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Background Uniquely in children, the existence of leptomeningeal spinal metastases does not confer a uniformly grave prognosis. Although the radiation tolerance of the spinal cord is of significant concern in these cases, the chemo- and radiosensitivity of these lesions argues for an aggressive approach where possible. Methods The records of the Indiana University Health Proton Therapy Center were reviewed for patients undergoing proton beam therapy with curative intent for LSM between January 1, 2004 and July 7, 2012. Patients with microscopic disease only on LP were not included. Particulars of therapy, including dose, field sizes, toxicities, and outcomes were collated. Results Twenty-two children received therapy as described, of median age 5 years (range 1.1–17.1). Patients had medulloblastoma (n = 9), ATRT (n = 4), ependymoma, and PNET (n = 3 each). Five lesions (23%) were chemo-recurrent, though no patient had prior radiation to the spine. Median follow-up was 14 months (range 4–33) for all living patients. Fifteen (68%) children continued to have local control at last follow-up visit. Median dose was 37.8 Gy (range 21.6–54 Gy). Eight patients with chemo-recurrent disease or diffuse cord seeding did poorly, with local control and overall survival achieved in four. The 12-month overall survival was 68% with grade 1 skin erythema as the most frequent toxicity. Conclusions We describe a cohort of LSM patients treated with RT with definitive intent, and the only available data from the proton environment. Durable response is possible for these children in over two-thirds of cases. Significant toxicity was infrequent using proton radiotherapy and these fractionation schemes. Pediatr Blood Cancer 2013;60:1839–1841. © 2013 Wiley Periodicals, Inc.

In patients treated with radical prostatectomy in the prostate-specific antigen (PSA) era, it has been demonstrated that the year of treatment in the PSA era is associated with better pathologic parameters and outcomes, independently of other well-recognized parameters such as clinical stage, pretreatment PSA level, or Gleason score. The purpose of the present study was to study a similar phenomenon with definitive radiotherapy (RT).The inclusion criteria were as follows: clinical Stage T1-T2, available pretreatment PSA level and biopsy Gleason score, treatment delivered before January 2000 with standard fractionation external beam radiotherapy to at least 70 Gy, no adjuvant androgen deprivation (AD), all neoadjuvant AD limited toor =6 months, and a minimum of 3 years of PSA follow-up. A total of 467 cases treated between January 1986 and December 1999 were included. Short-course AD in the adjuvant or neoadjuvant setting foror =6 months was given in 124 cases (27%). The median radiation dose was 74 Gy (range 70.0-78.0). A conformal technique was used in 293 cases (63%). The median follow-up was 62 months (range 37-189). A total of 4931 follow-up PSA levels were available for analysis (average 11 per patient). A multivariate analysis for factors affecting biochemical relapse-free survival rates using the proportional hazards model was performed for all cases using the following variables: age (continuous variable), race (black vs. white), clinical T stage (T1-T2a vs. T2b-T2c), pretreatment PSA (continuous variable), biopsy Gleason score (continuous variable), use of AD (yes vs. no), radiation dose (continuous variable), and year of treatment (continuous variable: 1986-1999).The projected 8-year biochemical relapse-free survival rate was 74%. The projected 5-year biochemical relapse-free survival rate for the 143 patients treated in the 1986-1995 period was 58% vs. 82% for the 324 patients treated in the 1996-1999 period (p0.001). The difference was attributable to a multitude of factors (earlier stage cancer, higher radiation doses, shorter follow-up). To study the confounding effects of these factors on the year of therapy, a multivariate analysis was performed. The multivariate analysis revealed the initial PSA level (p0.001), Gleason score (p0.001), RT dose (p = 0.045), and year of treatment (p0.001) to be independent predictors of outcome. Age (p = 0.41), race (p = 0.14), T stage (p = 0.10), and use of AD (p = 0.58) were not.When controlling for tumor, treatment, and follow-up parameters, the year in which RT was performed was still an independent predictor of outcome, consistent with observations made for radical prostatectomy patients. This indicates a more favorable presentation of localized prostate in current years probably related to a combination of factors such as screening and increased patient awareness leading to earlier diagnosis. Outcome predictions should be based on contemporaneous series.

