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Radiation therapy has long been known to be a very effective form of therapy in relieving symptoms and prolonging the life of patients with brain metastases. Novel developments in this field have allowed oncologists to improve on older forms of radiation therapy; these recent advances in radiotherapeutic techniques (stereotactic radiosurgery and hippocampal-avoidant whole brain radiation therapy) allow sparing of the healthy brain from receiving unnecessary radiation while delivering effective treatment to the metastases, thus improving the quality of life for surviving patients. Furthermore, multiple clinical trials have documented the increased loco-regional control in the brain when radiosurgery is interdigitated with immune check point inhibitors for treatment of melanoma brain metastases. Mild hyperthermia has been used for decades as an adjuvant to radiotherapy in the treatment of radiation resistant cancers; lately, however, thermal therapies, such as hyperthermia, cryoablation, radiofrequency ablation and high intensity focused ultrasound are being investigated to provide a new ablative approach to cancer while thermoacoustic imaging and thermometry have recently been proposed as new techniques for monitoring tissue temperature in the breast during ablation treatment. In addition, other hybrid techniques have emerged that combine ultrasounds with other forms of energy such as light to provide a more accurate diagnosis and enhance the efficacy of therapy for early and late stage cancers.

Radiotherapy for brain metastases has evolved tremendously over the past four decades, allowing for improved intracranial control of disease with reduced neurotoxicity. The main technological advance was provided by volumetric modulated arc therapy (VMAT), a computer-controlled delivery method that has opened the door for single-isocenter multi-metastases stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Other notable advances have occurred in the combination of immune checkpoint inhibitors (ICI) and radiosurgery. When these two modalities are combined in the proper sequence (within 30 days from each other), it provides promising results in the treatment of intracranial metastases from melanoma. There is emerging evidence of a synergistic interaction between ICI and SRS, providing better intracranial tumor control and lengthening the survival of patients afflicted by this common complication of cancer.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Treatment failures of glioblastoma (GBM) occur within high-dose radiation fields. We hypothesized that this is due to increased capacity for DNA damage repair in GBM. We identified 24 adult GBM patients treated with maximal safe resection followed by radiation with concurrent and adjuvant temozolomide. The mRNA from patients was quantified using NanoString Technologies’ nCounter platform and compared with 12 non-neoplastic temporal lobe tissue samples as a control. Differential expression analysis identified seven DNA repair genes significantly upregulated in GBM tissues relative to controls (&gt, 4-fold difference, adjusted p values &lt, 0.001). Among these seven genes, Cox proportional hazards models identified RAD51 to be associated with an increased risk of death (HR = 3.49, p = 0.03). Kaplan–Meier (KM) analysis showed that patients with high RAD51 expression had significantly shorter OS compared to low levels (median OS of 10.6 mo. vs 20.1 mo., log-rank p = 0.03). Our findings were validated in a larger external dataset of 162 patients using publicly available gene expression data quantified by the same NanoString technology (median OS of 13.8 mo. vs. 17.4 mo, log-rank p = 0.006). Within this uniformly treated GBM population, RAD51, in the homologous recombination pathway, was overexpressed (vs. normal brain) and inversely correlated with OS. High RAD51 expression may be a prognostic biomarker and a therapeutic target in GBM.

Purpose Total body irradiation (TBI) is an integral part of the conditioning regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic, hematopoietic, cell transplantation (allo-HCT). There are conflicting data in the literature regarding the utility of a cranial irradiation boost in high-risk adult ALL without evidence of preexisting central nervous system (CNS) involvement. This study investigates the posttransplant clinical outcomes of patients with high-risk adult ALL undergoing TBI conditioning for allo-HCT with or without a whole-brain boost, without overt CNS involvement at the time of diagnosis. Methods and materials A retrospective cohort study was conducted using a medical record analysis. We identified 58 patients who were treated between January 1998 and December 2016, and met our preset inclusion criteria of adults (age >18 years old) who carried a pathologically confirmed diagnosis of CNS-negative, high-risk ALL, who underwent hematopoietic stem cell transplantation with TBI conditioning. A multivariate analysis of correlation between patient outcomes and collected categorical variables was assessed with stepwise Cox logistic regression. Survival analyses were assessed using the Kaplan-Meier technique with a log-rank test. Results With a median follow-up time of 5.3 years, there was a statistically significant improvement in actuarial 7-year CNS relapse-free survival (100% vs 76.4%; P = .043) in favor of patients undergoing a cranial boost. There was no statistically significant improvement in 7-year progression-free survival (78.3% vs 62.5%; P = .076) or overall survival (49.4% vs 43.5%; P = .921) with versus without a cranial boost. On multivariate analysis, the presence of a cranial boost was the only identified variable with an independent relationship to CNS relapse-free survival. Conclusions Adult patients with high-risk, CNS-negative ALL were found to have a statistically significant improvement in CNS relapse-free survival and a trend toward improved progression-free survival with the inclusion of a cranial boost with TBI pretransplant conditioning. Our data indicate that further investigation into the use of cranial boost in this patient population is warranted.

