- Email: [email protected]
Viral-mediated gene therapy in combination with temozolomide in melanoma
Vol. 215, No. 3S, September 2012
work analysis of EX vs. RP LPS showed significant (p⬍0.05) differential regulation of G-protein signal transduction and cell adhesion pathways that mapped to networks involved primarily in cell adhesion (p⬍0.05). CONCLUSIONS: Differential expression patterns of genes in cell adhesion and lipid metabolism networks are seen depending on LPS location and grade. These expression patterns provide potential protein targets for further study and may help identify clinically aggressive LPS and therapeutic targets.
Viral-mediated gene therapy in combination with temozolomide in melanoma Michael E Egger, MD, JG Gomez-Gutierrez, PhD, H Hao, PhD, HS Zhou, PhD, Kelly M McMasters, MD, PhD, FACS University of Louisville, Louisville, KY INTRODUCTION: Temozolomide (TMZ) is an oral DNA alkylating agent used in metastatic melanoma. The therapeutic efficacy of TMZ is limited in part by the overexpression of O6-methylguanineDNA methyl transferase (MGMT). Adenoviral-mediated gene therapy with a mutated forkhead transcription factor (Ad-FKHRL1/ TM) that cannot be phosphorylated by the PI3/Akt pathway and induces apoptosis in combination with TMZ may work synergistically to enhance the therapeutic efficacy of TMZ. METHODS: Multiple melanoma cell lines were treated with AdFKHRL1/TM and TMZ, alone or in combination. Cell viability was determined at 72 hours. The combination effect of AdFKHRL1/TM and TMZ treatment was evaluated for synergism by the Chou-Talalay method. Western Blot analyses of apoptosis markers and MGMT were also performed. RESULTS: Combination therapy of Ad-FKHRL1/TM and TMZ resulted in greater cell killing (⬍20% cell viability) compared to single therapy and controls, p ⬍ 0.05. Combination indices of combined therapies were ⬍0.7 for all four cell lines, indicating significant synergistic effect. Western Blot analysis demonstrated greater activation of apoptotic markers PARP and procaspase-3 in combination therapy compared to single therapy. Levels of MGMT were decreased with treatment of Ad-FKHRL1/TM, suggesting a possible mechanism for the synergism. CONCLUSIONS: Combination therapy with Ad-FKHRL1/TM and TMZ results in synergistic cell killing effect in melanoma cells. Reduction in MGMT levels is the likely mechanism. The clinical implication is that the targeting of MGMT levels for manipulation by viral gene therapy, perhaps in a closed system such as that found during isolated limb perfusion, may enhance the therapeutic efficacy of TMZ.
Hemithyroidectomy: a meta-analysis of postoperative need for hormone replacement and complications Salem Noureldine, MD, Barath Krishnan, MD, Lu Yao, MS, Emad Kandil, MD, FACS Tulane University School of Medicine, New Orleans, LA
Abstracts S123
INTRODUCTION: We sought to determine the role of certain patient factors in predicting postoperative need for hormone replacement in patients who underwent hemithyroidectomy (HT). We hypothesize that preoperative prediction of patients who will eventually develop postoperative hypothyroidism will allow us to offer them a primary total thyroidectomy (TT), so as to avoid prolonged postoperative surveillance and possible need for a second surgery. METHODS: A search was conducted to identify studies published between Jan-2000 and May-2011. Outcomes of our interest included hypothyroidism and postoperative complications. RESULTS: Of 50,445 patients, 15,412 (30.6%) underwent HT. Patients who underwent HT were divided into two groups based on their need for postoperative hormone replacement. The reported incidence rate of postoperative hypothyroidism after a HT ranged from 10.9-48.8%. The pooled mean preoperative TSH level was 1.06 IU/l (0.83–1.29) higher in hypothyroid than euthyroid patients. A preoperative TSH level ⬎2.5 IU/l was associated with a RR (95%CI) of 3.16 (2.03-4.90) for postoperative hypothyroidism. There was a significant pooled RR of 3.52 (2.55-4.86) for thyroid antibodies and 3.30 (2.49-4.36) for thyroiditis on pathology for postoperative hormone replacement. The pooled RR for postoperative complications was 10.67 (5.75-19.31) for temporary hypocalcaemia, 3.17 (1.72-5.83) for permanent hypocalcaemia, 1.69 (1.302.20) for temporary RLN injury, 1.85 (1.28-2.69) for permanent RLN injury and 2.58 (1.69-3.93) for haemorrhage in patients who underwent TT as compared to HT. CONCLUSIONS: Higher preoperative TSH levels, presence of antithyroid antibodies and thyroiditis predict postoperative need for hormone replacement. We recommend consideration of total thyroidectomy in these patients, instead of partial resection.
Rate and predictors of thyroid malignancy in patients with follicular lesions of undetermined significance (FLUS) classification Parth Kishore Shah, MD, Kinjal K Shah, MD, Giorgos C Karakousis, MD, Rachel R Kelz, MD, FACS, Douglas L Fraker, MD, FACS University of Pennsylvania, Philadelphia, PA INTRODUCTION: The Bethesda Classification (BC) of thyroid FNA has emerged as a useful tool in categorizing thyroid nodules pre-operatively. BC Category III or FLUS is intermediate between benign and follicular neoplasm with a predicted malignancy rate of 10-12%. We examined a large series of patients with FLUS cytology to further establish the rate and predictors of malignancy in this category. METHODS: We performed a retrospective cohort study of patients undergoing surgery for nodular thyroid disease by a single surgeon (1997–2011). Patients were included in the study if they had FLUS by FNA. Those prior to the BC were retrospectively recategorized to include the FLUS designation. The Pearson’s Chi-square test was used for comparative statistics.
work analysis of EX vs. RP LPS showed significant (p⬍0.05) differential regulation of G-protein signal transduction and cell adhesion pathways that mapped to networks involved primarily in cell adhesion (p⬍0.05). CONCLUSIONS: Differential expression patterns of genes in cell adhesion and lipid metabolism networks are seen depending on LPS location and grade. These expression patterns provide potential protein targets for further study and may help identify clinically aggressive LPS and therapeutic targets.