To review the biochemical recurrence-free survival (bRFS) rates of treatment with either external beam radiotherapy or radical prostatectomy in patients with biopsy Gleason score 8 or above in the prostate specific antigen (PSA) era.A total of 297 localized prostate carcinoma patients diagnosed with biopsy Gleason score 8 or above were treated between 1987 and 2000 at the Cleveland Clinic with either prostatectomy or radiotherapy (RT). All patients had pretreatment PSA (iPSA) levels. Androgen deprivation was given as part of the initial treatment in 154 patients (52%). Radical prostatectomy (RP) was the primary treatment in 115 patients (39%) and 182 patients (61%) received RT. The median radiation dose was 70.2 Gy (range, 60.0-78.0 Gy). The median follow-up time was 42 months (range, 1-153 months).For the 297 patients, the 5 and 8-year bRFS rates were 45% (95% confidence interval [CI] 38-52%) and 31% (95% CI 20-42%), respectively. The 5-year bRFS rates for iPSA 10 or less versus. iPSA above10 were 66% (95% CI 54-78%) versus 31% (95% CI 22-40%), respectively (P0.001). The 5-year bRFS rates for use of androgen deprivation versus no androgen deprivation were 62% (95% CI 52-72%) versus 35% (95% CI 27-42%), respectively (P0.001). The 5-year bRFS rates for RT patients versus RP patients were 47% (95% CI 38-57%) versus 42% (95% CI 31-53%), respectively (P = 0.051). For RT patients, the 5-year bRFS rates for use of androgen deprivation versus no androgen deprivation were 71% versus 29%, respectively (P0.001). For RP patients, the 5-year bRFS rates for use of androgen deprivation versus no androgen deprivation were 39% versus 43%, respectively (P = 0.90). Multivariate time-to-failure analysis using the proportional hazards model showed iPSA level (P0.001) and the use of androgen deprivation (P = 0.001) to be the only independent predictors of biochemical recurrence. Age (P = 0.44), race (P = 0.80), clinical T stage (P = 0.10), biopsy Gleason scores (P = 0.39), and treatment modality (P = 0.13) were not independent predictors of biochemical failure. A total of 104 patients had Stage T1 or T2 disease, low iPSA levels (/= 10 ng/mL), and a high Gleason score (/= 8). For all 104 patients, the 5-year bRFS rate was 64%. For 52 of the 104 patients who received 6 months of androgen deprivation or less, the 5-year bRFS rate was 78%.Patients with localized prostate carcinoma with a biopsy Gleason score 8 or less have lower recurrence rates if iPSA levels are 10 or less. Biochemical control rates were encouraging for patients with biopsy Gleason score 8 or above, clinical Stage T1-T2, and iPSA levels less than or equal to 10 ng/mL treated with adjuvant androgen deprivation given only for 6 months or less. If longer follow-up confirms these findings, these patients might not need prolonged androgen deprivation for periods exceeding 6 months following local therapy.

BACKGROUND In a population of patients with brain metastases from melanoma, the authors sought to determine whether various therapies provided any benefit at all, whether local therapy was better than whole brain radiotherapy (WBRT), and whether combined local therapy and WBRT provided any advantage over local therapy alone. They also analyzed survival according to a Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) to determine how well the RTOG RPA classes predicted survival in this patient population and whether treatments varied in effectiveness from category to category. METHODS A total of 74 patients with brain metastases from melanoma were treated at The Cleveland Clinic Foundation between 1984 and 1998. For this study, the authors reviewed patient charts and confirmed survival status. Survival was compared by treatment modality (surgical resection, WBRT, stereotactic radiosurgery, or WBRT combined with local therapy). Survival also was compared according to the RTOG RPA prognostic classes (Class 1, Class 2, or Class 3), which has not been validated previously in patients with malignant melanoma. RESULTS The median survival was 5.5 months for all patients. Survival varied significantly by RTOG prognostic class; The median survival was 10.5 months (range, 2.2–99.2 months) for patients in Class 1, 5.9 months (range, 0.2–43.9 months) for patients in Class 2, and 1.8 months (range, 0.1–6.9 months) for patients in Class 3 (P < 0.0001). Survival analysis showed that combined treatment offered significantly better survival (P < 0.0001; combined vs. other). The median survival was 8.8 months (range, 1.8–99.2 months) for the combined therapy group, 4.8 months (range, 1.2–27.8 months) for the local therapy alone group, 2.3 months (range, 0.2–9.6 months) for the WBRT alone group, and 1.1 months (0.1–3.0 months) for the group that received no therapy. CONCLUSIONS Adding WBRT to local therapy may improve survival in this group of patients: Combined therapy was superior to WBRT alone. The RPA classification scheme likely has prognostic value for patients with brain metastases from malignant melanoma. Prospective studies are required to overcome selection bias and confirm these results. Cancer 2002;94:2265–72. © 2002 American Cancer Society. DOI 10.1002/cncr.10426

