Differentiating Radiation Necrosis and Metastatic Progression in Brain Tumors Using Radiomics and Machine Learning.

OBJECTIVES: Distinguishing between radiation necrosis (RN) and metastatic progression is extremely challenging due to their similarity in conventional imaging. This is crucial from a therapeutic point of view as this determines the outcome of the treatment. This study aims to establish an automated technique to differentiate RN from brain metastasis progression using radiomics with machine learning. METHODS: Eighty-six patients with brain metastasis after they underwent stereotactic radiosurgery as primary treatment were selected. Discrete wavelets transform, Laplacian-of-Gaussian, Gradient, and Square were applied to magnetic resonance post-contrast T1-weighted images to extract radiomics features. After feature selection, dataset was randomly split into train/test (80%/20%) datasets. Random forest classification, logistic regression, and support vector classification were trained and subsequently validated using test set. The classification performance was measured by area under the curve (AUC) value of receiver operating characteristic curve, accuracy, sensitivity, and specificity. RESULTS: The best performance was achieved using random forest classification with a Gradient filter (AUC=0.910±0.047, accuracy 0.8±0.071, sensitivity=0.796±0.055, specificity=0.922±0.059). For, support vector classification the best result obtains using wavelet_HHH with a high AUC of 0.890±0.89, accuracy of 0.777±0.062, sensitivity=0.701±0.084, and specificity=0.85±0.112. Logistic regression using wavelet_HHH provides a poor result with AUC=0.882±0.051, accuracy of 0.753±0.08, sensitivity=0.717±0.208, and specificity=0.816±0.123. CONCLUSION: This type of machine-learning approach can help accurately distinguish RN from recurrence in magnetic resonance imaging, without the need for biopsy. This has the potential to improve the therapeutic outcome.

Case report: Neuroendocrine breast carcinoma with a germline EGFR T790M mutation.

Background: The epidermal growth factor receptor (EGFR) p.Thr790Met (T790M) mutation was discovered as a resistance mechanism in patients with lung cancer treated with first- and second-generation tyrosine kinase inhibitors. Further studies revealed the EGFR T790M mutation in treatment-naive non-small cell lung carcinoma (NSCLC) and as a rare germline mutation strongly associated with NSCLC. Somatic EGFR T790M mutations have been reported in a limited population of patients with triple-negative breast cancer. There are no previous reports of a germline EGFR T790M mutation found in a patient with breast cancer. Case presentation: We present a rare case of a 42-year-old woman with a rapidly progressing 8 cm mass in the right lateral breast. An additional right breast mass with multiple lymph nodes characteristic or suspicious of metastasis was found. Ultrasound-guided biopsy showed high-grade, poorly differentiated invasive neuroendocrine carcinoma of the right breast and metastatic carcinoma of a right axillary lymph node. Genetic testing revealed a germline EGFR T790M mutation. The patient underwent neoadjuvant chemotherapy, right mastectomy with lymph node dissection, adjuvant radiation to the right chest wall and axilla, and adjuvant chemotherapy. Conclusion: This is the first reported case of a patient with high-grade neuroendocrine carcinoma, triple-negative breast cancer and a germline EGFR T790M mutation. Further investigation is needed to find a possible correlation between the cancer in this patient and her mutation. Since there are no current guidelines, further research is also needed to define screening protocols for patients with germline EGFR T790M mutations. Additional treatment options and cancer risk could also be found with further research, which would benefit all patients with a germline EGFR T790M mutation.

Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy.

PURPOSE: To report our experience in long-term follow-up of ocular melanoma patients treated with custom OSU-Nag eye plaques using (125)I sources. METHODS: A retrospective chart review was conducted for 113 consecutive ocular melanoma patients with follow-up visual acuity data who were treated with OSU-Nag plaque episcleral brachytherapy at The Ohio State University Medical Center from 1994 to 2009. Visual acuity, complication data, and recurrence rates were recorded up to 120 months after brachytherapy. RESULTS: Median age at presentation was 63.0 years (range, 22-93). Median follow-up was 65.5 months (range, 2-180). Median radiation dose at the prescription point was 85.8 Gy (range, 51.8-103.7). Preservation of useful visual acuity, defined as better than 20/200, was noted in 43 of 74 (58%) of patients in the present study at 36 months compared with 50.1% of Collaborative Ocular Melanoma Study participants. By 120 months, 17 of 30 (57%; 95% confidence interval, 45-69%) progressed to visual acuity worse than 20/200, whereas 9 of 30 (30%) retained visual acuity of 20/40 or better, and 4 of 30 (13%) were 20/50-20/200. The rate of retinopathy after radiation was approximately 40% of all those observed by 60 months. Baseline visual acuity, apical tumor height, American Joint Committee on Cancer tumor category, and distance between the tumor and the fovea were all significantly associated with loss of visual acuity. The local tumor control rate by 60 months of follow-up was 93% (95% confidence interval, 85-97%). CONCLUSIONS: The OSU-Nag custom (125)I plaque is an effective treatment for uveal melanoma, with preservation of useful visual acuity in 58% of eyes 3 years after treatment and 43% of eyes 10 years after treatment.

