapy and radiotherapy induced by hyperactivity of PI3K/Akt.

Adenoviridae↗

Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma.

PURPOSE: To evaluate the prognostic significance of molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR) in detecting occult melanoma cells in sentinel lymph nodes (SLNs) and circulating bloodstream. PATIENTS AND METHODS: In this multicenter study, eligibility criteria included patient age 18 to 71 years, invasive melanoma > or = 1.0 mm Breslow thickness, and no clinical evidence of metastasis. SLN biopsy and wide excision of the primary tumor were performed. SLNs were examined by serial-section histopathology and S-100 immunohistochemistry. A portion of each SLN was frozen for RT-PCR. In addition, RT-PCR was performed on peripheral-blood mononuclear cells (PBMCs). RT-PCR analysis was performed using four markers: tyrosinase, MART1, MAGE3, and GP-100. Disease-free survival (DFS), distant-DFS (DDFS), and overall survival (OS) were analyzed. RESULTS: A total of 1,446 patients with histologically negative SLNs underwent RT-PCR analysis. At a median follow-up of 30 months, there was no difference in DFS, DDFS, or OS between the RT-PCR-positive (n = 620) and RT-PCR-negative (n = 826) patients. Analysis of PBMC from 820 patients revealed significant differences in DFS and DDFS, but not OS, for patients with detection of more than one RT-PCR marker in peripheral blood. CONCLUSION: In this large, prospective, multi-institutional study, RT-PCR analysis on SLNs and PBMCs provides no additional prognostic information beyond standard histopathologic analysis of SLNs. Detection of more than one marker in PBMC is associated with a worse prognosis. RT-PCR remains investigational and should not be used to direct adjuvant therapy at this time.

Adult↗

A phase II study of extended dose temozolomide and thalidomide in previously treated patients with metastatic melanoma.

PURPOSE: To assess the efficacy and tolerability of extended dose temozolomide and continuous thalidomide in patients with advanced metastatic cutaneous melanoma. PATIENTS AND METHODS: Eligibility criteria included adults with histologic diagnosis of metastatic melanoma with adequate organ function and performance status. Temozolomide (75 mg/m(2)/day) was administered for 6 weeks followed by a 2-week rest. Thalidomide (200 mg/day) was given for the first 2 weeks and increased by 100 mg/day at weekly intervals up to a maximum of 400 mg/day, if no toxicity. For patients older than 70 years, thalidomide was started at 100 mg/day and the dose was increased by 50 mg/day up to a maximum of 250 mg/day. RESULTS: Twenty-six extensively pretreated subjects, with poor prognostic factors, were entered into this study and included in all analyses. According to the RECIST criteria, one (4%) subject achieved a complete response (CR), two (8%) partial response (PR), and five (19%) stable disease (SD), for a response rate (CR + PR) of 12% [95% confidence interval (CI), 0-24.7%] and a clinical benefit (CR + PR + SD) of 31%. Median time to progression was 1.8 months (95% CI, 1.2-2.4 months) and median survival was 5.2 months (95% CI, 4.1-6.2 months). CONCLUSIONS: The combination of temozolomide and thalidomide is well tolerated in patients with very advanced heavily pretreated metastatic melanoma. It has modest activity in this population with grave prognosis.

Adult↗

Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study.

BACKGROUND: Completion lymph node dissection (CLND) is considered the standard of care in melanoma patients found to have sentinel lymph node (SLN) metastasis. However, the therapeutic utility of CLND is not known. The natural history of patients with positive SLNs who do not undergo CLND is undefined. This multi-institutional study was undertaken to characterize patterns of failure and survival rates in these patients and to compare results with those of positive-SLN patients who underwent CLND. METHODS: Surgeons from 16 centers contributed data on 134 positive-SLN patients who did not undergo CLND. SLN biopsy was performed by using each institution's established protocols. Patients were followed up for recurrence and survival. RESULTS: In this study population, the median age was 59 years, and 62% were male. The median tumor thickness was 2.6 mm, 77% of tumors had invasion to Clark level IV/V, and 33% of lesions were ulcerated. The primary melanoma was located on the extremities, trunk, and head/neck in 45%, 43%, and 12%, respectively. The median follow-up was 20 months. The median time to recurrence was 11 months. Nodal recurrence was a component of the first site of recurrence in 20 patients (15%). Nodal recurrence-free survival was statistically insignificantly worse than that seen in a contemporary cohort of patients who underwent CLND. Disease-specific survival for positive-SLN patients who did not undergo CLND was 80% at 36 months, which was not significantly different from that of patients who underwent CLND. CONCLUSIONS: This study underscores the importance of ongoing prospective randomized trials in determining the therapeutic value of CLND after positive SLN biopsy in melanoma patients.

