Jordan Hankins

Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymphoma

PURPOSE To determine the maximum outpatient dose of iodine-131 tositumomab (up to 0.75 Gy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem-cell transplantation (ASCT) for the treatment of chemotherapy-resistant relapsed or refractory B-cell non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT. RESULTS The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%. CONCLUSION There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.

Predictive value and diagnostic accuracy of F-18-fluoro-deoxy-glucose positron emission tomography treated grade 1 and 2 follicular lymphoma

F-18-fluoro-deoxy-glucose positron emission tomography (PET) is a powerful tool for the imaging of aggressive B-cell lymphomas. In contrast, there is relatively little data on PET in follicular lymphoma grade 1 (FL-1) and grade 2 (FL-2). In this manuscript, we present our findings utilizing PET in treated FL-1 and FL-2. A retrospective review of patients who underwent PET examinations at our institution produced 95 PET examinations among 31 patients with FL-1 and FL-2. PET was obtained at initial staging, mid-induction and post-treatment. Results were compared with clinical follow-up. PET had high sensitivity (95%) and specificity (88%) for lesion detection in treated FL-1 and FL-2. Abnormal foci in FL-1 and FL-2 had similar intensities. Post-induction PET positive patients had shorter mean progression free survivals compared with PET negative patients (p-value ≤0.001), post-salvage PET positive trended toward shorter mean response duration compared with negative patients (p-value: 0.09). Our results indicate that PET is accurate in the diagnostic assessment of treated FL-1 and FL-2 and, post-treatment PET positive patients are likely to relapse prior to PET negative patients.

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.

Detection of Coronary Artery Disease with a Continuous Infusion of Definity Ultrasound Contrast during Adenosine Stress Real Time Perfusion Echocardiography

Background: Myocardial perfusion imaging during adenosine stress is an accurate method of detecting physiologically relevant coronary artery disease. Methods: Real time perfusion echocardiography (RTPE) was compared to nuclear scintigraphy (rest Thallium, stress Sestamibi) in 40 patients with intermediate to high pretest probability. RTPE was performed with a continuous infusion of intravenous microbubbles (Definity; Bristol Myers Squibb) and intermittent high mechanical index impulses, with visual examination of both the replenishment rate and plateau intensity of contrast. Results: Of the 119 coronary artery territories compared, SPECT and RTPE were in agreement in 105 (88% agreement; kappa 0.67). In patients who went on to quantitative coronary arteriography (QCA), there were three who had normal appearing radionuclide SPECT during adenosine, but subendocardial perfusion defects with RTPE. In all three cases, QCA confirmed the presence of a >50% diameter stenosis in the abnormal territory. Conclusions: We conclude from this study that adenosine stress imaging with RTPE is an accurate method of detecting coronary artery disease. The higher resolution of RTPE may identify subendocardial defects that would otherwise have gone undetected with radionuclide imaging.

Diffuse large B-Cell lymphoma: Prospective multicenter comparison of early interim FLT PET/CT versus FDG PET/CT with IHP, EORTC, deauville, and PERCIST criteria for early therapeutic monitoring

Purpose To compare the performance characteristics of interim fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (after two cycles of chemotherapy) by using the most prominent standardized interpretive criteria (including International Harmonization Project [IHP] criteria, European Organization for Research and Treatment of Cancer [EORTC] criteria, and PET Response Criteria in Solid Tumors (PERCIST) versus those of interim (18)F fluorothymidine (FLT) PET/CT and simple visual interpretation. Materials and Methods This HIPAA-compliant prospective study was approved by the institutional review boards, and written informed consent was obtained. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) underwent both FLT and FDG PET/CT 18-24 days after two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. For FDG PET/CT interpretation, IHP criteria, EORTC criteria, PERCIST, Deauville criteria, standardized uptake value, total lesion glycolysis, and metabolic tumor volume were used. FLT PET/CT images were interpreted with visual assessment by two reviewers in consensus. The interim (after cycle 2) FDG and FLT PET/CT studies were then compared with the end-of-treatment FDG PET/CT studies to determine which interim examination and/or criteria best predicted the result after six cycles of chemotherapy. Results From November 2011 to May 2014, there were 60 potential patients for inclusion, of whom 46 patients (24 men [mean age, 60.9 years ± 13.7; range, 28-78 years] and 22 women [mean age, 57.2 years ± 13.4; range, 25-76 years]) fulfilled the criteria. Thirty-four patients had complete response, and 12 had residual disease at the end of treatment. FLT PET/CT had a significantly higher positive predictive value (PPV) (91%) in predicting residual disease than did any FDG PET/CT interpretation method (42%-46%). No difference in negative predictive value (NPV) was found between FLT PET/CT (94%) and FDG PET/CT (82%-95%), regardless of the interpretive criteria used. FLT PET/CT showed statistically higher (P < .001-.008) or similar NPVs than did FDG PET/CT. Conclusion Early interim FLT PET/CT had a significantly higher PPV than standardized FDG PET/CT-based interpretation for therapeutic response assessment in DLBCL. (©) RSNA, 2016 Online supplemental material is available for this article.

