Citations

Abstract Introduction. For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. Materials and Methods. Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. Results. A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. Conclusion. Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.

Abstract Background Protein phosphatase (PP2A) is a multifunctional protein involved in regulation of cell cycle, DNA-damage response, and apoptosis. LB-100, a novel small molecule inhibitor of PP2A, inhibits the growth of a broad spectrum of leukemic and solid tumor cell lines. In addition, LB100 potentiates the effectiveness of cytotoxic drugs (cisplatin, docetaxel, doxorubicin, temozolomide) and radiation without significant increases in toxicity. The predominant mechanisms responsible for potentiation are inhibition of mitotic exit and homologous recombination repair. Methods This is an open label, first-time-in-human, multicenter, phase 1 study of LB-100 in patients with advanced cancer refractory to standard therapies. The first part of the study determines the maximum tolerated dose (MTD) of LB-100 as a single agent when given intravenously days 1-3 every 21 days. Utilizing a standard 3+3 design, patients (pts) are evaluated for dose limiting toxicities (DLT) through 2 cycles. Once the single agent MTD is determined, the dose will be reduced by 2 dose levels (DL) and combined with docetaxel given on day 2. Escalation will continue until the MTD of the combination is determined. Plasma sampling for pharmacokinetics of LB-100 will be collected on days 1 and 3 of cycle 1 in the MTD confirmation cohort. Results The starting dose of LB-100 was 0.25 mg/m2 and 21 pts have enrolled in part 1 of the study through six dose levels. At DL6, pts received 2.33 mg/m2 and no DLTs have been observed. One pt with metastatic colon cancer at DL6 had a grade 2 creatinine after 2 doses that resolved with hydration. This was related to LB-100 and the study was amended to increase the volume and infusion time. One pt on DL3 with stage 4 pancreas cancer had stable disease through 15 cycles of treatment and another pt on DL5 with metastatic thymoma remains on treatment through 8 cycles. Stable disease for 4-6 cycles was also observed in breast, ovarian, carcinoid and testicular cancer patients. Conclusions Rb and p53 mutations are common in malignancies leading to chromosomal instability and overexpression of the mitotic checkpoint gene Mad2. PP2A inhibition results in synthetic lethality of cancer cells overexpressing Mad2 which may be a biomarker for LB100 responsiveness. Through 6 DLs, LB-100 has been well tolerated without any DLTs and early activity has been observed with stabilization of disease in a wide variety of cancers. Correlative studies for biomarkers of response are planned. Clinical trial identifier: NCTO1837667 Citation Format: Vincent Chung, Donald Richards, Fadi Braiteh, John S. Kovach, Aaron Scott Mansfield. A phase 1 study of a novel inhibitor of protein phosphatase 2A alone or in combination with docetaxel. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A175.