Purpose: To study the impact of biochemical failure on overall survival rates during the first 10 years after definitive radiotherapy for localized prostate cancer. Methods and Materials: The analysis was performed on 936 cases treated at a single institution between 1986 and 1998 with definitive radiotherapy. The median age of treatment was 69 years (range: 46–86 years). Pretreatment PSA levels (iPSA) and biopsy Gleason scores (bGS) were available for all cases. The clinical stage was T1/T2A in 63%, T2B/C in 27%, and T3 in 10%. The median iPSA level was 9.6 ng/mL (range: 0.4–692.9 ng/mL). The iPSA was ≤10 in 53% and >10 in 47%. The bGS was ≤6 in 59% and ≥7 in 41%. Androgen deprivation (AD) was administered in 181 cases (19%) for a median duration of 6 months (range: 1–6 months). All 181 cases received AD neoadjuvantly, i.e., before and/or during the radiotherapy. No AD was delivered after the completion of radiation. The median radiation dose was 70 Gy (range: 60–78 Gy). The radiotherapy technique was conformal in 376 (40%) cases. The American Society of Therapeutic Radiology and Oncology definition of biochemical failure (bF) was used; 316 cases (34%) had failed biochemically, and 620 (66%) had not. The end point was overall survival (OS). Time to death was determined from the time of definitive radiotherapy. The median PSA follow-up was 58 months. The median follow-up times for bF vs. no-bF cases were 77 and 49 months, respectively. A multivariate analysis of factors affecting OS using the proportional hazards model was performed for all cases using the following variables: age (>65 vs. ≤65 years), race (African-American vs. Caucasian), clinical T stage (T1–2A vs. T2B–C vs. T3), bGS (≤6 vs. 7 vs. ≥8), iPSA (continuous variable), use of AD (yes vs. no), year of therapy (continuous variable), radiation dose (continuous variable), radiation technique (conformal vs. standard), and biochemical failure (yes vs. no). Results: The 5-year OS rate for the entire group was 89% (95% CI [confidence interval]: 86–91%). The 5-year OS rates for bF vs. no-bF patients were 89% (95% CI: 86–93%) and 89% (95% CI: 86–92%), respectively. The 10-year OS rate for the entire group was 68% (95% CI: 61–75%). The 10-year OS rates for bF vs. no-bF patients were 65% (95% CI: 56–74%) and 77% (95% CI: 69–84%), respectively. The difference between bF and no bF was not significant in predicting overall survival in univariate analysis (log-rank test, p = 0.68). On multivariate analysis, bGS ( p p = 0.003), radiation dose ( p = 0.017), year of therapy ( p = 0.031), and age ( p = 0.020) were independent predictors of death. iPSA levels ( p = 0.33), race ( p = 0.80), radiation technique ( p = 0.16), and use of AD ( p = 0.09) were not predictive of OS. Biochemical failure ( p = 0.052) showed only a trend for independently predicting overall survival on multivariate analysis. Conclusion: Biochemical failure after definitive radiotherapy for localized prostate cancer is not associated with increased mortality within the first 10 years after initial therapy, although a trend toward worse outcome was observed at 10 years. Longer follow-up from initial therapy is needed to fully understand the impact of biochemical failure on overall survival. With longer follow-up, significant differences might be observed at 15 or 20 years after therapy.

10506 Background: Metastatic RB is associated with a poor prognosis. Previous small series suggested that intensified systemic chemotherapy with or without radiation therapy (RT) may improve outcomes in this population. COG opened this prospective, multi-institutional, international trial to study the effectiveness of this approach. Methods: Patients with regional extra-ocular RB (stage 2 or 3) were treated with 4 cycles of intensive conventional chemotherapy (vincristine 0.05 mg/kg/day, cisplatin 3.5 mg/kg/day, cyclophosphamide 65 mg/kg x 2 days, etoposide 4 mg/kg x 2 days) followed by involved-field RT (4500 cGy). Two strata of patients with metastatic RB [stage 4a: distant metastases not involving the central nervous system involvement (CNS); and stage 4b (CNS metastases)/trilateral RB)] were treated with 4 cycles of the same chemotherapy. Patients with ≥ partial response then received 1 cycle of high-dose carboplatin (Calvert formula with AUC = 7/day, maximum 16.7 mg/kg/day) on days -8 to -6, thiotepa (10 mg/kg/day), & etoposide (8.3 mg/kg/day) on days -5 to -3 with autologous hematopoietic stem cell rescue on day 0. Patients with metastatic RB who did not achieve an adequate response to chemotherapy also received RT. Results: Sixty subjects (20 in each stratum) were enrolled; 57 were eligible and included in the analyses (based on data current to June 30, 2016). Toxicity was significant as expected and there were 2 therapy related deaths. Event-free survival (EFS) at 36 months was 87.7% (90% CI 65.4 to 96.0%) for subjects with stage 2 or 3 disease, 79.3% (90% CI 54.2 to 91.6%) for subjects with stage 4a disease and 8.0% (90% CI 1.0 to 25.1%) for subjects with stage 4b/trilateral disease. The observed results significantly improved the EFS in each stratum compared with historical results used for planning the study. Conclusions: This is the first prospective, multi-institutional, international study to show that intensive multi-modality therapy is highly effective for patients with regional extra-ocular RB and metastatic RB not involving the CNS. More effective therapy is required for patients with CNS RB. Clinical trial information: NCT00554788.

Brain tumors are the second most common group of malignancies in children. For some pediatric tumors such as medulloblastoma, supratentorial primitive neuroectodermal tumor (PNET), ependymoma and germ cell tumors, leptomeningeal dissemination is a route of spread. Imaging of the entire neuraxis is performed in addition to cerebral spinal fluid (CSF) cytology from a lumbar tap. For low-grade gliomas, surgery is the mainstay of treatment. Adjuvant therapy is not needed for patients who have gross total resections. Diffuse pontine gliomas are the most common brainstem gliomas in children. Radiation to a dose of 54 Gy in 30 fractions over 6 weeks is the standard treatment. Current treatment strategies in medulloblastoma, which include maximal safe resection, craniospinal irradiation (CSI) followed by primary site irradiation, and chemotherapy, have resulted in 5-year progression-free survivals of 80 and 70% for standard- and high-risk patients. The extent of resection is the most important prognostic factor for ependymoma. Adjuvant radiotherapy is currently recommended for ependymoma, regardless of extent of resection. Germ cell tumors are divided into germinoma and nongerminomatous germ cell tumor (NGGCT), with the former having a better prognosis. Germinomas are highly curable with radiotherapy alone, while NGGCT is best managed with a combination of radiation and chemotherapy. Late effects of radiotherapy in young children (

