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1. Data from STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair

Author

Marja T. Nevalainen, Sara M. Schmitt, William See, Ken Jacobsohn, Ken A. Iczkowski, Carmen Bergom, Ulrich Rodeck, Jonathan R. Brody, Karmel Cardenas, Kareem Malas, Vitali Alexeev, Lei Gu, David T. Hoang, Vindhya Udhane, and Cristina Maranto

Abstract

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.Conclusions: This work introduces a novel concept of a pivotal role of Jak2–Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2–Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917–31. ©2018 AACR.

Published
2023
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3. Effect of Obesity and Overweight Status on Complications and Survival After Minimally Invasive Kidney Surgery in Patients with Clinical T

Author

Michele, Marchioni, Francesco, Berardinelli, Chao, Zhang, Giuseppe, Simone, Robert G, Uzzo, Umberto, Capitanio, Andrea, Minervini, Clayton, Lau, Jihad, Kaouk, Peter, Langenstroer, Daniele, Amparore, Nicolo, de Luyk, James, Porter, Michele, Gallucci, Alexander, Kutikov, Alessandro, Larcher, Andrea, Mari, Patrick, Kilday, Koon Ho, Rha, Giuseppe, Quarto, Sisto, Perdonà, Wesley, White, Daniel D, Eun, Ithaar, Derweesh, Alexandre, Mottrie, Uzoma A, Anele, Ken, Jacobsohn, Francesco, Porpiglia, Benjamin, Challacombe, Chandru P, Sundaram, Riccardo, Autorino, Bo, Yang, and Luigi, Schips

Subjects
Humans, Minimally Invasive Surgical Procedures, Obesity, Neoplasm Recurrence, Local, Overweight, Kidney, Nephrectomy, Kidney Neoplasms, Body Mass Index
Published
2020

4. Robotic partial nephrectomy versus radical nephrectomy in elderly patients with large renal masses

Author

Giuseppe Simone, Giovanni Cacciamani, Chao Zhang, Geert De Naeyer, Monish Aron, Marco Carini, Alexandre Mottrie, Michele Gallucci, Umberto Capitanio, Francesco Porpiglia, Chandru P Sundaram, Alessandro Antonelli, Clayton Lau, Riccardo Campi, Andrea Mari, Claudio Simeone, Ithaar Derweesh, Lance J. Hampton, Benjamin Challacombe, Riccardo Autorino, Ken Jacobsohn, Sisto Perdonà, Paolo Dell'Oglio, Andrea Minervini, Cristian Fiori, Jad Kaouk, Uzoma A. Anele, Alessandro Veccia, James R. Porter, Aaron Bradshawh, and Daniel Eun

Subjects
Male, medicine.medical_specialty, Urology, medicine.medical_treatment, Blood Loss, Surgical, 030232 urology & nephrology, Renal function, Kidney Function Tests, Nephrectomy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Robotic Surgical Procedures, Blood loss, Humans, Medicine, Major complication, Patient outcome assessment, Propensity Score, Survival analysis, Aged, Proportional hazards model, business.industry, Survival Analysis, Kidney Neoplasms, Treatment Outcome, Nephrology, 030220 oncology & carcinogenesis, Propensity score matching, Female, business, Glomerular Filtration Rate, Cohort study
Abstract

BACKGROUND Recent evidence suggests that the "oldest old" patients might benefit of partial nephrectomy (PN), but decision-making for this subset of patients is still controversial. Aim of this study is to compare outcomes of robotic partial (RPN) or radical nephrectomy (RRN) for large renal masses in patients older than 65 years. METHODS We identified 417≥65 years old patients who underwent RRN or RPN for cT1b or ≥cT2 renal mass at 17 high volume centers. Propensity score match analysis was performed adjusting for age, ASA≥3, pre-operative eGFR, and clinical tumor size. Predictors of complications, functional and oncological outcomes were evaluated in multivariable logistic and Cox regression models. RESULTS After propensity score analysis, 73 patients in the RPN group were matched with 74 in the RRN group. R.E.N.A.L. Score (9.6±1.7 vs. 8.6±1.7; P