Viral-mediated gene therapy in combination with temozolomide in melanoma Michael E Egger, MD, JG Gomez-Gutierrez, PhD, H Hao, PhD, HS Zhou, PhD, Kelly M McMasters, MD, PhD, FACS University of Louisville, Louisville, KY INTRODUCTION: Temozolomide (TMZ) is an oral DNA alkylating agent used in metastatic melanoma. The therapeutic efficacy of TMZ is limited in part by the overexpression of O6-methylguanineDNA methyl transferase (MGMT). Adenoviral-mediated gene therapy with a mutated forkhead transcription factor (Ad-FKHRL1/ TM) that cannot be phosphorylated by the PI3/Akt pathway and induces apoptosis in combination with TMZ may work synergistically to enhance the therapeutic efficacy of TMZ. METHODS: Multiple melanoma cell lines were treated with AdFKHRL1/TM and TMZ, alone or in combination. Cell viability was determined at 72 hours. The combination effect of AdFKHRL1/TM and TMZ treatment was evaluated for synergism by the Chou-Talalay method. Western Blot analyses of apoptosis markers and MGMT were also performed. RESULTS: Combination therapy of Ad-FKHRL1/TM and TMZ resulted in greater cell killing (⬍20% cell viability) compared to single therapy and controls, p ⬍ 0.05. Combination indices of combined therapies were ⬍0.7 for all four cell lines, indicating significant synergistic effect. Western Blot analysis demonstrated greater activation of apoptotic markers PARP and procaspase-3 in combination therapy compared to single therapy. Levels of MGMT were decreased with treatment of Ad-FKHRL1/TM, suggesting a possible mechanism for the synergism. CONCLUSIONS: Combination therapy with Ad-FKHRL1/TM and TMZ results in synergistic cell killing effect in melanoma cells. Reduction in MGMT levels is the likely mechanism. The clinical implication is that the targeting of MGMT levels for manipulation by viral gene therapy, perhaps in a closed system such as that found during isolated limb perfusion, may enhance the therapeutic efficacy of TMZ.
Hemithyroidectomy: a meta-analysis of postoperative need for hormone replacement and complications Salem Noureldine, MD, Barath Krishnan, MD, Lu Yao, MS, Emad Kandil, MD, FACS Tulane University School of Medicine, New Orleans, LA
Abstracts S123
INTRODUCTION: We sought to determine the role of certain patient factors in predicting postoperative need for hormone replacement in patients who underwent hemithyroidectomy (HT). We hypothesize that preoperative prediction of patients who will eventually develop postoperative hypothyroidism will allow us to offer them a primary total thyroidectomy (TT), so as to avoid prolonged postoperative surveillance and possible need for a second surgery. METHODS: A search was conducted to identify studies published between Jan-2000 and May-2011. Outcomes of our interest included hypothyroidism and postoperative complications. RESULTS: Of 50,445 patients, 15,412 (30.6%) underwent HT. Patients who underwent HT were divided into two groups based on their need for postoperative hormone replacement. The reported incidence rate of postoperative hypothyroidism after a HT ranged from 10.9-48.8%. The pooled mean preoperative TSH level was 1.06 IU/l (0.83–1.29) higher in hypothyroid than euthyroid patients. A preoperative TSH level ⬎2.5 IU/l was associated with a RR (95%CI) of 3.16 (2.03-4.90) for postoperative hypothyroidism. There was a significant pooled RR of 3.52 (2.55-4.86) for thyroid antibodies and 3.30 (2.49-4.36) for thyroiditis on pathology for postoperative hormone replacement. The pooled RR for postoperative complications was 10.67 (5.75-19.31) for temporary hypocalcaemia, 3.17 (1.72-5.83) for permanent hypocalcaemia, 1.69 (1.302.20) for temporary RLN injury, 1.85 (1.28-2.69) for permanent RLN injury and 2.58 (1.69-3.93) for haemorrhage in patients who underwent TT as compared to HT. CONCLUSIONS: Higher preoperative TSH levels, presence of antithyroid antibodies and thyroiditis predict postoperative need for hormone replacement. We recommend consideration of total thyroidectomy in these patients, instead of partial resection.
Rate and predictors of thyroid malignancy in patients with follicular lesions of undetermined significance (FLUS) classification Parth Kishore Shah, MD, Kinjal K Shah, MD, Giorgos C Karakousis, MD, Rachel R Kelz, MD, FACS, Douglas L Fraker, MD, FACS University of Pennsylvania, Philadelphia, PA INTRODUCTION: The Bethesda Classification (BC) of thyroid FNA has emerged as a useful tool in categorizing thyroid nodules pre-operatively. BC Category III or FLUS is intermediate between benign and follicular neoplasm with a predicted malignancy rate of 10-12%. We examined a large series of patients with FLUS cytology to further establish the rate and predictors of malignancy in this category. METHODS: We performed a retrospective cohort study of patients undergoing surgery for nodular thyroid disease by a single surgeon (1997–2011). Patients were included in the study if they had FLUS by FNA. Those prior to the BC were retrospectively recategorized to include the FLUS designation. The Pearson’s Chi-square test was used for comparative statistics.