Lia M. Halasz

Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells

HSCs either self-renew or differentiate to give rise to multipotent cells whose progeny provide blood cell precursors. However, surprisingly little is known about the factors that regulate this choice of self-renewal versus differentiation. One candidate is the Notch signaling pathway, with ex vivo studies suggesting that Notch regulates HSC differentiation, although a functional role for Notch in HSC self-renewal in vivo remains controversial. Here, we have shown that Notch2, and not Notch1, inhibits myeloid differentiation and enhances generation of primitive Sca-1(+)c-kit(+) progenitors following in vitro culture of enriched HSCs with purified Notch ligands. In mice, Notch2 enhanced the rate of formation of short-term repopulating multipotential progenitor cells (MPPs) as well as long-term repopulating HSCs, while delaying myeloid differentiation in BM following injury. However, consistent with previous reports, once homeostasis was achieved, neither Notch1 nor Notch2 affected repopulating cell self-renewal. These data indicate a Notch2-dependent role in assuring orderly repopulation by HSCs, MPPs, myeloid cells, and lymphoid cells during BM regeneration.

Proton Stereotactic Radiosurgery for the Treatment of Benign Meningiomas

PURPOSE Given the excellent prognosis for patients with benign meningiomas, treatment strategies to minimize late effects are important. One strategy is proton radiation therapy (RT), which allows less integral dose to normal tissue and greater homogeneity than photon RT. Here, we report the first series of proton stereotactic radiosurgery (SRS) used for the treatment of meningiomas. METHODS AND MATERIALS We identified 50 patients with 51 histologically proven or image-defined, presumed-benign meningiomas treated at our institution between 1996 and 2007. Tumors of <4 cm in diameter and located≥2 mm from the optic apparatus were eligible for treatment. Indications included primary treatment (n=32), residual tumor following surgery (n=8), and recurrent tumor following surgery (n=10). The median dose delivered was 13 Gray radiobiologic equivalent (Gy[RBE]) (range, 10.0-15.5 Gy[RBE]) prescribed to the 90% isodose line. RESULTS Median follow-up was 32 months (range, 6-133 months). Magnetic resonance imaging at the most recent follow-up or time of progression revealed 33 meningiomas with stable sizes, 13 meningiomas with decreased size, and 5 meningiomas with increased size. The 3-year actuarial tumor control rate was 94% (95% confidence interval, 77%-98%). Symptoms were improved in 47% (16/34) of patients, unchanged in 44% (15/34) of patients, and worse in 9% (3/34) of patients. The rate of potential permanent adverse effects after SRS was 5.9% (3/51 patients). CONCLUSIONS Proton SRS is an effective therapy for small benign meningiomas, with a potentially lower rate of long-term treatment-related morbidity. Longer follow-up is needed to assess durability of tumor control and late effects.

Improved Outcomes of Breast-Conserving Therapy for Patients with Ductal Carcinoma in Situ

PURPOSE Patients treated for ductal carcinoma in situ (DCIS) with breast-conserving surgery (BCS) and radiation therapy (RT) at our center from 1976 to 1990 had a 15% actuarial 10-year local recurrence (LR) rate. Since then, improved mammographic and pathologic evaluation and greater attention to achieving negative margins may have resulted in a lower risk of LR. In addition, clinical implications of hormone receptor and HER-2 status in DCIS remain unclear. We sought to determine the following: LR rates with this more modern approach; the relation between LR and HER-2 status; and clinical and pathologic factors associated with HER-2(+) DCIS. METHODS AND MATERIALS We studied 246 consecutive patients who underwent BCS and RT for DCIS from 2001 to 2007. Of the patients, 96 (39%) were Grade III and the median number of involved tissue blocks was 3. Half underwent re-excision and 222 (90%) had negative margins (>2 mm). All received whole-breast RT (40-52 Gy) and 99% (244) received a tumor bed boost (8-18 Gy). Routine estrogen receptor (ER), progesterone receptor (PR), and HER-2 immunohistochemistry was instituted in 2003. RESULTS With median follow-up of 58 months, there were no LRs. Seven patients (3%) developed contralateral breast cancer (4 invasive and 3 in situ). Among 163 patients with immunohistochemistry, 124 were ER/PR(+)HER-2(-), 27 were ER/PR(+)HER-2(+), 6 were ER(-)/PR(-)HER-2(+), and 6 were ER(-)/PR(-)HER-2(-). On univariable analysis, HER-2(+)was significantly associated with Grade III, ER(-)/PR(-), central necrosis, comedo subtype, more extensive DCIS, and postmenopausal status. On multivariable analysis, Grade III and postmenopausal status remained significantly associated with HER-2(+). CONCLUSIONS In an era of mammographically identified DCIS, larger excisions, widely negative margins and the use of a tumor bed boost, we observed no LR regardless of ER/PR/HER-2 status. Factors associated with HER-2(+)DCIS included more extensive DCIS, Grade III, ER(-)/PR(-), central necrosis, comedo subtype, and postmenopausal status. Further follow-up and additional studies are required to confirm these results.

