bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and demographic characteristics of CLL patients receiving first-line bendamustine plus rituximab using the Flatiron Health database.
Authors: Tang Boxiong , Gabriel Susan , Pathak Ashutosh K. , Brander Danielle M. , Zhou Jifang
Published: September 2018

e19010

Background: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world, with 20,110 new cases estimated for 2017 in the US alone. Combination therapy with bendamustine plus rituximab (BR) is among the approved first-line therapies for CLL patients without the 17p deletion. The purpose of this analysis was to characterize CLL patients receiving first-line BR therapy using real-world data. Methods: CLL patients (ICD-9: 204.1x or ICD-10: C91.1x, C83.0x) receiving first-line BR therapy between 11/01/2008 and 11/01/2016 were identified in the Flatiron Health electronic health records database. This database is a large, longitudinal, demographically and geographically diverse database consisting of 250 cancer clinics representing more than 1.5 million active US cancer patients. Results: Of the 2736 CLL patients in the database, 738 patients (male = 70%; mean age = 68.71 years, SD = 9.070) received first-line BR therapy. The majority of patients received treatment in a community setting (93%; 7% in academic hospitals). Prior to first-line BR therapy, immunoglobulin heavy chain variable region ( IGHV) mutation analysis was conducted in 21% of patients, of which 46% were IGHV mutated. Fluorescence in situhybridization (FISH) testing was conducted in 60% of patients: 17p deletion was detected in 8% and 11q deletion in 19%. Trisomy 12 and 13q deletion as a single abnormality was identified in 17% and 27% of tested patients, respectively. Conclusions: CLL patients from the Flatiron database initiating first-line BR therapy have an older median age, male predominance, and community-based treatment setting, which offers a more real-world patient population in comparison with patients reported from clinical trials. Less than a quarter of these CLL patients were tested for IGHV mutations, and only 60% were tested for FISH. The low frequency of testing prior to first-line therapy is similar to other published registry data. This representative patient population offers an insight into the real-world use of BR in CLL patients.
Frequency, cell lineage, and clinical correlates of lymphopenia in untreated T-cell lymphomas (TCL).
Authors: Denlinger Nathan , Hwang Sook (Susan) , Kline David , McLaughlin Eric , Fabbro Stephanie , Brammer Jonathan Edward , Mishra Anjali , William Basem M. , Porcu Pierluigi
Published: September 2018

e19023

Background: Pre-treatment lymphopenia (Lp) independently predicts survival in TCL. However, lack of knowledge about the lineage of the decreased lymphocyte subset(s) prevents hypothesis formulation on pathophysiology of Lp and its effect on survival. Methods: We retrospectively identified 331 adult patients (pts) with biopsy-proven, newly diagnosed TCL between 2001-2016 at OSU. Pts had no prior chemotherapy or immunosuppressive treatment (tx). Clinical data including flow cytometry (FC) at diagnosis were abstracted from the EMR. Lp was defined as absolute lymphocyte count (ALC) <1,000/µL. Cutaneous TCL (CTCL) stage was defined according to modified EORTC/ISLC criteria. Lymphocyte subsets were defined by FC and reported as proportions of ALC. We examined group differences with Fisher’s Exact or the Wilcoxon Rank Sum tests. Survival was analyzed using Cox regression models. Results: Of 331 pts with TCL, 102 were excluded due to prior tx or incomplete data. Of the 229 pts included, 67 had peripheral TCL (PTCL) and 162 had CTCL; 112 mycosis fungoides/sezary syndrome; 99 (61%) early stage (Stage IA-B), 22 (13%) advanced stage (Stage IIB-IVB), and 41 (26%) cutaneous CD30+ lymphoproliferative disorder (CD30+ LPD). Lp was present in 10% of CTCL, 8% in early stage, 22% in late stage, 12% of CD30+LPD, and 34% of PTCL, with overall frequency of 17%. After median follow up of 1,105 days, Lp was associated with worse progression-free survival (PFS) in CTCL pts with an unadjusted hazard ratio of 3.19 (p=0.19). Adjusting for stage and albumin level on multivariate analysis, Lp retained statistical significance for PFS (HR 3.46, p=.04). For the entire cohort, lymphopenia was associated with inferior OS (p=.0027). Analysis of lymphocyte subsets in late stage CTCL compared to early stage showed a significant decrease in B (CD19+) p=.014, NK (CD56+) p=.012, and CD8+ (p=.0045) cell populations. Conclusions: Lp was prevalent (10-34%) in our cohort of newly diagnosed TCL pts and was associated with worse OS. Lp was more prevalent and lymphocyte subsets were significant altered in pts with advanced stage CTCL. These findings will inform further investigations into mechanisms of Lp in TCL, and its potential as predictive biomarker.
Autologous stem cell transplantation as a treatment modality for type 1 cryoglobulinemia in monoclonal gammopathy of renal significance.
Authors: Richter Joshua Ryan , Wang Zhen , Vesole David H. , Biran Noa , Donato Michele , Rowley Scott D. , Skarbnik Alan P. , Pecora Andrew , Siegel David Samuel DiCapua
Published: September 2018