Phase II trial of 131-Iodine tositumomab with high-dose chemotherapy and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma.

The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkins lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information.

Iatrogenic hyperthyroidism secondary to dextrothyroxine administration

Two patients are reported who presented with clinical hyperthyroidism, increased serum thyroid function studies, and depressed radioactive iodine uptake, secondary to chronic ingestion of D-T4. Symptoms abated, and function studies returned to normal, following discontinuation of D-T4. This uncommon effect of D-T4 may be more prevalent than is generally realized and must be recognized as another potential cause of low radioiodine uptake in patients with clinical hyperthyroidism.

Occult Breast Cancer Presenting as Metastatic Adenocarcinoma of Unknown Primary: Clinical Presentation, Immunohistochemistry, and Molecular Analysis

We report a rare presentation of a 66-year-old female with diffuse metastatic adenocarcinoma of unknown primary involving liver, lymphatic system and bone metastases. The neoplastic cells were positive for CK7 and OC125, while negative for CK20, thyroid transcription factor 1, CDX2, BRST-2, chromogranin, synaptophysin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu). Fluorescence in situ hybridization showed no amplification of the HER2/neu gene. Molecular profiling reported a breast cancer origin with a very high confidence score of 98%. The absence of immunohistochemistry staining for ER, PR, and HER2/neu further classified her cancer as triple-negative breast cancer. Additional studies revealed high expression levels of topoisomerase (Topo) I, androgen receptor, and ribonucleoside-diphosphate reductase large subunit; the results were negative for thymidylate synthase, Topo II-α and O6-methylguanine-DNA methyltransferase. The patient was initially treated with a combination regimen of cisplatin and etoposide, and she experienced a rapid resolution of cancer-related symptoms. Unfortunately, her therapy was complicated by a cerebrovascular accident (CVA), which was thought to be related to cisplatin and high serum mucin. After recovery from the CVA, the patient was successfully treated with second-line chemotherapy based on her tumor expression profile. We highlight the role of molecular profiling in the diagnosis and management of this patient and the implication of personalized chemotherapy in this challenging disease.

Erratum: MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer (Cancer Cell (2017) 32(1) (71–87.e7) (S1535610817302544) (10.1016/j.ccell.2017.06.004))

Surendra K. Shukla, Vinee Purohit, Kamiya Mehla, Venugopal Gunda, Nina V. Chaika, Enza Vernucci, Ryan J. King, Jaime Abrego, Gennifer D. Goode, Aneesha Dasgupta, Alysha L. Illies, Teklab Gebregiworgis, Bingbing Dai, Jithesh J. Augustine, Divya Murthy, Kuldeep S. Attri, Oksana Mashadova, Paul M. Grandgenett, Robert Powers, Quan P. Ly, Audrey J. Lazenby, Jean L. Grem, Fang Yu, José M. Matés, John M. Asara, Jung-whan Kim, Jordan H. Hankins, Colin Weekes, Michael A. Hollingsworth, Natalie J. Serkova, Aaron R. Sasson, Jason B. Fleming, Jennifer M. Oliveto, Costas A. Lyssiotis, Lewis C. Cantley, Lyudmyla Berim, and Pankaj K. Singh* *Correspondence: pankaj.singh@unmc.edu http://dx.doi.org/10.1016/j.ccell.2017.08.008

Pulmonary langerhans cell histiocytosis: PET/CT for initial workup and treatment response evaluation.

A 40-year-old man underwent pan-endoscopy owing to abdominal pain. Biopsies of the gastrointestinal tract demonstrated diffuse Langerhans cell histiocytosis. PET/CT was done, with CT demonstrating classic pulmonary manifestations of Langerhans cell histiocytosis that had association with intense FDG uptake on PET. Bowel appeared normal. Treatment was initiated with smoking cessation and 6 cycles of cytarabine. Follow-up PET/CT after initial treatment demonstrated improvement of parenchymal abnormalities seen on CT, with resolution of hypermetabolic activity. Maintenance chemotherapy was initiated. PET/CT is increasingly being used for initial staging and treatment response assessment in this rare disorder.