Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden

Background Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated. Objective To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection. Methods A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. Results In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P = .009, HR = 1.02; Surgical: P = .006, HR = 0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P = .049, HR = 0.44), but not the surgical cohort (P = .273, HR = 0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P = .036, HR = 0.43) but not in patients with high ADCL (P = .284, HR = 0.69). Conclusion Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.

SAT-131 Asymptomatic Severe Hypoglycemia with Lactic Acidosis in a Case of Non-Hodgkin’s Lymphoma - an Unusual Phenomenon of Hyper-Warburgism

INTRODUCTION Hypoglycemia in malignancy is well known with several etiologies; impaired liver function, insulin receptor autoantibodies, production of insulin-like substance by malignant cells or large tumor burden. Another possible mechanism is the Warburg effect where metabolism shifts towards glycolytic pathways over oxidative phosphorylation even under aerobic conditions leading to excess lactate production. This leads to glucose consumption due to shunting of glucose away from normal cells to cancer cells. Very few cases of lactic acidosis and severe hypoglycemia in Non-Hodgkin’s Lymphoma have been described in the literature. We report such an unusual case here. CASE DISCUSSION A 52-year-old, African-American male was admitted for severe malnutrition with 80 lb. weight loss, severe hypoglycemia and progressively increasing right chest wall mass. On arrival, he had no classic symptoms of hypoglycemia. Physical exam revealed persistent tachycardia, white patches on oral mucosa and posterior tongue, and an indurated mass on right chest wall with extensive swelling of right upper limb. Lab work was significant for blood glucose (BG) of 41 mg/dL (60–100), lactate 16 mmol/L (0.5 to 2), anion gap 26 mEq/L (3–10), albumin 2.3 g/dL (3.4 to 5.4) and normal renal and liver function tests. Fingerstick sugar readings were persistently in the 20s with no response to multiple boluses of dextrose and glucagon. He was started on dextrose 5% (D5) drip and intravenous solumedrol. Solumedrol was weaned off and D5 titrated down to investigate causes of hypoglycemia. BG dropped to 39 and corresponding labs showed insulin level of < 2 mcUnit/mL (2–20), C-peptide of 0.2 ng/mL (0.8–6.0) and ketone level of 0.2 mmol/L (<0.4). IGF-1 and IGF-2 were both low at 26 ng/mL (61–200) and 113 ng/mL (333–967) respectively. A CT torso with contrast showed bilateral pleural effusions, moderate pericardial effusions and a large ill-defined heterogeneous mass along anterior chest wall. He underwent ultrasound guided biopsy of the chest wall mass and diagnosed with diffuse large B-cell lymphoma. He also tested positive for HIV/AIDS and Hepatitis C. PET scan showed diffuse FDG (fluorodeoxyglucose) uptake consistent with advanced disease. He was started on chemotherapy and lactate and BG normalized soon after 1st cycle. CONCLUSION In our case; suppressed insulin, low C-peptide and IGF-2 levels indicate non-insulin mediated hypoglycemia due to rapid glucose utilization by cancer cells. Severe hypoglycemia with lack of neuroglycopenic symptoms suggests use of lactate (rather than glucose) as an alternative metabolic fuel for brain, thus preserving its function. Our patient presented with an exaggerated Warburg effect (hyper-Warburgism) as evident by extreme glucose consumption, severe lactic acidosis and large tumor burden on FDG/PET. Chemotherapy must be instituted timely to correct these abnormalities.

NIMG-54. DIFFUSION MRI PHENOTYPES PREDICT OVERALL SURVIVAL BENEFIT FROM BEVACIZUMAB IN RECURRENT GLIOBLASTOMA WITH A LARGE TUMOR BURDEN: EVIDENCE FROM CLINICAL PRACTICE AND A MULTICENTER PHASE 3 TRIAL

