Pharmacokinetics of Ferumoxytol in the Abdomen and Pelvis: A Dosing Study with 1.5- and 3.0-T MRI Relaxometry.

Background The off-label use of ferumoxytol (FE), an intravenous iron preparation for iron deficiency anemia, as a contrast agent for MRI is increasing; therefore, it is critical to understand its pharmacokinetics. Purpose To evaluate the pharmacokinetics of FE in the abdomen and pelvis, as assessed with quantitative 1.5- and 3.0-T MRI relaxometry. Materials and Methods R2*, an MRI technique used to estimate tissue iron content in the abdomen and pelvis, was performed at 1.5 and 3.0 T in 12 healthy volunteers between April 2015 and January 2016. Volunteers were randomly assigned to receive an FE dose of 2 mg per kilogram of body weight (FE2mg) or 4 mg/kg (FE4mg). MRI was repeated at 1.5 and 3.0 T for each volunteer at five time points: days 1, 2, 4, 7, and 30. A radiologist experienced in MRI relaxometry measured R2* in organs of the mononuclear phagocyte system (MPS) (ie, liver, spleen, and bone marrow), non-MPS anatomy (kidney, pancreas, and muscle), inguinal lymph nodes (LNs), and blood pool. A paired Student t test was used to compare changes in tissue R2*. Results Volunteers (six female; mean age, 44.3 years ± 12.2 [standard deviation]) received either FE2 mg (n = 5) or FE4 mg (n = 6). Overall R2* trend analysis was temporally significant (P < .001). Time to peak R2* in the MPS occurred on day 1 for FE2mg and between days 1 and 4 for FE4mg (P < .001 to P < .002). Time to peak R2* in non-MPS anatomy, LNs, and blood pool occurred on day 1 for both doses (P < .001 to P < .09). Except for the spleen (at 1.5 T) and liver, MPS R2* remained elevated through day 30 for both doses (P = .02 to P = .03). Except for the kidney and pancreas, non-MPS, LN, and blood pool R2* returned to baseline levels between days 2 and 4 at FE2mg (P = .06 to P = .49) and between days 4 and 7 at FE4mg (P = .06 to P = .63). There was no difference in R2* change between non-MPS and LN R2* at any time (range, 1-71 sec-1 vs 0-50 sec-1; P = .06 to P = .97). Conclusion The pharmacokinetics of ferumoxytol in lymph nodes are distinct from those in mononuclear phagocyte system (MPS) organs, parallel non-MPS anatomy, and the blood pool. © RSNA, 2019 Online supplemental material is available for this article.

A digital media attention diversion improves mood and fear in patients receiving chemotherapy for recurrent gynecologic malignancies: results of a randomized trial.

BACKGROUND: Recurrent gynecologic cancer patients experience symptoms that affect psychologic, emotional, social, and physical well-being. Chemotherapy can further exacerbate these symptoms. Poor mood, pain, and fatigue are linked and are detrimental to quality of life. Interventions targeting these symptoms may improve patient-reported outcomes and performance status. OBJECTIVES: To determine the ability of a humorous digital media attention diversion to improve symptom domains of positive and negative mood during chemotherapy for patients with recurrent gynecologic cancers. STUDY DESIGN: This randomized, crossover clinical trial enrolled women with recurrent gynecologic cancers. Subjects participated over three cycles of chemotherapy. The primary outcome was the change in mood on the validated Positive and Negative Affect Scale-Extended (PANAS-X) instrument, which measures positive and negative affect domains. All subjects completed the PANAS-X after receiving chemotherapy during cycle 1 on study. In atudy arm 1, subjects watched their choice of humorous movies on a digital media device while receiving chemotherapy during cycle 2 on study. They selected from non-humorous movies during cycle 3 on study. In arm 2, the order of movies was reversed. After each cycle, mood, fatigue, and other patient-reported outcomes were assessed for comparison with baseline measurements. RESULTS: The target enrollment of 66 subjects was achieved. Subjects watched humorous content for an average of 96.0 min and non-humorous content for an average of 62.5 min. Negative mood improved after exposure to humorous (p=0.017) and non-humorous content (p=0.001). Patient-reported fear also improved after exposure to both humorous (p=0.038) and non-humorous content (p=0.002). Subjects reported higher use of affiliating and self-effacing humor types. CONCLUSIONS: Offering patients a choice of digital media during chemotherapy significantly improved negative mood and fear. This was seen with both humorous and non-humorous content. This low-cost and low-risk intervention should be implemented as an attention diversion to improve negative mood and fear for patients receiving chemotherapy.

