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ABSTRACT: The addition of neoadjuvant chemoradiotherapy prior to surgical resection for esophageal cancer has improved clinical outcomes in some trials. Pathologic complete response (pCR) following neoadjuvant therapy is associated with better clinical outcome in these patients, but only 22% to 40% of patients achieve pCR. Because both chemotherapy and radiotherapy act by inducing DNA damage, we analyzed proteins selected from multiple DNA repair pathways, using quantitative immunohistochemistry coupled with a digital pathology platform, as possible biomarkers of treatment response and clinical outcome.
We identified 79 patients diagnosed with esophageal cancer between October 1994 and September 2002, with biopsy tissue available, who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsy samples to create tissue microarrays (TMA). TMA sections were stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1, and phosphorylated MAPKAP kinase 2 (pMK2). Stained TMA slides were evaluated using machine-based image analysis, and scoring incorporated both the intensity and the quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with clinical outcome.
Higher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. Staining of MLH1, PARP1, XPF, and PAR was associated with recurrence-free survival, and staining of PARP1 and FANCD2 was associated with overall survival on multivariable analysis.
DNA repair proteins analyzed by immunohistochemistry may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer. These results are hypothesis generating and need confirmation in an independent data set.
International journal of radiation oncology, biology, physics 10/2011; 83(1):164-71. · 4.59 Impact Factor
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ABSTRACT: To determine the toxicities of neoadjuvant chemoradiotherapy using a three-drug regimen (cisplatin, 5-fluorouracil, and paclitaxel) and a conventional radiotherapy (RT) schedule combined with a concurrent boost technique during chemotherapy cycles, and to determine the rate of tumor response, overall survival, and impact of pathologic tumor response on survival.
The eligibility criteria included resectable adenocarcinoma or squamous cell carcinoma (T2-T3N0-N1M0), performance score < or =2, and no significant comorbidities for trimodality therapy. Chemotherapy consisted of two cycles of cisplatin, 5-fluorouracil, and paclitaxel. A concurrent boost technique was used in RT for 2 levels of radiation doses: 58.5 Gy in 34 fractions within 5 weeks to the gross tumor volume and 45 Gy in 25 fractions within 5 weeks to the clinical target volume by administering a boost dose of 13.5 Gy in 9 fractions, 1.5 Gy/fraction, as a second daily fraction for 9 days on Days 1-5 and 29-32 of the chemotherapy cycles.
We enrolled 46 patients in the study. The paclitaxel dose was started at 75 mg/m(2) (n = 7) and escalated to 125 mg/m(2) (n = 5), at which point, dose-limiting toxicities occurred. Thereafter, paclitaxel at 100 mg/m(2) was used for an additional 34 patients. Toxicities included Grade 4 neutropenia (22%), febrile neutropenia requiring hospital admission (20%), Grade 3 (48%) and Grade 4 (7%) acute esophagitis, and paclitaxel-associated anaphylaxis (4%). Of the 46 patients, 3 (6.5%) died of treatment-related complications, 1 of pneumonia during induction therapy and 2 of postoperative complications (5% of the 40 patients who underwent resection). The histopathologic tumor response was a pathologic complete response (pT0N0) in 18 (45%) of 40 patients who underwent resection and 18 (39%) of all 46 registered patients. Minimal residual disease (pT1N0) at the primary site was present in 5 (11%) and residual disease in 23 (50%) of all 46 patients. The minimal follow-up for all long-term survivors (n = 16) was 5.5 years. The median survival time was 34 months, and the overall survival rate was 57%, 50%, and 37% at 2, 3, and 5 years, respectively. The 5-year overall survival (56% vs. 24%, p = 0.0214) and disease-free survival (48% vs. 6%) were significantly better statistically for patients with a pathologic complete response and minimal residual disease than for those with residual disease. All long-term survivors beyond 5.5 years without recurrence accrued from patient cohorts with a pathologic complete response or minimal residual disease.
An incorporation of twice-daily RT as a concurrent boost to the conventional daily RT schedule during chemotherapy cycles is feasible and warrants additional study for radiation dose intensification. Such research would be prudent for both improved long-term survival and organ preservation in esophageal carcinoma.
International Journal of Radiation OncologyBiologyPhysics 10/2004; 60(1):111-22. · 4.11 Impact Factor
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Ravi Salgia,
Thomas Lynch,
Arthur Skarin,
Joan Lucca,
Cathleen Lynch,
Ken Jung,
F Stephen Hodi,
Michael Jaklitsch,
Steve Mentzer,
Scott Swanson, [......],
Panos Fidias,
Dean Donahue,
Shirley Clift,
Steve Hardy,
Donna Neuberg,
Richard Mulligan,
Iain Webb,
David Sugarbaker,
Martin Mihm,
Glenn Dranoff
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ABSTRACT: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial.
Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals.
Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed.
Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.