Published
2020

5. Robotic versus laparoscopic radical nephrectomy: a large multi-institutional analysis (ROSULA Collaborative Group)

Author

Robert G. Uzzo, Michele Marchioni, Clayton Lau, Michele Gallucci, Ahmet Bindayi, Giuseppe Simone, Giuseppe Quarto, Francesco Porpiglia, Kidon Chang, Miguel Ramírez-Backhaus, Alexander Kutikov, Chao Zhang, Michael Liao, Alexandre Mottrie, Uzoma A. Anele, Umberto Capitanio, Jay Sulek, Ben Challacombe, Wesley M. White, James R. Porter, Francesco Berardinelli, Ken Jacobsohn, Cristian Fiori, Maria Carmen Mir, Peter Langenstroer, Andrea Minervini, Patrick Kilday, Ithaar Derweesh, Nicolo de Luyk, Bo Yang, Koon Ho Rha, Prokar Dasgupta, Andrea Mari, Luigi Schips, Lance J. Hampton, Chandru P. Sundaram, Alessandro Larcher, Monish Aron, Akbar Ashrafi, Sisto Perdonà, Riccardo Autorino, Anele, Uzoma A., Marchioni, Michele, Yang, Bo, Simone, Giuseppe, Uzzo, Robert G., Lau, Clayton, Mir, Maria C., Capitanio, Umberto, Porter, Jame, Jacobsohn, Ken, de Luyk, Nicolo, Mari, Andrea, Chang, Kidon, Fiori, Cristian, Sulek, Jay, Mottrie, Alexandre, White, Wesley, Perdona, Sisto, Quarto, Giuseppe, Bindayi, Ahmet, Ashrafi, Akbar, Schips, Luigi, Berardinelli, Francesco, Zhang, Chao, Gallucci, Michele, Ramirez-Backhaus, Miguel, Larcher, Alessandro, Kilday, Patrick, Liao, Michael, Langenstroer, Peter, Dasgupta, Prokar, Challacombe, Ben, Kutikov, Alexander, Minervini, Andrea, Rha, Koon Ho, Sundaram, Chandru P., Hampton, Lance J., Porpiglia, Francesco, Aron, Monish, Derweesh, Ithaar, and Autorino, Riccardo

Subjects
Nephrology, Male, medicine.medical_specialty, Complications, medicine.medical_treatment, Urology, 030232 urology & nephrology, Nephrectomy, 03 medical and health sciences, 0302 clinical medicine, Laparoscopic, Robotic Surgical Procedures, Interquartile range, Internal medicine, medicine, Humans, Risk factor, Laparoscopy, Aged, Retrospective Studies, medicine.diagnostic_test, Comparative outcomes, Radical nephrectomy, Robotic, Female, Kidney Neoplasms, Middle Aged, Treatment Outcome, Proportional hazards model, business.industry, Retrospective cohort study, Comparative outcome, 030220 oncology & carcinogenesis, Laparoscopic radical nephrectomy, business, Complication
Abstract

Objective: To compare the outcomes of robotic radical nephrectomy (RRN) to those of laparoscopic radical nephrectomy (LRN) for large renal masses. Methods: This was a retrospective analysis of RRN and LRN cases performed for large (≥ cT2) renal masses from 2004 to 2017 and collected in the multi-institutional international database (ROSULA: RObotic SUrgery for LArge renal masses). Peri-operative, functional, and oncologic outcomes were compared between each approach. Descriptive analyses were performed and presented as medians with interquartile ranges. Inverse probability of treatment weighting-adjusted multivariable analyses were used to identify predictors of peri-operative complications. Kaplan–Meier analysis and Cox regression models were used to assess survival outcomes. Results: A total of 941 patients (RRN = 404, LRN = 537) were identified. There was no difference in terms of gender, age, and clinical tumor size. Over the study period, RRN had an annual increase of 11.75% (95% CI [7.34, 17.01] p < 0.001) and LRN had an annual decline of 5.39% (95% CI [−6.94, −3.86] p < 0.001). Patients undergoing RRN had higher BMI (27.6 [IQR 24.8–31.1] vs. 26.5 [24.1–30.0] kg/m 2 , p < 0.01). Operative duration was longer for RRN (185.0 [150.0–237.2] vs. 126 [90.8–180.0] min, p < 0.001). Length of stay was shorter for RRN (3.0 [2.0–4.0] vs. 5.0 [4.0–7.0] days, p < 0.001). RRN cases presented more advanced disease (higher pathologic staging [pT3–4 52.5 vs. 24.2%, p < 0.001], histologic grade [high grade 49.3 vs. 30.4%, p < 0.001], and rate of nodal disease [pN1 5.4 vs. 1.9%, p < 0.01]). Surgical approach did not represent an independent risk factor for peri-operative complications (OR 1.81 95% CI [0.97–3.39], adjusted p = 0.2). The main study limitation is the retrospective design. Conclusions: This study represents the largest known multi-center comparison between RRN and LRN. The two procedures seem to offer similar peri-operative outcomes. Notably, RRN has been increasingly utilized, especially in the setting of more advanced and surgically challenging disease without increasing the risk of peri-operative complications.

