Daphne Haas-kogan | Harvard Medical School (original) (raw)

Papers by Daphne Haas-kogan

International Journal of Radiation Oncology*Biology*Physics, 2009

To evaluate the role of radiation therapy (RT) as a component of multimodality therapy for pediat... more To evaluate the role of radiation therapy (RT) as a component of multimodality therapy for pediatric desmoids. Twenty-one children diagnosed between 1987 and 2005 were identified. Median age at start of treatment was 13 years (range, 2-21). Primary therapy consisted of resection alone (10), resection + external beam radiation therapy (EBRT) (5), resection + chemotherapy (CT; 3), EBRT alone (1), and CT alone (2). The median follow-up from start of treatment is 75.7 months (range, 16-162). Examining patients with gross total resections (GTRs) (-) margins and those who had GTRs (+) margins followed by EBRT, only 2 of 7 failed primary treatment. Conversely, 13 of 14 patients with other primary treatments failed locally. Of the 15 patients who recurred, only 1 patient had a GTR (-) margins. Seven of these patients had salvage therapy that did not include RT, and of these only 2 have no evidence of disease (NED) at last follow-up. In contrast, the remaining 8 patients received RT as a component of their final salvage therapy and 7 of these are NED at last follow-up. At last follow-up, no patient has died, although toxicities of therapy have occurred. Local control is difficult to achieve in pediatric patients with desmoids. In the setting in which negative surgical margins cannot be achieved, RT plays a key role in achieving NED status. Even after multiple recurrences, successful salvage is achievable, particularly when high-dose focal therapy is incorporated.

International journal of radiation oncology, biology, physics, Jan 15, 2014

Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experi... more Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Of 159 MIBG-avid m...

Neuro-Oncology, 2006

The purpose of this study was to assess the impact of early radiation therapy and extent of surgi... more The purpose of this study was to assess the impact of early radiation therapy and extent of surgical resection on progression-free survival (PFS) and overall survival (OS) in children with WHO grade II low-grade gliomas (LGGs). We conducted a historical cohort study of 90 patients, ages 21 or younger, diagnosed with WHO grade II LGGs between 1970 and 1995. Median follow-up for surviving patients was 9.4 years (range, 0.5-22.6 years). Tests for variables correlating with OS and PFS were conducted by using log-rank tests and Cox proportional hazards models. Eleven patients underwent gross total resections (GTRs), 43 had subtotal resections, and 34 underwent biopsy only at diagnosis. Two patients underwent biopsy at time of recurrence. Of the 90 patients, 52 received radiation as part of their initial therapy following diagnosis (early-RT group). The overall five-year PFS and OS rates +/- SE were 56% +/- 5% and 90% +/- 3%, respectively. Ten-year PFS and OS rates were 42% +/- 6% and 81% +/- 5%, respectively. For patients older than three years and without GTRs, administration of early radiation did not appear to influence PFS or OS (P = 0.98 and P = 0.40, respectively; log-rank test). This was confirmed by multivariate analyses (P = 0.95 and P = 0.33 for PFS and OS, respectively). Of the 11 patients with GTRs, disease progressed in only two, and all were alive with no evidence of disease at last follow-up. Patients who underwent GTRs had significantly longer PFS (P = 0.02), but did not have significantly improved OS. Excellent long-term survival rates were achieved for children with WHO grade II LGGs. We were unable to demonstrate a benefit for administering radiation as part of initial treatment. An outcome benefit was seen with greater extent of resection.

Fuel and Energy Abstracts

Purpose: To assess the effect of local radiation administered to primary disease sites in childre... more Purpose: To assess the effect of local radiation administered to primary disease sites in children with high-risk neuroblastoma. Methods and Materials: A total of 539 eligible patients were entered on protocol CCG-3891, consisting of chemotherapy, primary surgery, and 10 Gy of external beam radiation therapy (EBRT) to gross residual disease, followed by randomized assignment to continuation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). ABMT patients received total body irradiation (TBI). Results: Estimated event-free survival and overall survival at 5 years were 25% ؎ 2% and 35% ؎ 2%, respectively. Estimated 5-year locoregional recurrence rates were 51% ؎ 5% and 33% ؎ 7% for CC and ABMT patients (p ‫؍‬ 0.004). For patients who received 10 Gy of EBRT to the primary, the addition of 10 Gy of TBI and ABMT decreased local recurrence compared with CC (22% ؎ 12% and 52% ؎ 8%, p ‫؍‬ 0.022). EBRT did not increase acute toxicity, except for increased total parenteral nutrition administration. Conclusions: In combination with EBRT to the primary tumor site, the addition of 10 Gy of TBI as a component of high-dose chemotherapy with ABMT improved local control compared with CC without TBI. Results suggest a dose-response relationship for local EBRT. Short-term toxicity of local EBRT is limited.