Outcomes after radiation therapy with concurrent weekly platinum-based chemotherapy or every-3–4-week 5-fluorouracil-containing regimens for squamous cell carcinoma of the vulva

OBJECTIVE To compare outcomes in patients with squamous cell carcinoma (SCC) of the vulva treated with radiation (RT) and concurrent weekly platinum-based or every-3-4-week regimens containing 5-fluorouracil (5-FU). METHODS Records of 44 patients with vulvar SCC treated with concurrent chemotherapy and radiation (chemoRT) from 1988 to 2008 were reviewed. Rates of disease-free survival (DFS), overall survival (OS), locoregional recurrence (LRR), and distant metastases (DM) were estimated using the Kaplan-Meier method. RESULTS The median age was 63 years (range, 44-90), 84.1% of patients had ECOG performance status 0-1, and patients had FIGO Stage II (n=6), III (n=31), or IVA (n=7) disease. Patients were treated preoperatively (n=10), postoperatively (n=10), or without surgery (n=24). The median RT dose to the vulva was 50.2 Gray (range, 22-75). Concurrent chemotherapy regimens included weekly platinum (n=16) or every 3-4 week regimens with 5-FU as the backbone (n=28). With a median follow-up of 31.5 months, there was no significant difference in 2-year OS (74.5% vs. 70.0%; p=0.65), DFS (61.9% vs. 56.0%; p=0.85), LRR (31.3% vs. 32.9%; p=0.93), or DM (6.3% vs. 10.6%; p=0.81) between the weekly platinum and every-3-4-week 5-FU regimens. Twenty patients (45.4%) recurred: 16 LRR, 2 DM, and 2 with both. The clinical and pathologic complete response rates were 58.8% (20/34), and 53.8% (14/26), respectively. There was a higher proportion of grade 3 or higher acute non-skin toxicities in patients receiving every-3-4-week 5-FU (46.1% vs. 13.3%; p=0.07), but more grade 3 or higher skin toxicity in patients receiving weekly platinum (62.5% vs. 32.0%; p=0.01). CONCLUSION OS, response rates, and recurrence rates were not significantly different after RT with concurrent weekly platinum-based versus every-3-4-week regimens containing 5-FU for vulvar SCC.

Use of Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer in the United States

PURPOSE The indications for treatment of brain metastases from non-small cell lung cancer (NSCLC) with stereotactic radiosurgery (SRS) remain controversial. We studied patterns, predictors, and cost of SRS use in elderly patients with NSCLC. METHODS AND MATERIALS Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients with NSCLC who were diagnosed with brain metastases between 2000 and 2007. Our cohort included patients treated with radiation therapy and not surgical resection as initial treatment for brain metastases. RESULTS We identified 7684 patients treated with radiation therapy within 2 months after brain metastases diagnosis, of whom 469 (6.1%) cases had billing codes for SRS. Annual SRS use increased from 3.0% in 2000 to 8.2% in 2005 and varied from 3.4% to 12.5% by specific SEER registry site. After controlling for clinical and sociodemographic characteristics, we found SRS use was significantly associated with increasing year of diagnosis, specific SEER registry, higher socioeconomic status, admission to a teaching hospital, no history of participation in low-income state buy-in programs (a proxy for Medicaid eligibility), no extracranial metastases, and longer intervals from NSCLC diagnosis. The average cost per patient associated with radiation therapy was 2.19 times greater for those who received SRS than for those who did not. CONCLUSIONS The use of SRS in patients with metastatic NSCLC increased almost 3-fold from 2000 to 2005. In addition, we found significant variations in SRS use across SEER registries and socioeconomic quartiles. National practice patterns in this study suggested both a lack of consensus and an overall limited use of the approach among elderly patients before 2008.

Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non-small cell lung cancer.

The optimal treatment for patients with brain metastases remains controversial as the use of stereotactic radiosurgery (SRS) alone, replacing whole‐brain radiation therapy (WBRT), has increased. This study determined the patterns of care at multiple institutions before 2010 and examined whether or not survival was different between patients treated with SRS and patients treated with WBRT.

Combined modality treatment for PET-positive non-Hodgkin lymphoma: favorable outcomes of combined modality treatment for patients with non-Hodgkin lymphoma and positive interim or postchemotherapy FDG-PET.

PURPOSE To evaluate outcomes of patients treated for aggressive non-Hodgkin lymphoma (NHL) with combined modality therapy based on [(18)F]fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) response. METHODS AND MATERIALS We studied 59 patients with aggressive NHL, who received chemotherapy and radiation therapy (RT) from 2001 to 2008. Among them, 83% of patients had stage I/II disease. Patients with B-cell lymphoma received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-based chemotherapy, and 1 patient with anaplastic lymphoma kinase-negative anaplastic T-cell lymphoma received CHOP therapy. Interim and postchemotherapy FDG-PET or FDG-PET/computed tomography (CT) scans were performed for restaging. All patients received consolidated involved-field RT. Median RT dose was 36 Gy (range, 28.8-50 Gy). Progression-free survival (PFS) and local control (LC) rates were calculated with and without a negative interim or postchemotherapy FDG-PET scan. RESULTS Median follow-up was 46.5 months. Thirty-nine patients had negative FDG-PET results by the end of chemotherapy, including 12 patients who had a negative interim FDG-PET scan and no postchemotherapy PET. Twenty patients were FDG-PET-positive, including 7 patients with positive interim FDG-PET and no postchemotherapy FDG-PET scans. The 3-year actuarial PFS rates for patients with negative versus positive FDG-PET scans were 97% and 90%, respectively. The 3-year actuarial LC rates for patients with negative versus positive FDG-PET scans were 100% and 90%, respectively. CONCLUSIONS Patients who had a positive interim or postchemotherapy FDG-PET had a PFS rate of 90% at 3 years after combined modality treatment, suggesting that a large proportion of these patients can be cured with consolidated RT.

Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy

Importance The use of a radiotherapy (RT) boost to the tumor bed after whole-breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. Objective To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. Design, Setting, and Participants This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; &agr; = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. Interventions Radiotherapy boost vs no boost. Main Outcomes and Measures Ipsilateral breast tumor recurrence. Results The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93-0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. Conclusions and Relevance This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist.

Low Levels of Acute Toxicity Associated With Proton Therapy for Low-Grade Glioma: A Proton Collaborative Group Study.

1Willis-Knighton Cancer Center, Shreveport, LA; 2Louisiana State University Health Sciences Center, Shreveport, LA; 3Northwestern Medicine Chicago Proton Center, Warrenville, IL; 4Procure Proton Therapy Center, Oklahoma City, OK; 5University of Washington Medical Center and SCCA Proton Therapy Center, SeaYle, WA; 6Mayo Clinic Arizona, ScoYsdale, AZ 7University of Texas MD Anderson Cancer Center, Houston, Texas; 8MassachuseYs General Hospital, Boston, MA; 9Miami Cancer Ins\tute, Bap\st Health South Florida, Miami, FL

Brain Metastases From Melanoma: Therapy at the Crossroads

In the United States, over 180,000 cancer patients will rate of 13% or 0% vs 11%, PZ.21). An increase in tumor present with brain metastases each year (1). Brain metastases are a particular problem in cases of malignant melanoma, with development of brain metastases in approximately half of all patients over the course of their disease (2). Survival in these patients is variable but limited, with Sperduto et al (3) reporting a posteradiation therapy median overall survival (OS) of 6.7 months in 481 patients with brain metastases from melanoma treated with whole-brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). It is worthwhile to note that patients in that study were treated before 2009 and that most of these patients would not have received the systemic therapies described later. Over the past 5 years, the introduction of agents targeted to enhance the immune system by reducing specific cellsignaling blockades has dramatically improved outcomes in patients with metastatic melanoma. In this Oncology Scan, we address the challenges and opportunities for the combination of these new agents and SRS in treating brain metastases from melanoma.