Published
2019

7. MP26-12 TRIFECTA OUTCOMES OF PARTIAL NEPHRECTOMY IN PATIENTS OVER 75 YEARS OLD: A MULTI-INSTITUTIONAL STUDY: ANALYSIS OF THE RENAL SURGERY IN ELDERLY (RESURGE) GROUP

Author

Andrea Minervini, Geert De Naeyer, Giuseppe Simone, Ahmet Bindayi, Clayton Lau, Aryeh Keehn, Michele Gallucci, Wesley M. White, Chao Zang, Riccardo Autorino, Nicole de Luyk, Alexander Kutikov, Kidon Chang, Peter Langenstroer, Robert G. Uzzo, Zachary Hamilton, David D. Y. Chen, Patrick Kilday, Andrea Mari, Lance J. Hampton, Marc C. Smaldone, Ithaar Derweesh, Marco Carini, Chandru P. Sundaram, Jay Sulek, Francesco Porpiglia, Uzoma A. Anele, Bo Yang, Ben Challacombe, Daniel Eun, Alexandre Mottrie, Madhumitha Reddy, Peter Dietrich, Umberto Capitanio, Michael Liao, Stephen Ryan, Manuela Costantini, Ken Jacobsohn, Francesco Berardinelli, Prokar Dasgupta, Matteo Ferro, Giuseppe Quarto, Francesco Montorsi, Gabriele Tuderti, Koon Ho Rha, R.G. Bertolo, Luigi Schips, James Porter, Alessandro Larcher, Kendrick Yim, Ottavio De Cobelli, and Sisto Perdonà

Subjects
medicine.medical_specialty, business.industry, Urology, medicine.medical_treatment, Renal surgery, Medicine, In patient, Study analysis, business, Nephrectomy, Surgery
Published
2018
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8. MP42-10 ROBOT-ASSISTED PARTIAL NEPHRECTOMY FOR CT2 RENAL TUMORS: PERIOPERATIVE, FUNCTIONAL AND ONCOLOGICAL OUTCOMES FROM A MULTICENTER ANALYSIS (THE ROSULA PROJECT)

Author

Giuseppe Simone, Clayton Lau, Uzoma A. Anele, Geert De Naeyer, Alexandre Mottrie, Robert G. Uzzo, David D. Y. Chen, Patrick Kilday, Umberto Capitanio, Nicolo de Luyk, Jay Sulek, Aryeh Keehn, Kidon Chang, Manuela Costantini, Wesley M. White, Francesco Porpiglia, Peter Dietrich, Ottavio De Cobelli, Monish Aron, Stephen Ryan, Chao Zang, Francesco Berardinelli, Marco Carini, Matteo Ferro, Michele Gallucci, Inderbir S. Gill, Bo Yang, Ben Challacombe, Daniel Eun, Peter Langenstroer, Ithaar Derweesh, Prokar Dasgupta, Ken Jacobsohn, Andrea Minervini, Andrea Mari, Lance J. Hampton, Chandru P. Sundaram, Michael Liao, Alexander Kutikov, Alessandro Larcher, James Porter, Riccardo Autorino, Ahmet Binday, Marc C. Smaldone, Akbar Ashrafi, Sisto Perdonà, Giuseppe Quarto, Francesco Montorsi, Gabriele Tuderti, Riccardo Bertolo, Koon Ho Rha, and Luigi Schips

Subjects
medicine.medical_specialty, business.industry, Urology, medicine.medical_treatment, medicine, Perioperative, business, Nephrectomy, Surgery
Published
2018
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9. MP59-16 ROBOTIC VERSUS LAPAROSCOPIC RADICAL NEPHRECTOMY: A MATCHED PAIRED MULTICENTER ANALYSIS (ROSULA GROUP)