e19500

Background: Type I cryoglobulinemia (CRYO) can be driven by disorders such as plasma cell dyscrasias. Monoclonal gammopathy of renal significance (MGRS) represents a group of kidney disorders characterized by the presence of a paraprotein; though not fitting the criteria for a hematologic malignancy. There exists no standard approach to manage these patients. Our patient is a 56-year-old man who was initially evaluated for edema. Workup revealed worsening renal function and proteinuria (Figure 1). Renal biopsy revealed abundant cryofibrinogen deposits and cryoglobulinemic glomerulonephritis with membranoproliferative pattern. Bloodwork showed type I (IgG Kappa) CRYO. Bone marrow evaluation revealed 7% clonal plasma cells. Further evaluation did not confirm a diagnosis of myeloma. Methods: Treatment was initiated with bortezomib, cyclophosphamide and dexamethasone. After 3 cycles of therapy the patient had normalization of his creatinine and marked improvement in edema. Peripheral blood stem cells were mobilized following the administration of high-dose cyclophosphamide (2gm/m2) plus filgrastim. He was subsequently conditioned for transplantation with high-dose melphalan (200mg/m2; HDM) followed by autologous stem cell rescue. He tolerated the procedure well without any unexpected toxicities; achieving prompt hematologic recovery Results: Evaluations post transplant revealed resolution of any circulating cryoglobulins and reduction in proteinuria. At 1 year post transplant, the patient has returned to his premorbid condition. Conclusions: Type 1 CRYO associated MGRS represents a complicated disorder for which there is no consensus treatment approach. As this process may be driven by clonal plasma cells, classical anti-myeloma therapy may provide a strategy for management. Given the typical low plasma cell burden in these patients, HDM has the potential to offer deep and durable remissions. Prospective studies are needed to validate this approach. [Table: see text]
Unusual disease characteristics of multiple myeloma in eastern North Carolina.
Authors: Addepalli Srikala , Brigham Denise , Liles Darla K.
Published: September 2018

e19512

Background:Multiple Myeloma (MM) is a relatively common malignancy in Eastern NC, especially in African American population. There have been several advances in treatment of MM but it is unclear how well current therapies are being utilized and what barriers prevent this. Our goal was to identify any unique clinical and epidemiological features of this disease in our patient population as this may help us to improve outcomes. Methods: Demographics, clinical features, FISH/ Cytogenetic features, clinical outcomes of the patients enrolled on MMRF CoMMpass study at our institution were reviewed and analyzed to identify any unusual features in our dataset. Results:The median age at diagnosis of MM is 69 years. There was a higher proportion of younger patients in our dataset, 40% of our patients were < 60 years and 11% of patients were < 40 years which may point to environmental and genetic factors in this population and needs to be studied further. About 20% of patients with MM are reported to have Light Chain Myeloma (LCM) while 30% patients had LCM in our dataset. More patients had a higher stage of disease, ISS stage III at diagnosis, 72%.The benefits of Autologous Stem Cell Transplant (ASCT) in management of Multiple Myeloma is well established but only 22% of the patients had ASCT as part of their management. This appears to be secondary to multiple factors including comorbidities, socioeconomic factors such as financial concerns, difficulty with access to treatment and availability of care givers Conclusions:There is a disproportionately high proportion of younger patients with Multiple Myeloma in Eastern NC, especially with LCM. The environmental and genetic factors responsible for this need to be studied further. Many patients have a high tumor burden at diagnosis. Improvement in access to care, enhancement of provider education, collaboration with regional oncologists and study of novel drug combinations to achieve deeper and more durable responses may help improve outcomes for this treatable malignancy. "These data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives (https://research.themmrf.org and www.themmrf.org)”.
Treatment outcomes and healthcare resource utilization (HRU) in patients (Pts) with newly diagnosed multiple myeloma (NDMM) with lenalidomide (LEN) only or no maintenance: Connect MM registry.
Authors: Rifkin Robert M. , Jagannath Sundar , Durie Brian G. , Shah Jatin J. , Narang Mohit , Terebelo Howard R. , Gasparetto Cristina , Toomey Kathleen , Hardin James W. , Wagner Lynne I. , Parikh Kejal , Abouzaid Safiya , Srinivasan Shankar , Kitali Amani , Zafar Faiza , Abonour Rafat
Published: September 2018

e19527

Background: Maintenance therapy (MT) post autologous stem cell transplant (ASCT) improves clinical outcomes in MM, but the effect of continued treatment on HRU is largely unknown. In the Connect MM registry, 1493 NDMM pts are enrolled in cohort 1 (Sept 2009–Dec 2011) in a mostly community setting; of pts receiving MT, 70% received LEN-only MT. The effect of LEN-only vs no MT on progression-free survival (PFS), overall survival (OS) and HRU was evaluated. Methods: Adults with NDMM who completed induction and single ASCT without subsequent consolidation and received LEN-only or no MT were compared. HRU (hospitalization, surgery/procedures, concomitant medications [growth factor, bisphosphonate, neuropathic pain medication]) was assessed from 100 days post-ASCT to end of years 1 and 2. Data cutoff was Jan 7, 2016 (median follow-up of 39.3 mo). Results: 421 pts met the analysis criteria stipulated above. Of these, 180 received LEN-only MT, and 165 did not receive MT. Median age was 60 y (range, 24-78 y); 60% were men; 86%, white. Besides serum creatinine, calculated International Staging System stage, history of monoclonal gammopathy of unknown significance, del(17p), and induction regimen, characteristics were similar across groups. PFS and OS were significantly improved with LEN-only vs no MT (Table). Rate of hospitalization/100 person-years (PY) was similar across groups ( P= NS, all comparisons) at the end of years 1 and 2. Median duration of hospitalization was numerically longer with no MT. Procedures/surgeries and concomitant medication use were similar across both groups at the end of years 1 and 2. Conclusions: For pts with NDMM, LEN-only vs no MT significantly improved survival outcomes without affecting HRU. Clinical trial information: NCT01081028. [Table: see text]
Analysis of efficacy and safety of POM as a replacement therapy for lenalidomide for relapsed/refractory multiple myeloma pts refractory to a lenalidomide-containing combination regimen.
Authors: Berenson James R. , Cohen Alexa , Spektor Tanya M. , Lashkari Ashkan , Mackintosh Roy , Bessudo Alberto , Robinson Michael Oren , Jhangiani Haresh S. , Gabrail Nashat Y. , Nakhoul Ibrahim , Kubba Samir V. , Neidhart Jeffrey D. , Maluso Tina , Swift Regina A. , Vescio Robert A. , Eshaghian Shahrooz
Published: September 2018