BACKGROUND: Post-transplant cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GvHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). While PT-CY has been met with great success in the haplo-BMT arena by suppressing GvHD, patients without acute GvHD have high relapse rates. OBJECTIVE: One of the strategies being explored by others to lessen relapse rates is the dose reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplant bendamustine (PT-BEN) would be advantageous, which is based on our pre-clinical research that delineated several beneficial immunomodulatory properties of BEN. STUDY DESIGN: We therefore initiated and completed a Phase Ia trial which evaluated the progressive substitution of PT-CY with PT-BEN (NCT02996773). Thirteen patients with high-risk hematologic malignancies have received PT-CY/BEN and their outcomes compared to 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning (MAC) regimens but receiving only PT-CY. RESULTS: We demonstrate that partial replacement of PT-CY with PT-BEN on day +4 (PT-CY/BEN) is well tolerated and associated with significantly earlier trilineage engraftment. We also show favorable trends to significant improvements in univariate and multivariate analyses, with PT-CY/BEN compared to PT-CY, with respect to chronic GvHD (HR, 0.08; 95% CI, 0.005, 1.11; P=0.06), and GvHD-free-relapse-free survival (GRFS) (HR, 0.22; 95% CI, 0.05, 0.86; P=0.039). Our human trial has transitioned to Phase Ib which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein, we also expand our pediatric, adolescent, and young adult (AYA) experience to 31 patients demonstrating an overall survival (OS), progression-free survival (PFS) and GRFS at 3 years of 85.6%, 76.1% and 58.2%, respectively in a largely racial/ethnic minority cohort. CONCLUSIONS: PT-CY/BEN appears to be a promising treatment option that requires further evaluation.

Radiation therapy has long been known to be a very effective form of therapy in relieving symptoms and prolonging the life of patients with brain metastases. Novel developments in this field have allowed oncologists to improve on older forms of radiation therapy; these recent advances in radiotherapeutic techniques (stereotactic radiosurgery and hippocampal-avoidant whole brain radiation therapy) allow sparing of the healthy brain from receiving unnecessary radiation while delivering effective treatment to the metastases, thus improving the quality of life for surviving patients. Furthermore, multiple clinical trials have documented the increased loco-regional control in the brain when radiosurgery is interdigitated with immune check point inhibitors for treatment of melanoma brain metastases. Mild hyperthermia has been used for decades as an adjuvant to radiotherapy in the treatment of radiation resistant cancers; lately, however, thermal therapies, such as hyperthermia, cryoablation, radiofrequency ablation and high intensity focused ultrasound are being investigated to provide a new ablative approach to cancer while thermoacoustic imaging and thermometry have recently been proposed as new techniques for monitoring tissue temperature in the breast during ablation treatment. In addition, other hybrid techniques have emerged that combine ultrasounds with other forms of energy such as light to provide a more accurate diagnosis and enhance the efficacy of therapy for early and late stage cancers.

PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p< 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.

BACKGROUND NRG-CC001 sought to evaluate the neuro-protective effects of avoiding the peri-hippocampal stem cell niche using intensity-modulated radiotherapy during WBRT. METHODS Patients with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+ Memantine (M) (30Gy in 10 fractions). Standardized NCF tests and the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) were obtained at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure defined using the reliable change index. Pre-specified secondary endpoints included patient-reported symptoms using the MDASI-BT. Time to NCF was reported as cumulative incidence (with death without NCF failure as a competing risk); between-arms differences were tested using Gray’s test. Deterioration at discrete time-points were tested using chi-square tests. MDASI-BT symptom burden, interference, and cognitive and neurologic burden were analyzed using mixed effects models and t-tests within the model using Hochberg’s multiplicity adjustment. RESULTS A total of 518 patients were randomized from 7/2016 to 3/2018. Median follow-up for alive patients was 12.1 mos, with no difference between arms in terms of toxicity, overall survival or intracranial progression-free survival. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.739, 95% CI: 0.577–0.945, p=0.0.016), with differences first noted at 4 mos in Trail Making Test Part-B (23.3% vs. 40.4% deteriorated, p=0.012). Age did not dilute treatment effect. HA-WBRT+M was associated with reduced cognitive symptom burden in an imputed model (estimate=-0.29, p=0.0425), and also reduced overall symptom burden (p< 0.0001) and interference (p< 0.0016) at 6 mos. CONCLUSIONS The addition of HA to WBRT+M preserved NCF and reduced patient reported cognitive symptom burden, overall symptom burden and symptom interference and should be considered standard of care for any patient fit enough to have WBRT. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