Journal of Clinical Oncology 03/2003; 21(4):624-30. · 18.37 Impact Factor
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ABSTRACT: To determine the dose-response relationship between the probability of tumor control on the basis of pathologic tumor response (pTCP) and the residual metabolic rate of glucose (MRglc) in response to preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer and to define the level of residual MRglc that corresponds to pTCP 50% and pTCP > or = 95%.
Quantitative dynamic 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography was performed to measure regional MRglc at the primary lesion before and 2 weeks after preoperative chemoradiotherapy in an initial group of 13 patients with locally advanced NSCLC. A simplified kinetic method was developed subsequently from the initial dynamic study and used in the subsequent 16 patients. The preoperative radiotherapy programs consisted of (1) a split course of 42 Gy in 28 fractions within a period of 28 days using a twice-daily treatment schedule for Stage IIIA(N2) NSCLC (n = 18) and (2) standard once-daily radiation schedule of 45-63 Gy in 25-35 fractions during a 5-7-week period (n = 11). The preoperative chemotherapy regimens included two cycles of cisplatin, vinblastine, and 5-fluorouracil (n = 24), cisplatin and etoposide (n = 2), and cisplatin, Taxol, and 5-fluorouracil (n = 3). Patients free of tumor progression after preoperative chemoradiotherapy underwent surgery. The degree of residual MRglc measured 2 weeks after preoperative chemoradiotherapy and 2 weeks before surgery was correlated with the pathologic tumor response. The relationship between MRglc and pTCP was modeled using logistic regression.
Of 32 patients entered into the study, 29 (16 men and 13 women; 30 lesions) were evaluated for the correlation between residual MRglc and pathologic tumor response. Three patients did not participate in the second study because of a steady decline in general condition. The median age was 60 years (range 42-78). One of the 29 patients had two separate lesions, and MRglc was measured in each separately. The tumor histologic types included squamous cell carcinoma (n = 9), adenocarcinoma (n = 13), large cell carcinoma (n = 6), and poorly differentiated carcinoma (n = 2). The extent of the primary and nodal disease was as follows: Stage IIB (T3N0M0), Pancoast tumor (n = 2); Stage IIIA, T2-T3N2M0 (n = 18); Stage IIIB: T1-T3N3M0 (n = 5) and T4N0M0 (n = 2); a second lesion, T1 (n = 1); and localized stump recurrence (n = 2). A pathologically complete response was obtained in 14 (47%) of the 30 lesions. The remaining 16 lesions had residual cancer. The mean baseline value of the maximal MRglc was 0.333 +/- 0.087 micromol/min/g (n = 16), and it was reduced to 0.0957 +/- 0.059 micromol/min/g 2 weeks after chemoradiotherapy (p = 0.011). The correlation between residual MRglc and pTCP was made using an increment value of 0.02 micromol/min/g between the maximal and minimal values of MRglc. A pathologically complete response was obtained in 6 of 6 patients with residual MRglc of < or = 0.050 micromol/min/g, 3 of 4 with < or = 0.070, 4 of 7 with < or = 0.090, 0 of 4 with < or = 0.110, 1 of 3 with < or = 0.130, and 0 of 6 with > or = 0.130 micromol/min/g. The fitted logistic model showed that residual MRglc corresponding to pTCP 50% and pTCP > or = 95% was 0.076 and < or = 0.040 micromol/min/g, respectively.
The correlation between the gradient of residual MRglc after chemoradiotherapy and pTCP is an inverse dose-response relationship. Residual MRglc of 0.076 and < or = 0.040 micromol/min/g, representing pTCP 50% and pTCP > or = 95%, respectively, may be useful surrogate markers for the tumor response to radiotherapy or chemoradiotherapy in lung cancer.
International Journal of Radiation OncologyBiologyPhysics 12/2002; 54(4):1024-35. · 4.11 Impact Factor
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Timothy P Padera,
Ananth Kadambi,
Emmanuelle di Tomaso,
Carla Mouta Carreira,
Edward B Brown,
Yves Boucher,
Noah C Choi,
Douglas Mathisen, John Wain,
Eugene J Mark,
Lance L Munn,
Rakesh K Jain
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ABSTRACT: Lymphatic metastasis contributes to mortality from solid tumors. Whether metastasizing cancer cells reach lymph nodes via intratumor lymphatic vessels is unknown. Here, we examine functional lymphatics associated with mouse tumors expressing normal or elevated levels of vascular endothelial growth factor-C (VEGF-C), a molecule that stimulates lymphangiogenesis. Although VEGF-C overexpression increased lymphatic surface area in the tumor margin and lymphatic metastasis, these tumors contained no functional lymphatics, as assessed by four independent functional assays and immunohistochemical staining. These findings suggest that the functional lymphatics in the tumor margin alone are sufficient for lymphatic metastasis and should be targeted therapeutically.
Science 07/2002; 296(5574):1883-6. · 31.20 Impact Factor