e19528

Background: Pomalidomide (POM) is a third –generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) for patients (pts) previously treated with bortezomib and lenalidomide (LEN) and in combination with dexamethasone it has been shown to overcome resistance in RRMM. In this phase 2 trial, we are evaluating the efficacy, safety and tolerability of POM as a replacement therapy for LEN for pts who have progressed receiving a LEN combination regimen. Methods: This is a phase 2, multicenter, open-label and non-randomized study. Pts who have failed a combination regimen containing LEN were treated with POM along with all of the other drugs previously used in the regimen. POM administered orally (dose is determined based on the previous regimen) on days 1-21 of a 28-day cycle, whereas other drugs are administered using the same schedule(s), dose(s) and drug combination as the last LEN-containing regimen that the patient received and failed. The planned enrollment on the study will be 45 pts. Results: To date, a total of 29 pts have been enrolled, 25 pts are evaluable and 12 pts have discontinued treatment. Of the evaluable pts, 9 (36%) and 16 (64%) received 3mg and 4mg of POM, respectively. The median age of all pts was 72 years (range, 52-81), and 17 (68%) were males. Pts have received a median of 3 prior treatments (range, 1-7). The median follow-up time for all pts is 3.1 months (range, 0.2-8.1). Amongst evaluable pts, 5 (23.8%) pts achieved at least a minimal response, 10 (47.6%) pts showed stable disease while 6 (28.6%) pts exhibited disease progression. At the time of data cutoff, only 17 pts have completed more than 1 full cycle of treatment; and, thus, the overall response and clinical benefit rates are fairly low (14.3% and 23.8%, respectively) but expected to improve with further follow up. The median PFS for the cohort was 7.6 months. Common ≥ Gr3 adverse events were neutropenia (8%), hypomania (4%) and leukopenia (4%). Conclusions: We show thatPOM appears to be promising replacement therapy for LEN in RRMM pts who have progressed within receiving a LEN combination regimen.
Efficacy and toxicities of gemcitabine and cisplatin combination chemotherapy in advanced thymoma and thymic carcinoma.
Authors: Fang Jian , Wang Yang
Published: September 2018

e20007

Background: Thymoma and thymic carcinoma are rare thymic epithelial tumours. This study investigated the efficacy of first-line gemcitabine and cisplatin combination chemotherapy in advanced thymoma and thymic carcinoma Methods: Retrospective review of patients with histologically-confirmed invasive, metastatic thymoma or thymic carcinoma treated with gemcitabine plus cisplatin as a first-line therapy between August 2008 and February 2016 at the Department of Respiratory Medicine II Peking University Cancer Hospital and Institute. The objective response rate was the primary end point. Results: Forty patients, 13 with thymoma and 27 with thymic carcinoma, were identified. Nine received gemcitabine and cisplatin combined with Endostar (injectable recombinant human Endostatin); 31 received gemcitabine and cisplatin only. Of the 13 patients with thymoma, four (30.8%) achieved a partial response (PR) and nine (69.2%) had stable disease (SD); no patients had a complete response (CR) or progressive disease (PD). Among the 27 patients with thymic carcinoma, 13 (48.1%) achieved a PR, 12 (44.4%) had SD and two (7.4%) had PD; no patients had a CR. In thymic carcinoma, progression free survival (PFS) was 25 months and median survival (OS) was 41 months; in thymoma, median PFS was 29 months and median OS was 77 months. As no patients achieved a complete response, objective response was defined as partial response in this study. Conclusions: This retrospective analysis indicates gemcitabine plus cisplatin has moderate efficacy and could represent a suitable first-line therapy for thymic carcinoma and thymoma, especially for patents who cannot tolerate anthracyclines. [Table: see text]
Prophylactic cranial irradiation (PCI) in limited-disease small-cell lung cancer (LD-SCLC) patients with brain imaging.
Authors: Mamesaya Nobuaki , Wakuda Kazushige , Kotake Mie , Fujiwara Takumi , Kobayashi Haruki , Kawamura Takahisa , Nakashima Kazuhisa , Omori Shota , Ono Akira , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Takahashi Toshiaki
Published: September 2018