Author

Jay Sulek, Robert G. Uzzo, David D. Y. Chen, Peter Langenstroer, Bo Yang, Alexandre Mottrie, Ahmet Bindayi, Umberto Capitanio, Sisto Perdonà, Giuseppe Simone, Monish Aron, Ithaar Derweesh, Luigi Schips, Wesley M. White, Chao Zang, Michael Liao, Ben Challacombe, Daniel Eun, Geert De Naeyer, Kidon Chang, Uzoma A. Anele, Prokar Dasgupta, Matteo Ferro, Alessandro Larcher, Andrea Minervini, Francesco Beradinelli, Stephen Ryan, Riccardo Autorino, Alexander Kutikov, Marco Carini, Riccardo Bertolo, Ross G. Everett, Andrea Mari, James Porter, Lance J. Hampton, Ken Jacobsohn, Chandru P. Sundaram, Patrick Kilday, Gabriele Tuderti, Koon Ho Rha, Nicolo de Luyk, Francesco Porpiglia, Peter Dietrich, M. Gallucci, Clayton Lau, Giuseppe Quarto, Francesco Montorsi, Marc C. Smaldone, and Manuela Constantini

Subjects
medicine.medical_specialty, Group (periodic table), business.industry, Urology, medicine, Laparoscopic radical nephrectomy, business, Surgery
Published
2018
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10. MP59-20 COMPARATIVE ANALYSIS OF MINIMALLY INVASIVE RADICAL AND PARTIAL NEPHRECTOMY FOR CLINICAL T2 RENAL MASS: ANALYSIS OF THE ROBOTIC SURGERY FOR LARGE RENAL MASS (ROSULA) GROUP

Author

Umberto Capitanio, Geert De Naeyer, Giuseppe Simone, Aryeh Keehn, Kidon Chang, Alessandro Larcher, Marc C. Smaldone, Robert G. Uzzo, Peter Dietrich, David D. Y. Chen, Peter Langenstroer, Wesley M. White, Uzoma A. Anele, Madhumitha Reddy, Andrea Mari, Clayton Lau, Ithaar Derweesh, Nicole de Luyk, Lance J. Hampton, Giuseppe Quarto, Patrick Kilday, Francesco Montorsi, James Porter, Chandru P. Sundaram, Stephen Ryan, Francesco Berardinelli, Francesco Porpiglia, Zachary Hamilton, Kendrick Yim, Ottavio De Cobelli, Ben Challacombe, Daniel Eun, R.G. Bertolo, Michele Gallucci, Alexander Kutikov, Gabriele Tuderti, Koon Ho Rha, Luigi Schips, Michael Liao, Sisto Perdonà, Riccardo Autorino, Bo Yang, Prokar Dasgupta, Marco Carini, Andrea Minervini, Ahmet Bindayi, Manuela Costantini, Chao Zang, Matteo Ferro, Jay Sulek, Ken Jacobsohn, and Alexandre Mottrie

Subjects
medicine.medical_specialty, business.industry, Urology, medicine.medical_treatment, Renal mass, Medicine, Robotic surgery, business, Nephrectomy, Surgery
Published
2018
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11. The effect of obesity and overweight status on complications and survival after minimally invasive kidney surgery in patients with clinical T2 renal masses: Evidences from rosula dataset

Author

L. Cindolo, Roberto Castellucci, Bisheng Yang, Ben Challacombe, Daniel Eun, Luigi Schips, G.P. Haber, Robert G. Uzzo, G. Quarto, Michele Marchioni, Manuela Costantini, James R. Porter, De Iorio Antonio, D. Amparone, Giuseppina De Simone, Ken Jacobsohn, U. Capitanio, Gabriele Tuderti, Wesley M. White, Andrea Minervini, Matteo Ferro, Alexandre Mottrie, P. De Francesco, Francesco Berardinelli, Andrea Mari, F. Montorsi, L. Spinozzi, Ithaar Derweesh, Marco Carini, M. Gallucci, Chandru P. Sundaram, O. De Cobelli, R. Autorino, F. Portpiglia, J. Kaouk, K.H. Rha, N. De Luyk, Alessandro Larcher, and S. Perdonà

Subjects
medicine.medical_specialty, business.industry, Urology, Internal medicine, medicine, In patient, Kidney surgery, Overweight, medicine.symptom, medicine.disease, business, Obesity
Published
2019
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12. Perioperative, functional and oncological outcomes of robot-assisted partial nephrectomy for cT2 renal tumors: A multicenter analysis (The ROSULA project)

