Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial.

BACKGROUND: Skeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs. METHODS: NRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity. RESULTS: 261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p = 0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p = 0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (> 2) had a negative impact on OS (p < 0.0001, p = 0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p = 0.02). No other group differences were noted for QOL or toxicity. CONCLUSION: The addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month. CLINICAL TRIAL REGISTRY: This protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1 .

Targeted Intraoperative Radiotherapy for the Management of Ductal Carcinoma In Situ of the Breast.

Multiple long-term studies have demonstrated a propensity for breast cancer recurrences to develop near the site of the original breast cancer. Recognition of this local recurrence pattern laid the foundation for the development of accelerated partial breast irradiation (APBI) approaches designed to limit the radiation treatment field to the site of the malignancy. However, there is a paucity of data regarding the efficacy of APBI in general, and intraoperative radiotherapy (IORT), in particular, for the management of ductal carcinoma in situ (DCIS). As a result, use of APBI, remains controversial. A prospective nonrandomized trial was designed to determine if patients with pure DCIS considered eligible for concurrent IORT based on preoperative mammography and contrast-enhanced magnetic resonance imaging (CE-MRI) could be successfully treated using IORT with minimal need for additional therapy due to inadequate surgical margins or excessive tumor size. Between November 2007 and June 2014, 35 women underwent bilateral digital mammography and bilateral breast CE-MRI prior to selection for IORT. Patients were deemed eligible for IORT if their lesion was ≤4 cm in maximal diameter on both digital mammography and CE-MRI, pure DCIS on minimally invasive breast biopsy or wide local excision, and considered resectable with clear surgical margins using breast-conserving surgery (BCS). Postoperatively, the DCIS lesion size determined by imaging was compared with lesion size and surgical margin status obtained from the surgical pathology specimen. Thirty-five patients completed IORT. Median patient age was 57 years (range 42-79 years) and median histologic lesion size was 15.6 mm (2-40 mm). No invasive cancer was identified. In more than half of the patients in our study (57.1%), MRI failed to detect a corresponding lesion. Nonetheless, 30 patients met criteria for negative margins (i.e., margins ≥2 mm) whereas five patients had positive margins (<2 mm). Two of the five patients with positive margins underwent mastectomy due to extensive imaging-occult DCIS. Three of the five patients with positive margins underwent successful re-excision at a subsequent operation prior to subsequent whole breast irradiation. A total of 14.3% (5/35) of patients required some form of additional therapy. At 36 months median follow-up (range of 2-83 months, average 42 months), only two patients experienced local recurrences of cancer (DCIS only), yielding a 5.7% local recurrence rate. No deaths or distant recurrences were observed. Imaging-occult DCIS is a challenge for IORT, as it is for all forms of breast-conserving therapy. Nonetheless, 91.4% of patients with DCIS were successfully managed with BCS and IORT alone, with relatively few patients requiring additional therapy.

RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation.

PURPOSE: The Radiation Therapy Oncology Group 9804 study identified good-risk patients with ductal carcinoma in situ (DCIS), a breast cancer diagnosis found frequently in mammographically detected cancers, to test the benefit of radiotherapy (RT) after breast-conserving surgery compared with observation. PATIENTS AND METHODS: This prospective randomized trial (1998 to 2006) in women with mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm, compared RT with observation after surgery. The study was designed for 1,790 patients but was closed early because of lower than projected accrual. Six hundred thirty-six patients from the United States and Canada were entered; tamoxifen use (62%) was optional. Ipsilateral local failure (LF) was the primary end point; LF and contralateral failure were estimated using cumulative incidence, and overall and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: Median follow-up time was 7.17 years (range, 0.01 to 11.33 years). Two LFs occurred in the RT arm, and 19 occurred in the observation arm. At 7 years, the LF rate was 0.9% (95% CI, 0.0% to 2.2%) in the RT arm versus 6.7% (95% CI, 3.2% to 9.6%) in the observation arm (hazard ratio, 0.11; 95% CI, 0.03 to 0.47; P < .001). Grade 1 to 2 acute toxicities occurred in 30% and 76% of patients in the observation and RT arms, respectively; grade 3 or 4 toxicities occurred in 4.0% and 4.2% of patients, respectively. Late RT toxicity was grade 1 in 30%, grade 2 in 4.6%, and grade 3 in 0.7% of patients. CONCLUSION: In this good-risk subset of patients with DCIS, with a median follow-up of 7 years, the LF rate was low with observation but was decreased significantly with the addition of RT. Longer follow-up is planned because the timeline for LF in this setting seems protracted.