Collagen organization of renal cell carcinoma differs between low and high grade tumors.

BACKGROUND: The traditional pathologic grading for human renal cell carcinoma (RCC) has low concordance between biopsy and surgical specimen. There is a need to investigate adjunctive pathology technique that does not rely on the nuclear morphology that defines the traditional grading. Changes in collagen organization in the extracellular matrix have been linked to prognosis or grade in breast, ovarian, and pancreatic cancers, but collagen organization has never been correlated with RCC grade. In this study, we used Second Harmonic Generation (SHG) based imaging to quantify possible differences in collagen organization between high and low grades of human RCC. METHODS: A tissue microarray (TMA) was constructed from RCC tumor specimens. Each TMA core represents an individual patient. A 5 µm section from the TMA tissue was stained with standard hematoxylin and eosin (H&E). Bright field images of the H&E stained TMA were used to annotate representative RCC regions. In this study, 70 grade 1 cores and 51 grade 4 cores were imaged on a custom-built forward SHG microscope, and images were analyzed using established software tools to automatically extract and quantify collagen fibers for alignment and density assessment. A linear mixed-effects model with random intercepts to account for the within-patient correlation was created to compare grade 1 vs. grade 4 measurements and the statistical tests were two-sided. RESULTS: Both collagen density and alignment differed significantly between RCC grade 1 and RCC grade 4. Specifically, collagen fiber density was greater in grade 4 than in grade 1 RCC (p < 0.001). Collagen fibers were also more aligned in grade 4 compared to grade 1 (p < 0.001). CONCLUSIONS: Collagen density and alignment were shown to be significantly higher in RCC grade 4 vs. grade 1. This technique of biopsy sampling by SHG could complement classical tumor grading approaches. Furthermore it might allow biopsies to be more clinically relevant by informing diagnostics. Future studies are required to investigate the functional role of collagen organization in RCC.

Disparities in the allocation of research funding to gynecologic cancers by Funding to Lethality scores.

PURPOSE: To analyze National Cancer Institute (NCI) funding distributions to gynecologic cancers compared to other cancers from 2007 to 2014. METHODS: The NCI's Surveillance, Epidemiology and End Results (SEER), Cancer Trends Progress Report, and Funding Statistics were used to analyze 18 cancer sites. Site-specific mortality to incidence ratios (MIR) were normalized per 100 cases and multiplied by person-years of life lost to derive cancer-specific lethality. NCI funding was divided by its lethality to calculate Funding to Lethality scores for gynecologic malignancies and compared to 15 other cancer sites. RESULTS: Ovarian, cervical, and uterine cancers ranked 10th (score 0.097, SD 0.008), 12th (0.087, SD 0.009), and 14th (0.057, SD 0.006) for average Funding to Lethality scores. The highest average score was for prostate cancer (score 1.182, SD 0.364). In U.S. dollars per 100 incident cases, prostate cancer received an average of $1,821,000 per person-years of life lost, while ovarian cancer received $97,000, cervical cancer $87,000, and uterine cancer $57,000. Ovarian and cervical cancers had lower average Funding to Lethality scores compared to nine other cancers, while uterine cancer was lower than 13 other cancers (p < 0.01 for all comparisons). Analyses of eight-, five-, and three-year trends for gynecologic cancers showed nearly universal decreasing Funding to Lethality scores. CONCLUSION: Funding to Lethality scores for gynecologic cancers are significantly lower than other cancer sites, indicating a disparity in funding allocation that persists over the most recent eight years of available data. Prompt correction is required to ensure critical discoveries for women with gynecologic cancers.

Evaluation of suspected musculoskeletal infection in children over 2 years of age using only fluid-sensitive sequences at MRI.

