bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperfractionated cyclophosphamide as urgent therapy: A single institution experience.
Authors: Landau Danny , El-Far Ahmad , Anscher Daniel , Landis Michael
Published: September 2018

e19045

Background: Hematologic cancers can present with severe issues such as airway compromise, hypercalcemia, etc. Due to high drug costs and payment concerns, therapies that are inexpensive but effective are necessary. Within our institution, we utilize hyperfractionated cyclophosphamide (cyclophosphamide 300 mg/m2 IV q 12 hours X 6) [HyperC] for these patients. We opted to see if this approach is justified. Methods: We reviewed data via our EMR of people who received HyperC. Data was limited to urgent therapy. Data was collected from 2015-2017. The cost of therapy was also looked at relative to other therapies with our pharmacy team. Categories are as per the charts below. Results: See Table. Conclusions: HyperC is cost effective and efficacious for patients who need urgent therapy. [Table: see text][Table: see text][Table: see text]
Mediastinal gray zone lymphoma-morphollogically heterogenous group of lymphomas.
Authors: Kharchenko Evgeniya Vladimirovna , Semiglazova Tatiana
Published: September 2018

e19050

Background: Mediastinal Gray zone lymphoma (MGZL) could be refer to group of large B-cell lymphomas of mediastinum, where Hodgkin’s lymphoma and Diffuse large B-cell lymphoma also included. These kinds of lymphomas have common pathogenic mechanisms, but different epidemiological,clinical , morphological, IHC features, different therapy and prognosis. Methods: We analyzedhistological and IHC features of 11 patients with MGZL. Middle age of patients were 35 years old (25-42), Man(7 )and woman (4) ratio was 1,75:1. Results: We distinguished 5 types of MGZL: 1) Hodgkin’s lymphoma-like variant (ring-shaped fibrosis, expressed cellular polymorphism, large cells seems like Hodgkin’s and Reed-Shteinberg cells,mixed-cell background infiltrate; high expression of CD 20 and another B-lines antigens. 2) type, seems like primary mediastinum large B-cell lymphoma (PMBL-like) (about monotonous composition of the cells, diffuse alveolar stroma’sfibrosis, scarce background infiltrate, high diffuse expression of CD 30 and/or lack of LCA and CD 20 expression 3) mixed variant (mixture of cells PMBL and Hodgkin's lymphoma, irregularly expressed fibrosis, lack of zonality, transientimmunophenotype. 4) dual-component variant (well-defined zonality, Hodgkin's like areas and structuresspecific for PMBL with appropriate or changed immunophenotype 5) Metachronous variant (during progression or relapse we observedmodification of morphological and IHC features). Conclusions: MGZL is heterogenous group of neoplasms with different morphological and IHC features causes difficulties in differential diagnostics in large B-cell lymphomas of mediastinum group.Diagnostic algorithm should be used for high efficacy and accuracy. Clinical features and prognostic factors in these subtypes of MGZL is still unclear and need further investigations.
Outcome after autologous transplantation in the terms of comorbidity for patients with lymphoproliferative diseases: Single center experience.
Authors: Pivkova Veljanovska Aleksandra , Genadieva-Stavrik Sonja Genco , Stojanoski Zlate , Chadievski Lazar , Panovska Stavridis Irina , Trajkova Sanja Aleksandar , Cevreska Lidija , Georgievski Borce
Published: September 2018

e19502

Background: Autologous stem cell transplantation (ASCT) improves survival in patients with myeloma and lymphoma but is associated with morbidity and nonrelapse mortality (NRM). Hematopoietic cell transplant comorbidity index (HCT-CI) was shown to predict risk of NRM and survival after allogeneic transplantation. We tested the utility of HCT-CI as a predictor of NRM and overall survival (OS) in patients undergoing ASCT. Methods: We analyzed outcomes of 220 patients after high-dose melphalan and high –dose anti lymphoma chemotherapy during year 2000 to 2015. Individual comorbidities were prospectively collected at the time of ASCT. The impact of HCT-CI and other potential prognostic factors, including Karnofsky performance score (KPS), on NRM and survival were studied in multivariate Cox regression models. Results: HCT-CI score was 0, 1, 2, 3, and >3 in 42%, 18%, 13%, 13%, and 14% of the study cohort, respectively. Subjects were stratified into 3 risk groups: HCT-CI score of 0 (42%) versus HCT-CI score of 1 to 2 (32%) versus HCT-CI score > 2 (26%). Higher HCT-CI was associated with lower KPS < 90 (33% of subject’s score of 0 versus 50% in HCT-CI score > 2). HCT-CI score > 2 was associated with melphalan dose reduction (22% versus 10% in score 0 cohorts). One-year NRM was low at 2% (95% confidence interval, 1% to 4%). On multivariate analysis, overall survival was inferior in groups with HCT-CI score of 1 to 2 (relative risk, 1.37, [95% confidence interval, 1.01 to 1.87], P = .04) and HCT-CI score > 2 (relative risk, 1.5 [95% confidence interval, 1.09 to 2.08], P = .01). Factors that affect OS in the autologous recipients among lymphoma and myeloma patients were: HCT-CI, Karnofsky score, number of CD34+ cells/kg and time from diagnosis until transplant (p<0.05). Factors that affect TRM/NRM were HCT-CI, ECOG, Karnofsky score and number of hospital days and body weight.(p<0.05). Conclusions: ASCT for MM and lymphoma is associated with low NRM, and death is predominantly related to disease progression. Comorbidity evaluation during autologous transplantation for lymphoproliferative diseases can be a useful tool in predicting transplant outcome.
Venous thromboembolism (VTE) in multiple myeloma (MM) patients undergoing autologous hematopoietic cell transplantation (HCT).
Authors: Covut Fahrettin , Pinto Raisa , Park Michelle , Malek Ehsan , Lazarus Hillard , Caimi Paolo Fabrizio , Tomlinson Ben Kent , Metheny Leland L. , De Lima Marcos J.G. , Cooper Brenda W.
Published: September 2018