Purpose: To study the radiation dose response as determined by biochemical relapse-free survival in patients with favorable localized prostate cancers, i.e., Stage T1–T2, biopsy Gleason score (bGS) ≤ 6, and pretreatment prostate-specific antigen (iPSA) ≤ 10 ng/mL. Methods and Materials: A total of 292 patients with favorable localized prostate cancer were treated with radiotherapy alone between 1986 and 1999. The median age was 69 years. Sixteen percent of cases (n = 46) were African-American. The distribution by clinical T stage was as follows: T1/T2A, 243 (83%); and T2B/T2C, 49 (17%). The distribution by iPSA was as follows: ≤ 4 ng/mL, 49 (17%); and > 4 ng/mL, 243 (83%). The mean iPSA level was 6.2 (median, 6.4). The distribution by bGS was as follows: ≤ 5 in 89 cases (30%) and 6 in 203 cases (70%). The median radiation dose was 70.0 Gy (range, 63.0–78.0 Gy). Doses of ≤ 70.0 Gy were delivered in 175 cases, 70.2–72.0 Gy in 24 cases, 74 Gy in 30 cases, and 78 Gy in 63 cases. For patients receiving < 72 Gy, the median dose was 68 Gy, vs. 78 Gy for patients receiving ≥ 72 Gy. A conformal technique was used in 129 (44%) of cases. The median follow-up was 43 months (range, 3–153). Results: For the entire cohort, the projected 5- and 8-year biochemical relapse-free survival (bRFS) rates were both 81%. For patients receiving ≥ 72 Gy, the 5- and 8-year bRFS rates were both 95% vs. only 77% for patients receiving < 72 Gy, p = 0.010. For patients receiving 74 Gy, the 4-year bRFS rate was 94% vs. 96% for patients receiving 78 Gy, p = 0.90. A multivariate analysis for factors affecting bRFS rates using Cox proportional hazards was performed for all cases using the following variables: age (continuous variable), race (black vs. white), iPSA (continuous variable), bGS (≤ 5 vs. 6), Stage (T1–2A vs. T2B–C), radiation dose (continuous variable), and radiation technique (conformal vs. standard). From the multivariate analysis, only iPSA (p = 0.017, χ2 = 5.7), and radiation dose (p = 0.021, χ2 = 5.3) were independent predictors of outcome. Age (p = 0.94), race (p = 0.89), stage (p = 0.45), biopsy GS (p = 0.40), and radiation technique (p = 0.45) were not. Conclusion: There is a clear radiation dose response in patients with favorable localized prostate cancers (i.e., Stage T1–T2, biopsy Gleason score ≤ 6, and iPSA ≤ 10 ng/mL). At least 74 Gy should be delivered to the prostate and periprostatic tissues. With our cohort of patients, longer follow-up will be needed to assess the importance of doses exceeding 74 Gy.

Uniquely in children, the existence of leptomeningeal spinal metastases does not confer a uniformly grave prognosis. Although the radiation tolerance of the spinal cord is of significant concern in these cases, the chemo- and radiosensitivity of these lesions argues for an aggressive approach where possible.The records of the Indiana University Health Proton Therapy Center were reviewed for patients undergoing proton beam therapy with curative intent for LSM between January 1, 2004 and July 7, 2012. Patients with microscopic disease only on LP were not included. Particulars of therapy, including dose, field sizes, toxicities, and outcomes were collated.Twenty-two children received therapy as described, of median age 5 years (range 1.1-17.1). Patients had medulloblastoma (n = 9), ATRT (n = 4), ependymoma, and PNET (n = 3 each). Five lesions (23%) were chemo-recurrent, though no patient had prior radiation to the spine. Median follow-up was 14 months (range 4-33) for all living patients. Fifteen (68%) children continued to have local control at last follow-up visit. Median dose was 37.8 Gy (range 21.6-54 Gy). Eight patients with chemo-recurrent disease or diffuse cord seeding did poorly, with local control and overall survival achieved in four. The 12-month overall survival was 68% with grade 1 skin erythema as the most frequent toxicity.We describe a cohort of LSM patients treated with RT with definitive intent, and the only available data from the proton environment. Durable response is possible for these children in over two-thirds of cases. Significant toxicity was infrequent using proton radiotherapy and these fractionation schemes.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry was used to obtain spectra of peptide-metal ion complexes formed by a zinc finger peptide of the transcription factor IIIA (Cys 2 -His 2 ) type and zinc and cobalt ions, as well as peptide-enzyme complexes. Peptides and proteins analyzed by mass spectrometry are generally dissolved in 0.1% aqueous TFA (pH < 2.0). At this pH, peptides and proteins denature. We therefore reasoned that MALDI mass spectrometry might be able to detect noncovalently bound compounds if conditions were used to prepare the samples that allowed macromolecular assemblies to retain tertiary structure. Samples were dissolved in 1 M ammonium bicarbonate, and a saturated matrix solution was prepared using ethanolammonium bicarbonate (1 :1) solution or ethanol-ammonium citrate (1 :1) solution. All preparations of zinc finger peptides were done in a glovebox under nitrogen to prevent oxidation of the metal binding cysteine residues. Using this approach, we have been able to demonstrate that MALDI mass spectrometry can be used to study both noncovalent metal binding complexes and noncovalent peptide-enzyme complexes.