Leptomeningeal carcinomatosis in sinonasal undifferentiated carcinoma.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is an uncommon neoplasm characterized by local extension and an aggressive course. Treatment often includes a combination of chemotherapy, radiation therapy, and surgery, although the optimal strategy remains unclear. Here, we present the first reported case of leptomeningeal carcinomatosis from SNUC. METHODS AND RESULTS: A 28-year-old man with rapidly progressive headaches, congestion, and exophthalmos was found to have a nasal mass. Biopsy revealed sinonasal undifferentiated carcinoma. He had a transient response to chemotherapy followed by a sustained response to concurrent chemoradiation. At the completion of radiation, he developed subtle neurologic findings and MRI revealed diffuse, bulky leptomeningeal spread. He was able to receive only a single fraction of external beam radiation to his spinal axis before his disease rapidly progressed, leading to respiratory failure and death. CONCLUSIONS: Sinonasal undifferentiated carcinoma can be associated with leptomeningeal carcinomatosis, which can lead to a fulminant clinical course.

Mammographic findings after intraoperative radiotherapy of the breast.

Intraoperative Radiotherapy (IORT) is a form of accelerated partial breast radiation that has been shown to be equivalent to conventional whole breast external beam radiotherapy (EBRT) in terms of local cancer control. However, questions have been raised about the potential of f IORT to produce breast parenchymal changes that could interfere with mammographic surveillance of cancer recurrence. The purpose of this study was to identify, quantify, and compare the mammographic findings of patients who received IORT and EBRT in a prospective, randomized controlled clinical trial of women with early stage invasive breast cancer undergoing breast conserving therapy between July 2005 and December 2009. Treatment groups were compared with regard to the 1, 2 and 4-year incidence of 6 post-operative mammographic findings: architectural distortion, skin thickening, skin retraction, calcifications, fat necrosis, and mass density. Blinded review of 90 sets of mammograms of 15 IORT and 16 EBRT patients demonstrated a higher incidence of fat necrosis among IORT recipients at years 1, 2, and 4. However, none of the subjects were judged to have suspicious mammogram findings and fat necrosis did not interfere with mammographic interpretation.

The use and misuse of positron emission tomography in lung cancer evaluation.

This article discusses the potential benefits and limitations of positron emission tomography (PET) for characterizing lung nodules, staging the mediastinum, identifying occult distant metastasis, determining prognosis and treatment response, guiding plans for radiation therapy, restaging during and after treatment, and selecting targets for tissue sampling. The key findings from the medical literature are presented regarding the capabilities and fallibilities of PET in lung cancer evaluation, including characterization of pulmonary nodules and staging in patients with known or suspected non-small-cell lung cancer. The discussion is limited to PET imaging with fluorodeoxyglucose.

Close or positive margins after mastectomy for DCIS: pattern of relapse and potential indications for radiotherapy.

PURPOSE: Mastectomies result in very high local control rates for pure ductal carcinoma in situ; however, close or involved tumor margins are occasionally encountered. Data regarding the patterns of relapse in this setting are limited. METHODS AND MATERIALS: Between 1994 and 2002, the pathology reports of 574 patients who had undergone mastectomy at our institution for pure ductal carcinoma in situ were retrospectively reviewed. Of the 574 patients, 84 were found to have margins of <10 mm. Of the 84 patients, 4 underwent postoperative radiotherapy and were excluded, leaving 80 patients for this analysis. Of the 80 patients, 31 had margins <2 mm and 49 had margins of 2.1-10 mm. High-grade disease was observed in 47 patients; 45 patients had comedonecrosis; and 30 had multifocal disease. Of the 80 patients, 51 were <60 years of age. RESULTS: With a median follow-up of 61 months, 6 (7.5%) of the 80 patients developed local recurrence. Of the 31 patients with a margin of

Initial size and dynamics of viral fusion pores are a function of the fusion protein mediating membrane fusion.

BACKGROUND INFORMATION: Protein-mediated merger of biological membranes, membrane fusion, is an important process. To investigate the role of fusogenic proteins in the initial size and dynamics of the fusion pore (a narrow aqueous pathway, which widens to finalize membrane fusion), two different fusion proteins expressed in the same cell line were investigated: the major glycoprotein of baculovirus Autographa californica (GP64) and the HA (haemagglutinin) of influenza X31. RESULTS: The host Sf9 cells expressing these viral proteins, irrespective of protein species, fused to human RBCs (red blood cells) upon acidification of the medium. A high-time-resolution electrophysiological study of fusion pore conductance revealed fundamental differences in (i) the initial pore conductance; pores created by HA were smaller than those created by GP64; (ii) the ability of pores to flicker; only HA-mediated pores flickered; and (iii) the time required for pore formation; HA-mediated pores took much longer to form after acidification. CONCLUSION: HA and GP64 have divergent electrophysiological phenotypes even when they fuse identical membranes, and fusion proteins play a crucial role in determining initial fusion pore characteristics. The structure of the initial fusion pore detected by electrical conductance measurements is sensitive to the nature of the fusion protein.