Author

Andrea Mari, Lance J. Hampton, Aryeh Keehn, R.G. Bertolo, Akbar Ashrafi, Kidon Chang, G. De Naeyer, M. Gallucci, J.D. Garisto Risco, Marc C. Smaldone, Andrea Minervini, Clayton Lau, Luigi Schips, Giuseppe Simone, K.H. Rha, Giuseppe Quarto, I.S. Gill, Wesley M. White, Alexandre Mottrie, Alexander Kutikov, Umberto Capitanio, Ben Challacombe, Daniel Eun, Matteo Ferro, C. Sanduram, R. Autorino, Marco Carini, Peter Langenstroer, J. Kaouk, Robert G. Uzzo, N. De Luyk, David D. Y. Chen, Monish Aron, Patrick Kilday, Ithaar Derweesh, Alessandro Larcher, Francesco Berardinelli, Bo Yang, S. Perdonà, Chao Zang, Jay Sulek, Ken Jacobsohn, Michael Liao, Uzoma A. Anele, James R. Porter, P. Dasgupta, and F. Porpiglia

Subjects
medicine.medical_specialty, business.industry, Urology, medicine.medical_treatment, Medicine, Perioperative, business, Nephrectomy, Surgery
Published
2018
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13. Outcomes of laparoscopic and robotic surgery for clinical T2 renal masses in obese patients: A multicenter international study

Author

Andrea Mari, James R. Porter, Chandru P. Sundaram, F. Montorsi, Ithaar Derweesh, Alessandro Larcher, F. Porpiglia, Roberto Castellucci, P. De Francesco, Gabriele Tuderti, Alexandre Mottrie, Bisheng Yang, Giuseppe Simone, G.P. Haber, Umberto Capitanio, J. Kaouk, S. Perdonà, L. Cindolo, N. De Luyk, R. Autorino, Luigi Schips, Marco Carini, Francesco Berardinelli, O. De Cobelli, M. Gallucci, K.H. Rha, Robert G. Uzzo, Wesley M. White, Daniele Amparore, Ben Challacombe, Daniel Eun, Manuela Costantini, Ken Jacobsohn, Matteo Ferro, Andrea Minervini, P. Castellan, Michele Marchioni, and Giuseppe Quarto

Subjects
medicine.medical_specialty, business.industry, Urology, General surgery, Medicine, Robotic surgery, business
Published
2018
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14. Abstract B073: Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair

Author

Mateusz Koptyra, Ulrich Rodeck, Lei Gu, William A. See, Karmel Cardenas, Ken Jacobsohn, Carmen Bergom, Vindhya Udhane, Marja T. Nevalainen, Sara M. Schmitt, Jonathan R. Brody, Vitali Alexeev, Kareem M. Malas, Ken A. Iczkowski, Ayush Dagvadorj, David T. Hoang, and Cristina Maranto

Subjects
Cancer Research, Prostate cancer, Oncology, DNA repair, business.industry, RAD51, Cancer research, medicine, medicine.disease, business, Blockade, STAT5A
Abstract

Purpose: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen-deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in PC, and if Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet assay and clonogenic survival assay, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end-joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors, and patient-derived PCs ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing PC xenograft tumors. Results: Stat5a/b is critical for Rad51 expression in PC via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not affecting radiation sensitivity of the neighboring tissues. Conclusion: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Citation Format: Cristina Maranto, Vindhya Udhane, Ayush Dagvadorj, David T. Hoang, Lei Gu, Vitali Alexeev, Kareem Malas, Karmel Cardenas, Mateusz Koptyra, Jonathan R. Brody, Ulrich Rodeck, Carmen Bergom, Ken A. Iczkowski, Ken Jacobsohn, William See, Sara M. Schmitt, Marja T. Nevalainen. Stat5a/b blockade sensitizes prostate cancer to radiation through inhibition of Rad51 and DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B073.

Published
2018
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15. PATIENTS WITH PRIOR TURP UNDERGOING ROBOTIC ASSISTED LAPAROSCOPIC RADICAL PROSTATECTOMY HAVE HIGHER POSITIVE SURGICAL MARGIN RATES

Author

Roger Satterthwaite, Lance J. Hampton, Rebecca A. Nelson, Ken Jacobsohn, Laura E. Crocitto, and Timothy G. Wilson

Subjects
medicine.medical_specialty, Laparoscopic radical prostatectomy, Robotic assisted, business.industry, Urology, medicine.medical_treatment, medicine, Positive Surgical Margin, business, Surgery
Published
2008
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