bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost effectiveness of G-CSF after allogeneic peripheral blood stem cell transplant.
Authors: Singh Vijendra , Kim Seongho , Jang Hyejeong , Alavi Asif , Bhutani Divaya , Ayash Lois Jeanne , Ratanatharathorn Voravit , Uberti Joseph P. , Deol Abhinav
Published: September 2018

e18540

Background: In spite of the fact G-CSF has been used post stem cell transplant (SCT) to accelerate neutrophil engraftment its use post allogeneic SCT remains controversial. ASCO does not recommend its use after allogeneic SCT. To further evaluate the effectiveness of its use, we compared outcomes in pts who underwent related and unrelated peripheral blood SCT(PBSCT) either with or without the use of G-CSF post SCT. Methods: This is a retrospective study comparing early outcomes in pts who received G-CSF starting on day + 6 post SCT until engraftment with pts who did not receive a planned course of G-CSF. Pts who underwent Allogeneic PBSCT between 2012-2014 at our institution were included. Pts who received marrow, haploidentical or cord blood transplants were excluded. Associations with survival outcomes were assessed by univariable and multivariable Cox proportional regression models. Results: A total of 162 patients were evaluated. Sixty-five pts received G-CSF post SCT and 97 did not. The only difference between the two groups was that more pts in the G-CSF group received myeloablative-conditioning (MAC) regimen (78% vs. 55%, p = 0.008). Other pt characteristics were not significantly different. Length of hospital stay was significantly lower in the G-CSF group (24 vs. 27 days P = 0.002). Pts who received G-CSF had earlier neutrophil engraftment (median, days 11 vs. 14 p = < 0.001). The median day of platelet engraftment was 15 days in both groups. There was no significant difference between the 2 groups in re-admissions in the first 100 days, and the incidence of acute or chronic GVHD. In multivariate analysis use of G-CSF did not significantly impact non- relapse mortality, relapse free survival and overall survival. However, relapse rate was significantly lower in G-CSF group in multivariable analysis (hazards ratio = 0.44, p = 0.03). Conclusions: Use of G-CSF post allogeneic PBSCT is associated with earlier neutrophil engraftment, shorter hospital stay and a suggestion of a reduced relapse rate after PBSCT. Our experience suggests that use of G-CSF (on average for approximately 5 days) in this setting is cost effective as it reduces hospitalization duration without adversely impacting post-transplant outcomes.
Nationwide in hospital outcomes of allogenic hematopoietic cell transplant (AHCT) in acute myeloid leukemia (AML).
Authors: Yogarajah Meera , Muthu Johnn
Published: September 2018

e18542

Background: AHCT is the definitive treatment for AML with unfavorable risk however with increased morbidity and mortality limiting its use in adults above 60 years of age. National in patient sample (NIS) database was analyzed to study trends and predictors of mortality in AML patients receiving AHCT. Methods: NIS database includes 20% of all hospitalizations in USA. NIS database from 2010 - 2014 was analyzed. ICD-9 codes were used to extract patients and to analyze demography, comorbidities, complications and outcomes. A multivariable logistic regression was performed to identify predictors of mortality. Results: 1755 patients with AML and AHCT were identified from the database. Males 55.2%, median age 52, age >60 years 35%, Whites 80.6%, Blacks 5.5%, Hispanics 6.7% and others 7.2%. Median length of stay was 26 days. Inpatient mortality showed a decreasing trend from 2010 to 2014 (6.7%, 4.6%, 3.9%, 4.8%, 4.6%) likely due to better supportive care. p (trend) = 0.29. Univariate analysis for age >60 years did not show increase in mortality however multivariate analysis did show increase in mortality (Odds ratio 2.281, p = 0.006). Other predictive factors of increased mortality were presence of complications of AHCT. Infection (OR 8.392, p < 0.001), acute graft versus host disease (GVHD) (OR 2.139, p = 0.033) and pneumonia (OR 3.584, p <0.001) were associated with increased mortality. Independent predictive factors of mortality were renal failure (OR 14.186, p < 0.001) and liver disease (OR 3.228, p < 0.001). Conclusions: Age more than 60 by itself is not associated with increased mortality in the absence of complications and comorbidities. Infection is a major predictor of mortality. [Table: see text]
Comparison of digital PCR with real-time PCR calibrated to the International Scale for BCR-ABL monitoring.
Authors: Shah Parth , Cossor Furha Iram , Murarka Shiva , Dixit Hemangi
Published: September 2018

e18545

Background: Monitoring BCR-ABL1 fusion transcripts is the cornerstone of management in chronic myeloid leukemia (CML). Real Time PCR(RTPCR) has been the tool of choice for its sensitivity and dynamic range. The International Scale was recently introduced to allow for standardization across laboratories. Chip based Digital PCR(dPCR) which allows for absolute quantitation may obliviate the need for such standardization by giving absolute results.It has the potential to increase sensitivity for detection of minimal residual disease. This assumes great significance as we move into the era of treatment free remission. Methods: A total of 31 EDTA-blood samples of CML patients with known values ranging from 0.003-0.5 IS were processed via an accredited RTPCR protocol calibrated to the IS scale and a parallel dPCR workflow without any specific calibration . The analysis of digital PCR samples was performed on the Thermofisher Cloud Platform. Results: Both RTPCR and dPCR yielded extremely concordant results. The Pearson correlation between the two methods was r = 0.6043 (95%CI: 0.318 to 0.789; p = 0.0003). The calculated BCR-ABL/ABL ratios were comparable with a median of 0.098 for RT-PCR calibrated to the IS (range 0.003-0.55; n = 26) and 0.11 for dPCR (range 0.003-0.37; n = 29). The mean difference for the ratios between the two methods used for the detection was around 0.08. Conclusions: We demonstrate here the capability of dPCR to provide a parallel result to an IS scale calibrated protocol without any standardization. This approach required no specific calibrators or standards and resulted in extremely cost effective testing. This freedom from routine calibration provides for a significantly more robust workflow and greatly increased reliability. Limitations do persist in dPCR on account of limited chip densities which are the main parameter for the Poisson statistics. This has limited the dynamic range on dPCR to a maximum of Log 4 for accurate quantification. However as chip densities and emulsion concentrations increase in these technologies, they are poised to introduce a new era in the quest of accurate quantification.
Improving diagnostic and prognostic accuracy of myeloid neoplasms (MNs) by next generation sequencing.
Authors: Schwartz Candice , Macklis Jason Nathaniel , Buckingham Lela , Shammo Jamile M.
Published: September 2018

