The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer.

Our group has previously published the Diagnosis-Specific Graded Prognostic Assessment (GPA) showing the prognostic factors associated with survival in patients with brain metastases (BM). The purpose of this study is to investigate the relationship of breast cancer subtype to the time interval from primary diagnosis (PD) to development of BM (TPDBM), number of BM at initial BM presentation and survival. We analyzed our previously described multi-institutional retrospective database of 865 breast cancer patients treated for newly-diagnosed BM from 1993 to 2010. Several factors found to be associated with survival were incorporated into the Breast-GPA, including tumor subtype. The GPA database was further analyzed to determine if the subtype correlated with the TPDBM, number of BM, and survival from PD. After exclusions for incomplete data, 383 patients remained eligible for analysis. The subtypes were approximated as follows: Luminal B: triple positive; HER2: HER2 positive/ER/PR negative; Luminal A; ER/PR positive/HER2 negative; Basal: triple negative. Patients with Basal (90), HER2 (119), Luminal B (98) and Luminal A (76) tumor subtypes had a median TPDBM of 27.5, 35.8, 47.4 and 54.4 months (p < 0.01), median survival from PD of 39.6, 66.4, 90.3 and 72.7 months (p < 0.01) and median survival from BM of 7.3, 17.9, 22.9 and 10.0 months (p < 0.01), respectively. Tumor subtype is an important prognostic factor for survival in patients with breast cancer and BM. Although TPDBM is not an independent prognostic factor for survival (and thus not part of the Breast-GPA), the TPDBM does correlate with tumor subtype but does not correlate with the number of BM. Patients with Basal and HER2 tumor subtypes have short TPDBM. Prospective studies are needed to determine if screening brain MRIs are indicated in patients with Basal or HER2 subtypes.

Apparent diffusion coefficient of fibrosis and regenerative nodules in the cirrhotic liver at MRI.

OBJECTIVE: The purpose of this article is to compare the apparent diffusion coefficient (ADC) of fibrosis and regenerative nodules in the cirrhotic liver at MRI, both in vivo and ex vivo. SUBJECTS AND METHODS: A prospective ex vivo and in vivo study was performed at a tertiary liver center. To characterize the diffusion properties of cirrhotic liver, 63 human liver specimens obtained anonymously from 23 freshly explanted cirrhotic livers underwent T1-, T2-, and diffusion-weighted MRI ex vivo. ADC values of fibrotic bridges and regenerative nodules were calculated. In vivo conventional and diffusion-weighted MRI was performed for 17 cirrhotic patients (12 men and five women; mean age, 54 years; range, 34-77 years) with focal areas of confluent fibrosis. ADC values of confluent fibrosis and background cirrhotic liver parenchyma were calculated. Log-transformed ADC values of fibrosis and regenerative nodules were compared between ex vivo and in vivo images. RESULTS: Ex vivo, the mean ADC of fibrotic bridges (0.55 +/- 0.24 mm(2)/s [SD]) was greater than that of regenerative nodules (0.36 +/- 0.18 x 10(-3) mm(2)/s) (p < 0.0001). In vivo, the mean ADC value of confluent fibrosis (2.07 +/- 0.39 x 10(-3) mm(2)/s) was greater than that of background cirrhotic liver parenchyma (1.53 +/- 0.35 x 10(-3) mm(2)/s) (p < 0.0001). CONCLUSION: The mean ADC of fibrosis is significantly greater than that of regenerative nodules both in vivo and ex vivo. The prevailing paradigm that fibrosis causes the reduced liver ADC observed in cirrhosis may need modification.

Double-contrast MRI for accurate staging of hepatocellular carcinoma in patients with cirrhosis.