e20010

Background: PCI is recommended for patients with LD-SCLC who have a good response to initial therapy. But this recommendation has been made based on studies in which brain imaging was not a standard component of initial staging or follow-up. The aim of this study was to evaluate the efficacy of PCI for LD-SCLC patients with brain MRI immediately before PCI administration. Methods: This single-center, retrospective study included patients with LD-SCLC who achieve a good response to initial therapy without BM confirmed by MRI between 09/2002 and 06/2015. Responses were classified as CR and PR, according to RECIST. We categorized these patients into three groups: C: patients who achieved CR and received PCI; P: patients who achieved PR and received PCI; N: patients who did not receive PCI, regardless of responses. We compared OS, progression free survival (PFS), and the cumulative incidence of BM at 3 years (3yBM) among these groups. Results: A total of 79 patients were included in this study. At baseline, age and PS differed significantly between C and N. In P, patients were also younger than N. Although there were no statistical significances in OS and PFS between C and N, differences in 3 years OS rate and median PFS were numerically large. The 3yBM in C revealed marginal significance compared with N. However, No differences were observed with OS, PFS, and 3yBM between P and N. Conclusions: PCI may not add clinical benefit to LD-SCLC patients who did not achieve CR after initial therapy if absence of BM could be confirmed by MRI immediately before PCI administration. [Table: see text]
Bone marrow examination (BMex) in staging of SCLC after implementation of PET/CT scan.
Authors: Holmskov Hansen Karin , Eriksen Mette Boes , Schytte Tine , Hansen Olfred
Published: September 2018

e20014

Background: Correct staging of small cell lung cancer (SCLC) in limited disease (LD) or extensive disease (ED) is crucial as it has an impact on the therapeutic decision-making. The staging procedures in SCLC in the late 1990s included chest X-ray, blood samples, abdominal ultrasonography (UL), and iliac crest BMex. The aim of this study was to evaluate the continued eligibility of performing BMex in patients (ptt) with SCLC as a routine staging procedure, and to see how often therapeutic decisions were influenced by a positive BM before and after the PET/CT scan era. Methods: All diagnostic and staging procedures were registered in ptt with SCLC referred to our department from 1995 to 1999 in cohort 1 (C1). Cohort 2 (C2) included SCLC patients referred from 2009 to 2013. In C2 results of PET/CT in terms of bone metastases were related to results of BMex. Results: In C1 194 ptt was referred with 136 (70%) having ED. BMex was omitted in 32 (17%) fragile ptt having known ED while all LD ptt underwent BMex. BM involvement was seen in 37 (23%) of all 162 BMex and 36% of the 104 ED ptt examined. When BM was negative the staging of ED was due to other imaging. The BM had an impact on therapeutic decision-making in 5 (4%) of 136 having ED and 5 (3%) of 162 BMex. In C2 211 ptt of 292 (72%) had ED and 203 (70%) of all ptt underwent BMex. BM biopsy was done in 137 (65 %) ED and in 66 (69 %) LD. Of 137 ED ptt BM involvement was found in 31 (23 %) cases. A PET/CT scan was performed in 13 (42 %) of these ptt of which bone metastases was found in 12 (92 %). One patient (8%) had a PET/CT without bone lesions. Bone metastases were seen at PET/CT scan in 61 ptt in C2, of these 22 (36%) had negative BM, whereas 12 (20%) had BM involvement and in 3 ptt (5%) BMex were inconclusive. No BMex was performed in 24 ptt (39%). BMex had an impact on therapeutic decision-making in 3 (1.4%) of 211 having ED and 5 (2.5%) of 203 BMex. Conclusions: Due to staging by PET/CT and CT scan in SCLC ptt the impact of BMex in the therapeutic decision-making has decreased and fewer ptt are undergoing BMex. Though a negative PET/CT cannot exclude BM involvement BMex may be considered omitted.
Immunogenomic profiling of non-small cell lung cancer: The ICON project.
Authors: Sepesi Boris , Lacerda Lara , Zhang Jianjun , Bernatchez Chantale , Karpinets Tatiana , Vaporciyan Ara A. , Wistuba Ignacio Ivan , Roarty Emily , Heymach John , Gibbons Don Lynn ,   ICON Team
Published: September 2018

e20034

Background: Previous attempts to define tumor immune environment in non-small cell lung cancer (NSCLC) did not present comprehensive analyses. We established immunogenomic profiling project of NSCLC (ICON) to integrate immune, proteomic, genomic, transcriptomic, demographic, clinical, pathologic, and outcome data from surgically resected lung cancers. Methods: Tumor, normal lung tissue, and blood are collected at the time of surgery and blood after surgery up to 1 year. Samples are processed for tumor infiltrating lymphocyte (TILs) isolation and expansion; generation of patient derived xenografts (PDX), immunohistochemical (IHC) evaluation of immune cells and markers, genomic and proteomic analyses. Results: 73 (75%) out of 98 enrolled patients, median age 66 years, contributed samples to ICON; 33 (46%) males, 62 (85%) former smokers, 11 (15%) never smokers. 50 (68%) had adenocarcinoma, 17 (23%) squamous cell carcinoma, 3 (4%) small cell, and 3 (4%) pleomorphic carcinoma. 30 (41%) had stage I, 28 (38%) stage II, and 14 (19%) stage III disease, and one stage 4; 9 (12%) patients received neoadjuvant chemotherapy. Median tumor size was 4.0 cm and 67 (92%) underwent R0 resection. TIL expansion was successful in 47/67 (70%) cases. Phenotypic and functional analysis of freshly isolated and cultured TIL is ongoing. Preliminary results show suppression of intratumoral CD8+ cells as demonstrated by low perforin (p = 0.0002) and high CD8+ PD1 (p = 0.0007) levels as compared to normal tissue; however tumor CD8+CD28 co-stimulatory molecule expression was high p = 0.0003. PDX success rate has been 27%. IHC analyses show higher CD8+PD1, CD3, CD8+BTLA expression in SCC than in adenocarcinoma (p = 0.05). Exome sequencing and RNA sequencing from 19 patients show median mutation burden 466/tumor. Subclonal analysis, neoantigen prediction and expression status of predicted neoantigens are ongoing. Conclusions: ICON is an ambitious multi-team project designed to integrate wide range of tumor related data. Preliminary analysis demonstrates the project to be feasible with high rate of data acquisition. Tumors profiled from ICON will serve as a reference for the upcoming neoadjuvant single and dual checkpoint immunotherapy trial.
Multifocal adenocarcinoma of the lung: Factors predictive for local therapy.
Authors: Mooradian Meghan , Price Melissa C , Muzikansky Alona , Lennes Inga Tolin , Lanuti Michael , Willers Henning , Digumarthy Subba , Sequist Lecia V.
Published: September 2018