e18567

Background: Molecular aberrations in MNs have been well described. Driver mutations such as JAK2, MPL, and CALR, are pathognomonic for MNs, whereas other somatic mutations are less specific but have prognostic significance. Multi-gene panel testing for known somatic mutations has been utilized for diagnostic and prognostic purposes, and testing for somatic mutations to identify clonal hematopoiesis has been adopted by the WHO 2016 classification of myeloid malignancies. We sought to assess the impact of testing for somatic mutations by NGS on diagnosis and management of pts with MNs. Methods: We employed a myeloid panel (MP) of 40 commonly mutated genes involving RNA splicing, chromatin remodeling, and signaling pathways. Testing was performed on ptswho presented to the clinic between 2/2015 and 12/2016. Initial diagnosis and rationale for testing (diagnostic or prognostic) were recorded. We then determined whether the MP resulted in a change in diagnosis, prognosis, or management. Results: 55 pts with a known or suspected MN had a MP performed.Diagnoses at presentation were: MDS (27), MF (8), MPN-U (8), MDS/MPN (4), multiple diagnoses (2), and no definitive diagnosis of MN (6). 87% (48/55) of pts had at least one somatic mutation.In 13 pts (23.6%) the MP led to a definitive diagnosis or a change in diagnosis. For example, 2 pts initially diagnosed with MPN-U were diagnosed with CNL after detection of CSF3R mutation. All 4 pts initially diagnosed with MDS with fibrosis were subsequently diagnosed with primary myelofibrosis; 3 had a MPL mutation and 1 had a CALR mutation. Management was altered in 12 pts (21.8%) and prognosis was changed in 11 pts (20.0%). For example, 2 pts were treated with a JAK-2 inhibitor and 2 pts with low risk MDS were referred for transplant evaluation due to the presence of a TP53mutation. Conclusions: Our study confirms that panel testing meaningfully improves diagnostic accuracy and provides prognostic value. In total, the MP resulted in a change in diagnosis, prognosis, or management in 43.6% (24/55) of cases. Confirmation of these observations merits prospective evaluation for a larger number of pts.
Clonal selection of TP53MUT and/or Del (p17) in CLL: Evaluation of 3,373 CLL patients, A real word data story.
Authors: Mpima Sheila , Moehler Thomas , Kanter Sean , Mitrofan Laura
Published: September 2018

e19004

Background: Del (p17) or TP53MUT are important negative prognostic indicators for CLL patients (pts). Using a large European database we evaluated the influence of chemotherapies on the detection of Del (p17) and TP53MUT in advanced CLL pts requiring CLL-specific therapy. Methods: Anonymized CLL pts-level data collected through a large web-based survey between Oct 2015-2016 in EU5 (France, Germany, Italy, Spain & UK) was used. Mutation testing was recorded at the beginning of each line of therapy. Chi-squared test was used to analyze the association between treatment and/or abnormalities (Del p(17) and TP53MUT). Results: Data of 3,737 CLL pts were analyzed. 33% received ≥2 prior regimens, 38% received 1 prior regimen and 29% are currently in 1L. A switch from negative to positive at 2ndor later line occurred in 68% of pts for Del (17p) and 41% for TP53. 40% of pts bearing a Del (p17) are simultaneously TP53MUT when treated with at least 2 lines of therapy. We compared the treatment regimen of pts that remained negative during the course of treatments with those who switched to Del (17p) or TP53Mut. Analysis showed a strong association (p-value < .0001) between treatment (alkylation agent in combination with an antiCD20 antibody or CYC/FLUD/R) and Del (p17) switch after 2L (total n = 906). Separately, same treatment groups showed lower association (p-value < .0015) with TP53 status change at the end of 2L (total n = 598). Separate ratios have been calculated for each treatment group between pts remaining negative for Del (p17) and TP53, respectively and those who became positive. CYC/FLUD/R treated pts had a 2.2 and 2.7 fold higher ratio of remaining negative versus becoming positive for Del (p17) and TP53MUT, respectively in 2L, when compared to alkylating agent/antiCD20 combination. In addition, there is a high association (p-value < .0001) across the two treatments groups between Del (p17) and TP53MUT for pts with 2L results (n = 868). Conclusions: Analysis shows that patient treated with the 3-drug regimen CYC/FLUD/R had a lower likelihood of undergoing a clonal selection for both Del (17p) and TP53MUT compared to 2-drug regimen including alkylating agent/rituximab combo.
Oligoclonal T cells transiently expand and express TIM3 and LAG3 following CD19 CAR t cell therapy.
Authors: Petersen Christopher Thomas , Jagirdar Neera , Waller Edmund K.
Published: September 2018

