Pittsburgh Cancer Institute

Pittsburgh, PA, United States

Pittsburgh Cancer Institute

Pittsburgh, PA, United States
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Varlotto J.M.,Pennsylvania State University | Medford-Davis L.N.,Harvard University | Recht A.,Harvard University | Recht A.,Beth Israel Deaconess Medical Center | And 6 more authors.
Chest | Year: 2013

Objective: An increasing proportion of patients with stage I non-small cell lung cancer (NSCLC) is undergoing sublobar resection (L-). However, there is little information about the risks and correlates of local recurrence (LR) after such surgery, especially compared with patients undergoing lobectomy (L+). Methods: Ninety-three and 318 consecutive patients with stage I NSCLC underwent L- and L+, respectively, from 2000 to 2006. Median follow-up was 34 months. Results: In the L- group, the LR rates at 2, 3, and 5 years were 13%, 24%, and 40%, respectively. The risk of LR was significantly associated with tumor grade, tumor size, and T stage. The crude risk of LR was 33.8% (21 of 62) for patients whose tumors were grade > 2. In the L+ group, the LR rates at 2, 3, and 5 years were 14%, 19%, and 24%, respectively. The risk of LR significantly increased with increasing tumor size, length of hospital stay, and the presence of diabetes. The L- group experienced a significant increase in failure in the bronchial stump/staple line compared with the L+ group (10% vs 3%; P = .04) and nonsignificant trends toward increased ipsilateral hilar and subcarinal failure rates. Conclusions: Patients with stage I NSCLC who undergo L- have an increased risk of LR compared with patients undergoing L+, particularly when they have tumors grade ≥ 2 or tumor size. > 2 cm. If L- is considered, additional local therapy should be considered to reduce this risk of LR, especially with tumors grade ≥ 2 or size > 2 cm. © 2013 American College of Chest Physicians.

News Article | October 11, 2016
Site: www.medicalnewstoday.com

Researchers at the University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute (UPCI) have demonstrated how Rad4, a protein involved in DNA repair, scans the DNA in a unique pattern of movement called 'constrained motion' to efficiently find structural faults in DNA. The findings, reported in the journal Molecular Cell, could lead to therapies that boost existing drug treatments and counter drug-resistance. "Rad4 is like the cop who is the first responder at an accident," said senior author Bennett Van Houten, Ph.D., Richard M. Cyert Professor of Molecular Oncology, Pitt School of Medicine, and co-leader of UPCI's Molecular and Cellular Cancer Biology Program. "The cop can move quickly to recognize where the incident is, and regulate traffic while directing the paramedics arriving in an ambulance." Constrained motion allows Rad4 to be fast enough to scan large lengths of DNA quickly, yet slow enough that it does not miss structural errors in DNA that could be caused by chemicals or ultraviolet (UV) light. Mutations in Rad4, called XPC in humans, and other proteins in the DNA repair machinery are known to cause a genetic condition called xeroderma pigmentosum, where individuals have sensitivity to sunlight and are at an extremely high risk for developing skin cancer. Muwen Kong, a graduate student in Dr. Van Houten's laboratory, along with his collaborators, tagged normal and mutant Rad4 molecules with light-emitting quantum dots. They then watched them move across strands of DNA suspended between beads using a fluorescence microscope. The results obtained suggest that the first responder, consisting of Rad4 and another protein, Rad23, quickly scans the DNA for accidents by attempting to bend it. Alterations in the structure of DNA, such as those caused by chemicals or UV light, change the ease with which DNA can be bent. Once a potential accident is recognized, the Rad4-Rad23 first-responder team slows down to a 'constrained motion' pattern to more carefully examine a smaller region of 500-1,000 base pairs in the DNA. When structural damage is confirmed, Rad4-Rad23 stays near the scene and flags down the 'paramedics,' comprised of the rest of the DNA repair machinery, to fix the damage. This mechanism, which Dr. Van Houten calls 'recognition-at-a-distance,' allows Rad4 to be near the error without impeding the rest of the DNA repair crew. Though much work is needed before these results can be translated to the clinic, the results provide new avenues to improve treatment methods, especially in cancer. Resistance is a major problem with current treatments, such as the drug cisplatin, which kills cancer cells by introducing DNA crosslinks similar to UV light. By developing drugs that target Rad4/XPC or other repair proteins, it could be possible to enhance the effects of current treatments when they are used together, and also reduce the chances of tumor cells developing resistance, Dr. Van Houten said. Co-investigators include Lili Liu Ph.D., Stefanie Böhm, Ph.D., Simon C. Watkins, Ph.D., and Kara A. Bernstein, Ph.D., all of the Pitt School of Medicine; Xuejing Chen, Ph.D., and Jung-Hyun Min, Ph.D., both of the University of Illinois at Chicago; Peng Mao, Ph.D., and John J. Wyrick, Ph.D., both of Washington State University; and Neil M. Kad, Ph.D., of the University of Kent, U.K. The research was funded by National Institutes of Health grants 5R01ES019566, 5R01ES024872, 5R01ES002614 and 2P30CA047904; and National Science Foundation grant MCB-1412692.