Volumetric planning in the form of proton therapy, intensity-modulated radiation therapy (IMRT), and three-dimensional (3D) conformal therapy is the standard technique for definitive craniospinal irradiation (CSI) and boost radiation therapy for medulloblastoma. These volumetric methods each can be delivered using a number of techniques; however, accurate delineation of target volumes is universally required.

To investigate the moving gap region dosimetry in proton beam cranio-spinal irradiation (CSI) to provide optimal dose uniformity across the treatment volume.Proton beams of ranges 11.6 cm and 16 cm are used for the spine and the brain fields, respectively. Beam profiles for a 30 cm snout are first matched at the 50% level (hot match) on the computer. Feathering is simulated by shifting the dose profiles by a known distance two successive times to simulate a 2 × feathering scheme. The process is repeated for 2 mm and 4 mm gaps. Similar procedures are used to determine the dose profiles in the moving gap for a series of gap widths, 0-10 mm, and feathering step sizes, 4-10 mm, for a Varian iX 6MV beam. The proton and photon dose profiles in the moving gap region are compared.The dose profiles in the moving gap exhibit valleys and peaks in both proton and photon beam CSI. The dose in the moving gap for protons is around 100% or higher for 0 mm gap, for both 5 and 10 mm feathering step sizes. When the field gap is comparable or larger than the penumbra, dose minima as low as 66% is obtained. The dosimetric characteristics for 6 MV photon beams can be made similar to those of the protons by appropriately combining gap width and feathering step size.The dose in the moving gap region is determined by the lateral penumbras, the width of the gap and the feathering step size. The dose decreases with increasing gap width or decreasing feathering step size. The dosimetric characteristics are similar for photon and proton beams. However, proton CSI has virtually no exit dose and is beneficial for pediatric patients, whereas with photon beams the whole lung and abdomen receive non-negligible exit dose.

Modern techniques of craniospinal radiation therapy (CSI) offer the advantage of modulating dose distribution to normal tissues in children and young adults. Reducing risks for second neoplasms and late effects to uninvolved tissues must be a priority for radiation oncologists. This manuscript reviews potential advantages and concerns moving forward with proton beam CSI.

Hypothalamic obesity syndrome can affect brain tumor patients following surgical intervention and irradiation. This syndrome is rare at diagnosis in childhood cancer, but has been reported with relapse of acute lymphoblastic leukemia. Here we present a case of hypothalamic obesity syndrome as the primary presentation of a toddler found to have CNS+ B-cell lymphoblastic lymphoma. Cytogenetic studies on diagnostic cerebrospinal fluid revealed MLL gene rearrangement (11q23). Hyperphagia and obesity dramatically improved following induction and consolidation chemotherapy. We describe a novel presentation of hypothalamic obesity syndrome in CNS B-cell lymphoblastic lymphoma, responsive to chemotherapy.

The kinetics of cobalt(II) and zinc(II) binding by a prototypical zinc finger peptide has been examined by stopped-flow spectrometry. Cobalt(II) binding was demonstrated to be second order, first order in each peptide and cobalt(II) concentration. At pH 6.55 in 100 mM HEPES, 100 mM NaCl buffer the second order rate constant was 7.5(±2.1)×10 4 M −1 s −1 . The displacement of cobalt(II) by zinc(II) was examined at pH 7.0 as a function of both cobalt(II) and zinc(II) concentration. The data are consistent with a dissociative mechanism with the rate of zinc(II) binding being substantially faster than cobalt(II) binding. The rate constant for cobalt(II) dissociation was 5.3(± 0.5)×10 −2 s −1 . The ratio of the rate constants for zinc(II) and cobalt(II) binding was found to be 66±3, indicating that the rate constant for zinc(II) is 2.8(±0.4)×10 7 M −1 s −1 at pH 7.0. This indicates that the rate of zinc(II) dissociation is of 1.6(±0.6)×10 −4 s −1 . The magnitude of the kinetic preference for zinc(II) over cobalt(II) revealed in metal binding rate constants is observed for many other zinc metalloproteins despite the fact that these rate constants vary over eight orders of magnitude.