e20041

Background: Multifocal Adenocarinoma (MAC) of the lung is a clinical entity of multiple synchronous or metachronous, often ground-glass opacities (GGO) on CT scan, typically indolent-behaving cancers. There is a paucity of clinical data to guide treatment decisions. MACs are often monitored via serial imaging with local therapy (radiation, surgery) employed at the discretion of the clinician. We sought to examine factors predictive of local therapy (Tx) at our institution, to develop standardized objective radiolographic parameters to guide treatment. Methods: We retrospectively reviewed pts seen in the MGH Thoracic Oncology Clinic from 2009-15. 39 pts with MAC were identified and serial CT scans were reviewed, assessing up to 5 nodules per pt. We excluded pts presumed to have MAC by imaging but without confirmatory pathology, those with calcified nodules and < 3 yrs of imaging. Demographics and clinical information were collected and univariant and multivariable logistic regression models were fit to assess correlation with Tx. Results: Among the 39 pts, 84% were female and 92% were smokers (18% active, 51% former > 10pkyr, 23% former < 10pkyr). 149 nodules were identified with median size 11mm (range 5-55mm); the majority of pts had ≥3 nodules (36/39). 66 (44%) nodules received Tx (10 RT, 56 surgery). Radiographic variables significantly associated with Tx were baseline nodule size (p = 0.02) and solid density (p < 0.001). Nodules > 2.5cm at baseline had Tx 77% of the time, while those ≤ 0.7cm had Tx 41%. Median length of monitoring before Tx was 2.1yrs for solid nodules, 3.5yrs for subsolid nodules, and > 11yrs for pure GGOs. Other observations included discordant genotypes between nodules within 1 pt and an overall pattern of nodule contraction just prior to growth acceleration. Conclusions: Lung MAC cases can be successfully managed with serial observation and intervention on growing solid or subsolid nodules. Those with GGO components can often be surveilled for yrs, or if pure GGO, for a decade or more. Larger size at baseline and solid density significantly correlate with the use of Tx. Examples of nodule contraction with concurrent enlargement of the solid component will be presented at ASCO, as this may be an important clinical warning sign.
Computer extracted measurements of intra-tumoral heterogeneity on H&E stained tissue images to distinguish short term and long term survivors in patients with non-small cell lung carcinoma.
Authors: Lu Cheng , Khunger Monica , Thawani Rajat , Velcheti Vamsidhar , Madabhushi Anant
Published: September 2018

e20052

Background: Molecular and morphologic heterogeneity is an important characteristic of cancer. This spatial and temporal tumor heterogeneity has important implications on tumor behavior and response to therapies. This study aims to evaluate the role of computer extracted features of intra-tumoral heterogeneity (ITH) from digitized whole slide H&E stained images of early stage NSCLC patients treated with surgery as a prognostic marker for survival. Methods: A cohort of 89 early stage NSCLC patients treated with surgery with long term survival data were identified. 28 patients had OS> 3 years from the date of definitive surgery and were defined as long term survivors and 61 patients had OS < 3 years, and were defined as short term survivors. Corresponding H&E stained whole mounted lung tissue images was digitally scanned and a thoracic pathologist marked the primary tumor margins on these images. Our computational approach involved determining the variance in measurements relating to nuclear size, shape, and texture across the tissue section; Each feature was then assigned a morphologic diversity score (MDS) based off the variance; the top predictive MDS features were identified via Wilcoxon Rank Sum Test and then evaluated via a quadratic classifier using 3-fold cross validation. Kaplan-Meier (KM) survival analysis was performed for the ITH features, as well as T- and N-stage. Results: The top ranked MDS features yielded a mean area under the receiver operating characteristic curve (AUC) of 0.66 in discriminating short term from long term survivors. A p=0.00657 (see Table) was obtained for KM-analysis of the ITH features. Conclusions: Computer extracted image features of ITH enabled differentiation of NSCLC patients with short and longer term survival. Large scale multi-site validation will need to be done to establish ITH measurements as a prognostic biomarker for NSCLC patients. [Table: see text]
Co-occurrence of targetable aberrations in non-small cell lung cancer patients harboring MAP2K1 mutations.
Authors: Holzem Alessandra , Nogova Lucia , Ihle Michaela A. , Wompner Claudia , Bitter Elisabeth , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Kron Anna , Gerigk Ulrich , Kern Jens , Kaminsky Britta , Randerath Winfried , Lorenz Joachim , Kambartel Karl-Otto , Merkelbach-Bruse Sabine , Büttner Reinhard , Scheffler Matthias , Wolf Juergen
Published: September 2018