e19017

Background: CAR T therapies targeted towards the CD19 antigen have shown tremendous promise in the treatment of multiple B cell malignancies. However, not all B cell malignancies show the same degree of response; B cell lymphomas such as DLBCL have been more resistant to CAR T-mediated lysis. The reasons for the higher treatment failures and relapse rates in this setting are poorly understood which prompts investigation into the dynamics of T cell responses following CAR T infusion. Methods: Peripheral blood was collected from a single DLBCL patient enrolled on a single-patient compassion-use CAR T cell protocol utilizing a single chain CD19 with 4-1BB co-stimulatory signaling domain (NCT02445248 IND 16130). Blood samples were obtained prior to and on day 1, 8, 17, 24, 31, and 58 post-CAR T infusion. A bone marrow aspirate was collected on day 58. Mononuclear cells were collected by ficoll gradient and cryopreserved. Flow cytometry was performed on thawed samples to identify CAR T cells and surface markers. TCR sequencing was performed using the ImmunoSeq platform on an additional sample from each time point. Results: TCR sequencing revealed distinct waves of oligoclonal T cells within the first two months following CAR T therapy. A population of T cells expressing Vβ 20 appeared early following CAR T infusion and contracted by day 17. Additionally, a population of cells expressing Vβ 27.1 also expanded at the peak of the response (D8), but remained at a high frequency up to two months post-treatment. A third wave of T cells expressing Vβ 7.3 expanded in the blood and marrow on day 58. The expression of TIM3 and LAG3 also changed over time. TIM3 was expressed predominantly in the CD8 compartment while LAG3 expression was limited to the CD4 compartment. Expression of both increased at peak and decreased over time. Low levels of PD-1 expression were detected in contrast to the much higher levels of TIM3. Conclusions: The waves of oligoclonal T cell expansion and dynamic expression of TIM3 and LAG3 provide further insight into the CAR T response and may provide new possible targets for supportive therapies that can enhance the overall response. Clinical trial information: NCT02445248.
Effectiveness of bendamustine in relapse or refractory lymphoma cases: A report from Turkey—The Turkish Oncology Group (TOG) study.
Authors: Karadurmus Nuri , Paydas Semra , Ocal Ramazan , Yildiz Birol , Nayir Erdinc , Dogan Mutlu , Sumbul Ahmet Taner , Surmeli Zeki , Barısta Ibrahim , Ferhanoglu Burhan , Ozgur Gokhan , Erturk Ismail , Ozaydin Sukru , Petekkaya Halil Ibrahim , Uskent Necdet
Published: September 2018

e19027

Background: Bendamustine is an old conventional agent which is used in the treatment of hodgkin's lymphoma (HL), non-hodgkin's lymphoma (NHL), and chronic lymphocytic leukemia (CLL) patients despite they are relapsed or refractory cases. In our study we wanted to reveal retrospectively the efficacy and side effects of bendamustine in relapse/refractory patients from Turkey. Methods: We included in the study relapse/refractory HL and NHL patients who underwent multiple line chemotherapy. Bendamustine was administered at 90 mg/m² on days 1 and 2, every 3 weeks by 60 minutes infusion. The primary endpoint of the study was to determine the objective response and toxicity. Results: Seventy-five patients (31 female) with a median age of 62.8 years (range 16-89 years) were included in the study. 58 of the patients were NHL (follicular lymphoma:8, diffuse large B-cell lymphoma: 17, mantle cell lymphoma: 11, marginal zone lymphoma: 4, Small lymphocytic lymphoma:11, Others:7) and 17 of them were HL patients. The patients were underwent median three lines chemotherapy (range 1-8) accept autologous stem cell transplantation, 20 patients (HL: 12, NHL:8) were underwent autologous stem cell transplantation. Bendamustine was performed an average of 6 cycles (range 1-38). The objective response rate was 73.3%, complete response rate was 44% (n = 33), partial response rate was 29.3% (n = 22), respectively. The response rate was 65% (11/17) in HL cases, 79% (30/38) in indolent NHL cases and 70% (14/20) in aggressive NHL cases. For median follow-up of 20.7 months, the median overall survival (OS) was 64.9 months, OS rate was 75.5% for 1 year, 67.6% for 2 years and 63.1% for 3 years. The most common side effects associated with treatment were lymphopenia, neutropenia, thrombocytopenia, abdominal pain, fatigue and diarrhea. Side effects which were seen as grade 3 and higher levels: 9.6% lymphopenia, thrombocytopenia 8% and 12% fatigue. Conclusions: Objective response rate of bendamustine with tolerable side effect profile was found to be 73.3% in relapsed / refractory HL and NHL patients as a rescue agent. It appears to be an ideal agent for rescue treatment which had previously received intensive treatment.
Adherence, quality of life, health care resource use, and functional impairment among patients with oral multiple myeloma (MM) treatments.
Authors: Ung Brian , Gupta Shaloo , Parikh Kejal , Liebert Ryan , Abouzaid Safiya , Rosenberg Aaron Seth
Published: September 2018