BACKGROUND Tumor hypoxia decreases the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). The purpose of this study was to evaluate the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. METHODS With ethics approval and informed consent, 11 adult GBM patients were enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) within 5–30 minutes prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) while breathing supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To evaluate the reversal of tumor hypoxia, patients underwent oxygen-sensitive (TOLD) MRI before and after DDFPe administration. Patients were also studied with serial MRI scans per standard of care and followed for survival. RESULTS The non-serious adverse events considered by the investigator to be possibly, probably, or definitely related to DDFPe administration included fatigue (n=4), headache (n=2) and decrease in platelet count (n=2). Serious adverse events included two patients with symptomatic radiation necrosis: one patient at each of dose levels 0.1 and 0.17 mL/kg. Enrollment continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. Historically, the average overall survival for GBM patients is about 14.6 months. The median overall survival for the study was 591 days, or 19.4 months. According to independent review of the serial MR images, the median time to progression was 555 days, or 18 months, compared to a historical control of 6.9 months. TOLD MRI showed a trend in improved tumor oxygenation. CONCLUSION Although small, this trial shows that DDFPe used as a radiosensitizer appears to be safe and may provide some survival benefit. The FDA has allowed a Phase II clinical trial to assess its effectiveness.

Apparent increases in the size of cerebral metastases after stereotactic radiosurgery (SRS) can be caused by pseudoprogression or true disease progression, which poses a diagnostic challenge at conventional MRI. The purpose of this study was to assess whether interval change in DWI and perfusion MRI parameters can differentiate pseudoprogression from progressive disease after treatment with SRS.Patients with apparent growth of cerebral metastases after SRS treatment who underwent pre- and post-SRS DWI, dynamic susceptibility contrast (DSC)-MRI, and perfusion dynamic contrast-enhanced (DCE)-MRI were retrospectively evaluated. Final assignment of pseudoprogression or progressive disease was determined at 6-month follow-up imaging using the Response Assessment in Neuro-Oncology Brain Metastases criteria. Mean values of apparent diffusion coefficient (ADC), DCE-MRI-derived volume transfer constant (KOf 102 cerebral metastases evaluated, 32 lesions in 29 patients met our inclusion criteria. The mean duration of follow-up was 7.2 months (range, 6-14 months). Twenty-two lesions were determined as pseudoprogression, and 10 lesions were determined as progressive disease using the Response Assessment in Neuro-Oncology Brain Metastases criteria at 6-month follow-up MRI. The interval change pattern of our imaging parameters matched the expected patterns of treatment response for ADC (23/32 lesions; 72%; p = 0.055; odds ratio, 5.1), KPseudoprogression can be distinguished from disease progression in cerebral metastases treated with SRS via an interval decrease in relative CBV and K

Differentiation of radiation necrosis (RN) from recurrent tumor (RT) in treated patients with glioblastoma remains a diagnostic challenge. The purpose of this study is to evaluate the diagnostic performance of multiparametric MRI in distinguishing RN from RT in patients with glioblastoma, with the use of a combination of MR perfusion and diffusion parameters.Patients with glioblastoma who had a new enhancing mass develop after completing standard treatment were retrospectively evaluated. Apparent diffusion coefficient (ADC), volume transfer constant (KOf a total of 70 patients evaluated, 46 (34 with RT and 12 with RN) met our inclusion criteria. Patients with RT had significantly higher mean rCBV (p0.001) and KIn patients with treated glioblastoma, rCBV outperforms ADC and K

We evaluated and compared the radiographic and clinical outcomes of patients with vestibular schwannomas treated with single fraction stereotactic radiosurgery (SRS), 5 fractions of hypofractionated stereotactic radiation therapy (hSRT), or 25 to 30 fractions of conventionally fractionated stereotactic radiation therapy (cfSRT).Fifty-six patients treated with LINAC-based SRS (median, 12.5 Gy), hSRT (25 Gy), or cfSRT (median, 54 Gy) were retrospectively reviewed. Fractionation was based on the size of the tumor, proximity to the brainstem, and potential risk of neurological sequelae. Median follow-up time was 55.2 months.The pretreatment median tumor diameter was significantly smaller for SRS (1.14 cm) compared with hSRT (1.7 cm) (P = .03) and cfSRT (2.0 cm) (P.001). The overall local tumor control was 96.4%: 100% SRS, 100% hSRT, and 90% cfSRT (P = .19). Tumor regression was observed in 53.3% of SRS, 76.2% of hSRT, and 90% of cfSRT (P = .05). There was less transient expansion of tumors treated with cfSRT (5%) than with SRS (53.3%) or hSRT (28.6%) (P = .005). The median time to regression was 13.8 months for SRS, 14.2 months for hSRT, and 5.5 months for cfSRT (P = .34). There was a 3.6% incidence of grade 3 trigeminal neuropathy, but there was no grade 3 facial neuropathy.All 3 regimens demonstrated similar excellent local control with minimal toxicity; however, the ability of hSRT to treat larger tumors with comparable outcomes to SRS and greater patient convenience when compared with cfSRT suggest that hSRT may offer the optimal treatment approach.