OBJECTIVE: The aim of this study was to evaluate the accuracy of a double-contrast MRI protocol in staging of hepatocellular carcinoma (HCC) in patients with cirrhosis. MATERIALS AND METHODS: This cross-sectional study was performed at a tertiary liver care center. Forty-eight patients with cirrhosis underwent double-contrast MRI for clinical care and liver transplantation. For each MRI examination, superparamagnetic iron oxide was infused, and 2D T2*-weighted spoiled gradient-recalled echo and T2-weighted echo-train spin-echo MR images were obtained for assessment of phagocytic function. Immediately afterward, a low-molecular-weight gadolinium compound was injected, and 3D T1-weighted spoiled gradient-recalled echo images were acquired dynamically for assessment of vascularity. Two blinded radiologists independently reviewed all MR images and assigned per-lesion and per-patient cancer confidence scores to determine the American Liver Tumor Study Group tumor stage. The imaging-based cancer scores and tumor stages were correlated with pathology reports. Performance parameters were computed for imaging-based measurements. RESULTS: Of the 48 study subjects, 25 had HCC (three, T1; 18, T2; one, T3; one, T4a; two, T4b). In total, there were 37 HCC nodules. The accuracy of MRI in prediction of pathologic tumor stage was 81-85% depending on the radiologist. Per-patient and per-lesion sensitivity in the diagnosis of HCC were 96% and 81% for one radiologist and 96% and 89% for the other. CONCLUSION: A double-contrast MRI protocol has high accuracy in staging of HCC in patients with cirrhosis.

Cirrhosis-associated hepatocellular nodules: correlation of histopathologic and MR imaging features.

Cirrhotic livers are characterized by advanced fibrosis and the formation of hepatocellular nodules, which are classified histologically as either (a) regenerative lesions (eg, regenerative nodules, lobar or segmental hyperplasia, focal nodular hyperplasia) or (b) dysplastic or neoplastic lesions (eg, dysplastic foci and nodules, hepatocellular carcinomas). The differentiation of these lesions is important because regenerative nodules are benign, whereas dysplastic and neoplastic nodules are premalignant and malignant, respectively. However, their accurate characterization may be difficult even at histopathologic analysis. Differential diagnosis may be facilitated by comparing the clinical and pathologic findings with radiologic imaging features; in particular, nodule size, vascularity, hepatocellular function, and Kupffer cell density assessed at magnetic resonance (MR) imaging are suggestive of the correct diagnosis. MR imaging is more useful than computed tomography for such assessments because it provides better soft-tissue contrast and a more nuanced depiction of different tissue properties. Moreover, a wider variety of contrast agents is available for use in MR imaging. Familiarity with the MR imaging characteristics of cirrhosis-associated hepatocellular nodules is therefore important for optimal diagnosis and management of cirrhotic disease.

Dural recurrence among esthesioneuroblastoma patients presenting with intracranial extension.

OBJECTIVE: To quantify the rate of late intracranial recurrences among esthesioneuroblastoma patients treated with surgical resection and postoperative radiation. STUDY DESIGN: Retrospective review. METHODS: All patients receiving definitive-intent therapy for esthesioneuroblastoma between March 1995 and September 2015 were reviewed. Presenting disease extent was categorized based on radiologic, operative, and pathologic findings. Between-group survival differences were assessed using Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional hazards model. RESULTS: Of 38 patients initially treated at our institution, 53% (20 of 38) presented with intracranial extension. At a median follow-up of 90 months (range, 6-199), 37% (14 of 38) recurred; 5- and 8-year disease-free survival rates were 69% and 54%; and overall survival rates were 81% and 72%, respectively. Among these patients, the dura was the most commonly involved site of relapse (8), followed by local (6), regional (5), and distant extracranial (3) sites; and five patients had ≥ two categories of failure. Eight-year dural disease-free survival was 57% versus 90% (P = 0.017) and 0% versus 87% (P < 0.0001), with and without intracranial extension and subtotal resection, respectively. Of six patients treated at recurrence, five (83%) experienced dural-based failure such that, among all 44 patients, 13 (65%) of 20 recurrences involved the dura. After dural recurrence, the median survival time was 42 months (range, 12-125); salvage treatments were effective in rare cases of isolated low-volume recurrence. CONCLUSION: Esthesioneuroblastoma patients presenting with intracranial extension are at substantial and unique risk for long-term dural-based relapse. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2226-2233, 2018.

Cross-sectional imaging of extranodal involvement in abdominopelvic lymphoproliferative malignancies.

