Karen De Amorim Bernstein

Early Clinical Outcomes Using Proton Radiation for Children With Central Nervous System Atypical Teratoid Rhabdoid Tumors

PURPOSE Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive tumor that often affects infants. Irradiation improves survival but has traditionally been avoided in patients under the age of 3 due to the increasing risk of neurocognitive side effects. We report the first cohort of AT/RT patients treated with proton therapy. METHODS AND MATERIALS All patients with AT/RT treated at Massachusetts General Hospital (MGH) Frances H. Burr Proton Beam Therapy Benter between July 2004 and November 2011 were included in this study. All patients were treated with 3-dimensional conformal proton therapy (3D-CPT). RESULTS Ten consecutive patients of a median 2.3 years of age and with a median follow-up of 27.3 months (range, 11.3-99.4 months) were identified. Two patients suffered distant relapse; 1 patient was successfully treated with involved field irradiation and chemotherapy, while the second patient died of disease. At last follow-up, 9 patients were alive without evidence of disease. Proton radiation demonstrated increasing sparing of the cerebrum, temporal lobe, cochlea, and hypothalamus. CONCLUSIONS Initial clinical outcomes with proton therapy are favorable. The advantages of proton therapy are particularly suited to the treatment of AT/RT, a tumor that often requires irradiation treatment at an age when avoiding irradiation to healthy tissues is most desirable.

Results of the 2005-2008 association of residents in radiation oncology survey of chief residents in the United States: Clinical training and resident working conditions

PURPOSE To document clinical training and resident working conditions reported by chief residents during their residency. METHODS AND MATERIALS During the academic years 2005 to 2006, 2006 to 2007, and 2007 to 2008, the Association of Residents in Radiation Oncology conducted a nationwide survey of all radiation oncology chief residents in the United States. Chi-square statistics were used to assess changes in clinical training and resident working conditions over time. RESULTS Surveys were completed by representatives from 55 programs (response rate, 71.4%) in 2005 to 2006, 60 programs (75.9%) in 2006 to 2007, and 74 programs (93.7%) in 2007 to 2008. Nearly all chief residents reported receiving adequate clinical experience in commonly treated disease sites, such as breast and genitourinary malignancies; and commonly performed procedures, such as three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. Clinical experience in extracranial stereotactic radiotherapy increased over time (p < 0.001), whereas clinical experience in endovascular brachytherapy (p <0.001) decreased over time. The distribution of gynecologic and prostate brachytherapy cases remained stable, while clinical case load in breast brachytherapy increased (p = 0.006). A small but significant percentage of residents reported receiving inadequate clinical experience in pediatrics, seeing 10 or fewer pediatric cases during the course of residency. Procedures involving higher capital costs, such as particle beam therapy and intraoperative radiotherapy, and infrequent clinical use, such as head and neck brachytherapy, were limited to a minority of institutions. Most residency programs associated with at least one satellite facility have incorporated resident rotations into their clinical training, and the majority of residents at these programs find them valuable experiences. The majority of residents reported working 60 or fewer hours per week on required clinical duties. CONCLUSIONS Trends in clinical training and resident working conditions over 3 years are documented to allow residents and program directors to assess their residency training.

Hypofractionated whole-breast radiation therapy: does breast size matter?

PURPOSE To evaluate the effects of breast size on dose-volume histogram parameters and clinical toxicity in whole-breast hypofractionated radiation therapy using intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS In this retrospective study, all patients undergoing breast-conserving therapy between 2005 and 2009 were screened, and qualifying consecutive patients were included in 1 of 2 cohorts: large-breasted patients (chest wall separation>25 cm or planning target volume [PTV]>1500 cm3) (n=97) and small-breasted patients (chest wall separation<25 cm and PTV<1500 cm3) (n=32). All patients were treated prone or supine with hypofractionated IMRT to the whole breast (42.4 Gy in 16 fractions) followed by a boost dose (9.6 Gy in 4 fractions). Dosimetric and clinical toxicity data were collected and analyzed using the R statistical package (version 2.12). RESULTS The mean PTV V95 (percentage of volume receiving>=95% of prescribed dose) was 90.18% and the mean V105 percentage of volume receiving>=105% of prescribed dose was 3.55% with no dose greater than 107%. PTV dose was independent of breast size, whereas heart dose and maximum point dose to skin correlated with increasing breast size. Lung dose was markedly decreased in prone compared with supine treatments. Radiation Therapy Oncology Group grade 0, 1, and 2 skin toxicities were noted acutely in 6%, 69%, and 25% of patients, respectively, and at later follow-up (>3 months) in 43%, 57%, and 0% of patients, respectively. Large breast size contributed to increased acute grade 2 toxicity (28% vs 12%, P=.008). CONCLUSIONS Adequate PTV coverage with acceptable hot spots and excellent sparing of organs at risk was achieved by use of IMRT regardless of treatment position and breast size. Although increasing breast size leads to increased heart dose and maximum skin dose, heart dose remained within our institutional constraints and the incidence of overall skin toxicity was comparable to that reported in the literature. Taken together, these data suggest that hypofractionated radiation therapy using IMRT is a viable and appropriate therapeutic modality in large-breasted patients.