Purpose: Electronic brachytherapy (eBT) is a form of contact radiation therapy used for thin superficial non-melano­matous skin cancers (NMSCs). An accurate measurement of diameter and depth is important for eBT treatment planning. Therefore, we compared clinical measurements by an experienced physician to measurements obtained using ultrasound (US), an objective imaging modality, in order to determine if clinical measurements were accurate enough for adequate NMSC treatment. Material and methods : Eighteen patients with 20 biopsy-proven NMSCs first had a clinical examination and then an US evaluation prior to starting eBT. One physician provided a clinical measurement for diameter and depth based on physical examination during radiation oncology consultation. The patients then had an US evaluation with a 14 or 18 MHz US unit, to determine both the diameter and depth measurements; eBT dose prescription was done using the US derived measurements. The clinical measurements and US measurements were compared using a t-test. Results: Seventeen lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). The difference between the clinical and the US derived measurements for the second largest diameter was found to be statistically significant (p = 0.03), while the difference for the largest diameter of the lesions was not (p = 0.24). More importantly, the depth measurements obtained with US were also found to be significantly different from the clinical estimates (p = 0.02). All patients have had a complete response to therapy with a median follow-up of 24 months. Conclusions : Statistically different measurements were obtained in 2 of 3 parameters used in choosing applicator size and prescription depth using an US assessment. The data presented suggests that US is a more objective modality than clinical judgment for determining superficial NMSC diameter and prescription depth for personalized eBT planning.

Primary melanoma of the pineal gland is a rare disease entity with an overall poor prognosis. Limited data exist to appropriately guide treatment decisions. Historical case reports have showed some success using a combination of surgical resection, radiotherapy, and chemotherapy, but long-term survival has been exceedingly rare. This report presents a female patient with a primary pineal melanoma who underwent subtotal resection followed by adjuvant focal radiation to the residual tumor. Immunohistochemistry identified a strong positivity for PD-L1 (70%). After radiation, systemic therapy with pembrolizumab was initiated with the plan to treat until progression. She has now completed 33 cycles of pembrolizumab without interruptions, complications, or disease progression. At the time of writing, the patient has had an excellent clinical outcome, with a durable near-complete response of >138 weeks. To our knowledge, this is the first patient with a pineal melanoma to be managed by targeting PD-L1. Furthermore, she has achieved the second longest overall survival and the longest progression-free survival reported in the literature.

PURPOSE: NRG CC001, a phase III trial of WBRT plus memantine with or without hippocampal avoidance, sought to evaluate the neuro-protective effects of avoiding the hippocampus using intensity-modulated radiotherapy. METHODS: Adult patients with brain metastases were stratified by RPA class and receipt of prior radiosurgery/surgery and randomized to WBRT+memantine (WBRT+M) versus hippocampal-avoidant WBRT+memantine (HA-WBRT+M) (30Gy in 10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months. The primary endpoint was time to NCF failure, defined as decline on at least one of the following tests using the reliable change index: Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence was used to estimate time to NCF failure (death without NCF failure was treated as competing risk) with between-arms differences tested using Grays test. To detect an 11% absolute reduction in 6-month NCF failure, 382 analyzable patients were required for 90% power with two-sided =0.05. Due to possible non-compliance, the sample size was increased by 25% (510 patients). RESULTS: From July 2016 to March 2018, 518 patients were randomized. Median age was 61.5 years. Median follow-up for alive patients was 6.1 months. Treatment arms did not differ in grade3 toxicity, overall survival, intracranial progression, or baseline NCF. Time to NCF failure was significantly longer in favor of HA-WBRT+M (p=0.012). The 6-month NCF failure rates were 69.1% (95% CI:61.8–75.3%) vs. 58.0% (95% CI:50.2–64.9%) for WBRT+M vs. HA-WBRT+M, respectively. After adjusting for stratification factors, HA-WBRT+M (hazard ratio (HR)=0.73, 95%CI:0.56–0.94, p=0.016) and age 61 years (HR=0.61, 95%CI:0.46–0.81, p=0.0006) remained significant. CONCLUSION: Preliminary analysis confirms that conformal avoidance of the neuro-regenerative hippocampal stem cell compartment during WBRT preserves neurocognitive function while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

Introduction Scleredema of Buschke is a rare connective tissue disorder presenting with woody thickening and induration of the nuchal and shoulder regions resulting in progressive decrease in the range of motion of the neck. Treatment options include several forms of systemic therapy with variable results. Local radiation therapy (RT) is often thought of as a secondary form of therapy. Few reports exist in the literature about the durability of its benefit, however. Here, we present a case report with the longest known follow-up after primary treatment with electron beam RT. Methods The patient was treated using 8-MeV en face electrons with 2000 cGy in 10 fractions with 2 separate but matched electron fields. The treatment fields included the posterior neck from the occiput superiorly to the mid-thoracic spine inferiorly with the lateral borders extending to the scapulae. The patient received no additional therapy either pre- or post-RT. Clinical follow-up was obtained at regular intervals. Published literature regarding RT for this disease was reviewed and consolidated. Results The patient was followed at regular intervals for 6 years with significant softening of the plaque starting at 2 months after RT, resulting in decrease in plaque size by 50% after 18 months. The patient regained 45° of lateral, bidirectional cervical motion from central axis and 50% improvement in neck extension that has remained durable 6 years after treatment with no additional therapy. Quality of life was restored with a simple nontoxic treatment limited to transient, grade 1 fatigue. Conclusion Scleredema of Buschke is a rare connective tissue disorder commonly treated with multimodal therapy, but it can be effectively and durably controlled with RT alone. This case report documents the durability of the benefit achieved with RT and suggests that RT should be considered earlier in the treatment of this disease.