e19503

Background: HCT is commonly used for consolidation for MM patients (pts). These pts have a significant risk of VTE and may potentially be candidates for prophylactic anticoagulation. However, incidence and outcomes of VTE in peri-transplant period remain unclear for MM pts. Methods: Between 2006 and 2016, 160 MM pts underwent autologous HCT at our institution. Peri-transplant period was defined as between initiation of stem cell collection (SCC) and 30 days after discharge from HCT hospitalization. No pts received routine VTE prophylaxis. Clinically significant bleeding was defined as a bleeding event that led to a specific clinical intervention, such as transfusion. We used Cox regression to assess risk factors for peri-transplant VTE. We compared overall survival (OS) using log-rank test. Results: In peri-transplant period, 18 symptomatic VTE occurred in 17 pts (10.6%; 95% CI 7 - 17). Twelve (7.5%) were catheter-related, 4 (2.5%) were non-catheter-related deep venous thrombosis, and 2 (1.3%) were pulmonary emboli. Seven VTE occurred between SCC and HCT. Importantly, among 11 VTE after HCT, only 1 VTE occurred before neutrophil engraftment and only 2 VTE occurred at a platelet count less than 50 x 109/L (median: 138, range: 30 - 464). Clinically significant bleeding occurred in 9 (5.6%) pts during peri-transplant period, without any fatal bleeding. Multivariate analysis was performed including; treatment with immunomodulatory drugs (p = 0.008), HCT comorbidity index ≥ 2 (p = 0.036), age > 60 (p = 0.07), smoking at any time (p = 0.07), BMI > 30 at HCT (p = 0.19), partial remission at HCT (p = 0.20), ISS stage 3 at diagnosis (p = 0.37). At median follow-up of 31 months since HCT, 3-year OS for pts with and without peri-transplant VTE was 58.8% (CI 38% - 91%) and 77.6% (CI 70% - 86%), respectively (p = 0.11). Conclusions: Peri-transplant symptomatic VTE was highly prevalent in our cohort of pts with MM and vast majority of VTE events occurred either between SCC and HCT or after neutrophil engraftment. Our findings indicate that routine VTE prophylaxis in peri-transplant period should be considered for MM pts and timing of VTE prophylaxis can be tailored to optimize balance between safety and efficacy.
Outcomes of G-CSF alone vs G-CSF with upfront plerixafor vs G-CSF/chemotherapy for collection of autologous stem cells in patients with multiple myeloma.
Authors: Talamo Giampaolo , George Melissa , Ehmann W. Christopher , Drabick Joseph J. , Mineishi Shin
Published: September 2018

e19504

Background: Strategies for optimizing the collection of peripheral blood stem cells (PBSC) for autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) vary among transplant centers, and include the use of G-CSF alone or in combination with plerixafor, or mobilization chemotherapy + G-CSF. In 2010, we started using “upfront” plerixafor, given on the day before the PBSC collection. Methods:We retrospectively analyzed the outcomes of 423 consecutive MM patients who underwent PBSC collections at the Penn State Hershey Cancer Institute. PBSC were collected after mobilization chemotherapy + G-CSF 5 mcg/Kg/day (group A, 91 pts), G-CSF alone, 10-16 mcg/Kg/day (group B, 72 pts), and G-CSF with “upfront” plerixafor 0.16-0.24 mg/Kg on the day before the stem cell collection (group C, 245 pts). Fifteen patients were excluded from the analysis because they collected with chemotherapy + plerixafor, received pegylated G-CSF, or plerixafor “on demand”, i.e., after failure to achieve an adequate number of stem cells on the first day of collection. We compared yields, number of days required for apheresis, clinical outcomes, and adverse events among these groups. Results: The median number of PBSC collected was 16.4 (range, 0.1-134), 4.2 (range, 0-12), and 6.2 (range, 0.2-41.2) million CD34+ cells/Kg in group A, B, and C, respectively (p<0.001). The mean number of days to collect PBSC was 1.5, 1.5, and 1.3 in group A, B, and C, respectively (p=0.033). Collection failure, defined as a yield <2 million CD34+cells/Kg, was observed in 5 (5.5%), 9 (12.5%), and 15 (6.1%) patients of group A, B, and C, respectively (p<0.001). Twenty patients in group A developed neutropenic fever requiring hospital admission, and 1 of them died of septic shock, whereas no mortality was observed in groups B or C. No difference in the rapidity of PBSC engraftment, progression-free survival, and overall survival was observed among the 3 groups. Conclusions:In patients with MM, the upfront use of plerixafor with G-CSF provided the best collection strategy: it avoided the morbidity and mortality associated with the mobilization chemotherapy, and it provided higher yields than G-CSF alone.
Reticulocytic indices in assessing erythropoiesis effectiveness in multiple myeloma.
Authors: Lysenko Irina B. , Guskova Nailya , Guskova Ekaterina , Avanesova Kristina , Tselishcheva Irina V. , Zakharchenko Viktoria , Donskaya Aliya K. , Gusareva Marina A. , Torpudzhyan Izabella , Golomeeva Nadezhda , Abakumova Svetlana V. , Gornostaeva Ekaterina , Belgova Svetlana V. , Nozdricheva Anastasia
Published: September 2018