Abstract Breast cancer diagnosis and death has risen in low to middle income countries (LMIC) in the past 20 years. Early detection, diagnosis and treatment in the LMIC setting are thought to impact morbidity and survivorship. The population of South Florida is composed of a significant portion of Afro-Caribbean immigrants from LMICs. We compared a cohort of recent Haitian immigrants with residents in Haiti who had a diagnosis of breast cancer to evaluate the effects of geographical location on presentation, treatment and outcomes. Methods: Retrospective cohort study. Participants were Haitian females with breast cancer that were living in Miami and presented to the University of Miami/Jackson Memorial Hospital (UM/JMH) between 2008 and 2014 and patients living in Haiti and presented to the Breast Cancer Treatment program at the Hospital Bernard Mevs Project Medishare (HBMPM) from 2013 to 2015 with a new diagnosis or who had been diagnosed as far back as 2008 and were presenting for continuation of care. The main outcome was the relationship between cohort location and breast cancer characteristics and cancer–specific survival by log-rank. Cox proportional hazards regression was used to compare breast cancer–specific survival overall and analyzed by stage and other significant explanatory factors. Results: 102 patients from UM/JMH and 94 patients from HBMPM were included in the analysis. The cohort in Haiti presented after longer median duration of symptoms (20 vs 3 months, p<0.001) and more advanced stage (31% Vs 20% with locally advance and 27% vs 19% with metastatic disease). The median age of diagnosis was 55 years in Miami compared to 50 years in Haiti (p=0.03). In Miami all patients had estrogen receptor (ER) and her-2 status ascertained at diagnosis, whereas only 52% and 27% of the Haitian cohort had them. Tumor characteristics in Miami vs Haiti in patients with reported status: ER + 74% (n=102) vs 55% (n=49), p=0.02, her-2+ 20% (n=102) vs 28% (n=25), p=0.36, triple negative 27% (n=102) vs 28% (n=25),p=0.49. Treatment modalities and censoring was available for all the patients in Miami and 72 patients in Haiti. In Haiti, radiation therapy was not widely available compared to Miami. Once patients had known ER and her-2 status, there was no difference in treatment with hormonal therapy (p=0.97) but none of the patients in Haiti received her-2 directed therapy (p<0.001). 50% of the patients with unknown ER status in Haiti received Tamoxifen. Twice as many Haitian women died after a median follow-up of 23 months (12% vs 24%), with median survival of 53 months for Haitians in Haiti (not reached for Miami cohort). Breast cancer specific survival was significantly different in the two cohorts (p<0.000). After exploratory analysis, the risk of death was higher for Haitians in Haiti than Haitians in Miami [HR 3.13 (CI 1.50-6.51)] and was higher for more advanced disease [HR 2.58 (CI 1.67-3.99)]. No other variable or interaction reached statistical significance in our model. Conclusion: Haitian women diagnosed with breast cancer in Haiti experience a significantly worse outcome than Haitians living in Miami that appears to be related to a more advanced stage, younger age, more ER negative tumors and lack of timely effective treatments including restricted access to trastuzumab and radiation. In addition there is a difference in the age of breast cancer onset (Caucasian 62, African American 58, Haitian American 55, Haitian 50) and ER positivity (Caucasian 70%, African American 48%, Haitian American 74%, Haitian 55%) depending on race and ethnic group that raises the question of whether there are disparities within subgroups of women of African origin who have breast cancer. Confounding epigenetic-related variables may impact survival and they need further exploration in these populations. Citation Format: Alexandra Gomez, Vincent DeGennaro, Jr., Sophia George, Estefania Santamaria, Gustavo Westin, Gabriel Dieudina, Judith Hurley. Presentation, treatment, and outcomes of Haitian women with breast cancer in Miami and Haiti: Disparities in breast cancer. A retrospective cohort study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C55.

BACKGROUNDAutologous stem cell transplantation (SCT) is a common management strategy for select patients with immunoglobulin light‐chain amyloidosis, but no trials have documented improved overall survival.METHODSEighty‐nine patients with biopsy‐proven immunoglobulin light‐chain amyloidosis were allowed to select treatment with melphalan plus dexamethasone (n = 34) or SCT (n = 55); all patients were transplant eligible. Treatment preference resulted in imbalanced study arms. Patients who selected SCT were younger, more frequently had an Eastern Cooperative Oncology Group performance status score less than 2, had lower‐stage amyloidosis, and had a lower incidence of cardiac amyloidosis.RESULTSPatients receiving melphalan plus dexamethasone had a 3‐year progression‐free survival rate of 29.1% and an overall survival rate of 58.8%. Patients undergoing SCT had a 3‐year progression‐free survival rate of 51.7% and an overall survival rate of 83.6%. An attempt to match patients between the 2 arms in terms of risk produced 24 matched triplet sets (2 SCT patients for each melphalan‐dexamethasone patient); there was no difference in hematologic response, but there was better survival after autologous SCT. A propensity score–matched analysis of the cohorts (melphalan plus dexamethasone vs SCT) showed an overall mortality hazard ratio of 2.56 (P < .01).CONCLUSIONSAlthough the study had limitations, similar hematologic responses and improved survival were observed after SCT versus melphalan plus dexamethasone. Cancer 2016;122:2197–205. © 2016 American Cancer Society.