e19519

Background: Few studies have assessed the relationship between adherence to prescribed therapies and patient (Pt)-reported outcomes (PRO) in Multiple Myeloma (MM). Pt-reported adherence and its association with quality of life (QoL), healthcare resource use (HRU) and functional impairment among pts on oral MM treatments were assessed. Methods: This was a cross-sectional survey of 118 US adult MM pts identified from the Light Speed Research panel, who were currently on a regimen which included an oral therapy. Pt’s experiences using the Morisky Medication Adherence Scale-4 (MMAS-4), the Work Productivity and Activity Impairment, and the Functional Assessment of Cancer Therapy (FACT)-MM were examined. Higher FACT-MM scores indicated better health-related QoL. Pts were characterized by their MMAS score; score =4 and score ≤3 (max score =4). Pts in each score grouping were summarized based on pt characteristics, treatment history, HRU and PROs. Multivariable analyses estimated the association between MMAS score group and study outcomes. Results: A total of 72 (61%) pts reported a MMAS score = 4 and 46 (39%) pts had a score ≤3. Pts with a score =4 were older (59.2 vs 50.7 years; p<0.001) and were on fewer treatments (1.42 vs 2.13; p<0.001) than with a score ≤3. No differences in race/ethnicity, marital status, income or education level were noted between the two groups. Pts with a score ≤3 had higher levels of absenteeism, impairment while at work (presenteeism), and overall work impairment in descriptive analysis, but only differences in activity impairment (56.5% vs. 39.8%; p=0.015) remained significant in the multivariable analyses. Pts with a score = 4 reported higher FACT-MM scores (106.9 vs 89.2; p<0.001) than pts with a score ≤3, a trend seen in all FACT-MM subscores. More pts with a score ≤3 also reported being overwhelmed or frustrated by having to reschedule MM appointments (64% vs. 26%; p=0.002). Conclusions: Among MM pts on oral treatments, high adherence is associated with improved QoL and a lower level of activity impairment. There may also be a relationship between frustration in managing MM related appointments and levels of adherence.
Allogeneic stem cell transplantation (Allo-SCT) for multiple myeloma (MM): The Mount Sinai experience.
Authors: Afshar Solmaz F. , Galitzeck Zachary , Pineda-Roman Mauricio , Steinberg Amir
Published: September 2018

e19520

Background: Allo-SCT has been used as a curative treatment for MM, particularly for refractory patients (pts), but outcomes across institutions have shown varying results. In this study, we examined patient-, disease-, and transplant (tx)-related variables in pts of allo-SCT for MM at Mount Sinai. Methods: Adult pts undergoing allo-SCT for MM at Mount Sinai from 2008-2015 were included in this study. Identifying variables were extracted from reports to the CIBMTR. This study was approved by the IRB, and all pts signed informed consent. Our results were compared to the 2011 CIBMTR analysis of allo-SCT for MM pts. Results: 21 pts underwent allo-SCT for MM at a median of 36 months post diagnosis (range, 12-211 mo), while the CIBMTR reported 12 mo. The median age of pts at the time of tx was 53 years (range, 38-62 yrs) with 48% White, and Hispanic, Asian or Black each 14%. Pts had one or more autologous SCT prior to allo-SCT (90%) and the median time between txs was 31.1 mo (range, 0.7-195 mo). Pts were in DS stage III (52%), and the disease was partially responsive (38%) or showed progression (33%). 81% of pts underwent nonmyeloablative/reduced-intensity conditioning, and 86% received GVHD prophylaxis. Still, 38% of pts developed acute GVHD while 19% had chronic GVHD by 1 year post-tx, lower than CIBMTR’s analysis. There was a 52% survival rate at 6 mo post SCT and 29% by year 1, considerably lower than the 46% reported by the CIBMTR. The median time to death was 5 months (range, 1-40 mo), and the main cause was primary disease (37%). At the time of analysis, 2 pts were alive with a maximum survival of 8 years post-tx. Conclusions: The Mount Sinai experience of allo-SCT for MM pts revealed overall suboptimal outcomes during the 2008-2015 study period. Our pts underwent tx much later in the disease course relative to the CIBMTR’s study. Given the noted outcomes, alternative therapies were considered in the last 4 years of our analysis, resulting in half as many allo-SCT for MM pts during the latter time period. For optimal benefit, allo-SCT in selected MM should be performed earlier in the course of disease with improved pt selection. These modifications will be implemented via participation in an upcoming BMT/CTN clinical trial at our institution.
Prognostic value of a 12-gene signature in platinum-based chemotherapy treated SCLC.
Authors: Zhang Jie , Tian Chen , Zhang Henghui , Chen Xiaoling , Han Jindi , Nie Jun , Dai Ling , Hu Weiheng , Tian Guangming , Ma Xiangjuan , Wu Di , Fang Jian
Published: September 2018

e20011

Background: Small cell lung cancer (SCLC), which accounts for 15-20% of lung cancer, is a highly aggressive neoplasm. Different from non-small cell lung cancer, SCLC is characterized by a high proliferation rate and early metastasis. Only about 25% of patients with limited stage disease will be cured after first-line standard treatment and majority of the patients will relapse after initial sensitivity to the chemotherapy and radiotherapy. The highly complex genetic landscape of SCLC may be the reason for its resistance to conventional therapy but the details are still unclear. Methods: Nine patients with SCLC received platinum-based chemotherapy and/or radiotherapy were included in this study. According to the prognosis, patients were classified into two groups: poor prognosis group (PP group, PFS < 6 months, n = 5) and better prognosis group (BP group, PFS > 24 months, n = 4). Tumor DNA was isolated from pre-treatment paraffin-embedded tumor tissue and subjected to enrichment for a 1.15M size panel cover exon regions from 1,086 genes. Followed by next generation sequencing on an Illumina X10 platform, the captured sequencing data was further processed using bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNV), short insertions/deletions (indels) and copy number variation (CNV). Changes in tumor DNA were compared with clinical efficiency. Results: We show that the tumor mutation burden in PP group is higher than the BP group (p = 0.06). Using the mutation burden of 12 genes (PTEN, TP53, JAK2, BCL2, CCNE1, EGFR, ROS1, NTRK3, MYC, FGFR1, RANBP2, and CREBBP) as a factor, the PP group can be distinguished from BP group. In addition, TP53 loss is more frequently appeared in the PP group. Conclusions: Our results suggest that high mutation burden status of 12 genes (PTEN, TP53, JAK2, BCL2, CCNE1, EGFR, ROS1, NTRK3, MYC, FGFR1, RANBP2, and CREBBP) might correlate with poor prognosis of small cell lung cancer.
Prognostic value of post treatment PET scan in small cell lung cancer.
Authors: Alsharedi Mohamed Farouq , Chowdhary Aneel A. , Shenouda Mina , Gress Todd W.
Published: September 2018