Pediatric Oncology, 2010

In the Greek language, Phakos means spot, mole, or lentil, and phakomatosis suggests the presence... more In the Greek language, Phakos means spot, mole, or lentil, and phakomatosis suggests the presence of a congenital lesion or birthmark (Berg 1991) . His-torically, this term was applied to a group of genetic disorders defined by the involvement of the central nervous system (CNS), skin, ...

Pediatric Oncology, 2010

Astrocytomas are the most common childhood tumor of the central nervous system (CNS), representin... more Astrocytomas are the most common childhood tumor of the central nervous system (CNS), representing approximately 40–50% of all pediatric tumors. The World Health Organization (WHO) clas-sifi es these tumors into low-grade (WHO grade I and II) and high-grade (WHO ...

International Journal of Radiation Oncology*Biology*Physics, 2015

Seminars in radiation oncology, 2014

Standard treatment for Glioblastoma Multiforme (GBM) consists of a combination of chemotherapy an... more Standard treatment for Glioblastoma Multiforme (GBM) consists of a combination of chemotherapy and radiation therapy followed by adjuvant chemotherapy. While the optimal dose of radiation therapy has been established, significant variability in volume of tissue irradiated exists. In this article we review the current guidelines, patterns of care, patterns of failure, imaging advances and toxicity related to radiation therapy volumes in the treatment of GBM.

Neurosurgery clinics of North America, 2012

High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and ... more High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and anaplastic astrocytoma subtypes. Brainstem gliomas and ependymomas are separate entities with respect to clinical presentation, treatment, prognosis, and outcome in comparison with supratentorial HGGs. In children, these tumors account for 3% to 7% of newly diagnosed brain tumors and 20% of all diagnoses of pediatric supratentorial brain tumors. These neoplasms are highly proliferative and mitotically active and of glial origin. This article reviews clinical, diagnostic, and pathologic features of HGG and current treatments and potential future therapies specific to pediatric patients with HGGs.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 18, 2015

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblast... more Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase 1 study was to determine the maximum tolerated doses of vorinostat and MIBG in combination. Experimental Design: Patients < 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily Days 1-14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on Day 3 and peripheral blood stem cells on Day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design. Results: 27 patients enrolled to 6 dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG / 230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG / 230 mg/m2 ...

Anticancer research, 2013

To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the t... more To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the treatment of neuroblastoma. Clonogenic survival assays were used to assess MK-4827, radiation and combination thereof in four neuroblastoma cell lines. In vivo efficacy was tested in a murine xenograft model of metastatic neuroblastoma. In vivo targeted inhibition and biological effects included measurement of cleaved caspase-3, γ-H2AX, and Ki 67 by immunohistochemistry (IHC) and poly-ADP-ribose by Enzyme-Linked Immunosorbent Assay. Treatment of neuroblastoma cell lines reduced clonogenicity and resulted in additive effects with radiation. In vivo treatment with MK-4827 and radiation prolonged survival (p<0.01) compared to single modalities. In vivo superiority of MK-4827 plus radiation was further documented by significant elevations of cleaved caspase-3 and γ-H2AX in tumors from the combination group compared to single modality cohorts. Combination of MK-4827 and radiation might prov...

Practical radiation oncology

Accurate International Classification of Diseases (ICD) diagnosis coding is critical for patient ... more Accurate International Classification of Diseases (ICD) diagnosis coding is critical for patient care, billing purposes, and research endeavors. In this single-institution study, we evaluated our baseline ICD-9 (9th revision) diagnosis coding accuracy, identified the most common errors contributing to inaccurate coding, and implemented a multimodality strategy to improve radiation oncology coding. We prospectively studied ICD-9 coding accuracy in our radiation therapy--specific electronic medical record system. Baseline ICD-9 coding accuracy was obtained from chart review targeting ICD-9 coding accuracy of all patients treated at our institution between March and June of 2010. To improve performance an educational session highlighted common coding errors, and a user-friendly software tool, RadOnc ICD Search, version 1.0, for coding radiation oncology specific diagnoses was implemented. We then prospectively analyzed ICD-9 coding accuracy for all patients treated from July 2010 to Ju...