The application of radiation therapy to the Pediatric Preclinical Testing Program (PPTP): results of a pilot study in rhabdomyosarcoma.

BACKGROUND: The Pediatric Preclinical Testing Program (PPTP) has been successfully used to determine the efficacy of novel agents against solid tumors by testing them within a mouse-flank in vivo model. To date, radiation therapy has not been applied to this system. We report on the feasibility and biologic outcomes of a pilot study using alveolar and embryonal rhabdomyosarcoma xenograft lines. PROCEDURES: We developed a high-throughput mouse-flank irradiation device that allows the safe delivery of radiotherapy in clinically relevant doses. For our pilot study, two rhabdomyosarcoma xenograft lines from the PPTP, Rh30 (alveolar) and Rh18 (embryonal) were selected. Using established methods, xenografts were implanted, grown to appropriate volumes, and were subjected to fractionated radiotherapy. Tumor response-rates, growth kinetics, and event-free survival time were measured. RESULTS: Once optimized, the rate of acute toxicity requiring early removal from study in 93 mice was only 3%. During the optimization phase, it was observed that the alveolar Rh30 xenograft line demonstrated a significantly greater radiation resistance than embryonal Rh18 in vivo. This finding was validated within the standardized 30 Gy treatment phase, resulting in overall treatment failure rates of 10% versus 60% for the embryonal versus alveolar subtype, respectively. CONCLUSIONS: Our pilot study demonstrated the feasibility of our device which enables safe, clinically relevant focal radiation delivery to immunocompromised mice. It further recapitulated the expected clinical radiobiology.

Cytogenetic profile of patients with acute myeloid leukemia and central nervous system disease.

BACKGROUND: Acute myeloid leukemia (AML) infrequently involves the central nervous system (CNS). This study was undertaken in patients with AML to determine whether cytogenetic findings predict CNS involvement. METHODS: The medical records of 1354 patients with AML who were treated at The University of Texas MD Anderson Cancer Center between January 2000 and December 2008 were reviewed. Forty patients (3%) had CNS involvement at time of presentation or disease recurrence, of whom 37 had conventional cytogenetics performed on bone marrow aspirate material. Demographics, treatment, and status at last follow-up were collected. RESULTS: Eleven patients (30%) had a diploid karyotype, and 14 patients (38%) had complex cytogenetics. Only 5 of the 40 patients had CNS disease at diagnosis, and the remaining patients had CNS disease at relapse. Patients who developed CNS disease were younger (P = .019), had a higher white blood cell (WBC) count at diagnosis (P = .001), had higher lactate dehydrogenase level (LDH) levels (P < .0001), and had higher percentages peripheral blast cells (P = .024) at diagnosis compared with the rest of the population. In addition, patients with CNS disease had higher rates of chromosome 16 inversion (P < .001), chromosome 11 abnormality (P = .005), and trisomy 8 (P = .02) and had a tendency toward complex cytogenetics (P = .2) compared with the control group (patients who had AML with no CNS involvement). CONCLUSIONS: Patients with AML and CNS disease often had higher LDH levels and WBC counts at diagnosis, and they often presented with chromosome 16 inversion and chromosome 11 abnormalities. The current study indicated that the overall survival of patients with AML who had CNS involvement is poor.

Recent advancements in multimodality treatment of gliomas.

Gliomas account for the vast majority of malignant adult brain tumors. Even though tremendous effort has been made to optimize treatment of patients with high-grade glioma, the prognosis remains poor, especially for patients with glioblastoma. The dismal prognosis conferred by these tumors is in part caused by the tendency to diffusely infiltrate into neighboring brain tissue, but also by the inherent resistance of these tumors to both chemotherapy and radiation. This article reviews the recent advancements in multimodality treatment of patients with gliomas, both in the primary and recurrent setting, with an emphasis on the emerging targeted therapies. Moreover, the external beam radiotherapy options, including intensity modulated radiotherapy and particle (proton and carbon ion) radiotherapy are reviewed.

Fertility drugs and the risk of breast cancer: a meta-analysis and review.

The risk of breast cancer has been associated with reproductive history. The purpose of this study was to determine the relationship between fertility drugs used in assisted reproductive procedures and the risk of breast cancer. We performed a literature search using the MEDLINE, the COCHRANE Library, and Scopus to identify studies linking breast cancer to fertility drugs. We excluded case series, case reports, and review articles from our analysis. The study populations included women who were treated for infertility with clomiphene, gonadotropins, gonadotropin-releasing hormones, or other unspecified fertility agents. We extracted information on study design, sample size, type of fertility drugs and number of treatment cycles, breast cancer incidence, and follow-up time from these studies. Eight case-control studies and fifteen cohort studies were included in the quantitative analyses. The Newcastle-Ottawa Quality Assessment Scales were used. Two investigators independently extracted study methods, sources of bias, and outcomes. We found that the risk of breast cancer was not significantly associated with fertility drug treatment. The follow-up periods were short in some of the studies analyzed in our study; however, we proceeded to test the trend in risk estimates across different durations of follow-up and found a trend for association using the nonparametric test; this was interpreted with caution in view of the lack of adjustment with other confounding factors. The current published data do not suggest higher risk of breast cancer in women who receive fertility treatment, but the lack of long-term follow up and the inherent weaknesses in some of the published studies have to be cautiously taken into account.