e19510

Background: The purpose of the study was to analyze changes in reticulocytic indices and their role in assessing the effectiveness of erythropoiesis in patients with multiple myeloma. Methods: Thestudy included 10 patients with primary multiple myeloma (MM) and 16 patients with recurrent MM, stage II-III. Parameters of the peripheral blood were studied: Hb, RBC, MCV, MCH, RBC-He (red cell hemoglobin content), RET (number and percentage), IRF (immature reticulocyte fraction), high (HFR), median (MFR) and low (LFR) fluorescence reticulocytes, RET-He (reticulocyte hemoglobin content), RPI (reticulocyte production index). Results: Anemia was found in21 (80.8%) patients before treatment: grade I in 30.8%, II in 46.1%, III in 3.8%; normocytic hypochromic anemia – 6, normocytic normochromic – 15. Anemia detection rate in primary MM was 60.0%, recurrent – 93.7%. RET levels in grade I-II anemia were close to the norm, but IRF was increased due to MFR increase by 3.7 times and HFR – by 4.7 times. Grade III anemia: RET number decreased by 1.6 times due to IRF reduction by 2 times, in particular MFR and HFR fractions. As a result, RET-He was decreased to varying degrees in all cases. Patients with complete or partial remission showed no significant changes in erythrocyte parameters, but had RET level increased by 2.5 times, IRF – by 9 times due to MFR increase by 6.5 times and HFR by 30.8 times, RPI - by 2.0 times. The data showed the effectiveness of erythropoiesis during anticancer therapy. We did not observe signs of increasing anemia syndrome in patients with stabilization or patients resistant to treatment, as well as in patients with initial grade III anemia. Hb, RBC, RET and RPI were unchanged, but the ratio of fractions changed: the number of mature ones - LFR increased by 1.4 times and young ones - HFR decreased by 2.5 times, RBC-He were increased and RET-He doubled compared to the levels before treatment, which indicated the activation of processes of erythrokaryocyte hemoglobinization. Conclusions: RET, IRF, RET-He and RPI indices adequately reflect the process of recovery of erythropoiesis and its effectiveness in real time which is extremely important in tumor therapy monitoring.
Real-world treatment patterns of adult multiple myeloma patients treated with carfilzomib in the US community oncology setting.
Authors: Panjabi Sumeet , Medhekar Rohan , Aguilar Kathleen , Wilson Thomas , Amirian E. Susan , Mezzi Khalid , Rifkin Robert M.
Published: September 2018

e19513

Background: The purpose of this retrospective cohort study was to describe the treatment regimens received by adult multiple myeloma (MM) patients who were exposed to carfilzomib (K) in the US Oncology Network (USON). Methods: Eligible patients received K-based regimens for MM at least once between 11/01/2013 and 02/29/2016, were ≥18 years old, were not in a clinical trial, and had at least 2 visits at a USON clinic. Data on systemic therapies, lines of therapy (LOT), clinic visits and treatment administration dates were abstracted from the electronic health records (EHR). Treatment sequencing logic was used to identify progression by LOT. Sequencing rules were based on regimens, duration, and administration dates. Treatment regimens utilized at any time during the study period were analyzed by LOT. Results: 718 MM patients received a K-containing regimen at least once over the course of treatment. The frequency distribution of regimens for K-exposed patients by LOT (2 to 5) are provided (see Table). Among these patients, K-based regimens comprised 66.6% of LOT2 regimens, 55.3% of LOT3 regimens, and 45.9% of regimens used beyond LOT3. K+ lenalidomide + dex (KRd) was the most common K-containing regimen used in LOT2 (24.7%). K-triplets containing an immunomodulatory agent were most frequent in LOT 2 and K-doublets (Kd) were most frequent in LOT 3. Conclusions: In our study, K-based regimens were used across LOTs 2 to 5 with highest frequency observed in LOT2. K-triplets with immunomodulatory drugs were more common in earlier LOTs. [Table: see text]
Clinical manifestation and prognostic features of extramedullary plasmacytomas.
Authors: Jung Hyun Ae , Maeng Chi Hoon , Jang Jun Ho , Jung Chul Won , Kim Kihyun
Published: September 2018

e19516

Background: Extramedullary plasmacytomas (EMPs) is a rare presentation of plasma cell neoplasm and accounts for 7 to 15% of all plasma cell neoplasm. Fluorescence in-situ hybridization (FISH)-detected abnormalities, including del(17p), del(13q), and t(4;14), have been associated with inferior prognosis. However, there are few data about the prognostic significance of cytogenetic abnormalities in multiple myeloma (MM) patients with EMPs. This study aimed the clinical features, FISH data and outcome of patients with EMPs Methods: The data were collected from multiple myeloma patients with EMPs, retrospectively. We excluded skeletal plasmacytomas. The clinic-pathologic variables and treatment outcome retrospectively reviewed. Results: Seventeen patients had solitary EMPs. Most common site of solitary EMP was nasal cavity and most patients received radiotherapy (n=7) and surgery (n=6). A total of 905 patients with newly diagnosed MM were included, and 53 patients (8.7 %) had EMPs at diagnosis. Thirty three patients had conventional FISH data. By conventional cytogenetic analysis and FISH, 35.8% (19/53) and 54.5% (18/33) patients were identified genetic abnormalities, respectively. By comprehensive cytogenetic/FISH approach, the most common genetic aberration was 1q21 amplification and/or 1p32 deletion (42.4%, 14/33), followed by -13 or del (13q) (24.3%, 8/33), del (17p) (15.2%, 5/33), IGH/FGFR3 rearrangement (15%, 2/33) and IGH/CCND1 rearrangement (12%, 2/33). Patients with initial EMPs had significantly worse overall survival compared to those without initial EMPs. Del(13q), and t(4;14), have been associated with inferior prognosis. Conclusions: In the current study, del(13q), and t(4;14) were associated with worse survival in MM patients with EMP.
Real-world outcomes with panobinostat in patients with penta- and quad-refractory multiple myeloma.
Authors: Biran Noa , Vesole David H. , Zhang Shijia , Richter Joshua Ryan , Kuo Yen Hong , Schmidt Linda , McBride Laura , Anand Palka , Ivanovski Kristin , Pierre Amy , Kumka Susan , Cucurrulo Carmella , Siegel David
Published: September 2018