Journal of Neuro-Oncology, 2014

To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of... more To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of the central nervous system (CNS). We reviewed a historical cohort of 79 patients between the ages of 3-35 years who received definitive treatment for newly diagnosed, pure CNS germinoma between 1985 and 2010 at the University of California, San Francisco (UCSF). Median age at diagnosis was 15 years (interquartile range, IQR 12-20 years) and 61 (77.2 %) patients were male. Median follow-up for the cohort was 111.1 months (IQR 45.7-185.1 months). Five-year PFS rate was 86.4 % (95 % CI 76.1-92.4) and 5 year OS rate was 93.0 % (95 % CI 84.1-97.1). Median PFS was 104.6 months (IQR 41.4-170.1 months). Fourteen patients progressed and 8 died of their disease. Patients who received focal irradiation (XRT) and chemotherapy had a significantly higher rate of progression compared to those who received whole brain irradiation (WBI) or whole ventricle irradiation (WVI). Three of 8 patients had a PR to chemotherapy and received focal XRT progressed whereas only 1 of 9 patients who had a CR to chemotherapy who went on to receive focal XRT progressed. Elevation of hCGβ &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 50 mIU/ml was not significantly associated with disease progression (HR 5.64, 95 % CI 0.97-32.7, p = 0.054). Patients treated with WBI or WVI with or without chemotherapy achieve better disease control compared to patients treated with focal XRT + chemotherapy.

Journal of child neurology, Jan 13, 2014

Rates and characteristics of intracerebral cavernous malformations after cranial radiation therap... more Rates and characteristics of intracerebral cavernous malformations after cranial radiation therapy remain poorly understood. Herein we report on intracerebral cavernous malformations detected on follow-up imaging in pediatric cancer patients who received cranial radiation therapy at age ≤18 years from 1980 to 2009. Through chart reviews (n = 362) and phone interviews (n = 104) of a retrospective cohort, we identified 10 patients with intracerebral cavernous malformations. The median latency time for detection of intracerebral cavernous malformations after cranial radiation therapy was 12 years (range 1-24 years) at a median age of 21.4 years (interquartile range = 15-28). The cumulative incidence was 3% (95% confidence interval 1%-8%) at 10 years post cranial radiation therapy and 14% (95% confidence interval 7%-26%) at 15 years. Three patients underwent surgical resection. Two surgical specimens were pathologically similar to sporadically occurring intracerebral cavernous malformat...

Cancer research, 2003

Our previous work showed that, compared with parental U87MG human glioblastoma cells, vascular en... more Our previous work showed that, compared with parental U87MG human glioblastoma cells, vascular endothelial growth factor (VEGF) mRNA levels are decreased in U87/T691, a derivative line in which epidermal growth factor receptor (EGFR) signaling is inhibited by introduction of a truncated p185(Neu) protein (A. Maity et al., Cancer Res., 60: 5879-5886, 2000). The effect of EGFR activation on VEGF was mediated at the level of transcription via a phosphatidylinositol 3'-kinase (PI3K)-dependent pathway. In the current study we investigated the effect of PTEN, a negative regulator of PI3K signaling commonly mutated in glioblastoma cells, on VEGF expression. Several glioblastoma cell lines containing mutant PTEN, including U87MG, U87/T691, and U251MG, were infected with adenovirus expressing wild-type PTEN. This led to a decrease in the levels of both VEGF mRNA and phosphorylated Akt, a marker for PI3K activation. Treatment of U87MG cells with LY294002, a PI3K inhibitor, or cotransfecti...

Science signaling, 2009

Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commo... more Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commonly in glioblastoma, leading to activation of downstream kinases including phosphatidylinositol 3'-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Here, we show that phosphorylation of mTOR and its downstream substrate rpS6 (ribosomal protein S6) are robust biomarkers for the antiproliferative effect of EGFR inhibitors. Inhibition of EGFR signaling correlated with decreased abundance of phosphorylated mTOR (p-mTOR) and rpS6 (p-rpS6) in cells wild type for the gene encoding PTEN (phosphatase and tensin homolog on chromosome 10), a negative regulator of PI3K. In contrast, inhibition of EGFR signaling failed to affect p-mTOR or p-rpS6 in cells mutant for PTEN, which are resistant to EGFR inhibitors. Although the abundance of phosphorylated Akt (p-Akt) decreased in response to inhibition of EGFR signaling, Akt was dispensable for signaling between EGFR and mTOR. We identifi...