e20013

Background: In most lymphomas, improving patient outcome rely on an assessment of response to therapy. Functional imaging with 18-fluoro-deoxyglucose (FDG) positron emission tomography (PET) increases sensitivity and specificity of disease assessment, predicts outcome and directs future therapies. Lately, PET-scan is more utilized in small cell lung cancer (SCLC) both for initial staging and to assess response to therapy. However, limited data in the literature have evaluated the prognostic value of post-therapy response on PET-scan in SCLC. Methods: This is a retrospective chart-review of SCLC patients who received their first-line chemotherapy between January-2007 and December-2013. Inclusion criteria included complete data on age, sex, race, cancer stage, histologic grade, chemotherapy, radiotherapy, and PET images pre- and post-therapy. CR was defined as either 100% drop in FDG uptake on post-therapy PET-scan. Results: Fifty patients met the inclusion criteria, and served as the basis for this study. 46% had Limited Stage Small Cell Lung Cancer (LS-SCLC), and 54% had Extensive stage small cell lung cancer (ES-SCLC). All were treated with platinum-based chemotherapy in addition to concurrently radiation therapy for the LS-SCLC group. Eleven patients out of the whole cohort achieved CR. Using COX regression model, we evaluated the correlation between achieving CR on post-therapy PET-scan and survival outcome. We found that achieving CR was significantly correlated with worse outcome in ES-SCLC group (HR = 2.70; 95%CI: 1.26-5.81; p = 0.01). While, in the whole cohort and LS-SCLC group, P-value was not statistically significant, nevertheless achieving CR indicated unfavorable outcome (HR = 1.18; 95%CI: 0.51-2.69; p = 0.49) and (HR = 1.99; 95%CI: 0.77-5.13; p = 0.15) respectively. Conclusions: Unlike lymphomas, achieving CR on post-therapy PET-scan in SCLC was associated with worse survival outcome. This might indicate that in aggressive small cell lung cancer, despite excellent response to first-line therapy, the prognosis is still dismal. These results suggest that further prospective studies are warranted to identify the prognostic rule of post-therapy PET-scan in SCLC patients particularly those with ES-SCLC.
A meta-analysis of trials of etoposide plus platinum agent versus irinotecan/topotecan plus platinum agent in first-line therapy of extensive stage small cell lung cancer (ES SCLC).
Authors: Ellis Peter Michael , Durocher-Allen Lisa , Vella Emily , Sun Alexander , Ung Yee , Ramchandar Kevin , Darling Gail Elizabeth , Goffin John R. ,   CCO PEBC Lung DST
Published: September 2018

e20019

Background: Etoposide plus a platinum agent (EP) represents the standard treatment of ES SCLC. A trial conducted in Japan demonstrated improved overall survival (OS) for irinotecan and cisplatin (IP), but subsequent trials could not consistently replicate these findings. Genotypic differences may explain these findings. These trials have not undergone systematic analysis. Methods: We conducted a systematic review and metaanalysis of randomized trials (RCT) comparing etoposide plus a platinum agent (EP) with irinotecan (IP) or topotecan (TP) plus a platinum agent. A literature search was undertaken of Cochrane Database, MEDLINE and Embase from 1996 to June 2016 to identify RCTs addressing this question. Data were extracted by one author and checked independently, then synthesized using RevMan software using a random effects model. Outcomes of interest were OS, quality of life (QoL) and toxicity. Results: Three RCTs compared TP and EP. There was no difference in OS (HR 0.97, 95%CI 0.87 – 1.07). Eight RCTs compared IP and EP, although only 7 had data that could be combined. IP significantly improved OS compared with EP (HR 0.84, 95%CI 0.74 – 0.95). The estimated improvement in 12 month OS is 6.4%. There was evidence of statistical heterogeneity. After removal of the trial by Noda et al, there was still a significant improvement in OS (HR 0.88, 95%CI 0.79 – 0.98). IP was associated with less grade 3/4 neutropenia, febrile neutropenia, anemia, thrombocytopenia, but more diarrhea. QoL was assessed in 2 trials and no differences observed. Conclusions: IP results in modest improvements in OS in comparison with EP. IP is associated with less hematological toxicity but more diarrhea and should be considered an acceptable alternative to EP in the first-line treatment of ES SCLC. [Table: see text]
Retrospective analysis to compare the efficacy of oral (O) vs. intravenous (IV) etoposide given in combination with carboplatin for small cell lung cancer (SCLC), extensive disease (ED).
Authors: Mellemgaard Anders , Hersby Ditte Stampe , Chaudhary Farruhk Naheed , Langer Seppo W.
Published: September 2018