e19522

Background: Panobinostat (pano) is a pan histone de-acetylatase inhibitor (HDAC-i) approved by the FDA for use with bortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had ≥2 prior lines of therapy including both btz and an immunomodulatory agent (IMiD). The goal of this retrospective study is to evaluate the efficacy and safety of pano in combination with a variety of FDA approved agents as would be utilized in a real world management in relapsed/refractory (RR) MM. Methods: Between February 2015 and July 2016, 37 consecutive patients with RRMM treated with commercial pano were identified and the electronic medical record was reviewed. Results: Median age was 62 (range 27-78), with 57% percent male. Ten (27%) had high-risk FISH as defined by t(14;16), t(4;14), del p53, and gain 1q21. Median number of prior lines was 6 (range 2-9). All patients were RR to their last line of therapy, and 20 (54%) were btz-refractory, 27 (73%) were lenalidomide-refractory, 29 (78%) were pomalidomide-refractory, and 29 (78%) were carfilzomib-refractory. Thirty-three (89%) were penta-refractory; eight (21%) were penta-refractory, and 4 (11%) were refractory to prior HDAC-i therapy. Median number of cycles with pano was 2 (range 0.25 - 10). The overall response rate (≥ partial response) was 29.4% and the clinical benefit rate (≥ minor response) was 71.4%. Median progression-free survival was 2.4 months (95% CI: [1.63 – 4.43]). Median duration of response (≥SD) was 4.1 months. Median overall survival from initiation of pano was 7.5 months (95% CI: [5.17, NA]). One patient discontinued pano due to AEs. Grade 3 and 4 non-hematologic toxicities were diarrhea (N = 1), and respiratory failure (N = 1). Grade 3 and 4 hematologic adverse events (AEs) occurred in 13 (35%) patients, with 7 (19%) anemia, 11 neutropenia (30%), and 10 (37%) thrombocytopenia. Serious AEs included acute kidney injury, GI bleed, and febrile neutropenia each occurring in 1 patient. Conclusions: Use of pano outside of the FDA indication in combination with PI and IMiD-based regimens has activity and is well tolerated in quad and penta-refractory MM patients.
Prognostic significance of t(11;14) expression by FISH in patients with newly diagnosed multiple myeloma in the era of novel therapies.
Authors: Gonzalez Velez Miguel , Parrondo Ricardo Daniel , Andrews Tracy , Duma Narjust , Richter Joshua Ryan , Vesole David H. , Siegel David Samuel DiCapua , Biran Noa
Published: September 2018

e19525

Background: Rearrangements of the immunoglobulin heavy chain (IGH) on chromosome 14 are identified by FISH in about 15-20% of patients (pts) with newly diagnosed multiple myeloma (MM). Historically there is variation on the significance on prognosis of these rearrangements: typically, t(4;14), t(14;16) and t(14;20) have high risk (HR), and t(11;14) have standard risk (SR). A recent study (Kaufman et al, Leukemia. 2016 30:633-9) suggests that t(11;14) may confer a worse prognosis We report the prognostic significance of t(11;14) in a single-institution MM cohort. Methods: 87 pts with t(11;14) by CD 138 selected FISH at diagnosis were identified, pts without symptomatic MM were excluded. Cox regression was used for statistical analysis. Progression free survival (PFS), and overall survivals (OS) from diagnosis and post autologous stem cell transplant (ASCT) were analyzed by Kaplan-Meier. Results: Median age at diagnosis was 62 years, 45 pts (52%) were male, and 24 pts (27%) had ISS 3. All pts received either a proteasome inhibitor or an immunomodulatory agent, and 42 (48%) received triplet treatment as induction. Sixty-nine (79%) pts had ASCT, and overall response rate (ORR, partial response or better) post ASCT was 73%. For pts with HR FISH (defined as t(14;16), p53 del, 1q21 gain or 1p del) compared to SR FISH, the ORR post ASCT was 70% vs 77% (p = 0.67). OS from diagnosis was 93% at 3 years, 74% at 4 years and 51% at 5 years. Seven patients (8%) developed plasma cell leukemia, and there was no association between HR and SR FISH (p = 0.66). In multivariate analysis, ISS stage was an independent risk factor for mortality; pts with stage 3 had 7.3 times (CI: 1.16-36.4) and 5.7 times (CI: 1.63-20.0) the risk of mortality than pts with stage 1 and 2. Having an ASCT reduced mortality by 87% (CI: 0.04-0.41). Conclusions: Despite the use of novel therapies the OS at 5 years of our pts with MM was not significantly improved compared to SEER data from 1992-2013 (51% vs 48.5%). Pts with t(11;14) who had ASCT had increased survival compared to those who did not. Our results suggest that t(11;14) may confer a worse prognosis. Further prospective studies evaluating the risk of t(11;14) are warranted.
Stromal infiltrating CD8+ and CD20+ lymphocytes and CD204+ M2 macrophages but not PD-L1 expression on tumor cells are prognosticators for patients with resectable thymic carcinoma.
Authors: Sato Jun , Motoi Noriko , Kitano Shigehisa , Yamamoto Noboru , Watanabe Shunichi , Ohe Yuichiro , Hiraoka Nobuyoshi
Published: September 2018