Tobacco use in the form of cigarettes has long been established as a major risk factor for coronary heart disease (CHD). It is the most preventable cause of mortality. Each year, cigarette smoking causes more than 400,000 deaths in the United States alone, more than the number of American lives lost during World War I, Korea, and Vietnam combined (1,2). Not only does this modifiable behavior cause pain and suffering, but it poses a significant economic burden. Total US Medicaid expenses caused by tobacco use are more than $6 billion a year (3). Total direct health care costs are in excess of $75 billion a year. Indirect losses, usually because of lost productivity, increase that figure by another $80 billion a year (3,4). For every cigarette pack sold in the United States, the country spends approx $7.18 in health care-related and lost productivity costs (5). In the mid1990s, state attorneys general participated in legal action with tobacco companies in hopes of winning back money spent on Medicaid expenses. In 1998, an out-of-court settlement was reached giving states billions of dollars upfront and billions more in annual payments (6). Since then, most states have failed to allocate the Centers for Disease Control and Prevention-recommended funding for tobacco prevention, despite the fact that states are taking in record amounts of tobacco-generated revenue from the settlement and from increased cigarette taxes (7).

The cyclins and their catalytic subunits, the cyclin-dependent kinases (CDKs), control cell cycle progression by regulating events that drive the transitions between cell cycle phases (13, 14). The activity of these CDKs is regulated positively by cyclins, their associated catalytic partners, and negatively by binding of CDK inhibitors (CKIs). Activation of cyclin/CDK complexes results in a cascade of protein phosphorylations that ultimately induces cell cycle progression. Cyclins were first identified in clam and sea urchin embryos, where they were observed to accumulate during interphase and to be degraded during mitosis (16). The human G1 cyclins, the D- and E-type cyclins, were identified functionally by screening of human cDNA libraries for sequences that could complement G1 cyclin mutations in Saccharomyces cerevisiae (31, 35, 65). The cyclin E mRNA levels show a periodic pattern of expression, being synthesized during the G1 phase of the cell cycle, with levels increasing sharply in late G1, followed by accumulation of cyclin E protein and then down regulation in S phase (11, 32, 35; reviewed in reference 51). Cyclin E binds Cdk2 with a resulting peak of associated kinase activity at the G1/S boundary (11, 32). Cyclin E/Cdk2 complexes have been shown to play an essential and rate-limiting role in the transition between G1 and S phase (46, 52, 61, 62), as well as for the initiation of DNA replication (26, 33, 46). How cyclin E/Cdk2 promotes S-phase entry is poorly defined, since few downstream effectors of cyclin E/Cdk2 are known. While cyclin E complexes phosphorylate the protein product of the retinoblastoma tumor suppressor gene (pRb), which is also phosphorylated by the D-type cyclin-Cdk4/6 complexes (10, 17, 28), it is likely that other substrates exist during late G1. Unlike cyclin D, cyclin E remains essential in the absence of pRb, since (i) its inducible expression in fibroblasts accelerates G1/S progression without affecting the kinetics of pRb phosphorylation (53); (ii) unlike the D-type cyclins, cyclin E is essential for cell cycle progression in pRb-deficient cells (46); (iii) ectopic expression of cyclin E bypasses pRb-mediated cell cycle arrest (1, 40); and (iv) cyclin E is required for S-phase entry in Drosophila melanogaster (12). These findings highlight a fundamental difference between the cyclin D and cyclin E complexes, strongly suggesting that other key rate-limiting substrates exist for cyclin E/Cdk2 (1, 40). Moreover, all functions of cyclin D1 can be replaced by cyclin E, suggesting that cyclin E is the downstream target of cyclin D1 and the master regulator of S-phase entry (18). Apoptosis, a universal genetic program of cell death in higher eukaryotes, is a basic process involved in cellular development and differentiation (50). Apoptosis may be essential for the prevention of tumor formation, and its deregulation is widely believed to be involved in pathogenesis of many human diseases, including cancer (reviewed in reference 60). In almost all instances, deregulated cell proliferation and suppressed cell death together provide the underlying platform for neoplastic progression (15). In cancer, called a disease of deregulated cell proliferation, one principal target is the late G1 cell cycle regulated by pRb (23). Defects in this pathway, which may be universal in human cancer, include deletions of the Rb gene itself and deregulation of the CDKs that phosphorylate and functionally inactivate pRb, either through direct overactivation of CDKs or through genetic loss of their inhibitors (56). We have shown that the absence of Rb is capable of activating an apoptotic response associated with p53 stabilization and increased expression of genes dependent on E2F transcription (2), such as cyclin E. Cyclin E has been shown to be deregulated and overexpressed in several solid tumors, including breast, colon, and prostate carcinomas (29, 56). We have recently shown that cyclin E levels are also regulated by genotoxic stress and that cyclin E activation plays a functional role in apoptosis of hematopoietic cells (43). The activation of a cascade of the ICE/CED-3 family of cysteine proteases (termed caspases) is a common and critical regulator of the execution phase of apoptosis, triggered by many factors, including genotoxic agents (e.g., γ-irradiation or treatment with anticancer agents [7, 19, 20]). Once the cells are committed to cell death, apoptogenic factors, the best known of which is cytochrome c, are released from mitochondria to initiate the caspase cascade (7, 38). Cytochrome c acts as a cofactor to stimulate the complexing of Apaf-1 with caspase 9 (36), which then initiates activation of the caspase cascade. Caspases are synthesized as inactive precursors, which are activated by proteolytic cleavage to generate active enzymes which then may further proteolytically cleave proteins crucial for the maintenance of cellular cytoskeleton, DNA repair, signal transduction, and cell cycle control (25). There are many in vivo caspase substrates, including transcription factors, kinases, enzymes involved in DNA repair, and cytoskeletal proteins (reviewed in reference 25). In addition, several proteins essential for cell cycle regulation, such as pRb (27, 59), MDM2 (6), PITSLRE (3), p21WAF1/CIP1, and p27Kip1 (34) are also caspase targets. Apoptotic targets of CDKs are likely to exist, given reports of an interplay between the cell cycle control processes and apoptosis (44, 45), with recent reports indicating that the apoptosis-regulatory proteins themselves can directly impinge on the cell cycle machinery (4, 37, 42, 47). Clearly, induction of apoptosis by various stimuli has been shown to require activation of Cdk2 (54, 66), whereas forced expression of CKIs in cultured cells (43, 66), in neurons (48), or during myocyte differentiation (63) prevents apoptosis. Importantly, similar observations were made in noncycling developing thymocytes, in which Cdk2 was activated; conversely, Cdk2 inhibition eliminates apoptosis (21). Moreover, conditional cyclin A expression was reported to be involved in apoptosis of fibroblasts (58), whereas ectopic expression of cyclins D1 in rat fibroblasts under conditions of serum starvation led to apoptotic cell death (22). We found that cyclin E was upregulated rapidly during apoptosis induced by genotoxic stress in hematopoietic cells, resulting in caspase activation and exposure of the phosphatidylserine on the plasma membrane. Consistent with a role of cyclin E in apoptosis, its overexpression greatly sensitizes these cells to radiation, while its inhibition by a dominant-negative Cdk2 blocks cell death (43). We have been interested in elucidating the role of cyclin E in apoptosis of hematopoietic cells. In this study, we show that the p50-cyclin E is proteolytically cleaved and thus converted to a p18 C-terminal cyclin E fragment. We examined the temporal expression of this cyclin E derivative, its genesis, and its potential role in apoptosis. p18-cyclin E becomes the most abundant form of cyclin E during the course of apoptosis induced by multiple genotoxic agents in all hematopoietic tumor cell lines we have examined. Cyclin E cleavage results in elimination of its binding to Cdk2 and, therefore, inactivation of its associated kinase activity and cell cycle function. Overexpression of p18-cyclin E276-395 (where cyclin E276-395 is the cyclin E fragment containing residues 276 to 395) triggers apoptosis, while expression of a cleavage-resistant mutant prevents it. Our data indicate that cyclin E has a dual role in apoptosis of tumor cells of hematopoietic origin, with a distinct role for cyclin E276-395 in the amplification of the apoptotic process.