Pediatric Radiology, 2009

Background Long-term CT follow-up studies are required in pediatric patients who have received in... more Background Long-term CT follow-up studies are required in pediatric patients who have received intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) to assess vascular toxicities and to determine the exact complication rate. Objective To analyze with CT the effects of radiation therapy (RT) on the growth of the aorta in neuroblastoma patients. Materials and methods Abdominal CT scans of 31 patients with intraabdominal neuroblastoma (stage II-IV), treated with RT (20 IORT±EBRT, 11 EBRT alone), were analyzed retrospectively. The diameter of the abdominal aorta was measured before and after RT. These data were compared to normal and predicted normal aortic diameters of children, according to the model of Fitzgerald, Donaldson and Poznanski (aortic diameter in centimeters=0.844+0.0599×age in years), and to the diameters of a control group of children who had not undergone RT. Statistical analyses for the primary aims were performed using the chi-squared test, t-test, Mann-Whitney test, nonparametric Wilcoxon matched-pairs test and analysis of variance for repeated measures. Clinical files and imaging studies were evaluated for signs of late vascular complications of neuroblastoma patients who had received RT. Results The mean diameter before and after RT and the growth of the aorta were significantly lower than expected in patients with neuroblastoma (P<0.05 for each) and when compared to the growth in a control group with normal and nonirradiated aortas. Among the patients who had received RT, there was no difference due to the type of RT. Seven patients from the IORT±EBRT group developed vascular complications, which included hypertension (five), middle aortic syndrome (two), death due to mesenteric ischemia (one) and critical aortic stenosis, which required aortic bypass surgery (two). Conclusion Patients with neuroblastoma who had received RT showed impaired growth of the abdominal aorta. Significant long-term vascular complications occurred in seven patients who received IORT±EBRT. Thus, CT evaluation of patients with neuroblastoma who receive RT should include not only reports of changes in tumor extension, but also documentation of perfusion, and the size and growth of the aorta and its branches over time.

New England Journal of Medicine, 2005

The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in... more The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown.

International Journal of Radiation Oncology*Biology*Physics, 2009

To evaluate the role of radiation therapy (RT) as a component of multimodality therapy for pediat... more To evaluate the role of radiation therapy (RT) as a component of multimodality therapy for pediatric desmoids. Twenty-one children diagnosed between 1987 and 2005 were identified. Median age at start of treatment was 13 years (range, 2-21). Primary therapy consisted of resection alone (10), resection + external beam radiation therapy (EBRT) (5), resection + chemotherapy (CT; 3), EBRT alone (1), and CT alone (2). The median follow-up from start of treatment is 75.7 months (range, 16-162). Examining patients with gross total resections (GTRs) (-) margins and those who had GTRs (+) margins followed by EBRT, only 2 of 7 failed primary treatment. Conversely, 13 of 14 patients with other primary treatments failed locally. Of the 15 patients who recurred, only 1 patient had a GTR (-) margins. Seven of these patients had salvage therapy that did not include RT, and of these only 2 have no evidence of disease (NED) at last follow-up. In contrast, the remaining 8 patients received RT as a component of their final salvage therapy and 7 of these are NED at last follow-up. At last follow-up, no patient has died, although toxicities of therapy have occurred. Local control is difficult to achieve in pediatric patients with desmoids. In the setting in which negative surgical margins cannot be achieved, RT plays a key role in achieving NED status. Even after multiple recurrences, successful salvage is achievable, particularly when high-dose focal therapy is incorporated.

International journal of radiation oncology, biology, physics, Jan 15, 2014

Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experi... more Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Of 159 MIBG-avid m...