Cohort Studies↗

Factors associated with surgical options for breast carcinoma.

BACKGROUND: Breast conservation surgery (BCS) and mastectomy have equivalent survival outcomes for women with breast carcinoma, but treatment decisions are affected by many factors. The current study evaluated the impact of patient and physician factors on surgical decision-making. METHODS: Statistical analyses were performed on a prospective multicenter study of patients with invasive breast carcinoma. Patient, physician, and geographic factors were considered. RESULTS: Of 4086 patients, BCS was performed in 2762 (67.6%) and mastectomy was performed in 1324 (32.4%). The median tumor size was 1.5 cm (range, < 0.1-9.0 cm) in patients undergoing BCS and 1.9 cm (range, 0.1-11.0 cm) in patients undergoing mastectomy (P < 0.00001). The median age of patients undergoing BCS was 59 years (range, 27-100 yrs), whereas patients who underwent mastectomy were older (median age of 63 yrs, range, 27-96 yrs [P < 0.00001]). Physicians in academic practices performed more lumpectomies than those who were not in an academic practice (70.9% vs. 65.7%; P = 0.001). More breast conservation procedures were performed by surgeons with a higher percentage of breast practice (P = 0.012). Geographic location was found to be significant, with the Northeast having the highest rate of breast conservation (70.8%) and the Southeast having the lowest (63.2%; P = 0.002). On multivariate analysis, patient age (odds ratio [OR]: 1.455; 95% confidence interval [95% CI], 1.247-1.699 [P < 0.001]), tumor size (P < 0.001), tumor palpability (OR: 0.613; 95% CI, 0.524-0.716 [P < 0.001]), histologic subtype (P = 0.018), tumor location in the breast (P < 0.001), physician academic affiliation (OR: 1.193; 95% CI: 1.021-1.393 [P = 0.026]), and geographic location (P = 0.045) were found to be significant. CONCLUSIONS: Treatment decisions were found to be related to patient clinicopathologic features, surgeon academic affiliation, and geographic location. Future studies will elucidate the communication and psychosocial factors that may influence patient decision-making.

Academic Medical Centers↗

A phase II study of radiofrequency ablation of unresectable metastatic colorectal cancer with hepatic arterial infusion pump chemotherapy.

BACKGROUND: Adjuvant hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve disease-free survival for colorectal cancer liver metastases. It is unclear if this improvement can be extrapolated to unresectable liver metastases that undergo RFA. The aim of this study was to evaluate the combination of RFA and HAI chemotherapy for unresectable liver metastases. METHODS: Phase II study was conducted from November 2000 to July 2003 evaluating the use of complete extirpation by RFA, or resection/ablation with adjuvant HAI consisting of FUDR for 6 months. RESULTS: Twenty-one patients had successful resection and/or RFA with HAI pump, which included treatment for 100 liver metastases (22 resected, 78 ablated; mean 4.8 tumors/patient). Four of 21 patients completed the full 6-month course of HAI. Six of these patients had 12 adverse events related to HAIP, most commonly elevated liver enzymes. After a median follow-up of 24 months, the median liver specific disease-free and overall survival rates for the entire group were 17 and 30 months, respectively. CONCLUSIONS: Given the complications and toxicity associated with HAI pump chemotherapy, adjuvant HAI chemotherapy after RFA of liver metastases may not be warranted as a first line treatment option.

Adult↗

Gene expression profiles of normal human lung cells affected by adenoviral E1B.

Adenoviruses with deletion of E1b gene can selectively replicate in cancer cells. The underlying mechanisms in tumor-selective replication of E1b-deleted adenoviruses are insufficiently understood. Identifying genes with altered expression patterns caused by the E1B proteins in virus-infected cells will further increase our understanding of E1B functions and provide insight into the tumor-selective replication of E1b-mutated adenoviruses on the molecular level. An approach based on large-scale gene array was applied to analyze molecular changes affected by viral E1B. We identified a total of 345 genes with expression changes of two-fold or greater affected by wild-type adenovirus compared with its E1b-deleted counterpart. The gene array data were confirmed by quantitative real-time PCR and Western blot. E1B proteins affect the expression of a diverse range of genes involved in cell cycle regulation, apoptosis, stress responses and angiogenesis. This is the first study of the global profile of gene expression altered by the viral E1B proteins in human lung cells, and the majority of the genes were previously not known to be affected by the viral proteins. The data presented in this study will lead to more detailed analysis of E1B functions and may also lead to development of new agents and approaches for oncolytic therapy.