e20020

Background: Approximately two thirds of patients diagnosed with SCLC will have ED at the time of diagnosis. Response rates to chemotherapy are high but median overall survival for patients treated with chemotherapy is only 9 to 10 months. Patients with ED SCLC considered fit for chemotherapy is normally treated with combination chemotherapy including cisplatin or carboplatin, and etoposide or irinotecan. The usual dosing scheme is 3 weeks intervals with the platin administered on day 1 and etoposide given day 1-3 or 1-5. Etoposide is available in as well intravenous as oral formulations. Concerns about the incomplete and variable bioavailability of oral etoposide have been raised. A randomized study of cisplatin with either oral or IV etoposide found no significant difference in treatment outcome but increased rate of severe or life-threatening hematologic toxicity. Methods: The two cancer hospitals serving the Copenhagen area are using carboplatin + etoposide for palliative treatment of SCLC ED. While carboplatin is used identically (AUC5, IV d1), etoposide is given IV by HUH (120mg/m2, IV d1-3) and orally by CUH (200mg/m2 O, d1-3). From the hospital patient database, we identified patients with SCLC, ED treated in 2011-2013. Route of etoposide administration, dose reductions and GCSF use was noted. PFS and OS was calculated from hospital records. Results: 200 SCLC, ED patients received treatment (116 at HUH, 84 at CUH). A non-significant higher proportion of women were treated at HUH while median age was identical. PFS was longer at HUH than CUH (195 vs 140 days), but the OS was identical (235 vs 227 days). Conclusions: The two dosing schemes: O and IV yield similar OS, but longer PFS with the IV schedule. The survival seen is in line with results from randomized trials although the present study includes all patients irrespectible of PS or comorbidity. We have no information on adverse events, quality of life or rates of hospitalization.
Radiation therapy for patients with extensive stage small cell lung cancer: A survey study of medical oncologists.
Authors: Luo Jia , Degnin Catherine , Chen Yiyi , Mitin Timur , Maggiore Ronald John
Published: September 2018

e20025

Background: National guidelines recommend prophylactic cranial irradiation (PCI) and consideration for thoracic radiation therapy (TRT) for patients with extensive stage small cell lung cancer (ES-SCLC) after chemotherapy. The referral practice patterns among US medical oncologists are unknown. Methods: We developed a survey that was sent to US medical oncologists. The survey evaluated demographics, self-rated knowledge of key TRT studies and approach to radiation oncology referral for ES-SCLC patients regarding TRT and PCI. A predefined knowledge score (KN) (from 0 to 4) was used to characterize self-rated knowledge of existing Jeremic et al and CREST TRT trials with “0” being unaware of the study, “1” being some knowledge, and “2” being knowing trial details. Associations between respondent characteristics and responses were evaluated using Chi-squared or Fisher’s exact tests. Results: 316 complete responses were analyzed. Most respondents had over 10 years of experience (74%; n = 233) and have taken care of more than 10 patients with lung cancer (73%; n = 230), with those treating more patients having higher KN (p = 0.001). 76% (n = 239) of respondents recommended TRT referral after chemotherapy and were more likely to refer if a complete response at metastatic sites had been achieved (p = 0.0001). Higher KN (p = 0.003) was associated with a higher likelihood of TRT referral. 24% (n = 77) did not recommend referral; of these, 84% (n = 65) cited insufficient evidence as their rationale. 75% (n = 237) would obtain brain imaging prior to PCI referral, and 90% (n = 283) supported PCI referral in the absence of brain metastases. Conclusions: Among surveyed US medical oncologists the majority refer patients with ES-SCLC to TRT after chemotherapy. Those physicians who do not refer feel the evidence supporting TRT is insufficient. This is in line with ambiguity reflected in recent ASCO and NCCN consensus guidelines. Most physicians recommend referral for PCI consideration. Additionally, most obtain brain imaging prior to PCI referral, a practice not supported by clinical evidence. These differences in practice patterns support the need for further research to determine the role of TRT and PCI in patients with ES-SCLC.
Treatment and outcomes of primary pericardial mesothelioma: A systematic review.
Authors: McGehee Elizabeth , Reisch Joan , Dowell Jonathan , Gerber David E.
Published: September 2018

e20027

Background: Primary pericardial mesothelioma (PPM) is a rare cancer, for which there is no consensus on treatment. We performed a retrospective systematic review of recently published PPM cases to characterize risk factors, treatment patterns, and clinical outcomes. Methods: Published literature from 2000-2016 was searched using the terms “primary pericardial mesothelioma”, “pericardial mesothelioma” and “malignant pericardial mesothelioma”. T-tests, Chi-square, and multivariable stepwise logistic regression were employed to correlate demographics, disease characteristics, and treatment with mortality. Results: We identified 6 case series and 84 case reports for a total of 103 PPM cases. Median age at diagnosis was 55; age range was 19 to 87. 39% were female and 61% were male. The mean time from diagnosis to death was 5.6 months. Tobacco exposure and asbestos exposure were reported in 15% and 25%, respectively. Neither exposure was predictive of mortality. 46% of patients underwent surgery, 8% received radiation, 37% received chemotherapy and 23% received no treatment. For 13% of patients, the treatment received, if any, was unknown. Radiation treatment was not associated with a mortality benefit (p = 0.54). A mortality benefit was seen for patients who had resection of their tumor (46% alive at last follow-up, p = 0.0061) but not in patients who had pericardiectomy (25% alive at last follow-up, p = 0.44). A mortality benefit was noted in those who received chemotherapy (p = 0.0022), specifically pemetrexed (p = 0.0038) or platinum agents (p = 0.003). Gemcitabine was not associated with a mortality benefit (p = 0.101). Conclusions: To the authors’ knowledge, this is the first comprehensive analysis of published PPM cases in the modern era. In this retrospective systematic review, a mortality benefit was seen with tumor resection and chemotherapy. Selection bias may account for some of this effect. However, given the inability to perform prospective studies in this population due to small patient numbers, it seems reasonable to offer surgical and medical therapy to eligible patients with PPM.
Age as a determinant of overall survival (OS) and progression free survival (PFS) in patients with stage III lung carcinoma: A Cleveland Clinic experience.
Authors: Seepana Jyothirmai , Mohapatra Suryanarayan , Khalid Sidra , Subramaniam Subanandhini , Spiro Timothy Peter , Daw Hamed , Haddad Abdo S.
Published: September 2018

