Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy

Joseph J. Safdieh,David Schwartz,Joseph Weiner,Jeffrey P. Weiss,Justin Rineer,Isaac Madeb,Marvin Rotman,David Schreiber 대한방사선종양학회 2014 Radiation Oncology Journal Vol.32 No.3

Purpose: To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. Materials and Methods: The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003–2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. Results: The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). Conclusion: In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.

Clinical and biochemical outcomes of men undergoing radical prostatectomy or radiation therapy for localized prostate cancer

David Schreiber,Justin Rineer,Jeffrey P. Weiss,Joseph Safdieh,Joseph Weiner,Marvin Rotman,David Schwartz 대한방사선종양학회 2015 Radiation Oncology Journal Vol.33 No.1

Purpose: We analyzed outcomes of patients with prostate cancer undergoing either radical retropubic prostatectomy (RRP) +/– salvage radiation or definitive radiation therapy (RT) +/– androgen deprivation. Materials and Methods: From 2003–2010 there were 251 patients who underwent RRP and 469 patients who received RT (≥7,560 cGy) for prostate cancer. Kaplan-Meier analysis was performed with the log-rank test to compare biochemical control (bCR), distant metastatic-free survival (DMPFS), and prostate cancer-specific survival (PCSS) between the two groups. Results: The median follow-up was 70 months and 61.3% of the men were African American. For low risk disease the 6-year bCR were 90.3% for RT and 85.6% for RRP (p = 0.23) and the 6-year post-salvage bCR were 90.3% vs. 90.9%, respectively (p = 0.84). For intermediate risk disease the 6-year bCR were 82.6% for RT and 59.7% for RRP (p < 0.001) and 82.6% vs. 74.0%, respectively, after including those salvaged with RT (p = 0.06). For high risk disease, the 6-year bCR were 67.4% for RT and 41.3% for RRP (p < 0.001) and after including those salvaged with RT was 67.4% vs. 43.1%, respectively (p < 0.001). However, there were no significant differences between the two groups in regards to DMPFS or PCSS. Conclusion: Treatment approaches utilizing RRP +/– salvage radiation or RT +/– androgen deprivation yielded equivalent DMPFS and PCSS outcomes. Biochemical control rates, using their respective definitions, appeared equivalent or better in those who received treatment with RT.

The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects.

Schwartz, David L,Powis, Garth,Thitai-Kumar, Arun,He, Yi,Bankson, James,Williams, Ryan,Lemos, Robert,Oh, Junghwan,Volgin, Andrei,Soghomonyan, Suren,Nishii, Ryuichi,Alauddin, Mian,Mukhopadhay, Uday,Pen American Association for Cancer Research, Inc 2009 Molecular Cancer Therapeutics Vol.8 No.4

<P>Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.</P>

Clinical and biochemical outcomes of men undergoing radical prostatectomy or radiation therapy for localized prostate cancer

Schreiber, David,Rineer, Justin,Weiss, Jeffrey P.,Safdieh, Joseph,Weiner, Joseph,Rotman, Marvin,Schwartz, David The Korean Society for Radiation Oncology 2015 Radiation Oncology Journal Vol.33 No.1

Purpose: We analyzed outcomes of patients with prostate cancer undergoing either radical retropubic prostatectomy (RRP) +/- salvage radiation or definitive radiation therapy (RT) +/- androgen deprivation. Materials and Methods: From 2003-2010 there were 251 patients who underwent RRP and 469 patients who received RT (${\geq}7,560cGy$) for prostate cancer. Kaplan-Meier analysis was performed with the log-rank test to compare biochemical control (bCR), distant metastatic-free survival (DMPFS), and prostate cancer-specific survival (PCSS) between the two groups. Results: The median follow-up was 70 months and 61.3% of the men were African American. For low risk disease the 6-year bCR were 90.3% for RT and 85.6% for RRP (p = 0.23) and the 6-year post-salvage bCR were 90.3% vs. 90.9%, respectively (p = 0.84). For intermediate risk disease the 6-year bCR were 82.6% for RT and 59.7% for RRP (p < 0.001) and 82.6% vs. 74.0%, respectively, after including those salvaged with RT (p = 0.06). For high risk disease, the 6-year bCR were 67.4% for RT and 41.3% for RRP (p < 0.001) and after including those salvaged with RT was 67.4% vs. 43.1%, respectively (p < 0.001). However, there were no significant differences between the two groups in regards to DMPFS or PCSS. Conclusion: Treatment approaches utilizing RRP +/- salvage radiation or RT +/- androgen deprivation yielded equivalent DMPFS and PCSS outcomes. Biochemical control rates, using their respective definitions, appeared equivalent or better in those who received treatment with RT.