mice per group for a total of 72 measurements. A t–test was used to determine differences in values between treatment groups (radiation + soy, radiation alone, and control). Results: Radiation caused significant thickening of the IEL, mean 66.5+/4.3um (SEM) compared with 22.7+/-0.8um IEL thickness in control mice (p

for proton therapy patients. The range uncertainty guidelines in treatment planning depend on the proton therapy center. At our institution we add 3.5% to the prescribed range plus 1 mm. Our results show that for some sites (e.g., liver) this seems to be generous, while for other sites, it largely depends on the tumor location and beam angle. We conclude that the use of site-specific range uncertainty margins in proton therapy might be appropriate. Note that TOPAS will be made available to the proton therapy community in 2013. Author Disclosure: H. Paganetti: None. J. Schuemann: None. C. Grassberger: None. J. Verburg: None. D. Giantsoudi: None. M. Moteabbed: None. C. Min: None. M. Testa: None. B. Faddegon: None. J. Perl: None.

Purpose: In this paper, we report an FMEA approach on CSI at the IU Health Proton Therapy Center. Methods: A process map in proton CSI is developed. Each process consists of a number of sub‐processes. For each sub‐process, possible failures that may affect the process are identified and their respective Risk Priority Number (RPN) are calculated based on their severities (S), likelihood of occurrence (O) and probability of being detected (D), following the TG100 guidelines. Failures that most adversely impact the treatment are identified and quality assurance procedures to safeguard these most serious failures are developed. Attention is also given to certain failures which have low RPN but which may have dire consequence if it occurs in a treatment. Results: Ten intermediate processes involved in the CSI are identified. The number of sub‐processes within each intermediate process varies, from as few as one to as many as 11. For the ten processes in PTCSI, there are total of 66 sub‐processes, 139 failure modes and 561 causes of failures. 6/10 processes have failures with RPN=300. Examples of failures with such large RPN values are errors in administering anesthesia, in‐correct patient setup for image guidance, problems in the handling of apertures and compensators, etc. Conclusions: The implementation of FMEA in CSI (or any treatments) is a team effort. Significant efforts are involved in setting up process trees, failure modes, estimating the RPN values for each cause of failures, etc. However, once a FMEA is properly aligned, it is relatively easy to identify the most critical factors that require special attentions or QA to ensure safe execution of the processes. A learning curve to implement FMEA in any radiation oncology department should be expected given the different analysis practice from traditional QA approaches.