Introduction Vertebral artery injury is a rare but serious complication of cervical spine surgery with an overall incidence rate of 1.4% (Rampersaud, 2006). Iatrogenic injury of the vertebral artery can lead to serious complications including lateral medullary (Wallenberg) syndrome, quadriparesis, and mortality. The high rate of vertebral artery anomalies in the general population mandates assessment via advanced imaging modalities in the preoperative period (Schroeder, 2013). The rarity of this complication makes it difficult to set expectations after an injury is encountered. This study utilized a multi-center database to compile outcomes data after vertebral artery injury during a cervical spine procedure. Materials and Methods A multi-center retrospective case series was compiled involving 23 medical institutions. Inclusion criteria included patients who underwent cervical spine surgery between 2005–2011 and who sustained a vertebral artery injury. IRBs were obtained from all institutions and data was sent to a private research organization that collected and collated all of the data. Patients were evaluated on the basis of condition-specific functional status using the Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA) score, the Nurick scale, and the 36-Item Short-Form Health Survey (SF-36). Results Vertebral artery injuries were identified in a total of 14 of 16,582 total patients screened (8.4 per 10,000). The mean age of patients with vertebral artery injury was 59 years (+/− 10) with a female predominance (78.6%). Diagnoses of affected patients included 7 with myelopathy, 3 with radiculopathy, 1 with cervical instability, and 2 with metastatic disease. The mean duration of operative time for cases was 4.7 hours (+/− 1.8). Vertebral artery injury was also associated with substantial blood loss (770 mL), although only 3 cases required transfusion. Of the 14 cases, 7 occurred with an anterior only approach, 3 cases with posterior only approach, and 4 during circumferential approach. Average length of hospital stay for these patients was 10 days (+/− 8). Notably, 13 of the 14 (92.86%) cases reportedly resolved without residual deficits. Compared with preoperative baseline NDI, Nurick, and SF-36 physical and mental component scores for these patients, there were no observed changes after surgery ( p = 0.20 Ð 0.94). Conclusion Vertebral artery injuries are potentially catastrophic complications that can be sustained from either anterior or posterior cervical spine approaches. This adverse event is associated with an increase in hospital stay and functional disability measured on NDI score. However, the data from this study suggests that with proper steps to ensure hemostasis, patients recover function at a high rate and do not exhibit residual deficits (13 out of 14). Preoperative imaging studies may provide insight into VA anomalies and anatomic variations and are vital to the preoperative assessment. Furthermore, although surgeons should expect increased blood loss once a vertebral artery injury is encountered, patients do not often require a blood transfusion.

Purpose The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI). Methods Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m 2 to 140 mg/m 2 ) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).

Over the past decade, a number of changes have occurred in the diagnostic evaluation, management, and long‐term follow‐up of patients with POEMS syndrome at our institution. This study included 291 patients with POEMS syndrome diagnosed at the Mayo Clinic between 1974 and 2014. Patients diagnosed after 2003 had more features of the syndrome identified at diagnosis and were more likely to receive an autologous transplant (49% versus 8%, P < 0.0001) and to have achieved a hematologic complete response (CR) to treatment (41% vs 25%, P < 0.0001). With 2273 person‐years of follow‐up, 10‐year overall survival (OS) was 62% (95% C.I., 56%, 67%). On multivariate analysis, the three factors associated with superior OS were younger age (RR 0.98 [0.96–1.00]), albumin greater‐than 3.2 g/dL (RR 0.5 [0.32–0.89]) and attainment of complete hematologic response (RR 0.4 [0.2, 0.9]). This study confirms the very good long‐term outcomes of patients with POEMS syndrome and identifies two new prognostic risk factors: albumin at diagnosis and attainment of complete hematologic response. Am. J. Hematol. 91:585–589, 2016. © 2016 Wiley Periodicals, Inc.

Osteosarcoma is an aggressive primary bone tumor. It is currently treated with multimodality therapy including en bloc resection, which has been demonstrated to confer a survival benefit over intralesional resection. The authors present the case of an 8-year-old girl with a C-1 lateral mass osteosarcoma, which was treated with a 4-stage en bloc resection and spinal reconstruction. While technically complex, the feasibility of en bloc resection for spinal osteosarcoma should be explored in the pediatric population.

Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. Results Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). Conclusion Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.