Radiation therapy continues to play an important role in the management of cancer. In this review, we discuss the use of radiation therapy to target and control micrometastatic disease (adjuvant use of radiation), or using stereotactic radiation therapy to address small volumes of gross disease, such as oligometastases, and finally the use of radiation therapy in the era of immunotherapy. Radiation therapy is commonly used to treat nodal basins suspected of harboring microscopic disease. More recently, computer and technical innovations have allowed radiation oncologists to treat small volumes of gross disease within the brain and also in the body with great success, adding to the cancer armamentarium. This modality of cancer treatment that began shortly after the discovery of X-rays by William Roentgen continues to evolve and finds new clinical applications which minimize toxicity while increasing effectiveness. The newly discovered interactions of high dose/fraction radiation (stereotactic radiosurgery) with immune check point inhibitors in melanoma is the latest example of how synergism can be achieved between two different modalities thus increasing the therapeutic ratio to control metastatic cancer.

To report an institutional experience with episcleral plaque brachytherapy for medium-sized uveal melanoma. Variations in prescription dose point and dose rate were compared with Collaborative Ocular Melanoma Study (COMS) Group.A retrospective review was performed for 116 patients treated with iodine-125 plaque brachytherapy. About 85 Gy was prescribed to either the tumor apex (108 patients) or at 5 mm (8 patients) with dose rate ranging from 50.6 to 98.2 cGy/h. Patients were followed up for local tumor control, eye preservation, and vision retention. Dose and dose rate to tumor and sensitive structures were calculated. Multivariate and univariate analyses were performed to investigate correlation between clinical outcomes and dose/dose rate variables.Patients in this study were slightly older with worse visual acuity at baseline, but tumor size and position and ratio of ciliary body involvement were comparable to COMS population. Outcomes data were comparable to COMS: 95.3% local tumor control at 5 years and 77.7% vision preservation at 3 years. Only 4 patients needed enucleation because of tumor growth. Significant correlation was found between enucleation and tumor height and maximal scleral dose/dose rate as well as vision retention and tumor height and macula dose/dose rate.For tumors with5 mm height, prescribing to tumor apex enabled to decrease dose to all sensitive structures without any loss of local control. Although dose rate was lowered to 50.6 cGy/h from the American Brachytherapy Society guidelines (60-105 cGy/h) because of limited availability of operating room (i.e., weekly), there was no difference in either local tumor control or complications.

Summary Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m 2 for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour 2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut. Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Funding Celldex Therapeutics, Inc.

Episcleral plaque brachytherapy for appropriately selected patients (medium-sized tumors with an apical height of 2.5–10 mm and maximum basal diameter of

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain cancer with a median life expectancy of 13–15 months after surgery and chemo-radiation treatment. GBM is hallmarked by a poor response to radiation therapy (RT), which is generally attributed to upregulation of several DNA repair pathways. To identify pathways which predict poor chemo-radiation treatment outcome, we conducted a retrospective clinical-genetic study in which we evaluated the mRNA expression profiles of 24 GBM tumor samples, stratified on the basis of patient survival post chemo-radiation treatment. All patients were treated at our institution by surgical resection and intensity-modulated RT with concurrent and adjuvant temozolomide. Expression profiles were obtained utilizing a commercially available PanCancer Pathways Panel (NanoString Technologies, Inc.). Our data analysis shows a distinctly significant correlation between 5 members of the Wnt pathway and overall patient survival. A 2- to 9-fold higher expression of negative regulators of the Wnt pathway and a 2- to 3-fold lower expression of positive Wnt regulators was observed in tumor material of patients with a longer than median survival. We conclude that upregulation of the Wnt pathway correlates with poor chemo-radiation treatment outcome in GBM. In vitro experimentation by other groups has recently demonstrated a role for Wnt signaling in activation of Non-Homologous End-Joining mediated DNA double-strand break repair and the subsequent onset of radio-resistance. These preliminary findings support the hypothesis that the Wnt pathway may be used as a predictive marker for RT outcome in GBM and suggest new strategies to increase the radiation sensitivity of GBM.

Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III trials. Larger prospective trials of Gliadel plus RT/TMZ are warranted.