PURPOSE: This study was conducted in order to evaluate whether an MRI protocol with only fluid-sensitive sequences can be used to evaluate for musculoskeletal (MSK) infection of the pelvis and limbs in children. MATERIALS AND METHODS: This retrospective study analyzed 90 contrast-enhanced (CE) MRI studies from 88 consecutive patients (52 boys and 36 girls; mean age 9 ± 4.3 years; range 2-17) that were performed for the clinical suspicion of MSK infection. Two radiologists reviewed each study twice. The initial study review included only the fluid-sensitive sequences (fluid-sensitive study); the second review, performed at least 1 month later, included all sequences of the contrast-enhanced study (CE study). At each review, anatomic sites of abnormal signal and overall suspicion for infection were recorded. Cohen's kappa and percent agreement were performed to compare agreement between readers, types of studies, and clinical diagnoses. RESULTS: Interreader agreement for both types of studies had kappa values between 0.86 and 1. For the assessment of MSK infection, the fluid-sensitive study had 100% sensitivity and 61.3% specificity, with 84.8% interreader agreement; and the CE study had 100% sensitivity and 71.0% specificity, with 88.6% interreader agreement. All cases of septic arthritis (13 cases) and osteomyelitis (25 cases) were identified as possible infection or infection until proven otherwise (negative predictive value 100%) with 100% interreader agreement on fluid-sensitive sequences. CONCLUSION: An abbreviated MRI study using only fluid-sensitive sequences has the same high degree of sensitivity as a CE study to identify MSK infection in children and could be used to exclude septic arthritis and osteomyelitis. KEY POINTS: • MRI with only fluid-sensitive sequences can be used to evaluate for musculoskeletal infection in children.

An analysis of factors associated with increased fluoroscopy time or the need for complex techniques at IVC filter retrieval.

OBJECTIVES: To evaluate factors associated with increased fluoroscopy time or the need for complex techniques at IVC filter retrieval. METHODS: This is a single-institution retrospective cohort study of 187 consecutive patients who underwent IVC filter retrieval. An analysis was performed on associations of patient factors with increased fluoroscopy time and/or the need for complex retrieval techniques. A complex retrieval was defined as one requiring more than standard sheath and snare technique. RESULTS: Access vein during filter placement was not associated with filter tilt at placement or removal (p = 0.61 and 0.48). Neither the direction of the hook nor its relationship to the tilt was associated with the need for complex retrieval or increased retrieval fluoroscopy time (p = 0.25, 0.23, p = 0.18, 0.23). Tilt angle at placement correlated with hook apposition at time of removal (p = 0.01). Hook apposition was associated with complex retrieval and increased fluoroscopy time (p < 0.01). Larger tilt angle at placement was not associated with complex retrieval (p = 0.22), but a larger angle at removal was (p < 0.01). Longer dwell time correlated with the need for complex retrieval (p = 0.02). Filter type, sex, and age were not associated with complex retrievals (p = 0.58, p = 0.90, p = 0.99). CONCLUSION: Contrary to previous hypotheses and studies, access vein for filter placement did not affect filter tilting, and direction of filter hook-tilt relationship did not affect retrieval fluoroscopy time or the need for complex retrieval techniques. Increased filter placement angle was associated with a larger angle at removal and hook-wall apposition, both of which were associated with complex retrievals. KEY POINTS: • Filter hook orientation did not correlate with retrieval complexity. • Filter insertion vein did not correlate with filter tilt. • Filter tilt and hook apposition to the caval wall at the time of retrieval correlated with retrieval procedure complexity.

Granulocyte colony-stimulating factor utilization postautologous hematopoietic stem cell transplant in multiple myeloma patients: Does one size fit all?

PURPOSE: To evaluate a single institution's experience with granulocyte colony-stimulating factor after autologous hematopoietic stem cell transplant in myeloma patients to identify populations that benefit most from granulocyte colony-stimulating factor administration. METHODS: Retrospective chart reviews were conducted on patients 18+ years with multiple myeloma that underwent autologous hematopoietic stem cell transplant at UW Health from January 2012 to May 2016. Data collection included demographics, length of stay, time to engraftment, Eastern Cooperative Oncology Group performance status score, and hematopoietic cell transplantation-comorbidity index. The primary outcome was days from transplant to engraftment, defined as absolute neutrophil count > 500/mm3 for two consecutive days or absolute neutrophil count > 1000/mm3 once. A subset analysis was performed on patients whose date of engraftment was known. RESULTS: In total, 216 individual patients were included in the full cohort and 122 patients included in the subset analysis. Median time to engraftment between patients administered granulocyte colony-stimulating factor and the nongranulocyte colony-stimulating factor group was 12 versus 19 days (P < 0.001) in the full cohort and 12 versus 14 days (P < 0.001) in the subset analysis. The average length of stay posthematopoietic stem cell transplant in the granulocyte colony-stimulating factor group was 15 days versus 17 days in the nongranulocyte colony-stimulating factor group (P = 0.026) in the subset analysis. Additionally, no difference in time to engraftment was seen when stratified by age, Eastern Cooperative Oncology Group performance status score, or hematopoietic cell transplantation-comorbidity index. CONCLUSION: Our study supports use of granulocyte colony-stimulating factor posthematopoietic stem cell transplant in myeloma patients to decrease time to engraftment and length of stay. Consideration should be given to utilization in all patients in this population posthematopoietic stem cell transplant. Further research is needed to identify the populations that benefit most from granulocyte colony-stimulating factor administration.