e20036

Background: Stage III NSCLC is defined as loco-regionally advanced disease due to primary tumor extension into the extra-pulmonary structures(T3 or T 4 ) or mediastinal lymph node involvement without evidence of distant metastasis. Methods: Retrospective study with 561 patients during study period 2003-2014. The most common method used for staging was contrast enhanced CT (97.5%) followed by PET(94.1%). The patients were further stratified into three subgroups < 65 years, 65-75 years and > 75 years. The overall median age was 66, and the median age for the groups was 57, 69and 79 years respectively. 33.9% patients received surgery; 43% patients received concurrent/sequential chemo-radiation, 7.8% patients received chemotherapy only, and 10.1% received radiotherapy only. In terms of type of chemotherapy, 21.4% had adjuvant chemotherapy, 8.8% had neo-adjuvant chemotherapy and 12.9% had both. 24.7% patients had target therapy and 3.7% had immunotherapy. The median survival was 57 months (95% CI). The two-year survival rate was 98% ± 0.7%, and the five-year survival rate was 47.3% ± 4.0%. 387 patients had relapsed. Relapse and death were both treated as PFS events, and the median PFS was 14 months (95%CI). The two-year PFS was 40% ± 0.23%, and the five-year PFS was 14.2% ± 1.7%. Results: see table. Conclusions: No difference was found for OS between < 65 versus 65-75 age groups, neither between 65-75 versus ≥75 age groups. PFS was not different between < 65 versus 65-75 age group. However PFS was marginally significantly different between 65-75 versus > 75 age groups (p = 0.088). [Table: see text]
Multiregion whole exome seuquencing of pre- and early neoplastic lung lesions.
Authors: Zhang Jianjun , Su Dan , Fujimoto Junya , Ying Lisa , Chow Chi-Wan , Sun Wenyong , Zhang Jianhua , Hu Jinlin , Behrens Carmen , Antonoff Mara , Ostrin Edwin Justin , Godoy Myrna , William William N. , Swisher Stephen , Lee J. Jack , Wistuba Ignacio Ivan , Hong Waun Ki , Futreal Phillip Andrew ,   Pre/Early Lung Neoplasm Study Team: Jaime Rodriguez Canales, Marcus Coyle, Curtis Gumbs, Jun Li, Latasha Little, Neda Kalhor, Xizeng Mao, Edwin R. Parra Cuentas, Xingzhi Song, Rebecca Thornton, Ara Vaporciyan, Annikka Weissferdt, Chang-Jiun Wu, Jiexin Zha
Published: September 2018

e20042

Background: The widespread use of CT for lung cancer screening and other reasons has resulted in a dramatic increase in the number of indeterminate ground glass opacities (GGOs). While many of GGOs can be resected with minimal morbidity, the cost has been called into question. Furthermore, multifocality is a relatively common, which makes decisions on extent of surgical resection and potential benefit less clear. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have been disappointing to date. This may be due to the constellation of many factors including lack of reliable biomarkers to identify high-risk patients, lack of appropriate molecular targets and appropriate drugs because of our rudimentary knowledge on early carcinogenesis of lung cancers. It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that can progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, the biology of these lesions is poorly understood and the definition and management of these lesions remain controversial. Methods: Study on early carcinogenesis is hampered by the small size of lesions and challenge of obtaining longitudinal samples at different stages of disease progression. Multiregion sequencing can depict genomic events relative to molecular time with early events ubiquitously present in all regions and late mutations confined to spatially separated regions of lesions. Using this approach, our recent work has reported that 20/21 canonical cancer gene mutations were early genetic events. Results: With intent to delineate the pivotal molecular events driving early carcinogenesis of lung cancer, we have collected 154 resected GGOs with including AAH (N = 40), AIS (N = 39), MIA (N = 55) and ADC (N = 20) based on the IASLC/ATS/ERS classification from 89 patients including 38 patients presenting with multifocal GGOs and 18 patients carry more than one type of pathology. Two to five spatially separated regions from each of the 154 lesions are subjected to whole exome sequencing. Conclusions: The data will be ready to present at the meeting.
The PI3K-Akt signaling leads to synergy of erlotinib and crizotinib in wild-type NSCLC.
Authors: Rolfo Christian Diego , Van Der Steen Nele , Pauwels Patrick , Reclusa Pablo , Peters Godefridus J. , Giovannetti Elisa
Published: September 2018