e20002

Background: Thymic carcinoma (TMCA) is a rare malignant disease, and standard systemic chemotherapy has not been established. Tumor microenvironment (TME) that consists of tumor cells (TCs), tumor-infiltrating immune cells (TIICs) and stromal cells is thought to be an important biological feature of cancer behavior. The aim of this study was to analyze TME of TMCA, focusing the TIICs’ characteristics and the PD-L1 expression in the TC and TIIs and their impact on the clinical outcome. Methods: Fifty-one TMCA specimen with median observation period 33.8 months (range: 0.2-351) were collected. We evaluated the immunohistochemical profile of TIIs using antibodies against CD8, CD20 and FoxP3 for TIICs, CD204 for tumor-associated macrophages (TAMs), and PD-L1(SP142) expression of both TIICs and TCs using representative FFPE specimen. The density (median positive cell number per 1 mm2) of TIICs or TAMs was evaluated in intraepithelial (IE) and tumor stromal (TS) areas separately by using an automated image analyzer. Statistical analysis was performed using SPSS (version 24) and used p < 0.05 as significant level. Results: 51.9% (n = 26) had recurrent disease, and 31% (n = 16) survive without tumor. Of recurrent group, the density of CD8+ (54.5 vs 432) and CD20+ (35.9 vs. 516) TIIs, as well as the CD8+/CD204+, CD20+/CD204+ ratio in TS were significantly lower and FOXP3+ (590 vs 176) in TS was higher than that of non-recurrent group (Mann-Whitney U-test, two-sided). In the IE area, the lower CD20+/CD204+ ratio associated with recurrence. The CD20 and FOXP3 TIIs in TS also associated with the overall survival. There was no significant association between CD204 or PD-L1 expression and patients’ outcome. Conclusions: Our retrospective study showed the density of CD8+, CD20+ and FOXP3+ stromal-infiltrating lymphocytes and CD204+ M2 macrophage were prognostic factors for patients with resectable TMCA. Host immune reaction in TME might be one of the important prognostic factors for TMCA.
Immunohistochemical staining for programmed cell-death ligand 1 (PD-L1) in malignant thymoma and thymic carcinoma.
Authors: Shimanovsky Alexei , Cartun Richard , Fiel-Gan Mary , Mandich Daniza , Earle Jonathan , Salner Andrew L. , Collins Katrina , Otterson Gregory Alan , Chu Benjamin F.
Published: September 2018

e20003

Background: Recent development of anti-PD-1/L1 antibodies has demonstrated activity in various neoplasms. Thymic malignancies (TMS) are rare and treatment in advanced disease is limited. To evaluate the potential impact of anti-PD-1/L1 therapy in TMS, we examined the expression of PD-L1 in previously resected thymoma (TM) and thymic carcinoma (TC). Methods: We examined resected specimens from patients at Hartford Hospital with TM and TC between 2000 and 2014. Expression of PD-L1 was evaluated on formalin-fixed paraffin-embedded tissue. Immunohistochemical testing was done using four different clones of PD-L1 antibodies on the Leica Bond Max automated platform. The four clones include: E1L3N (Cell Signaling Technology), 28-8 (Epitomics) and SP142 (Spring Bioscience), and CAL10 (BioCare). PD-L1 expression was evaluated based on the percentage of tumor cells positive and their intensity graded as negative, weak (1+), moderate (2+), and strong (+3). The scoring was performed by three pathologists and was blinded for clinicopathologic data and antibody clones. Results: We evaluated a total of 29 patients, including 26 patients with TM and 3 with TC. Among the 29 available specimens, 12 had completed PD-L1 expression assessment at the time of submission. PD-L1 expression is present in 75-100% of the evaluated patients. All had positive PD-L1 staining by SP142 and CAL10. Three patients showed strong intensity by CAL10, and one by SP142. E1L3N and 28-8 had positive PD-L1 expression in 9 and 8 patients respectively with weak/moderate intensity. SP142 and CLA10 demonstrated the strongest concordance (R2 = 0.91) but there was significant variation between antibodies (R2 = 0.31-0.91). No correlation was detected between tumor grade and PD-L1 expression. There were focal areas that lacked expression in all of the evaluated specimens. Conclusions: There is increased expression of PD-L1 in TMS. The level of PD-L1 expression varies between the four PD-L1 antibodies. Increased PD-L1 expression provides evidence for the use of PD-L1 inhibitors in TMS. The variable staining highlights the heterogeneity of TMS and challenges in developing predictive biomarker in this cancer.
Noninvasive EGFR testing in plasma circulating free DNA (cfDNA) by a new diagnostic method to detect point mutations, deletions and insertions associated to non small cell lung cancer: CLART CMA EGFR LB.
Authors: Sanchez Marta , Sanz Maria Jesus , Aragon Ana , Manjon Nuria , Carrillo Jaime , Romero Atocha , Provencio Mariano , García-Barberán Vanesa , Caldes Trinidad , Rodriguez-Peralto Jose Luis , Hernandez-Losa Javier , Cospedal Rosario , Villahermosa Maria Luisa
Published: September 2018

e20008

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) with activating EGFR gene mutations. Histological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible in advanced NSCLC patients. Moreover, a high percentage of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs such as T790M mutation. CLART CMA EGFR LB is a novel diagnostic assay able to detect 39 high-prevalence mutations associated with sensitivity or resistance to tyrosine kinase inhibitor treatment. Methods: A highly sensitive and specific method was developed for detection of EGFR mutations (G719X, T790M, L858R, L861Q, insertions in exon 20, and deletions in exon 19) in plasma samples (cfDNA). CLART CMA EGFR LB is based on a preamplification step with a multiplex ARMS-PCR and microarray detection system. Clinical testing was performed using 51 clinical plasma samples: 27 contained L858R, T790M, and deletions in exon 19; 24 contained wild type alleles. 20 samples were cross checked by next generation sequencing performed on the PGM platform (Ion Ampliseq™ Custom, deep-coverage 15000x). Results: Analytical sensitivity was assessed using recombinant plasmids, results ranged between 10-1000 copies/5µl for all mutations. cfDNA from cell lines with the mutations L858R, T790M and deletions in exon 19 at different frequencies (cfDNA Reference Standard, Horizon) were assessed. The system was able to detect the mutations present in a frequency of 2%. The analysis of 51 samples allowed establishing the diagnostic sensitivity and specificity in 93.33% and 100% respectively. CLART CMA EGFR LB showed similar analytical and diagnostic sensitivity than NGS for detecting L858R, T790M and deletions in exon 19. Conclusions: Our data support the use of CLART CMA EGFR LB for clinical testing prior to the selection of the appropriate treatment in NSCLC, monitoring the patient evolution and the emergence of resistance mutations such as T790M in plasma samples.
Novel prognostic markers for epithelioid malignant pleural mesothelioma.
Authors: Bruno Rossella , Poma Anello Marcello , Alì Greta , Giannini Riccardo , Puppo Gianfranco , Melfi Franca , Lucchi Marco , Mussi Alfredo , Falcone Alfredo , Chella Antonio , Fontanini Gabriella
Published: September 2018