Detection of pediatric musculoskeletal pathology using the fluid-sensitive sequence.

BACKGROUND: Musculoskeletal complaints are common among children, and magnetic resonance (MR) is increasingly used to supplement the clinical assessment. The validation of a short triage protocol could reduce the number of unnecessary contrast-enhanced MR studies that sometimes also require the need for sedation. OBJECTIVE: To compare the diagnostic accuracy between fluid-sensitive sequence and contrast-enhanced MR study in the detection of musculoskeletal pathology in the pelvis and the appendicular skeleton in children older than 2 years. MATERIALS AND METHODS: We performed a retrospective review between Feb. 1, 2016, and Oct. 31, 2016, and identified 99 studies from 96 patients (48 boys and 48 girls; mean age ± standard deviation, 11.1±4.6 years) without syndromic deformity, recent trauma, a history of infectious or inflammatory arthropathy, prior instrumentation or incomplete records. Two radiologists reviewed each study twice, at least 1 month apart, first using only the fluid-sensitive sequences (triage study) and later using the contrast-enhanced study. Readers rated the presence or absence of pathology independently and generated final impressions in consensus. We used Cohen's kappa (κ) and percentage agreement to compare agreement between readers and between studies, respectively. RESULTS: Inter-reader agreement was overall higher for the contrast-enhanced studies (κ range = 0.91-1) than for the triage studies (κ range = 0.49-1). Percentage agreement between studies was high for the detection of pathology (97-100%) and for the impressions (93%). Clinical diagnoses were stress reaction or overuse in 31%, infection in 21%, space-occupying process in 17%, normal in 15%, inflammatory in 14%, and both inflammatory and overuse in 1%. The full study increased diagnostic confidence in five studies and accuracy in two but did not alter management. CONCLUSION: The fluid-sensitive sequence had a near-perfect percentage of agreement with the contrast-enhanced study in the detection of musculoskeletal pathology and could possibly be used to screen children who need a contrast-enhanced MR study.

Incidence and implications of fracture in core muscle injury.

OBJECTIVE: To determine the pubic bone fracture incidence and associated injury patterns in patients with core muscle injury. MATERIALS AND METHODS: Ninety-three consecutive patients with core muscle injury protocol MRI showing rectus abdominis-adductor longus aponeurotic plate injuries from June 2007 through August 2017 were independently analyzed in blinded fashion by two musculoskeletal radiologists for the presence or absence of pubic bone fracture. A variety of other osseous and soft tissue injury characteristics were recorded. Pain duration prior to MRI and return to play time were taken from the clinical record. Statistical analysis included fracture incidence as well as the association of fracture with other injury characteristics, duration of pain, and return to play time. RESULTS: Eighty-seven men and six women with a mean age of 34.4 years (range, 16-66 years) were included in the study cohort. Overall fracture incidence was 18.3% (17/93) including 13 fatigue fractures of the pubic body and four elevated cortical fractures/fragments. After correction for multiple comparisons, no strong association was identified with osseous or soft tissue injury characteristics, pain duration, or return to play time. CONCLUSIONS: Pubic fractures-particularly fatigue fractures-are a common co-existing injury in patients with a wide range of core muscle injury patterns. The presence of fracture did not have a strong correlation with injury patterns, pain duration, or return to play time but may have implications for patient management.

Juvenile Osteochondritis Dissecans: Cartilage T2 Mapping of Stable Medial Femoral Condyle Lesions.

Purpose To determine whether a T2 mapping sequence could depict early changes in the composition and microstructure of cartilage overlying stable lesions of the medial femoral condyle in patients with juvenile osteochondritis dissecans (JOCD). Materials and Methods This retrospective study analyzed a sagittal T2 mapping sequence performed between September 1, 2015, and March 31, 2017, on 16 patients (10 boys and six girls; median age, 11.5 years) with 18 stable medial femoral condyle JOCD lesions and 18 age-, sex-, and skeletal maturation-matched control participants (11 boys and seven girls; median age, 11.5 years). Cartilage T2 values were quantitatively measured within regions of interest placed around the cartilage within and overlying the JOCD lesion in patients with JOCD and around the cartilage on the weight-bearing medial femoral condyle in patients with JOCD and controls. Wilcoxon signed rank and Wilcoxon rank sum tests were used to compare T2 values. Results T2 values were significantly higher (P < .001) for cartilage within the JOCD lesion than for cartilage overlying the JOCD lesion in patients with JOCD. However, there were no significant differences in T2 values between cartilage overlying the JOCD lesion and cartilage on the weight-bearing medial femoral condyle in patients with JOCD (P = .67) or in T2 values of the cartilage on the weight-bearing medial femoral condyle between patients with JOCD and controls (P = .30). Conclusion There were no significant quantifiable differences in T2 values of cartilage overlying stable JOCD lesions and normal cartilage on the medial femoral condyle, suggesting no substantial changes in cartilage composition and microstructure.