We have previously shown that diffusion MR characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-VEGF therapy; however, contemporary clinical use of bevacizumab is often limited to patients with very large tumors and/or after multiple recurrences. We hypothesize that diffusion MR characteristics can be used to predict long-term survival benefit in these patients, which may be beneficial for clinical decision-making. The current study identified 83 recurrent glioblastoma patients from our institution who were treated with bevacizumab over the past 5 years with high quality anatomic and diffusion MRI data. Of these 83 patients, 35 had large contrast enhancing tumors (>20cc or >3.4cm diameter, group average). Additionally, we identified 37 recurrent glioblastoma patients from the bevacizumab treated control arm of a recent multicenter phase III trial (NCT02511405) with high quality data and large enhancing tumors for validation. Pre-treatment tumor volume was quantified using T1 subtraction maps and apparent diffusion coefficient (ADC) histogram analysis was used to phenotype patients as having high (> 1.24 um2/ms) or low (< 1.24 um2/ms) ADCL, the mean value of the lower peak using a double Gaussian mixed model. Median overall survival in patients with large volume recurrent glioblastoma was ~5.7 months. High ADCL was associated with significantly longer overall survival (OS) compared with low ADCL in both single center (P=0.0271, HR=0.486, mOS=5.5 vs. 2.8mo) and multicenter phase III data (P=0.0457, HR=0.507, mOS=7.9 vs. 5.7mo). Accounting for absolute tumor volume and age, both cohorts showed that ADCL was an independent prognostic factor for OS (Cox, P< 0.01). In summary, pre-treatment diffusion MR imaging is an independent predictive biomarker for OS in recurrent glioblastoma with a large tumor burden.

Bevacizumab at first recurrence after standard radio-chemotherapy is associated with improved overall survival in glioblastoma patients with large tumor burden

Background Since its approval for use in recurrent glioblastoma (GBM), the survival benefit of bevacizumab (Bev) remains to be demonstrated. To address this issue, we retrospectively examined survival from first recurrence in patients treated with Bev, lomustine (CCNU), or Bev/CCNU. Methods We identified 168 primary GBM patients diagnosed at UCLA and Kaiser Permanente LA who received upfront radio-chemotherapy, followed by Bev and/or CCNU at first recurrence. Three patient groups, contemporaneously diagnosed from 2009 through 2015, were identified: (1) patients treated with Bev alone (n = 49), (2) CCNU alone (CCNU 09-15) (n = 36), and (3) Bev/CCNU (n = 53). Another CCNU control group (n = 30) diagnosed from 2001 through 2004 (CCNU 01-04) was also derived. We measured tumor size at first recurrence treatment initiation, using bidimensional (2D) and volumetric (3D) techniques, and analyzed overall survival (OS) from first recurrence. Results Among the entire cohort, larger tumor size at first recurrence was associated with poorer survival. The CCNU 01-04 group had similar tumor size as the Bev arms and low Bev crossover (7%). Treatment with Bev was associated with improved survival in patients with large tumor 2D measurements: Median OS for Bev and Bev/CCNU groups were 6.71 mo (n = 27) and 6.97 mo (n = 36) vs 4.03 mo (n = 10) in CCNU 01-04. Analysis by 3D measurement yielded similar results. Interestingly, the CCNU 09-15 group showed the highest survival, likely due to smaller tumor size and crossover to Bev (69%). Conclusion Survival advantage from Bev treatment was observed only among patients with large tumor burden as determined by either 2D or 3D measurement.

Retroperitoneal and Visceral Sarcomas: Issues for the General Surgeon

Sarcomas represent a rare, heterogeneous group of malignant tumors that arise from the mesenchymal tissues of the body. Although infrequently encountered, these tumors generate vigorous academic interest and an ever-expanding volume of medical literature. Chemotherapy is widely regarded as ineffective because of the often-large tumor burden and lack of good therapeutic drugs. Radiation therapy is often difficult to administer because of locoregional toxicity. Fortunately, targeted immunologic therapies have shown promise in some specific gastrointestinal mesenchymal tumors. To date, sarcoma remains a malignancy best treated operatively. Given the wide heterogeneity and biology of these tumors and the amount of new data available, a review of the current literature is warranted. The first installment of this review series1 dealt with extremity and trunk soft tissue sarcomas; this one will focus on retroperitoneal and visceral sarcomas and the management challenges they pose.