e20028

Background: Malignant pleural mesothelioma (MPM) is a deadly asbestos related tumour. The median survival is about 12 months and MPM patients are usually offered with a multimodality approach. With regard to chemotherapy the treatment of choice is the antifolate pemetrexed in combination with cisplatin or carboplatin. The high variability in the survival of patients with similar characteristics make it challenging to identify reliable prognostic markers. In this study we sought novel prognostic markers for epithelioid MPM, by investigating the expression levels of 117 genes involved in cancer. Methods: Gene expression analysis was evaluated on RNA from 15 epithelioid MPM patients undergoing pleurectomy (fomalin-fixed paraffin-embedded tissue) using a custom panel on nanoString platform. All patients were treated with cisplatin plus pemetrexed chemotherapy. Patients were divided in two groups for each gene (high and low expression level) on the basis of median. The correlation between gene expression, overall survival (OS) and progression free survival (PFS) was carried out by Log-rank test (Kaplan Meier). Results: A poorer OS was associated with a higher expression of 3 genes: MCM2 (p-value 0.005), PLK1 (p-value 0.005) and CCNB2 (p-value 0.01). These findings were in agreement with TCGA data ( PROGgeneV2: enhancements on the existing database. BMC Cancer 2014). Moreover, PLK1 showed a significant correlation also with PFS (p-value 0.01). Conclusions: Several biomarkers have been suggested as MPM prognostic factors, but sensitive and specific ones for the clinical practice are still missing. Despite the relatively small number of tissue samples, related to the rarity of this tumour, we identified 3 genes as potential prognostic markers. MCM2 is involved in the initiation of genome replication, PLK1 and CCNB2 regulate cell cycle by promoting mitosis. All these genes proved to be not only useful prognostic indicators but also promising therapeutic targets as reported in functional studies on different cancer models. The validation of these new markers, particularly of PLK1 which is correlated also with PFS, may improve the prognostic stratification at diagnosis, providing information valuable in the management of MPM patients.
Regional variation in high-resource utilization among lung cancer-related emergency department visits in the United States.
Authors: Ruban Cynthiya , Kowalkowski Marc , Blanchette Christopher Michael
Published: September 2018

e20038

Background: Regional variation is common in oncology care but is not defined for emergency department (ED) care for cancer patients, particularly patients with lung cancer (LC) who regularly utilize EDs for management of acute cancer or treatment related illness. This study analyzed regional variation and other factors associated with high total episodic charge (≥75th percentile; HTC) among LC patients evaluated in the ED in relation to discharge or admission. Methods: A retrospective study of LC-related ED visits in the US was conducted using the 2013 Nationwide ED Sample. LC-related ED visits among adults were identified by LC-specific Clinical Classification Software codes (CCS = 19; mapping to ICD-9 = 162.x, 209.21, 231.2, V10.11). Multivariable logistic regression analyzed the association between patient and hospital factors and HTC, weighted to represent ED visits nationwide. Results: Among 373,761 LC-related ED visits, 134,838 (36%) were treated and discharged and 238,923 (64%) were admitted (ranging from 51% (West [W]) to 76% (South [S]). HTC was ≥$5,655 (median = $2,993) for ED discharges and ≥$54,760 (median = $29,590) for admissions. The proportion of visits with HTC differed by region and admission status (discharged: 7% [W] to 27% [S]; admitted: 20% [Midwest] to 39% [W]). After adjusting for clinical and hospital factors associated with increased HTC odds (metastases, common acute comorbid disorder [chest and abdominal pain, pneumonia, sepsis, respiratory failure], diagnostic radiology use, thoracic/other surgery, chemo/radiotherapy, length of stay, primary payer, and hospital ownership, location and teaching status), significant HTC variation remained by hospital region with opposing relative HTC odds among discharged and admitted patients (discharged: W v S OR = 0.3 95%CI = 0.2-0.6, Northeast v S OR = 0.5 95%CI = 0.3-0.7; admitted: W v S OR = 3.8 95%CI = 2.5-5.7). Conclusions: Regional variation in HTC suggest differences in ED use and management patterns for LC and may reflect quality of care concerns. Clinical outcome linkage (including ED revisit tracking) is needed to better define the impact of variation and develop strategies to improve care for patients with LC.
Survival prediction using time-evolving tumor load: An approach to rationally design treatment sequencing, staging, and dosing strategies for oncology combinations.
Authors: Dunyak James , Onishchenko Dmitry , Masson Eric , Helmlinger Gabriel , Tomkinson Helen , Abdallah Kald , Stanski Donald , Al-Huniti Nidal
Published: September 2018