Maturation-Related Changes in T2 Relaxation Times of Cartilage and Meniscus of the Pediatric Knee Joint at 3 T.

OBJECTIVE: The objective of our study was to use a T2 mapping sequence performed at 3 T to investigate changes in the composition and microstructure of the cartilage and menisci of the pediatric knee joint during maturation. MATERIALS AND METHODS: This retrospective study was performed of MRI examinations of 76 pediatric knees without internal derangement in 72 subjects (29 boys [mean age, 12.5 years] and 43 girls [mean age, 13.0 years]) who were evaluated with a sagittal T2 mapping sequence. T2 relaxation time values were quantitatively measured in eight cartilage subregions and in the medial and lateral menisci. Wilcoxon rank sum and Kruskal-Wallis tests were used to analyze the relationship between cartilage and meniscus T2 relaxation time values and sex and skeletal maturation, respectively. A multivariate linear regression model was used to investigate the independent association between cartilage T2 relaxation time values and age, weight, and body mass index (BMI [weight in kilograms divided by the square of height in meters]). RESULTS: There were no significant sex differences (p = 0.26-0.91) in T2 relaxation time values for cartilage or meniscus. T2 relaxation time values in each individual cartilage subregion significantly decreased (p < 0.001) with progressive maturation. T2 relaxation time values in the lateral meniscus significantly increased (p = 0.001) with maturation, whereas T2 relaxation time values in the medial meniscus did not significantly change (p = 0.82). There was a significant association (p < 0.001) between cartilage T2 relaxation time values and age independent of weight and BMI, but no significant association between cartilage T2 relaxation time values and weight (p = 0.06) and BMI (p = 0.20) independent of age. CONCLUSION: Cartilage T2 relaxation time values significantly decreased in all cartilage subregions and meniscus T2 relaxation time values significantly increased in the lateral meniscus during maturation. These changes in T2 relaxation time values reflect age-related changes in tissue composition and microstructure.

Stereotactic body radiation therapy (SBRT) improves local control and overall survival compared to conventionally fractionated radiation for stage I non-small cell lung cancer (NSCLC).

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been adopted as the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC), with local control rates consistently >90%. However, data directly comparing the outcomes of SBRT with those of conventionally fractionated radiotherapy (CONV) is lacking. MATERIAL AND METHODS: Between 1990 and 2013, 497 patients (525 lesions) with early-stage NSCLC (T1-T2N0M0) were treated with CONV (n = 127) or SBRT (n = 398). In this retrospective analysis, five endpoints were compared, with and without adjusting for clinical and dosimetric factors. Competing risks analysis was performed to estimate and compare the cumulative incidence of local failure (LF), nodal failure (NF), distant failure (DF) and disease progression. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by the Cox regression model. Propensity score (PS) matched analysis was performed based on seven patient and clinical variables: age, gender, Karnofsky performance status (KPS), histology, T stage, biologically equivalent dose (BED), and history of smoking. RESULTS: The median dose delivered for CONV was 75.6 Gy in 1.8-2.0 Gy fractions (range 60-90 Gy; median BED = 89.20 Gy) and for SBRT 48 Gy in four fractions (45-60 Gy in three to five fractions; median BED = 105.60 Gy). Median follow-up was 24.4 months, and 3-year LF rates were 34.1% with CONV and 13.6% with SBRT (p < .001). Three-year OS rates were 38.9 and 53.1%, respectively (p = .018). PS matching showed a significant improvement of OS (p = .0497) for SBRT. T stage was the only variable correlating with all five endpoints. CONCLUSION: SBRT compared to CONV is associated with improved LF rates and OS. Our data supports the continued use and expansion of SBRT as the standard of care treatment for inoperable early-stage NSCLC.