Purpose: In this study, we investigated the dosimetry in the moving gap region in proton CSI for various combinations of field junction widths and feathering step sizes. We have also compared the dosimetry in the field junction between proton and photon beams. Methods: Dose profiles for two proton ranges, 11.6cm and 16cm, both with 10cm SOBP for the 30cm snout are used. Feathering of the junction is simulated by shifting the profiles by two successive steps. Three junction widths (0, 2, 4mm) and two feathering step sizes (5, 10 mm) are investigated. Similar simulations (but also include larger gap widths due to larger penumbra) are performed for 6 and 15 MV x‐ rays. Dose profiles at the field junctions are then compared for the proton and photon fields for various gaps and feathering step sizes. Results: For protons, full dose is achieved in the field junction for 0mm gap for both 5mm and 10mm featherings. However, with even a 2mm gap, the dose falls to below 90% in the moving gap due to the steep proton penumbra. For photons, even 4mm gap still results in >90% dose in the moving gap due to the large penumbra and the ‘tail’ in the profiles. Despite the different dose characteristics, it is possible to produce similar dose profiles in the moving gap for proton and photon fields by varying the gap and the feathering sizes for photon fields. Conclusion: Full dose can be safely achieved in the junction by ‘hot‐matching’ the spine and the brain fields in proton CSI and feathering the junctions. The steep proton penumbra results in a large dose gradient even with 2mm gap between fields. It is possible to produce similar dosimetry in the junction with photon CSI. The difference is that there is no exit dose with protons.

Purpose: A prototype immobilization board has been developed and implemented for proton therapy of the craniospinal axis at the IU Health Proton Therapy Center. This innovation is important because proton beam CSI spares the majority of the thoracic and abdominal organs, avoiding much of the acute and long term toxicity outside of the craniospinal axis associated with standard radiation therapy techniques. Proton CSI provides a significantly lower integral dose than otherwise achievable. The delivery of supine craniospinal irradiation (CSI) is a challenge due to the limitations of the treatment couches in routine clinical use. This is particularly true for protonradiation which requires the patient be reproducibly placed on a smoothly varying (“edgeless”) surface. Methods: Since the largest field available to us is 30 cm × 30 cm and field matching is required, the immobilization board attaches to a standard treatment couch mounted on a robotic patient positioner which moves precisely to cover all areas of the body above the mid‐femur for patients up to 200 cm. The weight tolerance of the production board exceeds the weight tolerance of the robot (360 pounds). Results: We discuss this immobilization device, and our experience treating pediatric and adult patients in the supine position with and without anesthesia. Conclusions: Anticipated modifications to the design of the immobilization board will increase access to the majority of the patient's body, including beams from oblique posterior angles. The cost effective device can be adapted to any standard tabletop (including photon units).

Purpose: The success of clinical treatments, such as ionizing radiation (IR), depends in great part on their ability to induce programmed cell death (apoptosis). Since apoptosis is deregulated in most cancers, apoptotic-modulating therapies offer an attractive opportunity for clinical therapy of many tumors, including that of the prostate. To identify genes whose expression contributes to radiation induced apoptosis of prostate cancer (CaP), we used oligonucleotide microarray technology to interrogate the expression of 60,000 human genes and ESTs following bolus and fractionated radiation and the kinetic response of 12,000 genes over 24 hours at ten time points.

Background Cranial reirradiation is clinically appropriate in some cases but cumulative radiation dose to critical normal structures remains a practical concern. The authors developed a simple technique in 3D conformal proton craniospinal irradiation (CSI) to block organs at risk (OAR) while minimizing underdosing of adjacent target brain tissue. Methods Two clinical cases illustrate the use of proton therapy to provide salvage CSI when a previously irradiated OAR required sparing from additional radiation dose. The prior radiation plan was coregistered to the treatment planning CT to create a planning organ at risk volume (PRV) around the OAR. Right and left lateral cranial whole brain proton apertures were created with a small block over the PRV. Then right and left lateral “inverse apertures” were generated, creating an aperture opening in the shape of the area previously blocked and blocking the area previously open. The inverse aperture opening was made one millimeter smaller than the original block to minimize the risk of dose overlap. The inverse apertures were used to irradiate the target volume lateral to the PRV, selecting a proton beam range to abut the 50% isodose line against either lateral edge of the PRV. Together, the 4 cranial proton fields created a region of complete dose avoidance around the OAR. Comparative photon treatment plans were generated with opposed lateral X-ray fields with custom blocks and coplanar intensity modulated radiation therapy optimized to avoid the PRV. Cumulative dose volume histograms were evaluated. Results Treatment plans were developed and successfully implemented to provide sparing of previously irradiated critical normal structures while treating target brain lateral to these structures. The absence of dose overlapping during irradiation through the inverse apertures was confirmed by film. Compared to the lateral X-ray and IMRT treatment plans, the proton CSI technique improved coverage of target brain tissue while providing the least additional radiation dose to the previously irradiated OAR. Conclusions Proton craniospinal irradiation can be adapted to provide complete sparing of previously irradiated OARs. This technique may extend the option of reirradiation to patients otherwise deemed ineligible for further radiotherapy due to prior dose to critical normal structures.