Medford-Davis L.,Ben Taub General Hospital | Decamp M.,Northwestern University | Recht A.,Beth Israel Deaconess Medical Center | Flickinger J.,Pittsburgh Cancer Institute | And 2 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

We review the evidence for optimal surgical management and adjuvant therapy for patients with stages I and II non-small cell lung cancer (NSCLC) along with factors associated with increased risks of recurrence. Based on the current evidence, we recommend optimal use of mediastinal lymph node dissection, adjuvant chemotherapy, and post-operative radiation therapy, and make suggestions for areas to explore in future prospective randomized clinical trials. © 2012 Elsevier Inc. All rights reserved.

Varlotto J.,Pennsylvania State University | Varlotto J.,Penn State College of Medicine | Fakiris A.,Indiana University | Flickinger J.,Pittsburgh Cancer Institute | And 13 more authors.
Cancer | Year: 2013

BACKGROUND Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non-small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging. METHODS Two databases were combined which contained patients treated from 1999 to 2008 by lobectomy (LR, n = 132), sublobar resection (SLR, n = 48), and SBRT (n = 137) after negative staging. Univariate and multivariate analysis were performed for survival (OS), total recurrence control (TRC comprises local-regional and distant control), and locoregional control (LRC) in our entire population. A matched-pair analysis was also performed that compared surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. RESULTS On univariate analysis, OS was significantly worse with SBRT and also correlated with histology, the Charlson comorbidity index, tumor size, and aspirin use; TRC correlated only with histology; and no variable significantly correlated with LRC. OS was significantly poorer for SBRT in the matched-pair analysis than for patients treated with surgery, but TRC and LRC were not significantly different between these groups. Multivariate analyses including propensity score as a covariate (controlling for all factors affecting treatment selection) found that OS correlated only with Charlson comorbidity index, and TRC correlated only with tumor grade. LRC correlated only with tumor size with or without propensity score correction. CONCLUSIONS This retrospective study has demonstrated similar OS, LRC, and TRC with SBRT or surgery after controlling for prognostic and patient selection factors. Randomized clinical trials are needed to better compare the effectiveness of these treatments. © 2013 American Cancer Society.

Varlotto J.M.,Penn State Hershey Cancer Institute | Recht A.,Beth Israel Deaconess Medical Center | Flickinger J.C.,Pittsburgh Cancer Institute | Medford-Davis L.N.,Harvard University | And 2 more authors.
Cancer | Year: 2010

BACKGROUND: The objective of this study was to examine the effects of different definitions of local recurrence on the reported patterns of failure and associated risk factors in patients who undergo potentially curative resection for stage I nonsmall cell lung cancer (NSCLC). METHODS: The study included 306 consecutive patients who were treated from 2000 to 2005 without radiotherapy. Local recurrence was defined either as "radiation" (r-LR) (according to previously defined postoperative radiotherapy fields), including the bronchial stump, staple line, ipsilateral hilum, and ipsilateral mediastinum; or as "comprehensive" (c-LR), including the same sites plus the ipsilateral lung and contralateral mediastinal and hilar lymph nodes. All recurrences that were not classified as "local" were considered to be distal. RESULTS: The median follow-up was 33 months. The proportions of c-LR and r-LR at 2 years, 3 years, and 5 years were 14%, 21%, and 29%, respectively, and 7%, 12%, and 16%, respectively. Significant risk factors for c-LR on multivariate analysis were diabetes, lymphatic vascular invasion, and tumor size; and significant factors for r-LR were resection of less than a lobe and lymphatic vascular invasion. The proportions of distant (nonlocal) recurrence using these definitions at 2 years, 3 years, and 5 years were 10%, 12%, and 18%, respectively, and 14%, 19%, and 29%, respectively. Significant risk factors for distant failure were histology when using the c-LR definition and tumor size when using the r-LR definition. CONCLUSIONS: Local recurrence increased nearly 2-fold when a broad definition was used instead of a narrow definition. The definition also affected which factors were associated significantly with both local and distant failure on multivariate analysis. Comparable definitions must be used when analyzing different series. © 2010 American Cancer Society.