Adenovirus E1B Proteins↗

Quality of survival reporting in chemotherapy and surgery trials in patients with metastatic colorectal carcinoma.

BACKGROUND: Patients with metastatic colorectal carcinoma (MCC) to the liver receive conflicting management recommendations because of the lack of prospective randomized controlled trials (RCTs) clarifying the optimal management in this disease. The objective of the current study was to evaluate the reporting of prognostic factors in MCC from chemotherapy and surgery trials and evaluate the ability to compare these results across treatments. METHODS: RCTs and retrospective series of greater than 75 MCC patients published between 1980-2004 were reviewed to identify 10 critical prognostic elements of overall survival reported in both types of journals. RESULTS: A review 92 RCTs and 116 retrospective reports with 64,898 patients analyzed found 7 (3%) reporting all prognostic factors, with both studies demonstrating no difference in the success of reporting criteria met. The only criterion that was universally reported among both chemotherapy and surgery trials was the mortality rates of the study. All remaining prognostic factors in the evaluation of overall survival were significantly different between both chemotherapy and surgical studies. Considerable variation was observed in the disease-free interval, number of hepatic metastases, size of hepatic metastases, and performance status, and were significantly different among some of the most significant factors for patients evaluating treatment: complication reporting, surgical margin evaluation, and overall response rate. CONCLUSIONS: The reporting of results in MCC in chemotherapy trials and surgical reports is limited to general outcomes, with a paucity of prognostic factors, which hinders any ability to compare results across treatments. A mandatory reporting criteria of all metastatic colorectal trials is imperative to optimally manage these patients in both academic and community centers.

Colorectal Neoplasms↗

Determinants of early distant metastatic disease in elderly patients with breast cancer.

BACKGROUND: The purpose of this analysis was to determine predictors of early distant metastasis in elderly breast cancer patients receiving hormonal therapy. METHODS: We analyzed data from 938 patients in the North American Fareston Tamoxifen Adjuvant Trial>or=65 years old to determine predictors of early metastatic disease. RESULTS: The median patient age was 73 (range 65 to 100). With a median follow-up of 34 months, 17 patients (1.8%) developed distant metastases. The median time to distant metastasis was 21 months. On univariate analysis, significant predictors of distant metastatic disease were as follows: progesterone receptor status (P=.032), lymphovascular invasion (P=.020), tumor grade (P=.007), tumor size (P<.01), and number of metastatic nodes (P<.01). On multivariate analysis, only the number of positive nodes (P=.029) remained significant. Patients with >or=4 positive nodes were more likely to develop early metastases than those with 0 to 3 positive nodes (odds ration 20.304; 95% confidence interval 2.777-148.456, P=.003). CONCLUSIONS: Lymph node status in the elderly breast cancer patient treated with hormonal therapy alone is a strong predictor of early distant recurrence.

Aged↗

Prediction of sentinel lymph node-only disease in women with invasive breast cancer.

BACKGROUND: The purpose of this study was to create a model that predicts which breast cancer patients will have sentinel lymph node (SLN)-only metastasis. METHODS: SLN-positive breast cancer patients (N = 1,253) were analyzed. Multivariate analysis was performed to identify factors predicting SLN-only disease; a prediction rule was created. RESULTS: Median tumor size was 2 cm. The median number of SLNs removed was 2; the median number of positive SLNs was 1. Multivariate analysis found tumor size, number of positive SLN, and proportion of SLN positive were significant predictors of SLN-only disease (P < .001). A prediction rule with 1 point being given for >1 positive SLN, 1 point for >50% of SLN positive, and up to 4 points for tumor size (T1a = 1, T1b or T1c = 2, T2 = 3, and T3 = 4) was established. Ninety-five percent of patients with 1 point had SLN-only disease (P < .0001). CONCLUSION: An integer-based model may predict SLN-only disease and may be useful in determining whether completion axillary lymph node dissection is required.