Background The new imaging technology made available today allows for an early detection of small subclinical breast lesions which frequently call for guided presurgical micro-histology. Purpose To evaluate the relationship between vacuum-assisted breast biopsy (VABB) histopathological diagnoses and mammographic findings in non-palpable breast lesions. Material and Methods The breast lesions of 1393 women who had received consecutive screening mammograms between 2001 and 2007 were assessed by VABB. The mammographic breast lesions, classified according to the Breast Imaging Reporting and Data System (BI-RADS), were subjected to VABB only if rated as highly suspicious (2%), suspicious (64.5%) for malignancy, or probably benign (33.5%). Results VABB findings included 981 (70.5%) probably benign lesions, 407 (29.2%) suspicious/malignant lesions, and five (0.3%) cases which were considered as inappropriate for diagnostic purposes. At histology, 10.2% of the suspicious/malignant lesions were classified as proliferative lesions, 11.1% as ductal carcinoma in situ (DCIS), and 8% as invasive ductal carcinoma (IDC). The positive predictive value (PPV) of BI-RADS assessment categories 3, 4 and 5 was 4.1%, 25.3% and 75%, respectively. The occurrence of obscured or spiculated masses was found to exhibit the highest PPV for malignancy (12.5% in BI-RADS 3 and 63% in BI-RADS 4), followed by microcalcifications which showed a malignancy rate of 6.4% in BI-RADS 3, and 20% in BI-RADS 4. Conclusion VABB turns out to be effective in the assessment of many malignant and benign preclinical tumour lesions thus allowing for a significant reduction of the number of surgical biopsies.

High energy X-rays have been used for cancer therapy since their discovery in 1895. Major radiobiological discoveries and technological advances in radiation physics have greatly increased the accuracy of radiation. The recent integration of radiation therapy and imaging systems provides radiation oncologists with sophisticated dose delivery capability allowing continued improvements in the control of loco-regional and metastatic disease while decreasing toxicity. Key technical aspects of current radiation therapy are described with examples extending to several clinical areas. J. Surg. Oncol. 2011;103:627–638. © 2011 Wiley-Liss, Inc.

IGFBP2 is overexpressed in the most common brain tumor, glioblastoma (GBM), and its expression is inversely correlated to GBM patient survival. Previous reports have demonstrated a role for IGFBP2 in glioma cell invasion and astrocytoma development. However, the function of IGFBP2 in the restricted, self-renewing, and tumorigenic GBM cell population comprised of tumor-initiating stem cells has yet to be determined. Herein we demonstrate that IGFBP2 is overexpressed within the stem cell compartment of GBMs and is integral for the clonal expansion and proliferative properties of glioma stem cells (GSCs). In addition, IGFBP2 inhibition reduced Akt-dependent GSC genotoxic and drug resistance. These results suggest that IGFBP2 is a selective malignant factor that may contribute significantly to GBM pathogenesis by enriching for GSCs and mediating their survival. Given the current dearth of selective molecular targets against GSCs, we anticipate our results to be of high therapeutic relevance in combating the rapid and lethal course of GBM.

We present a report of a 12-year-old boy diagnosed with medulloblastoma at 22 months of age. A gross total resection was performed followed by adjuvant systemic chemotherapy due to his young age; however, the tumor recurred locally in the posterior fossa 7 months later. The recurrent tumor was excised and he received craniospinal radiation with a boost given to the posterior fossa followed by high-dose chemotherapy. He remained disease free for approximately 10 years without major neurologic deficit and only mild cognitive impairment. A routine follow-up MRI of the brain revealed an enhancing mass. The patient underwent surgical debulking and pathological examination revealed no residual immature medulloblastoma cells but instead mature ganglion cells, consistent with a gangliocytoma. The apparent maturation of primitive medulloblastoma cells is a rare phenomenon, which may have ensued from the long-term effects of adjuvant therapies inducing advanced cellular maturation.

Purpose Treatment of glioblastoma multiforme (GBM) continues to pose a significant therapeutic challenge, with most tumors recurring within the previously irradiated tumor bed. To improve outcomes, we must be able to identify and treat resistant cell populations. Rad51, an enzyme involved in homologous recombinational repair, leads to increased resistance of tumor cells to cytotoxic treatments such as radiotherapy. We hypothesized that Rad51 might contribute to GBM's apparent radioresistance and consequently influence survival. Methods and Materials A total of 68 patients with an initial diagnosis of GBM were retrospectively evaluated; for 10 of these patients, recurrent tumor specimens were used to construct a tissue microarray. Rad51 protein expression was then correlated with the actual and predicted survival using recursive partitioning analysis. Results Rad51 protein was elevated in 53% of the GBM specimens at surgery. The Rad51 levels correlated directly with survival, with a median survival of 15 months for patients with elevated Rad51 compared with 9 months for patients with low or absent levels of Rad51 ( p = .05). At disease recurrence, 70% of patients had additional increases in Rad51 protein. Increased Rad51 levels at disease recurrence similarly predicted for improved overall survival, with a mean survival of 16 months from the second craniotomy compared with only 4 months for patients with low Rad51 levels ( p = .13). Conclusion Elevated levels of the double-stranded DNA repair protein Rad51 predicted for an increase survival duration in patients with GBM, at both initial tumor presentation and disease recurrence.