Varlotto J.M.,Pennsylvania State University | Medford-Davis L.N.,Harvard University | Recht A.,Harvard University | Recht A.,Beth Israel Deaconess Medical Center | And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non-small-cell lung cancer. Methods and Materials: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence. Results: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site of local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure. Conclusions: Patients with resected non-small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy. © 2011 Elsevier Inc.

Varlotto J.M.,Penn State Hershey Cancer Institute | Varlotto J.M.,Pennsylvania State University | Medford-Davis L.N.,Harvard University | Recht A.,Harvard University | And 5 more authors.
Journal of Thoracic Oncology | Year: 2011

Background: To compare the presenting and prognostic characteristics of patients with large cell neuroendocrine lung cancer (LCNELC) with those of patients with small cell lung cancer (SCLC) or other large cell carcinomas (OLCs) and to compare overall survival (OS) and lung cancer-specific survival (LCSS) rates for patients undergoing definitive resection without radiotherapy (S-NoRT). Methods: The Surveillance Epidemiology and End Results Database-17 from 2001 to 2007 was used. Differences between population characteristics were compared using χ and Wilcoxon tests. The log-rank test and Cox models were used to compare differences in OS and LCSS. Results: There were 1211 patients with LCNELC (324 in the S-NoRT group), 8295 patients with OLC (1120 S-NoRT), and 35,304 patients with SCLC (355 S-NoRT). The proportion of all large cell carcinomas constituted by LCNELC increased from 8 to 21% during the study period; and the proportion of patients with large cell carcinoma undergoing S-NoRT increased from 16 to 26%. Presenting and histopathologic characteristics and treatment factors of patients undergoing S-NoRT for patients with LCNELC were more similar to those of patients with OLC than to those with SCLC. OS and LCSS rates for patients with LCNELC undergoing resection without radiation were similar to those of patients with OLC and better than those for patients with SCLC, but the differences were not statistically significant on multivariate analysis. Conclusions: The clinical, histopathologic, and biologic features of LCNELC are more similar to OLC than to SCLC. Therefore, LCNELC should continue to be classified and treated as a large cell carcinoma. Copyright © 2011 by the International Association for the Study of Lung Cancer.

Varlotto J.M.,Pennsylvania State University | Recht A.,Beth Israel Deaconess Medical Center | Flickinger J.C.,Pittsburgh Cancer Institute | Medford-Davis L.N.,Harvard University | And 2 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2011

Objective: Stage I or II small cell lung cancer is rare. We evaluated the contemporary incidence of early-stage small cell lung cancer and defined its optimal local therapy. Methods: We analyzed the incidence, treatment patterns, and outcomes of 2214 patients with early-stage small cell lung cancer (1690 with stage I and 524 with stage II) identified from the Surveillance, Epidemiology, and End Results database from 1988 to 2005. Results: Early-stage small cell lung cancer constituted a stable proportion of all small cell lung cancers (3%-5%), lung cancers (0.10%-0.17%), and stage I lung cancers (1%-1.5%) until 2003 but, by 2005, increased significantly to 7%, 0.29%, and 2.2%, respectively (P < .0001). Surgery for early-stage small cell lung cancer peaked at 47% in 1990 but declined to 16% by 2005. Patients treated with lobectomy or greater resections (lobe) without radiotherapy had longer median survival (50 months) than those treated with sublobar resections (sublobe) without radiotherapy (30 months, P = .006) or those treated with radiotherapy alone (20 months, P < .0001). Patients undergoing sublobe without radiotherapy also demonstrated superior survival than patients receiving radiotherapy alone (P = .002). The use or omission of radiotherapy made no difference after limited resection (30 vs 28 months, P = .6). Multivariable analysis found survival independently related to age, year of diagnosis, tumor size, stage, and treatment (lobe vs sublobe vs radiotherapy alone). Conclusions: Surgery is an underused modality in the management of early-stage small cell lung cancer. Lobectomy provides optimal local control and leads to superior survival. Although sublobar resection proved inferior to lobectomy, it conferred a survival advantage superior to radiotherapy alone. The addition of radiotherapy to resection provided no additional benefit. Copyright © 2011 by The American Association for Thoracic Surgery.