Do Headache Patients Require More Care in Between Visits Than Other Neurology Outpatients?

BACKGROUND: There is evidence that time spent in patient care in between patient visits is increasing and a contributor to physician burnout. The extent of this work on providers in the field of headache medicine is unknown. OBJECTIVES: To establish whether headache outpatients require a high level of care in addition to clinic visits, based on the quantity of remote encounters per patient (phone calls and secure email communication to the clinics), in comparison to other neurologic clinics. METHODS: In an academic referral clinic, a total of 3164 established patients were included in this retrospective analysis, 275 from the headache clinic, the remainder from various other neurology clinics (2 physician providers per clinic except 3 physician providers in the headache clinic). Patients presenting for a follow-up visit between January 2014 and April 2016 were observed for a 12-month period during which the number of a) telephone and b) secure email (MyChart) encounters per patient was recorded, and in addition, the number of entries related to each of these encounters. This analysis did not require IRB approval as per institutional guidelines. RESULTS: Headache clinic patients required a high frequency of remote encounters (composite of both telephone and email messages) per patient, second only to the MS clinic patients. Use of secure email messaging (MyChart) per patient was much higher in the headache clinic compared to all other clinics. CONCLUSION: Patients in a headache clinic in an academic tertiary care setting require a high intensity of remote outpatient care, more so than patients in other neurology subspecialty clinics and general neurology clinic, with the exception of the neuroimmunology/MS clinic. This is to a large extent secondary to the very frequent use of secure email linked to the electronic medical record by headache patients.

Role of Early Pulmonary Hypertension as a Risk Factor for Late Pulmonary Hypertension in Extremely Preterm Infants.

OBJECTIVE: The evidence on the role of early pulmonary vascular disease (PVD) in the development of late pulmonary hypertension (PH) in the extremely preterm infants is limited. Objectives were to determine the incidence of early and late PH in extreme preterm infants and to evaluate the role of early PH as a risk factor for development of clinically detected late PH. METHODS: It was a retrospective analysis of early echocardiograms (day of life 5-14) in preterm infants, 22 to 27 weeks' gestation, admitted to the University of Iowa NICU between July 01, 2012 to June 30, 2015. Late echocardiograms performed for clinical suspicion of PH were also analyzed. RESULTS: A total of 154 infants were included in the study. Early PH was diagnosed in 31 (20%) infants. Twenty-four (16%) infants were evaluated for clinically suspected PH. Eight (5%) infants were diagnosed with late PH. Infants with early PH had echocardiograms performed earlier than infants without the evidence of early PH. Early PH was not associated with the development of late PH (p = 0.99). CONCLUSION: Early PH is common among extremely preterm infants (20%). Five percent of infants had clinically detected late PH. Infants with early PH had echocardiograms performed earlier than infants without the evidence of early PH. Early PH was not associated with the development of clinically detected late PH.

Outcomes of primary refractory diffuse large B-cell lymphoma (DLBCL) treated with salvage chemotherapy and intention to transplant in the rituximab era.

Rituximab-containing salvage chemotherapy followed by high-dose therapy and autologous stem cell transplant (ASCT) in chemosensitive patients remains the standard of care for patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, its role in those patients achieving less than a complete response to first-line therapy (primary refractory disease) in the rituximab era is not well defined. We reviewed the outcomes of 82 transplant-eligible patients with primary refractory DLBCL who underwent salvage therapy with the intent of administering high-dose therapy and ASCT to patients achieving chemosensitive remission. The estimated 3-year overall and progression-free survival for all patients was 38% and 29%, respectively, and 65% and 60% respectively for patients proceeding to stem cell transplant. Long-term remission was achieved in 45% of patients achieving a partial response (PR) to initial induction therapy and <20% of patients with stable or progression of disease following initial therapy. These results suggest that salvage chemotherapy with the intent of subsequent high-dose therapy and ASCT remains a feasible strategy in certain patients with primary refractory DLBCL, particularly for those achieving a PR to frontline therapy. The primary barrier to curative therapy in patients with primary refractory disease is resistance to salvage therapy, and future studies should be aimed towards increasing the response rate in this population.

Long-term Survival Based on the Surgical Approach to Lobectomy For Clinical Stage I Nonsmall Cell Lung Cancer: Comparison of Robotic, Video-assisted Thoracic Surgery, and Thoracotomy Lobectomy.