Neuro-Oncology, 2006

The purpose of this study was to assess the impact of early radiation therapy and extent of surgi... more The purpose of this study was to assess the impact of early radiation therapy and extent of surgical resection on progression-free survival (PFS) and overall survival (OS) in children with WHO grade II low-grade gliomas (LGGs). We conducted a historical cohort study of 90 patients, ages 21 or younger, diagnosed with WHO grade II LGGs between 1970 and 1995. Median follow-up for surviving patients was 9.4 years (range, 0.5-22.6 years). Tests for variables correlating with OS and PFS were conducted by using log-rank tests and Cox proportional hazards models. Eleven patients underwent gross total resections (GTRs), 43 had subtotal resections, and 34 underwent biopsy only at diagnosis. Two patients underwent biopsy at time of recurrence. Of the 90 patients, 52 received radiation as part of their initial therapy following diagnosis (early-RT group). The overall five-year PFS and OS rates +/- SE were 56% +/- 5% and 90% +/- 3%, respectively. Ten-year PFS and OS rates were 42% +/- 6% and 81% +/- 5%, respectively. For patients older than three years and without GTRs, administration of early radiation did not appear to influence PFS or OS (P = 0.98 and P = 0.40, respectively; log-rank test). This was confirmed by multivariate analyses (P = 0.95 and P = 0.33 for PFS and OS, respectively). Of the 11 patients with GTRs, disease progressed in only two, and all were alive with no evidence of disease at last follow-up. Patients who underwent GTRs had significantly longer PFS (P = 0.02), but did not have significantly improved OS. Excellent long-term survival rates were achieved for children with WHO grade II LGGs. We were unable to demonstrate a benefit for administering radiation as part of initial treatment. An outcome benefit was seen with greater extent of resection.

Fuel and Energy Abstracts

Purpose: To assess the effect of local radiation administered to primary disease sites in childre... more Purpose: To assess the effect of local radiation administered to primary disease sites in children with high-risk neuroblastoma. Methods and Materials: A total of 539 eligible patients were entered on protocol CCG-3891, consisting of chemotherapy, primary surgery, and 10 Gy of external beam radiation therapy (EBRT) to gross residual disease, followed by randomized assignment to continuation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). ABMT patients received total body irradiation (TBI). Results: Estimated event-free survival and overall survival at 5 years were 25% ؎ 2% and 35% ؎ 2%, respectively. Estimated 5-year locoregional recurrence rates were 51% ؎ 5% and 33% ؎ 7% for CC and ABMT patients (p ‫؍‬ 0.004). For patients who received 10 Gy of EBRT to the primary, the addition of 10 Gy of TBI and ABMT decreased local recurrence compared with CC (22% ؎ 12% and 52% ؎ 8%, p ‫؍‬ 0.022). EBRT did not increase acute toxicity, except for increased total parenteral nutrition administration. Conclusions: In combination with EBRT to the primary tumor site, the addition of 10 Gy of TBI as a component of high-dose chemotherapy with ABMT improved local control compared with CC without TBI. Results suggest a dose-response relationship for local EBRT. Short-term toxicity of local EBRT is limited.

Pediatric Oncology, 2010

In the Greek language, Phakos means spot, mole, or lentil, and phakomatosis suggests the presence... more In the Greek language, Phakos means spot, mole, or lentil, and phakomatosis suggests the presence of a congenital lesion or birthmark (Berg 1991) . His-torically, this term was applied to a group of genetic disorders defined by the involvement of the central nervous system (CNS), skin, ...

Pediatric Oncology, 2010

Astrocytomas are the most common childhood tumor of the central nervous system (CNS), representin... more Astrocytomas are the most common childhood tumor of the central nervous system (CNS), representing approximately 40–50% of all pediatric tumors. The World Health Organization (WHO) clas-sifi es these tumors into low-grade (WHO grade I and II) and high-grade (WHO ...

International Journal of Radiation Oncology*Biology*Physics, 2015

Seminars in radiation oncology, 2014

Standard treatment for Glioblastoma Multiforme (GBM) consists of a combination of chemotherapy an... more Standard treatment for Glioblastoma Multiforme (GBM) consists of a combination of chemotherapy and radiation therapy followed by adjuvant chemotherapy. While the optimal dose of radiation therapy has been established, significant variability in volume of tissue irradiated exists. In this article we review the current guidelines, patterns of care, patterns of failure, imaging advances and toxicity related to radiation therapy volumes in the treatment of GBM.

Neurosurgery clinics of North America, 2012

High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and ... more High-grade gliomas (HGGs) are malignant tumors and typically include glioblastoma multiforme and anaplastic astrocytoma subtypes. Brainstem gliomas and ependymomas are separate entities with respect to clinical presentation, treatment, prognosis, and outcome in comparison with supratentorial HGGs. In children, these tumors account for 3% to 7% of newly diagnosed brain tumors and 20% of all diagnoses of pediatric supratentorial brain tumors. These neoplasms are highly proliferative and mitotically active and of glial origin. This article reviews clinical, diagnostic, and pathologic features of HGG and current treatments and potential future therapies specific to pediatric patients with HGGs.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 18, 2015

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblast... more Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase 1 study was to determine the maximum tolerated doses of vorinostat and MIBG in combination. Experimental Design: Patients < 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily Days 1-14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on Day 3 and peripheral blood stem cells on Day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design. Results: 27 patients enrolled to 6 dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG / 230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG / 230 mg/m2 ...