e20059

Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive with known driver mutations. Activation of the MEK1-cascade might play a pivotal role in resistance to targeted inhibition of BRAF V600E, EML4-ALK and EGFR T790M. So far, however, only MAP2K1 K57N could be identified and linked functionally to resistance in preclinical models. Clinical trials combining specific inhibitors for predefined NSCLC subgroups with MEK inhibitors are ongoing. We sought to characterize frequency and type of MAP2K1-mutated NSCLC regarding curated targetable aberrations. Methods: Tumor tissue collected consecutively from 4590 NSCLC patients within the German Network Genomic Medicine (NGM) between 07/2014 and 07/2015 was analyzed for MAP2K1 mutations using next-generation sequencing (NGS) with a set of 102 amplicons in 14 genes. Clinical and molecular characteristics of these patients were determined and compared with an internal control group of NSCLC patients and an independent control group of The Cancer Genome Atlas (TCGA). Results: We identified 21 (0.5%) patients with MAP2K1 mutations. They were frequently found in adenocarcinomas (n = 20) and were significantly associated with smoking. The most common MAP2K1 mutation was K57N. Most of the patients (n = 16) had additional oncogenic driver aberrations, including mutations in ALK, EGFR or BRAF, ROS1 rearrangements and MET amplification. TP53 mutations were found in 11 patients. In only five patients (23.8%) MAP2K1 occurred exclusively. TCGA analysis revealed additional 10 patients with MAP2K1 mutations, whereof 9 had additional TP53 mutations and one had BRAF mutation. Whereof most patients in our cohort had stage IV NSCLC, all patients in TCGA were systemic treatment naive. Compared with local stages in TCGA, our findings strongly suggest that targetable co-occurring mutations might occur more frequently in advanced stage NSCLC patients. Conclusions: MAP2K1 mutations co-occur frequently with targetable aberrations in smoking stage IV patients. Combination of targeted therapy against known driver aberrations with MEK inhibitors might be a promising therapeutic approach for such patients.
Endobronchial ultrasound-guided transbronchial needle aspiration versus cervical mediastinoscopy in lung cancer diagnosis and mediastinal staging: A retrospective comparison study.
Authors: Zhang Rong , Ma Yuxiang , Xu Guoliang , Gao Xiaoyan , Luo Guangyu , Lin Qingguang , Yang Yunpeng , Wang Xin , Zhang Li
Published: September 2018

e20066

Background: Invasive mediastinal lymph node staging is essential for resectable lung cancers. This retrospective study compares the diagnosis yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and cervical mediastinoscopy (CMS). Methods: Consecutive patients were analyzed from Jan 2009 to March 2016. Only pathologically confirmed results were accepted, and systematic mediastinal lymphadenectomy (SML) were used as the standard. The disease diagnosis and N stagingaccuracywere compared in this study. Results: 103 EBUS-TBNA patients and 232 CMS patients were included, 1014 mediastinal lymph nodes were biopsied in lung cancer patients. In per case analysis, there was no significant differences between EBUS-TBNA and CMS in disease diagnosis accuracy (89.4% vs. 81.2%, P = 0.097), and no significant difference in N staging accuracy (75.0% vs. 78.3%, P = 0.629). However, EBUS-TBNA had significantly higher disease diagnosis sensitivity than CMS (82.4% vs. 47.6%, P < 0.001). In lymph nodes diagnosis comparison (station #2, #4 and #7), both EBUS-TBNA and CMS showed very high accuracy, sensitivity, and specificity (94.7% vs. 99.6%, 88.6% vs. 94.8%, 97.2% vs. 100%), however CMS were slightly better. Positive lymph nodes had longer major and minor axes than negative nodes, and the positive rateswere as high as 59.2% in lymph nodes with a minor axis measuring ≥21mm. More complications and injuries were found in patients receiving CMS. Conclusions: For clinically suspected lung cancers, both EBUS-TBNA and CMS are favorable options for invasive mediastinal staging. EBUS-TBNA may be preferred for its higher disease diagnosis sensitivity and fewer complications.
Amenorrhea in lung cancer patients.
Authors: Cathcart-Rake Elizabeth Jane , Ruddy Kathryn Jean , Gupta Ruchi , Partridge Ann , Stewart Elizabeth A. , Vachon Celine , Yang Ping
Published: September 2018

e20092

Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.
Efficacy of PD-1 inhibitors in patients with metastatic non-small cell lung cancer (NSCLC) with KRAS or EGFR T790M mutations.
Authors: Sharma Nitika , Stroud Chipman Robert Geoffrey , Walker Paul R. , Cherukuri Sulochana Devi , Muzaffar Mahvish , Cherry Cynthia R. , Parent Teresa , Hardin Jessica
Published: September 2018