OBJECTIVE: To compare the long-term outcomes among robotic, video-assisted thoracic surgery (VATS), and open lobectomy in stage I nonsmall cell lung cancer (NSCLC). BACKGROUND: Survival comparisons between robotic, VATS, and open lobectomy in NSCLC have not yet been reported. Some studies have suggested that survival after VATS is superior, for unclear reasons. METHODS: Three cohorts (robotic, VATS, and open) of clinical stage I NSCLC patients were matched by propensity score and compared to assess overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed to identify factors associated with the outcomes. RESULTS: From January 2002 to December 2012, 470 unique patients (172 robotic, 141 VATS, and 157 open) were included in the analysis. The robotic approach harvested a higher number of median stations of lymph nodes (5 for robotic vs 3 for VATS vs 4 for open; P < 0.001). Patients undergoing minimally invasive approaches had shorter median length of hospital stay (4 d for robotic vs 4 d for VATS vs 5 d for open; P < 0.001). The 5-year OS for the robotic, VATS, and open matched groups were 77.6%, 73.5%, and 77.9%, respectively, without a statistically significant difference; corresponding 5-year DFS were 72.7%, 65.5%, and 69.0%, respectively, with a statistically significant difference between the robotic and VATS groups (P = 0.047). However, multivariate analysis found that surgical approach was not independently associated with shorter OS and DFS. CONCLUSIONS: Minimally invasive approaches to lobectomy for clinical stage I NSCLC result in similar long-term survival as thoracotomy. Use of VATS and robotics is associated with shorter length of stay, and the robotic approach resulted in greater lymph node assessment.

Unification of favourable intermediate-, unfavourable intermediate-, and very high-risk stratification criteria for prostate cancer.

OBJECTIVE: To improve on the existing risk-stratification systems for prostate cancer. PATIENTS AND METHODS: This was a retrospective investigation including 2 248 patients undergoing dose-escalated external beam radiotherapy (EBRT) at a single institution. We separated National Comprehensive Cancer Network (NCCN) intermediate-risk prostate cancer into 'favourable' and 'unfavourable' groups based on primary Gleason pattern, percentage of positive biopsy cores (PPBC), and number of NCCN intermediate-risk factors. Similarly, NCCN high-risk prostate cancer was stratified into 'standard' and 'very high-risk' groups based on primary Gleason pattern, PPBC, number of NCCN high-risk factors, and stage T3b-T4 disease. Patients with unfavourable-intermediate-risk (UIR) prostate cancer had significantly inferior prostate-specific antigen relapse-free survival (PSA-RFS, P < 0.001), distant metastasis-free survival (DMFS, P < 0.001), prostate cancer-specific mortality (PCSM, P < 0.001), and overall survival (OS, P < 0.001) compared with patients with favourable-intermediate-risk (FIR) prostate cancer. Similarly, patients with very high-risk (VHR) prostate cancer had significantly worse PSA-RFS (P < 0.001), DMFS (P < 0.001), and PCSM (P = 0.001) compared with patients with standard high-risk (SHR) prostate cancer. Moreover, patients with FIR and low-risk prostate cancer had similar outcomes, as did patients with UIR and SHR prostate cancer. RESULTS: Consequently, we propose the following risk-stratification system: Group 1, low risk and FIR; Group 2, UIR and SHR; and Group 3, VHR. These groups have markedly different outcomes, with 8-year distant metastasis rates of 3%, 9%, and 29% (P < 0.001) for Groups 1, 2, and 3, respectively, and 8-year PCSM of 1%, 4%, and 13% (P < 0.001) after EBRT. This modified stratification system was significantly more accurate than the three-tiered NCCN system currently in clinical use for all outcomes. CONCLUSION: Modifying the NCCN risk-stratification system to group FIR with low-risk patients and UIR with SHR patients, results in modestly improved prediction of outcomes, potentially allowing better personalisation of therapeutic recommendations.

Treatment outcomes and secondary cancer incidence in young patients with hairy cell leukaemia.

Repeated therapy of hairy cell leukaemia (HCL) with treatments that have potential long-term toxicities has raised concerns regarding increased risk for younger patients. We compared clinical outcomes and disease complications in 63 patients with HCL aged ≤40 years at diagnosis with 268 patients >40 years treated at Memorial Sloan Kettering Cancer Center. The rate of complete remission following initial therapy was 87% and 83% (P = 0·71) and estimated 10-year overall survival was 100% and 82% (P = 0·25) in younger and older patients, respectively. Younger patients required therapy earlier and had a significantly shorter time between first and second therapy (median: 63 months vs. 145 months) (P = 0·008). Younger patients required significantly more lines of therapy during follow-up. The 10-year cumulative incidence of secondary malignancies in young and old patients was 0·205 and 0·287, respectively (P = 0·22). The incidence of secondary cancers in patients aged >40 years at diagnosis increased with the number of treatments for HCL (P = 0·018). These results highlight that young patients with HCL have shorter responses to treatment and require more lines of therapy to maintain disease control, while attaining similar long-term survival. This has implications in the design of future clinical trials given our findings that secondary malignancies increase with more chemotherapy exposure.