Orbital lymphoma and Grave's ophthalmopathy (GO) are successfully treated with radiation therapy. The lenses are blocked to prevent cataract formation. However, blocking of the lens by traditional methods can be difficult for tumors located anteriorly and extending into the retrobulbar space. We present a series of 3 patients with orbital lymphoma and 1 with GO treated with stereotactic intensity modulated radiation therapy (IMRT) to spare normal structures, including the lens. Three patients with orbital lymphomas and 1 with unilateral GO were treated with IMRT using a linac with stereotactic capabilities. Avoidance structures included the ipsilateral lens and globe, the contralateral lens and globe, the chiasm, and the brainstem. Two patients with orbital lymphoma were treated with 24 Gy in 12 fractions, and 1 patient was treated with 30.6 Gy in 17 fractions. The patient with GO was treated with 20 Gy in 10 fractions. The dosimetry was analyzed to determine the dose to normal tissues. Patient follow-up varies between 8 and 24 months. The mean minimal dose to the ipsilateral lens was 13.6% of the total dose, the mean maximal dose was 33.5%, and the mean median dose was 19.3%. The mean median dose to the contralateral eye was 1.1% of the total dose. The mean median dose to the chiasm was 14.9% of the total dose. The mean median dose to the brainstem was 1.9% of the total dose. No cataracts or other complications were noted in the 4 patients treated with this technique so far. IMRT gives a more conformal treatment to the orbital contents while sparing normal tissues such as the ipsilateral lens and adjacent critical structures. This should result in fewer complications such as cataracts.

Temporary, low dose rate brachytherapy to the margins of resected brain tumors, using a balloon catheter system (GliaSite Radiation Therapy System) and liquid I-125 radiation source (Iotrex), began in 2002 at the University of Arizona Medical Center. Initially, all patients were treated on an inpatient basis. For patient convenience, we converted to outpatient therapy. In this article we review the exposure data and safety history for the 37 patients treated as outpatients. Proper patient selection and instruction is crucial to having a successful outpatient brachytherapy program. A set of evaluation criteria and patient instructions were developed in compliance with the U.S. Nuclear Regulatory Commission's document NUREG-1556 Volume 9 (Appendix U) and Arizona State Nuclear regulatory guidelines, which specify acceptable exposure rates for outpatient release in this setting. Of the 37 patients monitored, 26 patients were treated for recurrent glioblastoma multiforme (GBM), six for primary GBM, and five for metastatic brain tumors. All 37 patients and their primary caregivers gave signed agreement to follow a specific set of instructions and were released for the duration of brachytherapy (3-7 days). The typical prescription dose was 60 Gy delivered at 0.5 cm from the balloon surface. Afterloaded activities in these patients ranged from 90.9 to 750.0 mCi and measured exposure rates at 1 m from the head were less than 14 mR/h. The mean exposure to the caretaker measured by personal radiation Landauer Luxel + whole body dosimeters for 25 caretakers was found to be 9.6 mR, which was significantly less than the mean calculated exposure of 136.8 mR. For properly selected patients, outpatient brachytherapy is simple and can be performed within established regulatory guidelines.

Purpose To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT). Patients and Methods Southwest Oncology Group (SWOG) study S0014 enrolled patients with newly diagnosed, aggressive, CD20-expressing non-Hodgkin's lymphoma (NHL). Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index (nonbulky stage II disease, age > 60 years, WHO performance status of 2, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days −7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46 Gy of IFRT. Results Sixty patients with aggressive NHL were eligible. With the median follow-up of 5.3 years, treatment resulted in a progression-free survival (PFS) of 93% at 2 years and 88% at 4 years. Overall survival (OS) was 95% at 2 years and 92% at 4 years. These results were compared with those from a historic group of patients treated without rituximab on S8736, demonstrating PFS of 78% and OS of 88% at 4 years. Conclusion In limited-stage DLBCL, the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy, with 2-year PFS of at least 84%, meriting further investigation. There is a pattern of continuing relapse with modest survival gains. We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma.

Purpose Electronic brachytherapy (eBT) has gained acceptance over the past 5 years for the treatment of non-melanomatous skin cancer (NMSC). Although the prescription depth and radial margins can be chosen using clinical judgment based on visual and biopsy-derived information, we sought a more objective modality of measurement for eBT planning by using ultrasound (US) to measure superficial (< 5 mm depth) lesions. Material and methods From December 2013 to April 2015, 19 patients with 23 pathologically proven NMSCs underwent a clinical examination and US evaluation of the lesions prior to initiating a course of eBT. Twenty lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). A 14 or 18 MHz US unit was used by an experienced radiologist to determine depth and lateral extension of lesions. The US-measured depth was then used to define prescription depth for eBT planning without an added margin. A margin of 7 mm was added radially to the US lateral extent measurements, and an appropriate cone applicator size was chosen to cover the target volume. Results The mean depth of the lesions was 2.1 mm with a range of 1-3.4 mm, and the mean largest diameter of the lesions was 8 mm with a range of 2.6-20 mm. Dose ranged from 32-50 Gy in 8-20 fractions with a median dose of 40 Gy in 10 fractions. All patients had a complete response and no failures have occurred with a median follow-up of 12 months (range of 6-22 months). Also, no prolonged skin toxicities have occurred. Conclusions A routinely available radiological US unit can objectively determine depth and lateral extension of NMSC lesions for more accurate eBT treatment planning, and should be considered in future eBT treatment guidelines.