Naick H.,Pondicherry University | Jin S.,Pittsburgh Cancer Institute | Baskaran R.,Pondicherry University
Molecular and Cellular Biochemistry | Year: 2016

Colorectal cancer is a critical health concern because of its incidence as the third most prevalent cancer in the world. Currently, 5-fluorouracil (5-FU), 6-thioguanine, and certain other genotoxic agents are mainstays of treatment; however, patients often die due to emergence of resistant population. Curcumin, a bioactive compound derived from the dietary turmeric (Curcuma longa) is an effective anticancer, anti-inflammatory, and antioxidant agent. Previously, we reported that human colorectal cancer cell lines compromised for mismatch repair (MMR) function exhibit heightened sensitivity to curcumin due to sustained curcumin-induced unrepaired DNA damage compared to proficient population counterparts. In this report, we show that the protein levels of gadd45α, whose transcript levels are increased during DNA damage and stress signals, are upregulated following curcumin treatment in a dose- and time-dependent manner. We further observed that cells compromised for Mlh1 function (HCT116 + Ch2) displayed ~twofold increased GADD45α upregulation compared to similarly treated proficient counterparts (HCT116 + Ch3). Similarly, suppression of Mlh1 using ShRNA increased GADD45α upregulation upon curcumin treatment. On the other hand, suppression of GADD45α using SiRNA-blocked curcumin-induced cell death induction in Mlh1-deficient cells. Moreover, inhibition of Abl through ST571 treatment and its downstream effector JNK through SP600125 treatment blocked GADD45α upregulation and cell death triggered by curcumin. Collective results lead us to conclude that GADD45α modulates curcumin sensitivity through activation of c-Abl > JNK signaling in a mismatch repair-dependent manner. © 2016, Springer Science+Business Media New York.

Jiang Z.,University of Pittsburgh | Kamath R.,University of Pittsburgh | Jin S.,University of Pittsburgh | Balasubramani M.,Genomics and Proteomics Core Laboratories | And 3 more authors.
Molecular Cancer | Year: 2011

Background: The proto-oncogene, c-Abl encodes a ubiquitously expressed tyrosine kinase that critically governs the cell death response induced by genotoxic agents such as ionizing radiation and cisplatin. The catalytic function of Abl, which is essential for executing DNA damage response (DDR), is normally tightly regulated but upregulated several folds upon IR exposure due to ATM-mediated phosphorylation on S465. However, the mechanism/s leading to activation of Abl's apoptotic activity is currently unknown.Results: We investigated the role of acetyl modification in regulating apoptotic activity of Abl and the results showed that DNA strand break-inducing agents, ionizing radiation and bleomycin induced Abl acetylation. Using mass spectrophotometry and site-specific acetyl antibody, we identified Abl K921, located in the DNA binding domain, and conforming to one of the lysine residue in the consensus acetylation motif (KXXK--X3-5--SGS) is acetylated following DNA damage. We further observed that the S465 phosphorylated Abl is acetyl modified during DNA damage. Signifying the modification, cells expressing the non acetylatable K921R mutant displayed attenuated apoptosis compared to wild-type in response to IR or bleomycin treatment. WT-Abl induced apoptosis irrespective of new protein synthesis. Furthermore, upon γ-irradiation K921R-Abl displayed reduced chromatin binding compared to wild type. Finally, loss of Abl K921 acetylation in Tip60-knocked down cells and co-precipitation of Abl with Tip60 in DNA damaged cells identified Tip60 as an Abl acetylase.Conclusion: Collective data showed that DNA damage-induced K921 Abl acetylation, mediated by Tip60, stimulates transcriptional-independent apoptotic activity and chromatin-associative property thereby defining a new regulatory mechanism governing Abl's DDR function. © 2011 Jiang et al; licensee BioMed Central Ltd.

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