e20513

Background: Immune checkpoint blockade(ICB) has revolutionized the treatment of progressive NSCLC with its durable benefit when compared to cytotoxic agents. In the era of personalized medicine, there is a need to identify effective predictive biomarkers to detect exceptional responders to ICB. Immune modulating interventions with cytotoxic or biologic agents can maximize clinical responses from ICB in poorly immunogenic tumors. KRAS mutations are a negative prognostic factor for survival and generally lack targeted therapies. The T790M mutation in EGFR is the most common cause of acquired resistance to first line TKIs. As a group, patients with EGFR mutations generally do not derive clinical benefit from ICB versus cytotoxic chemotherapy. Preclinical data suggests that mutations like T790 m are associated with higher immunogenicity leading to avid stimulation of antigen specific T-cells (Ofuzi et al, 2014) and better response to ICB (Yamada, 2013). However, the efficacy of ICB by specific molecular mutations remains poorly defined. Methods: We reviewed data for 83 pts with recurrent or progressive metastatic lung cancer treated with nivolumab from June 2015-Dec 2016. All pts were treated with ICB as a second or subsequent line of treatment. The patients were assessed for pathology, mutational status and overall survival. Mutational status was checked on either tissue biopsy or serum samples submitted for proteomic veristrat/genestrat (Biodesix Inc., Boulder, CO, USA) assay. Results: Of the 83 patients treated with nivolumab, 65 patients were found to have NSCLC. Eleven pts were found to have KRAS mutation which was further subdivided as: 6 pts with KRAS G12C, 4 with KRAS G12V, 1 with KRAS G12D. Two pts were found to have T790M mutation. 81%(9/11) pts with KRAS mutation died. Median survival in pts with KRAS G12C mutation was 10 weeks and KRAS G12V was 12 weeks (p = 0.17). Median survival was not reached for patients with T790M mutation. Conclusions: KRAS mutations tend to have a shorter overall survival with ICB as compared to patients with EGFR T790M mutations. Further studies are necessary to isolate poorly immunogenic subtypes of NSCLC and develop novel treatment approaches to optimize outcomes.
Differences in survival between usual practice and clinical trial participants in advanced NSCLC by age.
Authors: Ortega Granados Ana Laura , Cárdenas Quesada Nuria , de la Torre Cabrera Capilla , Fernández Navarro Mónica , Ruiz Sanjuan María , Marin Pozo Juan Francisco , Millán García Rosa , García Verdejo Francisco José , Luque Caro Natalia , Fernández Garay David , Plata Fernández Yessica , López Leiva Pedro , Navarro Pérez Victor , Martínez Ortega Esther , Dueñas García Rosario , Lomas Garrido Maria , Álamo de la Gala Maria Carmen , Jaén Morago Ana , Moreno Jimenez Miguel Angel , Sánchez Rovira Pedro
Published: September 2018

e20515

Background: It is known that outcome of patients included in clinical trials have a better outcome than patients treated with standard therapy. This is a retrospective case-control study of outcome of patients with stage III and IV non-small cell lung cáncer (NSCLC) recruited in clinical trials vs advanced NSCLC patients in usual clinical practice in our institution. Methods: We performed a case-control study matching all patients participating in trials with chemotherapy and/or TKis (immunotherapy was not included) in a 5 year period (January 2010-November 2014) in 1st line setting, matching them in a ratio 1:2 with individuals in usual clinical practice. There were 36 patients in trials and 72 patients treated by our protocol. Cases were matched by age ( < 65 and > 65), histology (adenocarcinoma and squamous), EGFR status (mutated and wild-type). All patients were WHO performance status 0-1. Results: Patients in each group were matched for stage, histological subtype, previous surgery and systemic therapy. Median follow up for patients treated on a trial was 3.3 years, compared with 2.9 years for matched patients who received standard 1st line therapy. Median overall survival for patients included a trial was 19.6 months, and 15.7 months for control group. The difference between groups was not significant (Log rank test, HR 0.81, 95% CI: 0.42 to 1.30, p = 0.53). Median overall survival in younger patients in trials ( < 65) was 19.3 months, and in elderly patients was 19.8 months. The median progression-free survival in the two groups was 6.8 and 5.5 months respectively (HR 0.72, 95% CI 0.30 to 1.43, p = 0.21). Conclusions: In our institution, we didn’t found significant differences for overall survival or progression-free survival, but there is a trend for a better outcome for those items. Benefit seems to be similar in younger patients than in older patients, so this encourages recruiting of selected elderly patients.
Targeted gene sequencing panel for identifying actionable genomic alterations in Taiwanese lung cancer patients.
Authors: Lu Yen-Jung , Tan Kien Thiam , Chen Chun-Jung , Jhou Ren-Shiang , Yang Yi-Ting , Chen Chien-Hung , Chen Hua-Chien , Chen Shu-Jen , Chung David T.
Published: September 2018

e20522

Background: Lung cancer boasts an arsenal of targeted therapies directed at various molecular aberrations such as EGFR mutations and fusion genes. Simultaneous assessment for genetic alterations provides biomarkers to assist clinicians in their treatment selections. Methods: A total of 43 FFPE (formalin-fixed, paraffin-embedded) samples obtained from lung cancer patients in Taiwan were subjected to next-generation sequencing (NGS), using a compact panel encompassing 17 potentially actionable, lung cancer-associated genes. NGS was performed on the Ion Torrent PGM or Proton System with a targeted average depth of > 800x. Genomic alterations detected were categorized as single nucleotide variants (SNV) or chromosomal copy number alterations (CNA). Results: A total of 74 putatively actionable genomic alterations were detected across 38 patients (88.4%), which may predict sensitivity or resistance to established and/or therapies that are still in clinical development. 19 patients (44.2%) had tumors harboring activating EGFR mutations in the tyrosine kinase (TK) domain – L858R substitution or exon 19 deletion, which may suggest clinical benefit to first- and second-generation EGFR TK inhibitors (TKIs). Three patients (7.0%) whose tumor had acquired the EGFR T790M mutation were advised to switch to third-generation EGFR TKI. Possible resistance mechanisms to EGFR TKIs via increased copy number of EGFR (14.0%, n = 6) and MET (11.6%, n = 5) were observed. Deletion or loss of CDKN2A gene were detected in 14 patients (32.6%), which may confer sensitivity to CDK4/6 inhibitors. Inhibition of downstream effectors in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways were suggested for patients whose tumor harbored PIK3CA and/or KRAS oncogenic mutations. Conclusions: Next-generation sequencing using a compact panel of genes may be sufficient to identify biomarkers for targeted therapies selection for most lung cancer patients in Taiwan.
The first- or second-line use of pemetrexed sequentially with EGFR-TKI did not differ in PFS for advanced NSCLC patients harboring EGFR-mutant tumors.
Authors: Ding Zhen-Yu , Chen Yue-Yun
Published: September 2018