Efaproxiral (Efaproxyn, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O(2)) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction x 10 days), plus supplemental O(2) (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (or =483 microg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.

OBJECTIVE: To review the cumulative experience of 10 institutions in treating recurrent malignant gliomas with the brachytherapy device, GliaSite Radiation Therapy System. METHODS: The patient population consisted of 95 patients with recurrent grade 3 or 4 gliomas, a median age of 51 years, and a median Karnofsky performance status score of 80. All patients had previously undergone resection and had received external beam radiotherapy as part of their initial treatment. After recurrence, each patient underwent maximal surgical debulking of their recurrent lesion and placement of an expandable balloon catheter (GliaSite) in the tumor cavity. The balloon was afterloaded with liquid 125 I (lotrex) to deliver a median dose of 60 Gy to an average depth of 1 cm with a median dose rate of 52.3 Gy/hr. Patients were carefully followed with serial magnetic resonance imaging and monthly examinations for tumor progression, side effects, and survival. RESULTS: The median survival for all patients, measured from date of GliaSite placement, was 36.3 weeks with an estimated 1 year survival of 31.1%. The median survival was 35.9 weeks for patients with an initial diagnosis of glioblastoma multiforme and 43.6 weeks for those with non- glioblastoma multiforme malignant gliomas. Analysis of the influence of various individual prognostic factors on patient survival demonstrated that only Karnofsky performance status significantly predicted for improved survival. There were three cases of pathologically documented radiation necrosis. CONCLUSION: Reirradiation of malignant gliomas with the GliaSite Radiation Therapy System after reresection seems to provide a modest survival benefit above what would be expected from surgery alone. This report not only confirms the initial results of the feasibility study but provides evidence that similar outcomes can be obtained outside of a clinical trial.

Purpose Efaproxiral (RSR13) reduces hemoglobin oxygen–binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non–small-cell lung cancer (NSCLC). Patients and Methods Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10. Results Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%). Conclusion Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.

Vascular endothelial growth factor (VEGF) is known to play a central role in tumour angiogenesis. However, no data have been published with regard to the clinical-biological significance of serum (S)-VEGF in hepatocellular cancer (HCC) patients undergoing to percutaneously radiofrequency thermal ablation (PRFA). The aim of this study was to assess the modifications of S-VEGF levels in a series of 28 HCC patients in hepatitis C virus-positive cirrhosis before and after PRFA, respectively. Samples of S were taken before, 2 and 5 days after PRFA respectively and VEGF levels were assessed by ELISA. No significant difference was found between pre- and post-VEGF levels (p= n.s.; by Wilcoxon test). We suggest that S-VEGF level is not useful as early predictive marker of response to PRFA.

Background: Before starting a molecular screening program for breast cancer risk and in order to develop ad hoc educational strategies, a population survey in Apulia, Italy, was performed to gather information on women’s awareness of breast cancer genetics and their attitude toward genetic testing for breast cancer risk. Patients and methods: A consecutive series of 677 healthy women with or without a family history of breast cancer, who attended the outpatient clinics of Lega Italiana per la Lotta contro i Tumori in Bari, Italy, for preventive visits, were asked to complete a 20-item questionnaire on socio-demographics, risk perception, psychological characteristics and interest in genetic testing for breast cancer predisposing genes. Results: Most women (77%) reported knowing something about the genetics of breast cancer; only 7% of the women were not interested at all in genetic testing. These figures were not significantly different for women with or without a family history of breast cancer. The two most frequently cited reasons for being interested in genetic testing, accounting for more than 50% of collected responses, were ‘to learn about your children’s risk’ and ‘to help advance research’. On multiple logistic regression analysis, only older age [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.3– 2.9] was associated with women’s knowledge of genetic testing. Moreover, marital status (OR 4.0; 95% CI 1.1– 14.6) and thinking of cancer (OR 2.2; 95% CI 1.0 – 4.7) independently predicted the interest in having genetic testing. Conclusions: Southern Italian women seem highly interested in genetic testing for breast cancer risk. However, their expectations mainly regard their concerns about their children or their altruistic need to help research rather than the idea of a direct clinical benefit. The great interest of the women in genetic testing probably reflects their inappropriate knowledge of the information that genetic testing can provide for breast cancer risk analysis.

Purpose: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). Patients and Methods: Eligibility criteria were age ≥ 18 years, Karnofsky performance score ≥ 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. Results: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P = .0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P = .006). There was a 54% reduction in the risk of death for RSR13 patients (P = .0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. Conclusion: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.