Extranodal lymphoproliferative diseases are common, and their prevalence is increasing. Non-Hodgkin lymphomas and Hodgkin disease, in particular, frequently involve extranodal structures in the abdomen and pelvis, including both the solid organs (liver, spleen, kidneys, and pancreas) and the hollow organs of the gastrointestinal tract. Because virtually any abdominopelvic tissue may be involved, many different imaging manifestations are possible, and lymphoproliferative diseases may mimic other disorders. Familiarity with the imaging manifestations that are diagnostically specific for extranodal lymphoproliferative diseases is important because imaging plays an important role in the noninvasive management of disease. However, a definitive diagnosis requires a biopsy (of bone marrow, a lymph node, or a mass), a peripheral blood analysis, and other laboratory tests. In patients with known disease, the goals of imaging are staging, evaluation of response to therapy, and identification of new or recurrent disease or of complications of therapy. In patients without known disease, imaging permits a provisional diagnosis.

Comparison between target margins derived from 4DCT scans and real-time tumor motion tracking: insights from lung tumor patients treated with robotic radiosurgery.

PURPOSE: A unique capability of the CyberKnife system is dynamic target tracking. However, not all patients are eligible for this approach. Rather, their tumors are tracked statically using the vertebral column for alignment. When using static tracking, the internal target volume (ITV) is delineated on the four-dimensional (4D) CT scan and an additional margin is added to account for setup uncertainty [planning target volume (PTV)]. Treatment margins are difficult to estimate due to unpredictable variations in tumor motion and respiratory pattern during the course of treatment. The inability to track the target and detect changes in respiratory characteristics might result in geographic misses and local tumor recurrences. The purpose of this study is to develop a method to evaluate the adequacy of ITV-to-PTV margins for patients treated in this manner. METHODS: Data from 24 patients with lesions in the upper lobe (n = 12), middle lobe (n = 3), and lower lobe (n = 9) were included in this study. Each patient was treated with dynamic tracking and underwent 4DCT scanning at the time of simulation. Data including the 3D coordinates of the target over the course of treatment were extracted from the treatment log files and used to determine actual target motion in the superior-inferior (S-I), anterior-posterior (A-P), and left-right (L-R) directions. Different approaches were used to calculate anisotropic and isotropic margins, assuming that the tumor moves as a rigid body. Anisotropic margins were calculated by separating target motion in the three anatomical directions, and a uniform margin was calculated by shifting the gross tumor volume contours in the 3D space and by computing the percentage of overlap with the PTV. The analysis was validated by means of a theoretical formulation. RESULTS: The three methods provided consistent results. A uniform margin of 4.5 mm around the ITV was necessary to assure 95% target coverage for 95% of the fractions included in the analysis. In the case of anisotropic margins, the expansion required in the S-I direction was larger (8.1 mm) than those in the L-R (4.9 mm) and A-P (4.5 mm) directions. This margin accounts for variations of target position within the same treatment fraction. CONCLUSIONS: The use of bony alignment for CyberKnife lung stereotactic body radiation therapy requires careful considerations, in terms of the potential for increased toxicity or local miss. Our method could be used by other centers to determine the adequacy of ITV-to-PTV margins for their patients.

Management of prostate cancer patients with lymph node involvement: a rapidly evolving paradigm.

Although widespread PSA screening has inevitably led to increased diagnosis of lower risk prostate cancer, the number of patients with nodal involvement at baseline remains high (nearly 40% of high risk patients initially staged cN0). These rates probably do not reflect the true incidence of prostate cancer with lymph node involvement among patients selected for external beam radiotherapy (EBRT), as patients selected for surgery often have more favorable prognostic features. At many institutions, radical treatment directed only at the prostate is considered standard and patients known to have regional disease are often managed palliatively with androgen deprivation therapy (ADT) for presumed systemic disease. New imaging tools such as MR lymphangiography, choline-based PET imaging or combined SPECT/CT now allow surgeons and radiation oncologists to identify and target nodal metastasis and/or lymph nodes with a high risk of occult involvement. Recent advances in the field of surgery including the advent of extended nodal dissection and sentinel node procedures have suggested that cancer-specific survival might be improved for lymph-node positive patients with a low burden of nodal involvement when managed with aggressive interventions. These new imaging tools can provide radiation oncologists with maps to guide delivery of high dose conformal radiation to a target volume while minimizing radiation toxicity to non-target normal tissue. This review highlights advances in imaging and reports how they may help to define a new paradigm to manage node-positive prostate cancer patients with a curative-intent.

Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases.

PURPOSE: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. METHODS AND MATERIALS: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. RESULTS: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. CONCLUSIONS: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.

PURPOSE: Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. METHODS: A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. RESULTS: Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. CONCLUSION: Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

Mapping of lymphatic drainage from the prostate using filtered 99mTc-sulfur nanocolloid and SPECT/CT.

UNLABELLED: We have developed a practice procedure for prostate lymphoscintigraphy using SPECT/CT and filtered (99m)Tc-sulfur nanocolloid, as an alternative to the proprietary product (99m)Tc-Nanocoll, which is not approved in the United States. METHODS: Ten patients were enrolled for this study, and all received radiotracer prepared using a 100-nm membrane filter at a commercial radiopharmacy. Whole-body scans and SPECT/CT studies were performed within 1.5-3 h after the radiotracer had been administered directly into 6 locations of the prostate gland under transrectal ultrasound guidance. The radiation dose was estimated from the first 3 patients. Lymphatic drainage mapping was performed, and lymph nodes were identified. RESULTS: The estimated radiation dose ranged from 3.9 to 5.2 mSv/MBq. The locations of lymph nodes draining the prostate gland were similar to those found using the proprietary product. CONCLUSION: When the proprietary radiolabeled nanocolloid indicated for lymphoscintigraphy is not available, prostate lymph node mapping and identification are still feasible using filtered (99m)Tc-sulfur nanocolloid.

Gamma Knife radiosurgery for brain metastases from primary breast cancer.

PURPOSE: The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients. MATERIALS AND METHODS: We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method. RESULTS: Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >or=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time. CONCLUSION: We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >or=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

Prognostic value of posttreatment [18F] fluorodeoxyglucose uptake of primary non-small cell lung carcinoma treated with radiation therapy with or without chemotherapy: a brief review.

In patients treated with radiation therapy for non-small cell lung carcinoma, positron emission tomography and computed tomography are commonly used to assess response to treatment. Seven rather small single-institution series have documented the ability of posttreatment positron emission tomography to predict local control and survival through measurements of [F] fluorodeoxyglucose uptake. The ability to make prognostic assessments using this information would be a major clinical breakthrough by allowing early alterations in patient management. Here, we review the current literature on the prognostic value of posttreatment [F] fluorodeoxyglucose uptake in patients treated with radiation therapy with or without chemotherapy for non-small cell lung carcinoma.

Gamma knife radiosurgery for brainstem metastases: the UCSF experience.

PURPOSE: To assess clinical and imaging outcomes in patients treated with Gamma Knife stereotactic radiosurgery (SRS) for brainstem metastases. MATERIALS AND METHODS: We reviewed all patients with brain metastases treated with SRS at the University of California, San Francisco from 1991-2005 to identify patients who had SRS to a brainstem metastasis. Survival time and freedom from progression (FFP) were calculated from date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the log-rank test and Cox proportional hazards model. RESULTS: From 1991 through 2005, 42 consecutive patients with brainstem metastases had SRS to 44 lesions (seven midbrain, 31 pontine, and six medullary) in 42 sessions. Primary diagnoses included 14 cases of lung cancer (one small-cell), 10 melanoma, 12 breast cancer, five renal cell, and one unknown. The median age was 55 years (range, 25-79). The median survival time was 9 months after SRS. Longer survival time was associated with single metastasis, non-melanoma histology, and extracranial disease control. The median target volume was 0.26 ml (0.015-2.8 ml) and the median prescribed dose was 16.0 Gy (10.0-19.8 Gy). Brainstem lesion FFP was 90% at 6 months and 77% at 1 year. Four patients had brainstem complications following treatment. Poor brainstem outcome was associated with melanoma and renal cell histology as well as brainstem lesion volume > or =1 ml. CONCLUSIONS: In this series, SRS using a median dose of 16 Gy provided excellent local control with relatively low morbidity in patients with brainstem metastases less than 1 ml or non-melanoma, non-renal cell histology.