Juvenile Probation in the United States : Current Practices and How It Can Be Improved

Ira M. Schwartz,Peter Jones,David Schwartz. 한국보호관찰학회 2009 보호관찰 Vol.9 No.2

소년사법에 신경회로망을 이용한 선구적 연구는 미국에서 진행되었는데, 우리는 신경회로망 기술이 다른 나라에서도 적용되면 미국의 경우만큼의 성과가 있을지 궁금하다. 한국에서도 그러한 성과가 있을지 살펴보는 것은 흥미로운 일이 아닐 수 없다. 나의 동료들과 나는 그 가능성에 대해 낙관적이며 체계적 방법으로 조심스레 가능성을 타진하는 것이 중요하다고 생각한다. 그러므로 우리는 한국의 보호관찰 관계자들이 우리와 유사한 연구의 진행을 고려해볼 것을 권하고자 한다. 의미 있는 결과를 산출하기 위해 종종 수년이 소요되는 전통적인 기존의 연구방법과 달리, 신경회로망을 활용한 연구는 비교적 저렴한 수행비용이 들며, 1년 이내에 완료 할 수 있는 장점이 있다. 신경회로망 기반 모델을 형성할 만큼 의 충분한 데이터가 필요할 뿐이며, 모델 형성 후 현장에서 검증 절차를 거치고 기존의 도구와 비교하면 일단락된다. 또한 이와 같은 연구를 수행하기 위해 새로운 데이터를 수집할 필요가 없다. 예를 들어, 미국에서 신경회로망을 이용하였던 연구는 소년사법과 사회복지 기관에서 일상적으로 수집되는 자료를 활용하여 수행되었으므로 새로운 데이터를 수집하거나 기존의 자료 축적체계를 수정할 필요가 없었다. 한국 소년사법 자료와 그 수집과정에 대해 아는 바가 없으나, 이미 수집된 자료만으로도 이연구가 수행될 수 있을 것으로 생각한다.

Stereotactic radiotherapy of the prostate: fractionation and utilization in the United States

Joseph P. Weiner,David Schwartz,Meng Shao,Virginia Osborn,Kwang Choi,David Schreiber 대한방사선종양학회 2017 Radiation Oncology Journal Vol.35 No.2

Purpose: To analyze the utilization and fractionation of extreme hypofractionation via stereotactic body radiotherapy (SBRT) in the treatment of prostate cancer. Materials and Methods: Data was analyzed on men diagnosed with localized prostate cancer between 2004–2012 and treated with definitive-intent radiation therapy, as captured in the National Cancer Database. This database is a hospital-based registry that collects an estimated 70% of all diagnosed malignancies in the United States. Results: There were 299,186 patients identified, of which 4,962 (1.7%) were identified as receiving SBRT as primary treatment. Of those men, 2,082 had low risk disease (42.0%), 2,201 had intermediate risk disease (44.4%), and 679 had high risk disease (13.7%). The relative utilization of SBRT increased from 0.1% in 2004 to 4.0% in 2012. Initially SBRT was more commonly used in academic programs, though as time progressed there was a shift to favor an increased absolute number of men treated in the community setting. Delivery of five separate treatments was the most commonly utilized fractionation pattern, with 4,635 patients (91.3%) receiving this number of treatments. The most common dosing pattern was 725 cGy × 5 fractions (49.6%) followed by 700 cGy × 5 fractions (21.3%). Conclusions: Extreme hypofractionation via SBRT is slowly increasing acceptance. Currently 700-725 cGy × 5 fractions appears to be the most commonly employed scheme. As further long-term data regarding the safety and efficacy emerges, the relative utilization of this modality is expected to continue to increase.

Stereotactic radiotherapy of the prostate: fractionation and utilization in the United States

Weiner, Joseph P.,Schwartz, David,Shao, Meng,Osborn, Virginia,Choi, Kwang,Schreiber, David The Korean Society for Radiation Oncology 2017 Radiation Oncology Journal Vol.35 No.2

Purpose: To analyze the utilization and fractionation of extreme hypofractionation via stereotactic body radiotherapy (SBRT) in the treatment of prostate cancer. Materials and Methods: Data was analyzed on men diagnosed with localized prostate cancer between 2004-2012 and treated with definitive-intent radiation therapy, as captured in the National Cancer Database. This database is a hospital-based registry that collects an estimated 70% of all diagnosed malignancies in the United States. Results: There were 299,186 patients identified, of which 4,962 (1.7%) were identified as receiving SBRT as primary treatment. Of those men, 2,082 had low risk disease (42.0%), 2,201 had intermediate risk disease (44.4%), and 679 had high risk disease (13.7%). The relative utilization of SBRT increased from 0.1% in 2004 to 4.0% in 2012. Initially SBRT was more commonly used in academic programs, though as time progressed there was a shift to favor an increased absolute number of men treated in the community setting. Delivery of five separate treatments was the most commonly utilized fractionation pattern, with 4,635 patients (91.3%) receiving this number of treatments. The most common dosing pattern was $725cGy{\times}5fractions$ (49.6%) followed by $700cGy{\times}5fractions$ (21.3%). Conclusions: Extreme hypofractionation via SBRT is slowly increasing acceptance. Currently $700-725cGy{\times}5fractions$ appears to be the most commonly employed scheme. As further long-term data regarding the safety and efficacy emerges, the relative utilization of this modality is expected to continue to increase.

Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy

Safdieh, Joseph J.,Schwartz, David,Weiner, Joseph,Weiss, Jeffrey P.,Rineer, Justin,Madeb, Isaac,Rotman, Marvin,Schreiber, David The Korean Society for Radiation Oncology 2014 Radiation Oncology Journal Vol.32 No.3

Purpose: To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. Materials and Methods: The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. Results: The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). Conclusion: In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.

Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity.

Ihle, Nathan T,Lemos, Robert,Schwartz, David,Oh, Junghwan,Halter, Robert J,Wipf, Peter,Kirkpatrick, Lynn,Powis, Garth American Association for Cancer Research, Inc 2009 Molecular Cancer Therapeutics Vol.8 No.1

<P>The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade is an important component of the insulin signaling in normal tissues leading to glucose uptake and homeostasis and for cell survival signaling in cancer cells. Hyperglycemia is an on-target side effect of many inhibitors of PI3K/Akt signaling including the specific PI3K inhibitor PX-866. The peroxisome proliferator-activated receptor gamma agonist pioglitazone, used to treat type 2 diabetes, prevents a decrease in glucose tolerance caused by acute administration of PX-866. Our studies have shown that pioglitazone does not inhibit the antitumor activity of PX-866 in A-549 non-small cell lung cancer and HT-29 colon cancer xenografts. In vitro studies also showed that pioglitazone increases 2-[1-(14)C]deoxy-D-glucose uptake in L-6 muscle cells and prevents inhibition of 2-deoxyglucose uptake by PX-866. Neither pioglitazone nor PX-866 had an effect on 2-deoxyglucose uptake in A-549 lung cancer cells. In vivo imaging studies using [18F]2-deoxyglucose (FDG) positron emission tomography showed that pioglitazone increases FDG accumulation by normal tissue but does not significantly alter FDG uptake by A-549 xenografts. Thus, peroxisome proliferator-activated receptor gamma agonists may be useful in overcoming the increase in blood glucose caused by inhibitors of PI3K signaling by preventing the inhibition of normal tissue insulin-mediated glucose uptake without affecting antitumor activity.</P>

A single-molecule barcoding system using nanoslits for DNA analysis : nanocoding.

Jo, Kyubong,Schramm, Timothy M,Schwartz, David C Humana Press 2009 METHODS IN MOLECULAR BIOLOGY -CLIFTON THEN TOTOWA- Vol.544 No.-

<P>Single DNA molecule approaches are playing an increasingly central role in the analytical genomic sciences because single molecule techniques intrinsically provide individualized measurements of selected molecules, free from the constraints of bulk techniques, which blindly average noise and mask the presence of minor analyte components. Accordingly, a principal challenge that must be addressed by all single molecule approaches aimed at genome analysis is how to immobilize and manipulate DNA molecules for measurements that foster construction of large, biologically relevant data sets. For meeting this challenge, this chapter discusses an integrated approach for microfabricated and nanofabricated devices for the manipulation of elongated DNA molecules within nanoscale geometries. Ideally, large DNA coils stretch via nanoconfinement when channel dimensions are within tens of nanometers. Importantly, stretched, often immobilized, DNA molecules spanning hundreds of kilobase pairs are required by all analytical platforms working with large genomic substrates because imaging techniques acquire sequence information from molecules that normally exist in free solution as unrevealing random coils resembling floppy balls of yarn. However, nanoscale devices fabricated with sufficiently small dimensions fostering molecular stretching make these devices impractical because of the requirement of exotic fabrication technologies, costly materials, and poor operational efficiencies. In this chapter, such problems are addressed by discussion of a new approach to DNA presentation and analysis that establishes scaleable nanoconfinement conditions through reduction of ionic strength; stiffening DNA molecules thus enabling their arraying for analysis using easily fabricated devices that can also be mass produced. This new approach to DNA nanoconfinement is complemented by the development of a novel labeling scheme for reliable marking of individual molecules with fluorochrome labels, creating molecular barcodes, which are efficiently read using fluorescence resonance energy transfer techniques for minimizing noise from unincorporated labels. As such, our integrative approach for the realization of genomic analysis through nanoconfinement, named nanocoding, was demonstrated through the barcoding and mapping of bacterial artificial chromosomal molecules, thereby providing the basis for a high-throughput platform competent for whole genome investigations.</P>