e20040

Background: Longitudinal tumor burden has long been used for the clinical diagnosis, staging, prognosis and treatment of non-small cell lung cancer (NSCLC). Tumor burden and growth rate correlate directly with survival and RECIST (measurement of tumor) is widely used as a surrogate endpoint. RECIST doesn’t take into account the impact of the therapy on the speed of growth over time, and poorly correlates with survival, especially in IO therapies. Surrogate endpoints such as progression-free survival (PFS) or dichotomous RECIST-based overall response rate (ORR) allow early assessment of efficacy based on reduced study population size. Unfortunately, ORR and PFS are poorly predictive of OS in NSCLC. This well-known loss of information during categorization emphasizes the potential benefits of continuous tumor load modeling. Methods: This research provides a statistically valid basis for modeling and interpretation of longitudinal response dynamics, in the context of time-to-event (survival) censoring, through development of a joint longitudinal/event model. Using clinical data from the Phase 3 IPASS study of Iressa (gefitinib), we build a generalizable model relating tumor load dynamics to a time-evolving hazard of progression. Results: Using longitudinal data from other smaller and shorter studies, we identify the time-progression of patient’s risk, including post-treatment time of minimum hazard of progression and the time when hazard rapidly increases. This is applied at both the population strata and individual patient level to assess different treatment paradigms. The model shows that EGFR-mutated patients on gefitinib have stable hazard of progression for about 8 months, as which point hazard increases rapidly. EGFR-mutated patients treated with carboplatin/paclitaxel started with a 72% higher initial progression hazard which then increased rapidly after 4 months. Conclusions: Because of their continuous-in-time nature, joint longitudinal/event models provide a basis for exploring the complex timing issues in oncology treatment sequencing, treatment staging strategies for combinations, and dosing regimes.
A new diagnostic method based on RT-PCR and CLART technology for non-small cell lung cancer (NSCLC) to detect major EML4-ALK and ROS.1 translocations: CLART CMA ALK and ROS.1.
Authors: Manjon Nuria , Martinez Jaime , Garcia Gonzalo , Aragon Ana , Carrillo Jaime , Rodriguez-Peralto Jose Luis , Antunez Lopez Jose Ramón , Hernandez-Losa Javier , Cospedal Rosario , Villahermosa Maria Luisa
Published: September 2018

e20045

Background: EML4-ALK and ROS1 translocations represent 3-6% and 1-2% of NSCLC patients, respectively. These patients would benefit for a tyrosine kinase inhibitor therapies. Currently, the gold standard for ALK and ROS.1 detection are break-apart fluorescence in situ hybridization (FISH) or inmunodetection (IHC) of the chimeric fusion proteins. FISH has both high sensitivity and specificity, although often present technical interpretation problems due to signal instability and scoring. IHC is a rapid and low cost technique; however it presents several challenges regarding sensitivity and reproducibility. CLART CMA ALK & ROS.1 kit is based RT-PCR and detection of the amplified product was carried out by a low-density microarray platform: CLART (Clinical Arrays Technology) of major fusion transcripts of EML4-ALK and ROS.1 translocations ( V1: E13;A20 , V6: E13; ins69;A20 , V2: E20;A20 , V3a: E6:A20 , V3b: E6;ins33 A20 ,V5a: E2;A20 and V5b: E2;ins117A20 for EML4-ALK and SDC4-ROS1 S2;R32/ S2;R34, CD74-ROS1 C6;R34 and SLC34A2-ROS1 S4;R32/S4;R34). Methods: The translocations analysis was performed with CLART CMA ALK & ROS.1 kit. Clinical testing was performed using the RNA extracted from 115 samples of NSCLC patients being 34 patients with translocations detected in ALK or ROS.1 genes and 81 patients without any translocations. The results were cross-checked by comparison to Next GenerationS methodology performed on the PGM platform with the Ion Ampliseq Panel Oncomide Solid Tumor Fusion and the concordance was 95.6%. Results: Analytical sensitivity was assessed using fusion transcripts cloned in recombinant plasmids. Results ranged from 10 to 100 copies/5µl of recombinant plasmids. The analysis of 115 clinical samples allowed establishing the diagnostic sensitivity and specificity in 90.9-100% and 99-100% respectively. Conclusions: CLART CMA ALK & ROS.1 emerges as a suitable alternative of FISH/IHQ for diagnosis of the most common translocations in EML4-ALK and ROS.1 genes in NSCLC samples and therefore selecting patients that would best benefit from a target therapy.
Treatment outcome and lung toxicities of volumetric modulated arc therapy in the treatment of inoperable non-small-cell lung cancer patients.
Authors: Xie Congying , Lin Baochai , Jin Xiance
Published: September 2018

e20046

Background: Volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time and less MU compared to conventional intensity-modulated fixed-field treatment (IMRT) in the treatment of inoperable non–small-cell lung cancer (NSCLC). However, published data on clinical outcome and lung toxicities of VMAT in the treatment of NSCLC are scarce. Methods: The clinical outcome, acute and late pulmonary toxicities of 134 consecutive inoperable NSCLC patients treated by VMAT with or without concurrent chemotherapy were retrospectively reviewed. Univariate and multivariate analysis on the dosimetric and characteristic factors associated with acute radiation pnuemonitis (RP) and pulmonary fibrosis were evaluated. Results: The average prescriptions dose to these patients were 5736.38±649.11 cGy (range from 5200 to 6400 cGy) with a median follow-up of 18.6 months (range, 2–45 months) for the enrolled 134 patients. The two-year progression-free survival (PFS) and overall survival (OS) for all patients was 18.2% and 38.4% with a median PFS and OS of 7.6 months and 18.6 months, respectively. There were 14 and 12 out of 134 patients experienced grade III/higher RP (10.45%) and pulmonary fibrosis (8.95%), respectively. Age, chemotherapy exposure, dose prescription, V10, V13, V20 and V30 were significantly associated with acute RP. Dose prescription was related to pulmonary fibrosis. Only V13 (p = 0.02) and age (p = 0.02) were independently associated with acute RP according to multivariate analysis. Based on regression analysis, the threshold for lung dosimetric metrics V10,V13,V20 andV30 were 50%,40%,28% and 18% in VMAT treatment of NSCLC to limit the RP rate < 10%. Conclusions: VMAT can be delivered safely with acceptable acute and late toxicities for NSCLC. Lung dosimetric metrics were valuable in predicting acute RP. A threshold of 40% of Lung V13 in VMAT treatment of NSCLC was helpful to limit the RP rate < 10%.
Factors associated with the growth of ground-glass opacity nodules on chest computed tomography.
Authors: Lee Jin Hwa , Bae Ji Yun , Han Ye ji , Ryu Yon Ju , Shim Sung Shine , Kim Yookyung , Chang Jung Hyun
Published: September 2018