Anticancer research, 2013

To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the t... more To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the treatment of neuroblastoma. Clonogenic survival assays were used to assess MK-4827, radiation and combination thereof in four neuroblastoma cell lines. In vivo efficacy was tested in a murine xenograft model of metastatic neuroblastoma. In vivo targeted inhibition and biological effects included measurement of cleaved caspase-3, γ-H2AX, and Ki 67 by immunohistochemistry (IHC) and poly-ADP-ribose by Enzyme-Linked Immunosorbent Assay. Treatment of neuroblastoma cell lines reduced clonogenicity and resulted in additive effects with radiation. In vivo treatment with MK-4827 and radiation prolonged survival (p<0.01) compared to single modalities. In vivo superiority of MK-4827 plus radiation was further documented by significant elevations of cleaved caspase-3 and γ-H2AX in tumors from the combination group compared to single modality cohorts. Combination of MK-4827 and radiation might prov...

Practical radiation oncology

Accurate International Classification of Diseases (ICD) diagnosis coding is critical for patient ... more Accurate International Classification of Diseases (ICD) diagnosis coding is critical for patient care, billing purposes, and research endeavors. In this single-institution study, we evaluated our baseline ICD-9 (9th revision) diagnosis coding accuracy, identified the most common errors contributing to inaccurate coding, and implemented a multimodality strategy to improve radiation oncology coding. We prospectively studied ICD-9 coding accuracy in our radiation therapy--specific electronic medical record system. Baseline ICD-9 coding accuracy was obtained from chart review targeting ICD-9 coding accuracy of all patients treated at our institution between March and June of 2010. To improve performance an educational session highlighted common coding errors, and a user-friendly software tool, RadOnc ICD Search, version 1.0, for coding radiation oncology specific diagnoses was implemented. We then prospectively analyzed ICD-9 coding accuracy for all patients treated from July 2010 to Ju...

Journal of Neuro-Oncology, 2014

To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of... more To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of the central nervous system (CNS). We reviewed a historical cohort of 79 patients between the ages of 3-35 years who received definitive treatment for newly diagnosed, pure CNS germinoma between 1985 and 2010 at the University of California, San Francisco (UCSF). Median age at diagnosis was 15 years (interquartile range, IQR 12-20 years) and 61 (77.2 %) patients were male. Median follow-up for the cohort was 111.1 months (IQR 45.7-185.1 months). Five-year PFS rate was 86.4 % (95 % CI 76.1-92.4) and 5 year OS rate was 93.0 % (95 % CI 84.1-97.1). Median PFS was 104.6 months (IQR 41.4-170.1 months). Fourteen patients progressed and 8 died of their disease. Patients who received focal irradiation (XRT) and chemotherapy had a significantly higher rate of progression compared to those who received whole brain irradiation (WBI) or whole ventricle irradiation (WVI). Three of 8 patients had a PR to chemotherapy and received focal XRT progressed whereas only 1 of 9 patients who had a CR to chemotherapy who went on to receive focal XRT progressed. Elevation of hCGβ &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 50 mIU/ml was not significantly associated with disease progression (HR 5.64, 95 % CI 0.97-32.7, p = 0.054). Patients treated with WBI or WVI with or without chemotherapy achieve better disease control compared to patients treated with focal XRT + chemotherapy.

Journal of child neurology, Jan 13, 2014

Rates and characteristics of intracerebral cavernous malformations after cranial radiation therap... more Rates and characteristics of intracerebral cavernous malformations after cranial radiation therapy remain poorly understood. Herein we report on intracerebral cavernous malformations detected on follow-up imaging in pediatric cancer patients who received cranial radiation therapy at age ≤18 years from 1980 to 2009. Through chart reviews (n = 362) and phone interviews (n = 104) of a retrospective cohort, we identified 10 patients with intracerebral cavernous malformations. The median latency time for detection of intracerebral cavernous malformations after cranial radiation therapy was 12 years (range 1-24 years) at a median age of 21.4 years (interquartile range = 15-28). The cumulative incidence was 3% (95% confidence interval 1%-8%) at 10 years post cranial radiation therapy and 14% (95% confidence interval 7%-26%) at 15 years. Three patients underwent surgical resection. Two surgical specimens were pathologically similar to sporadically occurring intracerebral cavernous malformat...