e20531

Background: Both EGFR-TKI and pemetrexed doublet chemotherapy (P) are two effective therapies in advanced NSCLC patients with EGFR mutant tumors. But which one should be used in first-line remains controversial. Methods: This was a retrospective study where patients prescribed with EGFR-TKI (gefitinib or icotinib) from Jan 2013 to Jan 2016 were screened. Patients must have metastastic diseases harboring TKI-sensitizing EGFR mutation. They must be older than 18 years, and have evaluable target lesions. Whether TKI or P was used in the first line, it must be switched to the other in the second line. PFS in both first line (PFS1) and second line (PFS2) was collected. Results: We screened totally 550 patients (gefitinib n = 455, icotinib n = 95) to enroll a cohort of 36 patients. They were all adenocarcinoma except 1 adenosquamous carcinoma. Gender (M or F), PS (0 or 1), mutation type (Exon19Ddel or other) were equally distributed. The median age was 50.5 years. For the whole cohort, the total PFS (PFS1+PFS2) was 18.1 m (95%CI: 15.2-21.1 m). For those (n = 24) receiving first-line TKI, PFS1, PFS2, and total PFS were 10.3 m, 6.6 m, and 19.2 m. And for those receiving first-line P (n = 12), they were were 3.4 m, 11.5 m, and 16.5m. The total PFS in both groups did not differ significantly (p = 0.548). Conclusions: Our results argued the sequential usage of TKI and P achieve a comparable PFS irrespective of the sequence.
Short course pembrolizumab in complete responders with advanced non-small cell lung cancer.
Authors: Chan Daniel Boon Yeow
Published: September 2018

e20537

Background: Pembrolizumab has been available in Singapore since October 2014 for clinical use. All clinical trial protocols of Pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) require a 2 year period of treatment in responders, even in complete responders. It is not known if shorter treatment durations in complete responders can afford reasonable progression free interval (PFS). Such abbreviated treatment in complete responders would result in significant cost savings and lesser side effects. Methods: A single physician practising at a single private medical oncology center in Singapore collated consecutive cases of advanced NSCLC seen by him and treated with Pembrolizumab from October 2014 till December 2016. All were smokers except for 2 patients. All patients were biopsy and imaging proven to have advanced NSCLC. 46 patients were treated with Pembrolizumab 2mg/kg body weight 3 weekly and observed with sequential imaging every 3-6 months with the first assessment scan after Cycle 4. All complete responders by imaging stopped treatment after 4 cycles of Pembrolizumab by mutual consent. PD-L1 IHC testing by DAKO 22C3 was not done on any of the patients’ tumours as the test has only been available in Singapore since December 2016. Results: Cut-off date for analysis of data was 1 Feb 2017. 4 out of 46 patients (9%) achieved a complete metabolic response on FDG PET by irRC and/or CT scans by RECIST 1.1. All 4 patients with complete response (CR) (except Patient #3) were smokers. All 4 patients remain in CR with ECOG Performance Status (PS) 0 without any further treatment. Conclusions: Real world clinical usage of Pembrolizumab in advanced NSCLC can afford long PFS in complete responders in spite of abbreviated treatment of 4 cycles. Clinical trials should be designed to address this issue due to its impact on health care costs. [Table: see text]
Impact of primary tumor resection in oligometastatic non-small cell lung cancer: Experience of a resource-limited cancer center in southern Brazil.
Authors: Nunes Filho Paulo Ricardo Santos , da Silva Caroline Albuquerque Moreira , Tsukazan Maria Teresa Ruiz , Fay Andre Poisl , Barrios Carlos H. , Debiasi Marcio
Published: September 2018

e20552

Background: Stage IV non-small cell lung cancer (NSCLC) with low volume disease represents a more indolent phenotype within the biological spectrum of lung cancer. Recent data suggest that aggressive local therapy may impact clinical benefit in this subgroup of patients, with 5-year overall survival (OS) rate around 20%. Methods: We analyzed patients with oligometetastatic (≤3 metastasis) NSCLC treated with primary tumor resection at Hospital São Lucas da PUCRS. Clinico-pathological features and survival data were retrospectively collected using standard templates. The primary endpoint was OS. Survival was estimated using the Kaplan-Meier method and log-rank test was used to univariate analysis. Results: Between April 1991 and December 2015, 25 patients with oligometastatic NSCLC underwent surgery of the primary tumor. Clinico-pathological data are summarized in Table 1. Overall, median OS was 16 months (95% CI: 8.87-23.13 months) with a 5-years survival rate of 7%. Age less than 65 years old was associated with longer OS (HR 0.34 95%CI 0.13-0.92 p = 0.02). Patients with brain metastasis had a non-significant lower OS than those without (16 vs. 24 months, respectively). Conclusions: This analysis suggests that in a resource-limited center, where immunotherapies and targeted-therapies are not available, local therapy for oligometastatic NSCLC did not provide the same clinical benefit seen in the same population from high-income countries. See table. [Table: see text]