e20051

Background: Chest computed tomography (CT) has become increasingly popular for screening and various reasons, and many cases of ground-glass opacity pulmonary nodules (GGN) that cannot be detected by simple chest radiography have been found incidentally. However, the natural history of GGN is not well understood and guidelines for the evaluation and follow-up of GGN have not yet been established yet. The purpose of this study was to investigate the clinical and CT scan characteristics associated with the growth of GGNs. Methods: We retrospectively reviewed GGN on chest CT performed between March 2011 and February 2014 at a tertiary referral hospital. Data were collected for the patient's age, sex, underlying lung disease, history of malignancy or comorbidities, size, border, number of GGN and presence of solid portion in GGN. For each GGN, an increase in size over time was investigated. We applied a Cox regression analysis to identify factors associated with the growth of GGN. Results: In a total of 504 patients, 916 GGN were found on chest CT. The mean age of the subjects was 59.6 years and 37% of men. The mean follow-up was 17.1 months. Cox regression analysis was performed on age, sex, history of malignancy, maximum diameter of GGN, number of GGN, margins of GGN, and presence of solid portion in GGN. History of malignancy (adjusted hazard ratio [HR] 1.770, 95% confidence intervals [CI] 1.049-2.986, p = 0.032), solitary nodule (adjusted HR 2.335, 95% CI 1.401-3.867, p = 0.001), and nodules with the longest diameter of 10 mm or more (adjusted HR 1.833, 95% CI 1.032-3.253, p = 0.039) were associated with the growth of GGN. Conclusions: A history of malignancy, solitary nodule, and nodules with the longest diameter of 10 mm or more may increase in size in the future. Therefore, the history of malignancy and the size and number of nodules should be considered to determine the duration of follow-up and appropriate biopsy timing.
The role of race and economic characteristics in the presentation and survival of patients with surgically-resected non-small cell lung cancer.
Authors: McKie Kerri , Varlotto John M. , Voland Rick , Flickinger John Charles , DeCamp Malcolm M. , Maddox Debra , Rava Paul , Fitzgerald Thomas J. , Walsh William Vincent , Liebmann James Edward , Uy Karl , Oliveira Paulo , Rassaei Negar , Wakelee Heather A. , Patel Manali I. , Zhang Jianying , Ali Suhail M. , Belani Chandra Prakash , Baima Jennifer , Stock Cameron
Published: September 2018

e20053

Background: To investigate the inter-relation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of surgically-resected lung cancer patients in nine different ethnic groups. Methods: A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses(MVA) were used to detect overall survival(OS) differences in the total surgical population (TS, N = 35,689) and in an early-stage (T1-T2 < 4cm N0) surgically-resectable population(ESR, N = 17,931). Results: In the TS population, as compared to Whites, Blacks and Hispanics were more likely to present with younger age, adenocarcinomas, less married partnerships, no insurance, fewer stage I tumors, and fewer nodes examined, but their surgical procedure types and OS/LCSS were the same. MVA demonstrated that lower OS was associated with males, single/divorced/widowed partnership, lower income(TS only), and Medicaid insurance. MVA also found that all ethnic groups had a similar (Hispanics, Blacks) or better OS compared to Whites. 90-day mortality and positive nodes were correlated with not having insurance and not being married, but not ethnicity. Conclusions: In TS and ESR groups, OS was not different in the two largest ethnic groups (Black, Hispanic) as compared to Whites, but was related to single/widowed/divorced status, Medicaid insurance, and income (TS group only). Nodal positivity was associated with patients who did not have a married partner or insurance suggesting that psycho-social variables may impact disease biology in addition to the known histopathologic and treatment variables in patients undergoing surgical resection of early-stage lung cancer.
Preexistence of CT findings with usual interstitial pneumonia (UIP) pattern correlates to radiation pneumonitis (RP) in non-small cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT).
Authors: Koyama Junji , Kitazono Satoru , Ariyasu Ryo , Saiki Masafumi , Sonoda Tomoaki , Kawashima Yosuke , Takano Natsuki , Oguri Tomoyo , Nishikawa Shingo , Yanagitani Noriko , Horiike Atsushi , Ohyanagi Fumiyoshi , Oikado Katsunori , Kozuka Takuyo , Nishio Makoto
Published: September 2018

e20063

Background: RP is a major toxicity commonly observed in NSCLC patients who receive CRT; RP prediction is a critical issue. Although preexisting interstitial pneumonia (IP) is considered as one of the risk factors of RP, the correlation between interstitial lung shadows (ILSs) in the pretreatment CT scan and RP is not well examined. Methods: We reviewed patients with stage III NSCLC who received CRT at our hospital from January 2011 until December 2014. The pretreatment CT scans were retrospectively evaluated, and preexisting ILSs were classified according to the ATS/ERS/JRS/ALAT statement for idiopathic pulmonary fibrosis (IPF) as follows: UIP pattern, possible UIP pattern, and others (not UIP pattern). The incidence, severity, and features of RP were compared between ILS patterns. Results: In total, 105 patients with stage III NSCLC had received CRT. ILSs in pretreatment CT scans were identified in 16 (15.2%) of 105 patients. Of all the identified patterns, one (0.9%) was UIP pattern, six (5.7%) were possible UIP pattern, and nine (8.6%) were not UIP pattern. Grade 3 or higher RP was observed in 2 of 7 (28.6%) patients with UIP pattern or possible UIP pattern and 1 of 9 (11.1%) patients with not UIP pattern ( P = 0.55). RP that extended outside the irradiation field like an acute exacerbation of IP was observed in 4 of 7 (57.1%) patients with UIP pattern or possible UIP pattern and 1 of 9 (11.1%) patients with not UIP pattern ( P = 0.106). Conclusions: Preexistence of ILSs classified as UIP pattern or possible UIP pattern should be considered as a risk factor for severe or extensive RP after CRT.