Stereotactic body radiation therapy (stereotactic ablative radiotherapy) for stage I non-small cell lung cancer--updates of radiobiology, techniques, and clinical outcomes.

Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has emerged as one of the standard treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. Its use has also been explored in operable patients. A large body of experience, either from retrospective studies or clinical trials, has been accumulated over the years and more is known about the radiobiology, cancer biology, technical aspects, clinical outcomes, and toxicities of SBRT. This article provides updates of these aspects of SBRT for stage I NSCLC.

Current therapeutic paradigms in glioblastoma.

Glioblastoma (GBM), a WHO grade IV malignant glioma, is the most common and lethal adult primary brain tumor. Median survival rates range from 12-15 months. The current standard of care for GBM has evolved from resection followed by adjuvant radiotherapy to resection, concurrent adjuvant chemotherapy (temozolomide) and radiation, and additional adjuvant chemotherapy. The expression of specific molecular biomarkers, especially O-6-methylguanine methyltransferase (MGMT) status, may determine the response of the tumor to treatment, and helps in identifying the magnitude of benefit from this regimen. By identifying further biological subtypes of GBM at the molecular level, specific targeted therapies could be developed and used in the future for more individualized therapeutic regimens. This article will review the current therapies for GBM and the investigation of new molecular and targeted therapies, such as EGFR inhibitors, mTOR/PI3Kinase inhibitors, and anti-angiogenesis agents.

CNS germinomas: what is the best treatment strategy?

CNS germ cell tumors are rare primary brain malignancies. Germinomas comprise approximately two-thirds of CNS germ cell tumors. Owing to their radiosensitivity, radiotherapy has been used to treat patients with CNS germinomas, with favorable treatment outcomes. Historically, craniospinal irradiation has been used. Given the concerns over long-term toxicities associated with craniospinal irradiation, reduced volume radiotherapy with or without chemotherapy has been employed. Data on the use of different strategies in the treatment of CNS germinomas are emerging but a standard strategy has not been established. This article reviews the different strategies used in the management of CNS germinomas.

Palliative treatment of poor prognosis patients with malignant gliomas.

High-grade gliomas are the most commonly diagnosed malignant brain tumor in adults. Prognosis can be estimated by examining risk factors, including histology, age and performance status. Postoperative radiation therapy is associated with improved survival and standard treatment includes external beam radiotherapy to a dose of 60 Gy in 30-33 fractions. Patients with poor prognostic features have a more limited benefit from radiotherapy. This article reviews the current state of knowledge on risk stratification and analyzes strategies that can be employed to better individualize treatment for poor-prognosis patients.

What is the best adjuvant treatment for very young patients with medulloblastoma?

The standard treatment for medulloblastoma is surgery followed by adjuvant chemotherapy and external beam radiotherapy to the craniospinal axis and posterior fossa. However, in very young children, craniospinal irradiation has a more significant detrimental effect in terms of neurocognitive function and growth. This article reviews the different strategies used for very young patients with medulloblastoma.

Global ischemic duration and reperfusion function in the isolated perfused rat heart.

Post-ischemic myocardial dysfunction has been observed in a variety of clinical situations including cardiac arrest. Potentially survivable cardiac arrest following short-term global myocardial ischemia may be of insufficient duration to cause irreversible myocyte injury, but still results in contractile and bioenergetic dysfunction. The purpose of this study was to characterize the ischemic transition from reversible to irreversible injury in the isolated perfused rat heart. Isolated, buffer perfused, male Sprague-Dawley rat hearts underwent normothermic ischemia of 15, 20, 25 or 30 min with or without 30 min of reperfusion and were freeze clamped in liquid nitrogen for bioenergetic analysis of LV tissue. Post-ischemic LV function and measurements of bioenergetic recovery were made between groups and with non-ischemic controls. Baseline LV function was similar in all groups. Post-ischemic contractile function was markedly depressed in the 25 and 30 min ischemia groups with persistent depression of high-energy phosphates, total adenine nucleotide pool, myocardial oxygen consumption, elevated CK release and evidence of significant mitochondrial edema in the 30 min group. In contrast with longer ischemic periods, the reduction in LV contractile function after 15 and 20 min of ischemia was mild, with more complete bioenergetic recovery, minimal CK release, and normal appearing mitochondrial. This data suggests a period of transition from reversible to irreversible injury occurring at approximately 20 min of normothermic global ischemia in the isolated perfused rat heart.