e20043

Background: Targeted therapies caused a revolution in treatment of non-small cell lung cancer (NSCLC). Response to Epidermal Growth Factor Receptor such as erlotinib, can be predicted by the presence of sensitizing mutations in EGFR. In case of cMET, amplification or exon 14 skipping serve as biomarkers for response to cMET-TKIs, crizotinib. Methods: In this study, we investigated the combination of erlotinib and crizotinib on several squamous NSCLC cell lines wild-type for EGFR and cMET. Growth inhibition was determined using the sulforhodamine B-assay. Combination indexes (CI) were calculated based on the method of Chou and Talalay. A CI below 0.8 was considered synergistic, between 0.8 and 1.2 was considered additive and above 1.2 was considered antagonistic. The influence of treatment on the cell cycle, cell migration, 3D cell cultures and phosphorylation was studied. Results: The H1703 cell line gave an antagonistic (CI = 1.20±0.15), the Calu1 (CI = 0.81±0.04), H520 (CI = 0.87±0.06) and SKMES1 (CI = 0.81±0.02) were additive and LUDLU (CI = 0.39±0.07) was synergistic. A G1 phase arrest occurred after treatment with erlotinib (38 to 76%), whereas crizotinib caused a G2/M phase arrest (13 to 64%). In the combination, the effect of crizotinib was dominant (13 to 52%). A decrease in p-ERK1/2 (Thr202/204), p-PRAS40 (Thr246) and p-GSK3 β (Ser9) was observed. Phospho-PRAS40 showed a decrease after treatment with erlotinib or crizotinib, whereas combination treatment almost abolished p-PRAS40. In the SKMES1 cell line, p-PRAS40 only decreased after the combination, whereas H1703 cells showed no change in p-PRAS40 levels. Phospho-PRAS40 activity is strongly linked to PI3K/Akt signaling. Her3 is able to heterodimerize both with EGFR and cMET, thus activating downstream PI3K/Akt signaling. No expression of Her3 in the antagonistic cell line was detected. In the LUDLU, levels of p-Her3 were not detectable after erlotinib treatment and in the combination, whereas in the SKMES1 levels of p-Her3 slightly decreased only after combination treatment. Conclusions: To conclude, the simultaneous inhibition of both EGFR and cMET leads to a strong inhibition of PI3K/Akt signaling, leading to synergy in the LUDLU wild-type squamous NSCLC cells.
One year experience of MET gene exon 14 skipping analysis in lung cancer: Identification of 18 cases by NGS.
Authors: Dubbink Hendrikus J , Geurts-Giele Willemina , Meijssen Isabelle , van der Leest Cor , Peric Robert , Von Der Thusen Jan , Aerts Joachim , Dinjens Winand N.M.
Published: September 2018

e20055

Background: Lung adenocarcinoma (LAC) is the most common histological type of non-small-cell lung cancer and is one of the malignancies with the most evolved personalized treatments based on molecular characteristics of the tumor. Mutations in EGFR, HER2 and BRAF, specific translocations of ALK, ROS1, RET and amplification of MET all have standard diagnostic importance and lead to specific treatment options for the individual LAC patients. Recently, in 2-4% of LAC MET gene mutations leading to skipping of exon 14 were found. These mutations were described to occur more frequently in tumors with sarcomatoid histology. LAC with MET exon 14 skipping mutations showed impressive, although temporary, responses to MET tyrosine kinase inhibitors (TKI) crizotinib, cabozantinib and capmatinib. We will present our experience with routine molecular diagnostic detection of the most common MET exon 14 skipping mutations. Methods: In January 2016 we included in our standard, DNA based, molecular diagnostics custom-made NGS analyses 4 amplicons for detection of MET skipping mutations. The analyses were performed on microdissected FFPE tissue sections or routine histology or cytology stained preparations. Nine different mutations were validated for their effect on splicing by RT-PCR on RNA isolated from the same tissue samples. Results: Between January 2016 and January 2017 676 routine molecular diagnostic analyses on LAC were performed. In 18 (2.7%) cases MET mutations were detected possibly resulting in exon 14 skipping. Nine out of 16 different mutations were tested by RT-PCR and all 9 were demonstrated to result in MET exon 14 skipping. Conclusions: MET exon 14 skipping mutations can reliably be detected in routine pathology tissue samples. These analyses can easily be included in routine molecular diagnostic NGS. When necessary, confirmation of the mutational effect on RNA splicing can be implemented as well. Routine identification of MET skipping mutations (2.7% of cases) adds substantially to the personalized targeted treatment strategies for LAC patients.
Outcomes of video assisted thoracic surgery compared with open thoracotomy in patients with early stage lung cancer.
Authors: Shaheen Shagufta , Jabo Brice , Kaur Manmeet , Senthil Maheswari , Mirshahidi Saied , Zaheer Salman , Mirshahidi Hamid R.
Published: September 2018

e20061

Background: Video Assisted Thoracic Surgery (VATS) has become the recommended approach for treatment of early stage lung cancer; however, no large randomized clinical trial has been conducted to formally compare VATS to open thoracotomy (OT). The current study sought to assess differences in patients and tumor characteristics for VATS and OT. Additionally, treatment outcomes that included margin status, postoperative length of stay (LOS) and overall survival (OS) were also compared. Methods: A single institution retrospective charts review was conducted for patients diagnosed with stage I-III lung cancer and treated with VATS or OT from May 2005 - May 2015. Patients and tumor characteristics included age at diagnosis, sex, tobacco use, tumor location, stage, size and receipt of chemotherapy or radiotherapy. Chis-square and Wilcoxon-Mann-Whitney tests were used to compare demographic, tumor characteristics and LOS. Multiple logistic and Cox regressions were used to compute relative risk (RR) for positive margins and mortality hazards ratio along with 95 percent confidence interval limits (95%CI), respectively. Results: A total of 232 patients underwent lung resection for cancer diagnosis; VATS n = 99 and OT n = 133. Age at diagnosis, sex, tobacco use, tumor location, and size were not significantly different between the two groups. VATS was more frequently performed for stage I lung cancer compared to OT, p = 0.043. The risk of positive margin RR = 0.49 (95%CI = 0.15, 1.60) and mortality HR = 1.49 (95%CI = 0.90, 2.46) were similar between the two groups. However, the median LOS was significantly shorter (4 days) for VATS than OT (6 days), p = 0.001. Conclusions: Our results show that both short and long-term oncologic outcomes are comparable between VATS and OT. VATS results in shorter LOS and should be considered as the approach of choice for patients undergoing lung resection for cancer. [Table: see text]