Adult↗

Should all melanoma patients undergo sentinel lymph node biopsy?

PURPOSE OF REVIEW: It is now well established that sentinel lymph node biopsy is a powerful test to predict prognosis for melanoma patients. Controversy exists, however, regarding the appropriate selection of patients for sentinel lymph node biopsy, especially among patients with thin melanomas (< 1 mm Breslow thickness), thick melanomas (> 4 mm Breslow thickness), or locally recurrent melanoma. RECENT FINDINGS: The majority of the studies in the past 2 years regarding sentinel lymph node biopsy have been concerned with identifying factors that can better predict regional nodal metastasis and survival. Other studies have proposed a better risk stratification model, which includes these factors, to best select those patients at increased risk of nodal positivity. SUMMARY: Although much research has been done to select appropriate patients for sentinel lymph node biopsy based on multiple prognostic factors, further studies are necessary to completely define the indications for this procedure in patients with thin, thick and locally recurrent melanomas.

Humans↗

Gender-related differences in outcome for melanoma patients.

OBJECTIVE: To better understand the factors associated with the well-established gender difference in survival for patients with melanoma. SUMMARY BACKGROUND DATA: Gender is an important factor in patients with cutaneous melanoma. Male patients have a worse outcome when compared with females. The reasons for this difference are poorly understood. METHODS: This prospective multi-institutional study included patients aged 18 to 70 years with melanomas > or =1.0 mm Breslow thickness. Wide excision and sentinel lymph node (SLN) biopsy was performed in all patients. Clinicopathologic factors, including gender, were assessed and correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: A total of 3324 patients were included in the covariate analyses; 1829 patients had follow-up data available and were included in the survival analyses. Median follow-up was 30 months. On univariate analysis, men (n = 1906) were more likely than women to be older than 60 years (P < 0.0001), have thicker melanomas (P < 0.0001), have primary tumor regression (P = 0.0054), ulceration (P < 0.0001), and axial primary tumor location (P < 0.0001). On multivariate analysis, age (P = 0.0002), thickness (P < 0.0001), ulceration (P = 0.015), and location (P < 0.0001) remained significant in the model. There was no difference in the rate of SLN metastasis between men and women (P = 0.37) on multivariate analysis. When factors affecting survival were considered, the prognosis was worse for men as validated by lower DFS (P = 0.0005), DDFS (P < 0.0001), and OS (P < 0.0001). CONCLUSIONS: Male gender is associated with a greater incidence of unfavorable primary tumor characteristics without an increased risk for nodal metastasis. Nonetheless, gender is an independent factor affecting survival.

Adolescent↗

Sentinel lymph node biopsy in breast cancer.

Sentinel lymph node biopsy is now a widely accepted method of axillary lymph node staging for invasive breast cancer. This review encompasses the historical perspective of surgical management of the axilla; the data that has emerged over the last decade highlighting the accuracy, safety, and applicability of this procedure; and the technical details necessary to perform this procedure. Successful adaptation of sentinel node biopsy implies that the operator has a high identification rate and a low false-negative rate, as well as the collaborations with the other involved disciplines: pathology, radiology, and nuclear medicine.

Breast Neoplasms↗

Treatment of sentinel node-positive breast cancer.

Sentinel node biopsy has become well accepted as a minimally invasive means of accurately staging the axilla in breast cancer patients. Patients with metastases in the sentinel node(s) have traditionally proceeded to completion of axillary node dissection, whereas patients who are node negative can be spared the morbidity of this procedure. Recently, there has been some debate as to what constitutes node-positive disease and whether patients with metastasis in the sentinel node(s) require completion axillary dissection. This review addresses the controversies regarding the management of sentinel node-positive breast cancer patients.

Biopsy↗

Soft tissue sarcoma of the extremity and trunk: issues for the general surgeon.

Soft tissue sarcomas represent a heterogeneous group of malignant tumors that arise from mesenchymal tissues. The majority of these tumors arise on the extremity or trunk. Despite their rarity, soft tissue sarcomas continue to generate vigorous academic interest, and as a result, the ever-expanding medical literature dealing with sarcomas continues to grow. Many general surgeons will see few of these tumors during their careers, and a review of the current literature and how it applies to patients afflicted with soft tissue sarcoma of the extremity or trunk is warranted.

Biopsy↗