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma.

LESSONS LEARNED: Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from preclinical models.Because of toxicity and lack of efficacy, BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma. BACKGROUND: Allosteric inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) are approved for advanced renal cell carcinoma (RCC). Preclinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase (PI3K) and mTOR kinase may establish superior anticancer effect. We aimed to establish safety for BEZ235, a potent inhibitor of both PI3K and mTOR, in advanced RCC. METHODS: Patients with advanced RCC who had previously failed standard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity. Primary endpoints were to identify the maximally tolerated dose (MTD) and to determine the recommended dose for the phase II study. RESULTS: The study was terminated early because of high incidence of dose-limiting toxicities (DLTs) across all dose levels tested. Ten patients were treated with BEZ235-six with clear cell and four with non-clear cell subtypes. Five of these patients suffered DLTs: 2 of 2 patients in the original 400 mg b.i.d. cohort, 1 of 6 in the 200 mg b.i.d. cohort, and 2 of 2 in the 300 mg b.i.d. COHORT: DLTs included fatigue, rash, nausea and vomiting, diarrhea, mucositis, anorexia, and dysgeusia. Five patients were evaluable for response: Two had stable disease as best response, and three had progressive disease. CONCLUSION: BEZ235 twice daily resulted in significant toxicity without objective responses; further development of this compound will not be pursued in this disease.

Brain Tumors: The Influence of Tumor Type and Routine MR Imaging Characteristics at BOLD Functional MR Imaging in the Primary Motor Gyrus.

Purpose To evaluate the effects of histologic features and anatomic magnetic resonance (MR) imaging characteristics of brain tumors on the functional MR imaging signal in the primary motor cortex (PMC), as false-negative blood oxygen level-dependent (BOLD) functional MR imaging activation can limit the accurate localization of eloquent cortices. Materials and Methods Institutional review board approval was obtained, and informed consent was waived for this HIPAA-compliant retrospective study. It comprised 63 patients referred between 2006 and 2014 for preoperative functional MR imaging localization of the Rolandic cortex. The patients had glioblastoma multiforme (GBM) (n = 20), metastasis (n = 21), or meningioma (n = 22). The volumes of functional MR imaging activation were measured during performance of a bilateral hand motor task. Ratios of functional MR imaging activation were normalized to PMC volume. Statistical analysis was performed for the following: (a) differences between hemispheres within each histologic tumor type (paired Wilcoxon test), (b) differences across tumor types (Kruskal-Wallis and Fisher tests), (c) pairwise tests between tumor types (Mann-Whitney U test), (d) relationships between fast fluid-attenuated inversion recovery (FLAIR) data and enhancement volume with activation (Spearman rank correlation coefficient), and (e) differences in activation volumes by tumor location (Mann-Whitney U test). Results A significant interhemispheric difference was found between the activation volumes in GBMs (mean, 511.43 voxels ± 307.73 [standard deviation] and 330.78 voxels ± 278.95; P < .01) but not in metastases (504.68 voxels ± 220.98 and 460.22 voxels ± 276.83; P = .15) or meningiomas (424.07 voxels ± 247.58 and 415.18 voxels ± 222.36; P = .85). GBMs showed significantly lower activation ratios (median, 0.49; range, 0.04-1.15) than metastases (median, 0.79; range, 0.28-1.66; P = .043) and meningiomas (median, 0.91; range, 0.52-2.05; P < .01). There was a moderate correlation with the volumes of FLAIR abnormality in metastases (ρ = -0.50) and meningiomas (ρ = -0.55). Enhancement volume (ρ = -0.11) and tumor distance from the PMC (median, 0.73 and range, 0.04-2.05 for near and median, 0.82 and range, 0.39-1.66 for far; P = .14) did not influence activation. Conclusion BOLD functional MR imaging activation in the ipsilateral PMC is influenced by tumor type and is significantly reduced in GBMs. FLAIR abnormality correlates moderately with the activation ratios in metastases and meningiomas. © RSNA, 2016 Online supplemental material is available for this article.