Role of radiation therapy for non-extremity soft tissue sarcomas

Negative surgical margins are uncommon for non‐extremity soft tissue sarcomas. Radiation therapy is usually recommended to improve local control; however, appropriate RT dosing is challenging due to nearby dose‐limiting normal structures.

MiR‐15b modulates multidrug resistance in human osteosarcoma in vitro and in vivo

The development of multidrug resistance (MDR) in cancer cells to chemotherapy drugs continues to be a major clinical problem. MicroRNAs (miRNA, miR) play an important role in regulating tumour cell growth and survival; however, the role of miRs in the development of drug resistance in osteosarcoma cells is largely uncharacterized. We sought to identify and characterize human miRs that act as key regulators of MDR in osteosarcoma. We utilized a miR microarray to screen for differentially expressed miRs in osteosarcoma MDR cell lines. We determined the mechanisms of the deregulation of expression of miR‐15b in osteosarcoma MDR cell lines, and its association with clinically obtained tumour samples was examined in tissue microarray (TMA). The significance of miR‐15b in reversing drug resistance was evaluated in a mouse xenograft model of MDR osteosarcoma. We identified miR‐15b as being significantly (P < 0.01) downregulated in KHOSMR and U‐2OSMR cell lines as compared with their parental cell lines. We found that Wee1 is a target gene of miR‐15b and observed that transfection with miR‐15b inhibits Wee1 expression and partially reverses MDR in osteosarcoma cell lines. Systemic in vivo administration of miR‐15b mimics sensitizes resistant cells to doxorubicin and induces cell death in MDR models of osteosarcoma. Clinically, reduced miR‐15b expression was associated with poor patient survival. Osteosarcoma patients with low miR‐15b expression levels had significantly shorter survival times than patients with high expression levels of miR‐15b. These results collectively indicate that MDR in osteosarcoma is associated with downregulation of miR‐15b, and miR‐15b reconstitution can reverse chemotherapy resistance in osteosarcoma.

Preoperative radiation therapy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma.

Local recurrence (LR) is the primary cause of death in patients with retroperitoneal liposarcoma (RP‐LPS). The purpose of this study was to evaluate if the addition of preoperative radiation therapy (XRT) to radical resection for RP‐LPS at a single institution was associated with improved LR.

Chordomas and chondrosarcomas—The role of radiation therapy

Achieving negative surgical margins can be challenging for skull base and spinal/paraspinal sarcomas. Data shows that pre‐ or post‐operative radiation therapy improves local control. Delivery of sufficient dose of radiation can be difficult because of the proximity to normal organs/tissues that are sensitive to radiation therapy and therefore dose‐limiting. A comprehensive literature search was conducted using PubMed search engine. The scarcity of prospective, randomized data limits the ability to generate definitive treatment recommendations. J. Surg. Oncol. 2016;114:564–569.

Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance

Background Multi-drug resistance (MDR) remains a significant obstacle to successful chemotherapy treatment for osteosarcoma patients. One of the central causes of MDR is the overexpression of the membrane bound drug transporter protein P-glycoprotein (P-gp), which is the protein product of the MDR gene ABCB1. Though several methods have been reported to reverse MDR in vitro and in vivo when combined with anticancer drugs, they have yet to be proven useful in the clinical setting. Results The meta-analysis demonstrated that a high level of P-gp may predict poor survival in patients with osteosarcoma. The expression of P-gp can be efficiently blocked by the clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system (CRISPR-Cas9). Inhibition of ABCB1 was associated with reversing drug resistance in osteosarcoma MDR cell lines (KHOSR2 and U-2OSR2) to doxorubicin. Materials and Methods We performed a meta-analysis to investigate the relationship between P-gp expression and survival in patients with osteosarcoma. Then we adopted the CRISPR-Cas9, a robust and highly efficient novel genome editing tool, to determine its effect on reversing drug resistance by targeting endogenous ABCB1 gene at the DNA level in osteosarcoma MDR cell lines. Conclusion These results suggest that the CRISPR-Cas9 system is a useful tool for the modification of ABCB1 gene, and may be useful in extending the long-term efficacy of chemotherapy by overcoming P-gp-mediated MDR in the clinical setting.

Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas

Purpose To conduct phase 1 and 2 trials with photon intensity modulated radiation therapy and intensity modulated proton therapy (IMPT) arms to selectively escalate the retroperitoneal sarcoma preoperative radiation dose to tumor volume (clinical target volume [CTV] 2) that is judged to be at a high risk for positive margins and aim to reduce local recurrence. We report on the IMPT study arm in phase 1. Methods and materials Patients aged ≥18 years with primary or locally recurrent retroperitoneal sarcoma were treated with preoperative IMPT, 50.4 GyRBE in 28 fractions, to CTV1 (gross tumor volume and adjacent tissues at risk of subclinical disease) with a simultaneous integrated boost to CTV2 to doses of 60.2, 61.6, and 63.0 GyRBE in 28 fractions of 2.15, 2.20, and 2.25 GyRBE, respectively. The primary objective of the phase 1 study was to determine the maximum tolerated dose to CTV2, which will be further tested in the phase 2 study. Results Eleven patients showed increasing IMPT dose levels without acute dose limiting toxicities that prevented dose escalation to maximum tolerated dose. Acute toxicity was generally mild with no radiation interruptions. No unexpected perioperative morbidity was noted. Eight months postoperatively, one patient developed hydronephrosis that was treated by stent with ureter dissected off tumor and received 57.5 GyRBE. Retained ureter(s) was (were) subsequently constrained to 50.4 GyRBE without further problem. With an 18-month median follow-up, there were no local recurrences. Conclusions IMPT dose escalation to CTV2 to 63 GyRBE was achieved without acute dose limiting toxicities. The phase 2 study of IMPT will accrue patients to that dose. Parallel intensity modulated radiation therapy phase 1 arm is currently accruing at the initial dose level. Ureters that undergo a high dose radiation and/or surgery are at risk for late hydro-ureter. Future studies will constrain retained ureters to 50.4 GyRBE to avoid ureteral stricture.

Results of the 2005 to 2008 association of residents in radiation oncology surveys of chief residents in the United States: Didactics and research experience

ObjectivesTo analyze the didactics and research experience reported by chief residents during their residency training. MethodsDuring the academic years 2005 to 2006, 2006 to 2007, and 2007 to 2008, the Association of Residents in Radiation Oncology (ARRO) conducted a nationwide survey of all radiation oncology chief residents in the United States. Chi-square statistic was used to assess for changes in didactics and research experience over time. ResultsDuring the years surveyed, an increasing percentage of programs offered curriculum-based didactics in clinical oncology (P=0.042), with a similar trend of borderline significance observed in biostatistics (P = 0.056). Each year, the majority of programs offered >40 hours of curriculum-based training in clinical oncology and physics, >20 hours in radiobiology, and 10 hours or fewer in biostatistics. 11% to 13% of residents reported having no full-time equivalent radiation biologists affiliated with their training program. Less than 64% of programs incorporated mock oral boards into their training. An increasing percentage of programs evaluated residents in a “360 degree” manner, with a trend to significance (P=0.073). Over 80% of programs required resident participation in research activities and allocated dedicated elective research time, typically 4 months or longer. Though the vast majority of programs make clinical research activities available to interested residents, borderline significance (P = 0.051) was observed for a decreasing percentage of such programs during the years analyzed. ConclusionsTrends in didactics and research experience over three years are documented to allow residents and program directors to assess their residency training.