Cancer research, 2003

Our previous work showed that, compared with parental U87MG human glioblastoma cells, vascular en... more Our previous work showed that, compared with parental U87MG human glioblastoma cells, vascular endothelial growth factor (VEGF) mRNA levels are decreased in U87/T691, a derivative line in which epidermal growth factor receptor (EGFR) signaling is inhibited by introduction of a truncated p185(Neu) protein (A. Maity et al., Cancer Res., 60: 5879-5886, 2000). The effect of EGFR activation on VEGF was mediated at the level of transcription via a phosphatidylinositol 3'-kinase (PI3K)-dependent pathway. In the current study we investigated the effect of PTEN, a negative regulator of PI3K signaling commonly mutated in glioblastoma cells, on VEGF expression. Several glioblastoma cell lines containing mutant PTEN, including U87MG, U87/T691, and U251MG, were infected with adenovirus expressing wild-type PTEN. This led to a decrease in the levels of both VEGF mRNA and phosphorylated Akt, a marker for PI3K activation. Treatment of U87MG cells with LY294002, a PI3K inhibitor, or cotransfecti...

Science signaling, 2009

Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commo... more Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commonly in glioblastoma, leading to activation of downstream kinases including phosphatidylinositol 3'-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Here, we show that phosphorylation of mTOR and its downstream substrate rpS6 (ribosomal protein S6) are robust biomarkers for the antiproliferative effect of EGFR inhibitors. Inhibition of EGFR signaling correlated with decreased abundance of phosphorylated mTOR (p-mTOR) and rpS6 (p-rpS6) in cells wild type for the gene encoding PTEN (phosphatase and tensin homolog on chromosome 10), a negative regulator of PI3K. In contrast, inhibition of EGFR signaling failed to affect p-mTOR or p-rpS6 in cells mutant for PTEN, which are resistant to EGFR inhibitors. Although the abundance of phosphorylated Akt (p-Akt) decreased in response to inhibition of EGFR signaling, Akt was dispensable for signaling between EGFR and mTOR. We identifi...

Pediatric Radiology, 2009

Background Long-term CT follow-up studies are required in pediatric patients who have received in... more Background Long-term CT follow-up studies are required in pediatric patients who have received intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) to assess vascular toxicities and to determine the exact complication rate. Objective To analyze with CT the effects of radiation therapy (RT) on the growth of the aorta in neuroblastoma patients. Materials and methods Abdominal CT scans of 31 patients with intraabdominal neuroblastoma (stage II-IV), treated with RT (20 IORT±EBRT, 11 EBRT alone), were analyzed retrospectively. The diameter of the abdominal aorta was measured before and after RT. These data were compared to normal and predicted normal aortic diameters of children, according to the model of Fitzgerald, Donaldson and Poznanski (aortic diameter in centimeters=0.844+0.0599×age in years), and to the diameters of a control group of children who had not undergone RT. Statistical analyses for the primary aims were performed using the chi-squared test, t-test, Mann-Whitney test, nonparametric Wilcoxon matched-pairs test and analysis of variance for repeated measures. Clinical files and imaging studies were evaluated for signs of late vascular complications of neuroblastoma patients who had received RT. Results The mean diameter before and after RT and the growth of the aorta were significantly lower than expected in patients with neuroblastoma (P<0.05 for each) and when compared to the growth in a control group with normal and nonirradiated aortas. Among the patients who had received RT, there was no difference due to the type of RT. Seven patients from the IORT±EBRT group developed vascular complications, which included hypertension (five), middle aortic syndrome (two), death due to mesenteric ischemia (one) and critical aortic stenosis, which required aortic bypass surgery (two). Conclusion Patients with neuroblastoma who had received RT showed impaired growth of the abdominal aorta. Significant long-term vascular complications occurred in seven patients who received IORT±EBRT. Thus, CT evaluation of patients with neuroblastoma who receive RT should include not only reports of changes in tumor extension, but also documentation of perfusion, and the size and growth of the aorta and its branches over time.

New England Journal of Medicine, 2005

The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in... more The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown.