bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of flow cytometry in acute promyelocytic leukemia.
Authors: Hadid Tarik H. , Sahovic Entezam A. , Lister John
Published: March 2020

7075

Background: Acute promyelocytic leukemia (APL) is a highly curable disease, with the majority of failures related to hemorrhagic complications. Hence, rapid diagnosis and early initiation of therapy can drastically prevent these complications and reduce mortality. The current diagnostic strategy utilizing fluorescent in situ hybridization (FISH) is often time-consuming and not readily available in some institutions. This is a review of our institutional experience with the use flow cytometry for diagnosis of APL. Methods: All cases with t(15;17) by FISH and karyotype between 2006 and 2012 were identified. A second group of consecutive cases of non-M3 acute myeloid leukemia (AML) and negative FISH and karyotype for t(15;17) was used for comparison. A total of 21 APL and 42 non-M3 AML cases were analyzed. Results: Both groups were comparable in regard to age, gender, white blood cell count, hemoglobin, blast count and lactate dehydrogenase level. The APL group had significantly higher prevalence of thrombocytopenia, disseminated intravascular coagulation and clinical bleeding at time of admission. Expression of CD11c was lacking in 92.3% (12/13) of APL and 14.6% (6/41) of non-M3 AML cases (p<0.0001). CD34 expression was lacking in 68.4% (13/19) of APL and 42.9% (18/42) of non-M3 AML cases (p=0.06). HLA-DR expression was lacking in 88.9% (16/18) of APL and 9.5% (4/42) of non-M3 AML cases (p<0.0001). Given that APL prevalence is 5% among all AML cases, lack of expression of CD11c, CD34 and HLA-DR have negative predictive values (NPVs) of 99.5%, 97.1% and 9933%, respectively. Among various immunophenotypic profiles, lack of expression of CD11c had the highest NPV (99.5%, p<0.0001) and simultaneous lack of expression of CD11c and HLA-DR had the highest specificity (95.1%, p<0.0001). Conclusions: Expression of CD11c reliably excludes the diagnosis of APL in the majority of AML cases. Flow cytometry has the potential of replacing FISH as the initial test to prompt initiating therapy in APL patients.
Plasma trough imatinib levels and molecular response in patients of chronic myeloid leukemia (CML): A single institution study from India.
Authors: Malhotra Hemant , Sharma Pratibha , Bhargava Shipra , Rathode Om Singh , Malhotra Bharti , Gota Vikram
Published: March 2020

7079

Background: One of the reasons proposed for suboptimal responses in Chronic Myeloid Leukemia (CML) patients receiving standard-dose Imatinib has been low blood levels of the drug. Our study aimed to determine the correlation between mean trough Imatinib plasma levels and molecular response in CML chronic phase patients at our centre. We also attempted to compare imatinib plasma levels in patients receiving Gleevec (Novartis) versus patients who were on the generic version of the drug. Methods: One hundred and thirty one (131) CML Chronic phase patients were included in this study. All patients had received 400 mg of imatinib for more than 2 year. Plasma Imatinib trough levels were estimated by high-performance liquid chromatography (HPLC). In order to estimate a threshold for plasma imatinib level that correlates with a favorable response, a receiver operating characteristic (ROC) curve was constructed. Patients were divided into two groups: those with Major Molecular Response (MMR) [bcr/abl : abl ratio <1% as assessed by RQ-PCR] or better (Responders) and those without MMR (bcr/abl : abl ratio =/> 1% as assessed by RQ-PCR) [Non Responders]. Imatinib plasma levels were also compared in patients who were on Gleevec versus those who were on the generic version of the drug. Results: The mean trough imatinib plasma level in the responders was significantly higher (2.10±1.18µg/ml) than in the non responders (1.31±0.72µg/ml) with p value of 0.001. The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 µg/ml. There was no significant difference between the mean trough plasma imatinib levels of the patients who were on Gleevec as compared to those who were on generic Imatinib (p value > 0.05). Conclusions: Plasma Imatinib trough levels were statistically similar in the Gleevec and generic Imatinib groups. These levels showed a statistically significant correlation with molecular response. Trough plasma imatinib levels may be a marker for suboptimal response to Imatinib and may identify patients in whom increase of drug dose or change to second generation tyrosine kinase inhibitors may be indicated.
Clinical features and outcome of B-cell acute lymphoblastic leukemia in patients older than 9 years: A single center experience of 241 cases from AIIMS, New Delhi, India.
Authors: Sharma Atul , Cyriac Sunu Lazar , Sahai Siddharth Kumar , Bakhshi Sameer , Gupta Ritu , Kumar Lalit , Kumar Rajive , Iqbal Sobuhi , Raina Vinod
Published: March 2020

7082

Background: Data on B cell Acute Lymphoblastic leukemia (ALL) in the poor prognostic age group of > 9 years from India is minimal. Methods: This is an analysis of patients of above 9 years that were diagnosed and treated from January 2000 to December 2010 at a single institute . All patients who completed at least 4 weeks of induction therapy were analysed for various outcomes. Results: Of the 241 newly registered patients, the median age was 19 years (Range 10-78 years) with an M:F ratio of 1.9:1. Out of this 47%, 25% & 28% patients belonged to 10-18, 19-30 & > 31 years age group respectively. Twenty seven (11.6%) and 5(2%) had CSF and testicular involvement respectively. Thirty nine per cent had a total leucocyte count (TLC) of above 30x109/L. Philadelphia chromosome (Ph) positivity was seen in 27% and was equally distributed among the different age groups. Patients available for outcome analysis were 213(88.4%). Complete remission rate (CRR) was 66.6% and induction mortality was 26.3%.At a median follow up of 65.8 months 5 year leukemia free survival was 30.5%. Seventy eight (55%) patients relapsed (median relapse time of 13.5 months, range 1.7 to 53.4 months) , 55% during maintenance phase. The 5 year overall survival (OS) was 30.3% with a median OS of 15.8 months. The OS was similar in 10-18 and 19-30 age groups (5 year OS 35% vs. 27.5%, p=0.641) but it was significantly lower in >31 years (5year OS 21%, p=0.008). Apart from this, extramedullary disease, not attaining a CR in 1st induction, albumin at presentation below 3.5gm% and TLC of >100x109/L were significant poor prognostic markers for survival. Conclusions: This is a large study of B-ALL outcomes in patients above 9 years from a single center in India. Patients above 30 years had a worse prognosis while the prognosis of 10-18 and 19-30 years age group were similar. Induction mortality was higher mainly because of advanced disease and poor performance status at presentation.
mTOR inhibition in MDR acute myeloid leukemia.
Authors: Karmakar Aditi , Gangopadhyay Sudeshna , Bhattacharyya Gouri Shankar , Mukhopadhyay Ashis
Published: March 2020

7085

Background: Signaling through the PI3K/PTEN/AKT/mTOR pathway is aberrantly activated in several human cancers, including Acute Myeloid Leukemia (AML) patients where it contributes to leukemic cell proliferation, survival and drug resistance. In leukemia patients treated with drugs such as anthracyclines, vinca alkaloids, chemo-resistance one of the major problems contributing to therapeutic failure, where all this drugs are modulated in their intracellular retention by a 170 kDa Phospho-glycoprotein, an mdr-1 gene product. The role of mTOR in various processes such as proliferation, growth, has been comprehensively described in many reviews, following its inhibition by rapamycin. Thus inhibition of mtor signaling in AML blasts could account for enhancing their sensitivity to cytotoxic agents. This study is to embrace the effect of Rapamycin, an allosteric mTOR inhibitor on MDR AML patients. Methods: We selected samples of 25 MDR AML patients isolated from bone marrow or peripheral blood and cultured in vitro. The effects of Rapamycin on fresh AML samples were analyzed by treating the cells with intermediate drug concentrations (100 nM) for 24 h, 48 h, 72 h, 96 h respectively followed by cytotoxicity assay (MTT assay). The effects of the drug on proliferation of cells were analyzed also by cell counting. Results: A marked reduction in cell viability at 96 h was detected in 25 samples treated with rapamycin. Out of the 25 analyzed samples, 16 were sensitive to the drug where it was observed that the leukemic cell count came down to almost 2% whereas 9 samples displayed various degree of resistance to the drug. Overall, these findings demonstrated that rapamycin has a cytotoxic activity against primary cells from AML patients with up-regulated mTOR signaling. Conclusions: We have evaluated the in vitro effects of Rapamycin on AML patient samples where reduced cell viability primary cells from AML patients were observed. However, further studies of the additional effects of rapamycin will be of the supreme importance, as they could help in designing more efficient curative protocols, for the treatment of acute leukemia patients.
Evolution of bosutinib (BOS) toxicity in patients (pts) with Ph+ leukemia after resistance/intolerance to prior therapy.
Authors: Gambacorti-Passerini Carlo , Brummendorf Tim H. , Cortes Jorge E. , Lipton Jeffrey H. , Kim Dong-Wook , Leip Eric , Turnbull Kathleen Wyant , Kantarjian Hagop M. , Khoury Hanna Jean
Published: March 2020

7099

Background: BOS is an oral dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of Ph+ CML following resistance/intolerance to prior therapy. Prior reports from this phase I/II trial indicated the BOS safety profile was primarily characterized by myelosuppression, gastrointestinal events, and rash. The current analysis compares the incidence of toxicity in Year 1 (Y1) for pts on treatment ≤1 y and within Y1 and Year 2 (Y2) for pts on treatment for >1 y. Methods: BOS 500 mg/d was evaluated in 3 cohorts: chronic phase (CP) CML after imatinib only (CP 2L cohort; n = 286); CP CML after imatinib + dasatinib and/or nilotinib (CP 3L cohort; n = 119); and accelerated/blast phase CML or ALL after prior TKI therapy (ADV cohort; n = 164). Results: The most common treatment-emergent adverse events (TEAEs) in each cohort occurred more frequently within Y1 than Y2 (Table). The incidence for grade 3/4 events followed a similar pattern. AEs were the most common reason for BOS discontinuation in Y1 (CP 2L, 53%; CP 3L, 32%; ADV, 41%). Of the pts whose primary reason for discontinuing BOS was an AE during the first 2 y, most did so during Y1 (CP 2L, n = 51/60 [85%]; CP 3L, n = 22/24 [92%]; ADV, n = 24/25 [96%]); the most common reasons during Y1 were thrombocytopenia (12%; 9%; 4%), increased ALT (6%; 4%; 2%), neutropenia (3%; 6%; 0%), diarrhea (4%; 3%; 0%), and vomiting (3%; 4%; 1%). Serious AEs were more common among pts who discontinued BOS ≤1 y versus on treatment >1 y in the CP 3L and ADV cohorts, but similar in the CP 2L cohort (Table). Conclusions: Discontinuation due to AEs was observed primarily in Y1. For pts on BOS for >1 y, the incidence of common TEAEs decreased substantially after Y1, suggesting BOS tolerability improves after long-term exposure. Clinical trial information: NCT00261846. [Table: see text]
Outcomes of first-line treatment for chronic lymphocytic leukemia (CLL) with 17p deletion (del17p).
Authors: Strati Paolo , Keating Michael J. , O'Brien Susan Mary , Ferrajoli Alessandra , Burger Jan Andreas , Faderl Stefan , Jain Nitin , Wierda William G.
Published: March 2020

7102

Background: Patients (pts) with relapsed CLL bearing del17p are very high-risk for poor clinical outcomes. We summarize outcomes for first-line treatment of del17p CLL. Methods: We identified pts with CLL and del17p by FISH who received first-line treatment at MDACC between 1/04 and 12/12. Log-rank test and Cox regression were used for univariable and multivariable analyses. Results: Baseline characteristics are shown (Table). Median time from diagnosis to first treatment (TTFT) was 15 (11-19) mos; no association between % del17p positive cells at diagnosis and TTFT was noted (p=.45). With first-line therapy (Table), 19 pts (30%) achieved complete remission (CR), 2 (3%) nodular partial remission (nPR), 18 (30%) PR, and 24 (37%) were non-responders. Fourteen CR pts (78%) were minimal residual disease negative by flow cytometry. The median time-to-treatment failure (TTF) was 14 (10-18) mos (43 events); the median follow-up was 33 (1-89) mos. Univariable analyses showed age >65 yrs (p=.04), complex karyotype (p=.02), lack of response to therapy (p<.001) and >50% cells positive for del17p by FISH (p=0.009) associated with shorter TTF. The multivariable model showed karyotype (p=.005) and quality of response (p<.001) independently associated with TTF. Median Overall Survival (OS) was 63 (43-83) mos (48 deaths). Fifteen pts (23%) developed Richter Syndrome (RS) after a median of 12 (1-27) mos; 8 deaths (29%) were related to RS. Univariable analysis showed that only lack of response was associated with a shorter OS (p=.001). Conclusions: Del17p CLL is high-risk for first-line therapy; better response to therapy was observed in young patients with low % del17p positive cells by FISH who received FCR. New strategies and agents must aim at both improving response and maintaining remission, particularly in pts with complex karyotype. [Table: see text]
Evaluating oncogenic pathway dysregulation in adolescents and young adults with acute myeloid leukemia.
Authors: Rao Arati , Livingston John Andy , Dave Sandeep S.
Published: March 2020

7107

Background: Adolescent and young adults (AYAs) with Acute Myeloid Leukemia (AML) have been shown to have better outcomes with induction chemotherapy when compared to older young adults (OYAs). Multiple psychosocial, treatment, and host-related factors unique to AYAs have been identified but the contribution of disease biology to these outcomes has not yet been fully characterized. The purpose of this study was to evaluate disease biology as it relates to age-specific differences in outcomes for AYAs with AML. Methods: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets: GSE1159; and GSE12417 were analyzed. Age-specific cohorts (AYAs ≤ 30 years; n = 58 and OYAs >30 but ≤ 60 years; n=276) were prospectively identified. Patients in GSE1159 were treated according to protocols of the Dutch–Belgian Hematology–Oncology Cooperative group and included 111 patients who ultimately underwent stem-cell transplantation. Patients in GSE12417 were treated per the AMLCG-1999 protocol. Gene expression analysis was conducted by applying previously defined and tested signature profiles reflecting deregulation of oncogenic signaling pathways and altered tumor environment. All statistical analysis was performed using S-plus and survival analysis by Cox proportional-hazards regression was used to assess differences in overall survival (OS) between age-specified study cohorts and a one-sided p-value ≤ 0.05 was considered statistically significant. Results: AYA patients had a significantly better OS (median survival 24.1 months vs. 13.0 months in OYAs; p=0.0285), but there was no difference in Event Free Survival (p=0.23). Analysis of oncogenic pathways revealed that AYA patients likely had better OS because of lower TNF (p=0.03) and higher myc (p=0.02) pathway activation. Conclusions: AML arising in AYAs may represent a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to OS. We hope these findings will enable clinically meaningful adjustments of treatment strategies in the AYA AML patient population.
Evidence for selective benefit of sequential treatment with azanucleosides in patients with myelodysplastic syndromes (MDS).
Authors: Komrokji Rami S. , Apuri Susmitha , Al Ali Najla , Padron Eric , Pinilla-Ibarz Javier , Ho Viet , List Alan F. , Lancet Jeffrey E.
Published: March 2020

7113

Background: Azanucleosides (AZN) remain the mainstay of therapy in myelodysplastic syndrome (MDS). Sequential use of AZNs is common practice given the limited alternatives. The only published experience described 14 patients showing a 28% response with decitabine (DAC) after failure or lack of response to azacitidine (AZA). To investigate the potential benefit of this approach,we reviewed cases of sequential AZN treatment. Methods: Patients who received treatment with both AZNs were identified through the Moffitt Cancer Center MDS database. Two groups were identified; group one who received DAC after AZA failure and group 2, who received AZA after DAC failure. The primary objective was to estimate overall response rates according to the International Working Group (IWG) 2006 criteria. The Kaplan–Meier method was used to estimate median OS. Results: A total of 39 MDS patients were identified who received treatment with both AZNs. Complete records were available in 31 patients, including 21 patients in group 1 (DAC after AZA) and 10 patients in group 2 (AZA after DAC). The Table summarizes baseline characteristics and response rates. The median OS for Group 1 from diagnosis was 48 months and for group 2 was 100 months (p=0.7). Conclusions: Sequential use of AZNs after failure of first line may be an effective alternative outside the context of clinical trials. Response rate is higher in patients who receive AZA after DAC. Sequential use of HMA should be considered in context of randomized clinical trial of novel agent as the control arm. [Table: see text]
Cytidine deaminase status as a predictive marker in patients with hematologic malignancies treated with azacytidine or cytarabine.
Authors: Mercier Cedric , Fanciullino Raphaelle , Serdjebi Cindy , Ciccolini Joseph , Pourroy Bertrand , Milano Gerard , Costello Regis , Ouafik L'houcine
Published: March 2020

7117

Background: Cytarabine and azacytidine are mainstays for treating haematological malignancies. As most nucleosidic analogs, both azacytidine and cytarabine are metabolized in the liver by an exclusive enzymatic step driven by cytidine deaminase (CDA). CDA is highly polymorphic and dysregulations have been repeatedly associated with poor clinical outcome with gemcitabine. Methods: We have used a test to determine, on a phenotype basis, CDA status in patients. This test was used prospectively in a subset of 39 adult patients (16F, 23M, mean age 77 years), all treated for various haematological malignancies (i.e., CML, AML, lymphomas, myelodysplastic syndromes) with either aza-cytidine or a cytarabine-containing regimen. Response and treatment-related toxicities were monitored following current standards. In addition, impact of CDA status on azacytidine tolerance was evaluated in mice with or without CDA deficiency, as a proof of concept for the actual implication of metabolic deregulations in the toxicities observed in patients. Results: In patients, mean CDA activity was 3.7 +/-2.8 U/mg (min: 1, max: 14.8 U/mg). Ten out of 39 patients (i.e., 25%) showed low CDA activities and were considered as PM. Conversely, 8 patients (i.e., 20%) displayed CDA activities particurlary elevated (i.e., > 6U/mg) and were considered as UM patients. Of note, PM patients all showed severe toxicities, including two toxic-deaths. Conversely, UM patients showed little efficacy when treated with either azacytidine or cytarabine. In mice with CDA-deficiency, standard azacytidine led to profound and long-lasting neutropenia, as compared with normal mice. Drug monitoring confirmed that individuals with low CDA activity and toxicities showed higher concentrations of azacytidine as compared with normal individuals. Conclusions: Overall this pilot study strongly suggests that CDA status could be a relevant marker for predicting clinical outcome in patients treated with either azacytidine or cytarabine. CDA status could be further used as a covariate to tailor drug dosage so as to ensure an optimal efficacy/toxicity balance in patients with haematological malignancies.
Long-term follow-up of autologous hematopoietic stem cell transplantation for stage II/III breast cancer.
Authors: Meyer Andrew D. , Tolentino Angelica L. , Bitran Jacob D. , Klein Leonard M.
Published: March 2020

7121

Background: In the 1980s and 1990s, adjuvant chemotherapy with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) was utilized for the treatment of high-risk breast cancer. Previous studies showed that ASCT significantly reduced the risk of relapse in these patients, but failed to provide evidence of improved overall survival when compared with standard therapy in randomized trials. Due to the mortality, morbidity, and cost associated with ASCT and lack of a clear overall survival benefit, the use of HDC with ASCT for high-risk breast cancer was halted. In this retrospective, observation study, we analyzed the toxicity and efficacy of ASCT in high-risk breast cancer at a large community hospital. Methods: The study population consisted of 57 women diagnosed with high-risk primary breast cancer who underwent treatment with HDC followed by ASCT from 1991-1999. Women receiving treatment for metastatic breast cancer were excluded. The medical records of the study population were retrospectively reviewed, with particular attention to long-term toxicities and efficacy. Results: Fifty seven patients were evaluated: 54 with ductal and/or lobular breast cancer and 3 with inflammatory breast cancer. Median age was 44 years (29- 61). Twenty six patients (46%) were alive at time of review. Twelve patients (21%) experienced a recurrence of their breast cancer. Four patients (7%) developed secondary malignancies. Two patients (4%) experienced cardiac toxicities. Estrogen/progesterone receptor-positive breast cancers accounted for 42% of recurrences, 100% of secondary malignancies, and 50% of cardiac toxicities. HER-2/neu status analysis revealed amplification in 17% of breast cancer recurrences, but in no cases of secondary malignancy or cardiac toxicity. Conclusions: High-dose chemotherapy and ASCT can be effective in reducing long-term recurrences in women with high-risk, Stage II/III breast cancer. This treatment, however, carries an associated risk of secondary malignancies and cardiac toxicities. Estrogen/progesterone receptor-positive breast cancer appears to have a greater association with disease recurrence and secondary malignancies.
A randomized phase II study adding axitinib to pemetrexed-cisplatin in patients with malignant pleural mesothelioma (MPM): Clinical results of a single-center trial.
Authors: Buikhuisen Wieneke A. , Vincent Andrew D. , Scharpfenecker Marion M. , Korse Catharina M. , Griffioen Arjan W. , van Pel Renee , Baas Paul
Published: March 2020

7528

Background: Since standard chemotherapy treatment does not lead to long-term survival, new treatment approaches are required. MPM is known for a high vessel count and high levels of vascular growth factors. Suppression of the neo-vasculature by adding the oral VEGF-TKI axitinib to standard chemotherapy may lead to improvement. This study had both clinical and translational objectives. We here report the secondary endpoints response, PFS, OS and toxicity. Methods: Treatment naïve patients with suspected or proven malignant mesothelioma and medically suitable for limited surgical intervention were eligible after informed consent. Patients were treated with pemetrexed (500mg/m2q3wk) and cisplatin (75mg/m2q3wk) and were randomised to daily axitinib (2x5mg tablets). Before treatment a thoracosopy was performed to confirm the diagnosis. After 3 cycles of chemotherapy a palliative pleurectomy was performed. During both interventions material was obtained for research purposes. Patients could receive an additional 2 cycles of chemotherapy. Results: From July 2009 until October 2012, 26 patients were randomised. Six consecutive patients who received chemotherapy plus axitinib to demonstrate the feasibility and safety of the study design, were also included. In total twenty patients received axitinib. There was one protocol violation in the control arm. Median age: 61 yrs (35 yrs – 75 yrs), 84% epithelial type, 94% WHO 0-1 and 6% WHO 2. Median follow up was 18 months. Toxicity: There was more grade 3, 4 toxicity in the axitinib group concerning neutropenia (40% vs. 9%; p=0.11). One patient in the axitinib group developed a CVA, one patient pulmonary emboli. No thromboembolic events occurred in the control arm. Partial response was observed in 35% of patients in the experimental arm vs. 27% in the control group (p=0.99). Median PFS was 8 months in the experimental arm vs. 8.3 months in the control arm. There was also no difference in overall survival 17 vs 18 months, respectively. Conclusions: Axitinib was well tolerated in combination with cisplatin and pemetrexed. There was no evidence of benefit in response rate, progression free or overall survival. Clinical trial information: NCT01211275.
Lymphovascular invasion as a prognostic indicator in stage I non small cell lung cancer: A systematic review and meta analysis.
Authors: Mollberg Nathan M , Bennette Carrie , Howell Eric , Backhus Leah M. , Ferguson Mark K.
Published: March 2020

7535

Background: Identification of pathologic features able to predict outcomes in resected stage I non-small cell lung cancer (NSCLC) may help to further stratify patients into risk groups, allowing for further refinement of adjuvant treatment recommendations. We performed a systematic review and meta-analysis to evaluate whether the presence of lymphovacular invasion (LVI) is associated with disease outcome in stage I NSCLC patients. Methods: A systematic search of the literature was performed (1990 to December 2012; Medline/Embase) using search terms related to lymphovascular invasion, lung cancer and prognosis. Studies were considered eligible if they reported the outcome of lung cancer in patients with LVI compared to those without. Pooled Hazard Ratios (HR) were estimated with a random effects model. Two different endpoints were independently analyzed: recurrence-free survival (RFS) and overall survival (OS). We analyzed both unadjusted and adjusted effect estimates, for a total of four separate meta-analyses. Several studies presented multiple results (i.e. adjusted and unadjusted and/or recurrence-free and overall survival) and were therefore included in more than one pooled analysis. Results: Of 2,878 titles identified, 20 articles met the inclusion criteria. Of these, 5 studies were excluded from the analysis due to duplication of results (n=4) and lack of data to calculate HR (n=1). The unadjusted models consisted of 808 (RFS) and 1675 (OS) patients, while the adjusted models consisted of 1,545 (RFS) and 2,601 (OS). The unadjusted pooled effect of LVI was significantly associated with worse both RFS (HR: 4.71, 95% Confidence Interval (CI): 3.08-7.21), and OS (HR: 3.05, 95% CI: 2.34-3.98). Adjusting for potential confounders yielded the same results with both RFS (HR: 2.49, 95% CI: 1.6-3.89), and OS (HR: 1.80, 95% CI: 1.44-2.25) being significantly worse for patients exhibiting LVI in their pathologic specimens. Conclusions: The present study indicates that LVI is an adverse prognostic factor in patients with surgically managed stage I lung cancer. Based on these results, the use of LVI as a stratifying factor in future prospective lung cancer trials seems to be justifiable.
Effect of age on impact of adjuvant chemotherapy for resected non-small cell lung cancer.
Authors: Ganti Apar Kishor , Williams Christina D. , Gajra Ajeet , Kelley Michael J.
Published: March 2020

7539

Background: Adjuvant chemotherapy (AC) is considered standard of care in patients with resected stages 2 and 3 non-small cell lung cancer (NSCLC). However data regarding its utility in older patients are sparse. This analysis was conducted to evaluate the role of AC in older patients with early stage NSCLC. Methods: We conducted a retrospective analysis of patients with stages 1-3 NSCLC between 2001 and 2008 in the VA Central Cancer Registry. Patients were divided into two groups based on age: <70 yrs and ≥70 yrs. Descriptive statistics were used to examine patterns of AC use and to obtain survival rates associated with use of AC in the two age groups. Chi-square was used to compare distributions. Results: Of the 10,036 patients who underwent surgical resection, 3958 (39.4%) were ≥70 yrs, while 6078 were <70 yrs old. Overall, 11.2% of older patients (6.3% - stage 1, 21% - stage 2, 26.2% - stage 3) and 22.3% of younger pts (11.6% - stage 1, 41.1% - stage 2, 47.1% - stage 3) received AC. Of the patients who received AC, a greater proportion of younger patients received platinum-based AC (91.8 vs 86.4% vs; p=0.0008). Also, in each stage younger patients had a better 3 yr overall survival (OS) (Stage 1-69.2 vs 58%, stage 2 – 52.8 vs 39.1%, stage 3 – 42.5 vs 33.7%). Younger patients with stages 2 and 3 NSCLC who received AC had improved 3 yr OS (58.8 vs 48.6%; p=0.0009 and 48.8 vs 36.9%; p=0.0002 respectively). There was no difference in 3 yr OS for older patients based on AC when all stages were included. For patients with stages 2 and 3, a larger proportion of younger patients received cisplatin-based AC (11.3 vs 3.5%). Older patients with stages 2 and 3, who received cisplatin-based AC had a better 3 yr OS compared to those who received carboplatin-based AC or no AC (55.3 vs 42.2 vs 35.3% respectively; p=0.01). Similarly cisplatin-based AC had an improved 3 yr OS in younger patients with stages 2 and 3 NSCLC (61.4 vs 52 vs 43.4% respectively; p=0.0001). Conclusions: This analysis suggests that older patients do not benefit from AC after resection of stage 1-3 NSCLC to the same degree as younger patients. This differential effect may be due to less common use of cisplatin among older patients. Multivariate analyses are planned.
Outcomes of elderly stage I lung cancer patients treated with segmentectomy via video assisted thoracoscopic surgery or open resection.
Authors: Smith Cardinale B. , Mhango Grace , Wisnivesky Juan P.
Published: March 2020

7543

Background: Video-assisted thoracic surgery (VATS) is considered an alternative to open lobectomy for the treatment of non-small cell lung cancer (NSCLC). Limited data is available however, regarding the equivalence of open vs. VATS segmental resections, particularly among elderly patients. In this study, we used population-based data to compare postoperative and oncologic outcomes following open vs. VATS segmentectomy for early NSCLC. Methods: We identified all stage I NSCLC patients >65 year treated with VATS or open segmentectomy from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims. We used propensity score methods to control for differences in the baseline characteristics of patients. Overall and lung cancer-specific survival of patients treated with VATS vs. open segmentectomy was compared after adjusting, stratifying, or matching patients based on their propensity score. We performed secondary analyses evaluating perioperative complications, need for intensive care unit (ICU) admission, extended length of stay, and perioperative mortality. These were repeated adjusting for physician characteristics (sociodemographics, specialty, and procedure volume). Results: Of the 577 study patients, 27% underwent VATS resection. VATS were mostly performed by high volume surgeons (p<0.001). Overall (hazard ratio [HR]: 0.80, 95% CI: 0.60-1.06) and lung cancer-specific (HR: 0.71, 95% CI: 0.45-1.12) survival was similar among treatment groups. VATS-treated patients had lower rates of postoperative complications (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.37-0.83), need for ICU admission (OR: 0.18, 95% CI: 0.12-0.28), and decreased length of stay (OR: 0.41, 95% CI: 0.41-0.81) after adjusting for propensity scores. The distribution of all postoperative complications, ICU admission, extended length of stay, and perioperative mortality was not significantly different across groups after adjusting for surgeon characteristics. Conclusions: VATS segmentectomy can be safely performed among elderly patients with early stage NSCLC and is associated with equivalent postoperative and long-term oncologic outcomes.
Association of miR-141 and miR-200c with time to recurrence (TTR) and overall survival (OS) in resected non-small-cell lung cancer (NSCLC) adenocarcinoma (ADC) patients (p).
Authors: Campayo Marc , Navarro Alfons , Tejero Rut , Cabanas Maria L , Molins Laureano , Marrades Ramon M , Ramirez Jose , Monzo Mariano , Vinolas Nuria
Published: March 2020

7547

Background: Surgical resection remains the standard curative treatment for early-stage NSCLC, but nearly 50% of p experience recurrence, highlighting the need for novel diagnostic and therapeutic strategies. Moreover, treatments in NSCLC are often histology-dependent, underlining the need for histology-related markers. MicroRNAs (miRNAs) are promising molecular markers in cancer, with marked differences in expression according to histology. miR-200 family members have been associated in vitro with the regulation of epithelial-mesenchymal transition. We have examined their impact on outcome in resected NSCLC p. Methods: We analyzed miRNA expression using TaqMan assays in 160 tumor samples from NSCLC p who had undergone surgical resection and correlated our findings with TTR and OS. Results: p characteristics: age, 67 (51-83); 140 male; 96 (60%) stage I, 34 (21.3%) stage II, 30 (18.7%) stage III; 77(48.1%) ADC, 71(44.4%) squamous cell carcinoma (SCC); 16 (9.1%) received adjuvant treatment. With a median follow-up of 28 months (m), 64 p (40%) had relapsed. TTR for the 107 p with high miR-200c was 26.7 m vs 100.2 m for the 52 p with low miR-200c (P=0.032). OS for p with high miR-200c was 71.2 m vs. 125 m for p with low miR-200c (P=0.01). TTR for 112 p with high miR-141 was 26.7 m vs. 100.2 m for 46 p with low miR-141 (P=0.06). OS for p with high miR-141 was 72 m vs. 118 m for p with low miR-141 (P=0.02). Interestingly, neither miR-200c nor miR-141 correlated with TTR or OS in SCC p. In contrast, in ADC p, the prognostic value of both miRNAs increased: miR-200c (TTR, P=0.01; OS, P<0.0001) and miR-141 (TTR, P=0.003; OS, P<0.0001). This prognostic value was maintained in the subgroup of stage I p: miR-200c (TTR, P=0.011; OS, P<0.001) and miR-141 (TTR, P=0.018; OS, P<0.001). In the multivariate analysis, miR-200c and miR-141 emerged as an independent prognostic factor for OS (OR: 3.2, P=0.006; OR:2.5, P=0.02, respectively) together with age>65 (OR: 3.3, P=0.001) and stage I (OR: 0.3, P=0.004). Conclusions: miR-200c and miR-141 expression is associated with TTR and OS in resected ADC but not in SCC NSCLC p.
Reducing futile thoracotomy rates in PET-CT staged non small cell lung cancer: Clinical risk factors from a population-based review.
Authors: Smoragiewicz Martin , Laskin Janessa J. , Wilson Don , Ramsden Katherine , Zhai Yongliang , Ho Cheryl
Published: March 2020

7551

Background: The use of PET-CT in staging NSCLC reduces futile thoracotomy (FT) rates to approximately 30%. We aimed to identify pre-operative clinical risk factors for FT in patients (pts) staged with PET-CT. Methods: The British Columbia Cancer Agency (BCCA) provides care to 4.5 million people. A retrospective chart review was conducted on all pts referred to the BCCA in 2009-2010 who had staging PET-CT and thoracotomy for NSCLC. Exclusion criteria: tri-modality therapy, clinical N2 disease, or cancer within 5 years. FT was defined as benign lung lesion, exploratory thoracotomy, pathologic N2 disease, stage IIIB/IV, or recurrence or death < 1 year of surgery (sx). The FT and non-FT groups were compared with the Fisher test in univariate analysis and logistic regression model multivariate analysis. Results: 108 pts met inclusion criteria. Baseline characteristics: male 42%, median age 67 (45-82), ECOG 0-1/+2: 85%/15%, never/former/current smoker 18.5/42.5/39%, weight loss >10% 9%. Disease characteristics: nonsquamous/ squamous histology 72/28%, median primary tumor size 3.2 cm, median SUVmax 10.1, PET + N1 24%. Median time from PET to sx 29 days. 29% pts received adjuvant chemotherapy. Thoracotomy was futile in 27 pts (25%); 14 recurred < 1 yr of sx, 10 pathologic N2 and 1 each incomplete resection, pleural disease at sx, death within 1 yr. On univariate analysis, PET + N1 (odds ratio [OR] 3.77, p 0.008) and primary tumor size > 3.2cm (OR 2.93, p 0.026) were associated with FT. On multivariate analysis, ECOG >1 (OR 4.57, p 0.017), PET + N1 status (OR 4.24, p 0.006) and primary tumor size > 3.2cm (OR 2.87, p 0.039) were associated with FT. Among the 26 pts wth PET + N1, 44% underwent FT; 23% due to N2 disease, 19% relapsed within 1 yr, 4% incomplete sx. 27% had mediastinoscopy or EBUS staging. Among the 82 pts with PET – N1,18% underwent FT; 5% due to N2 disease, 11% relapsed < 1 yr, 2% pleural dx or death < 1 yr. Conclusions: Pre-operative ECOG >1, primary tumor size > 3.2 cm and PET + N1 are associated with higher rates of FT in NSCLC. PET + N1 disease corresponds to higher rates of N2 disease and surgical staging may reduce FT in this population. These factors should be taken into consideration to reduce FT rates in NSCLC.
Association of germ-line single nucleotide polymorphisms (SNPs) with pathologic response to neoadjuvant cisplatin-based chemotherapy in patients with resectable non-small cell lung cancers.
Authors: Chaft Jamie E. , Shah Sohela , Drill Esther N. , Sima Camelia S. , Joseph Vijai , Dutra-Clarke Ana Virginia Calogeras , Littman Jason , Kris Mark G. , Travis William D. , Rizvi Naiyer A. , Offit Kenneth
Published: March 2020

7558

Background: Pathologic response to neoadjuvant chemotherapy correlates with survival in resected lung cancers. Predictive biomarkers of response are needed. Tumor-specific biomarkers have been hindered by reproducibility and specimen adequacy. Genome-wide association studies (most in SE Asia) have identified candidate SNPs that correlate with clinical outcomes after cisplatin-based chemotherapy. We evaluated whether these candidate SNPs are predictive of pathologic response to neoadjuvant chemotherapy in a US population. Methods: We aimed to correlate SNPs with near complete PR (ncPR) to neoadjuvant cisplatin + docetaxel in patients with resectable lung cancers. ncPR was defined as 90% necrosis, inflammation and fibrosis across serial 1cm sections of the resected tumor. Germline DNA was extracted and 50 candidate SNPs were genotyped by Sequenom Mass ARRAY iPLEX. SNPs were analyzed for correlation with ncPR using recessive (aa vs AA/aA) , dominant (AA vs aa/aA) and log-additive (linear increase in risk with each additional allele) genetic models. In this exploratory dataset, a p-value <0.1 was considered worthy of further study. Results: 60 patients were treated and had sufficient DNA for analysis. Nine patients had a ncPR. 7 of 50 SNPs (table) correlated with pathologic response in one of the three models. Conclusions: Of the candidate SNPs identified from the literature, 7 showed a promising correlation to ncPR to neoadjuvant chemotherapy. This expands upon the experience evaluating SNPs and chemotherapy sensitivity into a North American population. Study of these 7 SNPs is ongoing in our current multimodality trial as a validation cohort. This study was funded by the Lung Cancer Research Foundation. [Table: see text]
Prognostic impact of FGFR1 amplification in patients with early-stage resected squamous cell carcinomas of the lung (SQCLC).
Authors: Hellmann Matthew David , Wang Lu , Wynne Melissa , Sima Camelia S. , Kris Mark G. , Moreira Andre L. , Rekhtman Natasha , Paik Paul K.
Published: March 2020

7559

Background: The spectrum and frequency of oncogenes in squamous cell lung cancers (SQCLCs) has recently been defined. Amplification of fibroblast growth factor receptor 1 (FGFR1) occurs in ~20% of SQCLCs; clinical trials of FGFR1 inhibitors for advanced SQCLCs are ongoing. The frequency, clinicopathologic features, and prognosis of FGFR1 amplification in early-stage, resected SQCLCs have been reported but with discrepant results (Kim et al, J Clin Oncol 2012, Heist et al, J Thorac Oncol 2012). Methods: A cohort of histopathologically-defined and clinically-annotated resected SQCLCs was tested for FGFR1 amplification by FISH (Zytovision Dual Color Probe). Amplification was defined by FGFR1 copy number ≥2.2x CEP8 control copy number and was assessed by two evaluators (MW, LW) who were blinded to clinical results. Disease-free survival (DFS) was defined as date of resection until relapse, recurrence, or death, whichever occurred first. We assessed association between FGFR1status and clinical features (Fisher’s exact test) and DFS (long-rank test). Multivariate DFS analysis was performed using Cox regression analysis. Results: 63 resected SQCLCs were evaluated. FGFR1 amplification was detected in 16 (24%). The median age of the cohort was 70 years (range 48-88). 15 (24%) currently smoked, 47 (75%) former, 1 (1%) never. 7 (11%) received neo-adjuvant therapy. 35 (56%) were stage I, 15 (24%) were stage II, and 13 (20%) were stage IIIA. There was no association between FGFR1 amplification and age (p>0.99), sex (p>0.99), smoking status (p=0.32), or stage of disease (p=0.18). 1-year and median DFS in FGFR1-amplified vs non-amplified cases were 86% vs 71% (p=0.022) and not reached vs 2.3 yrs (95% CI 1.1-3.4 yrs), respectively. Multivariate analysis (FGFR1 status, sex, and stage) found FGFR1amplification significantly associated with improved DFS (HR 3.2, 95% CI 1.1-9.4). Conclusions: In this cohort of resected SQCLCs FGFR1 amplification was associated with improved outcomes. There was no association between FGFR1 status and sex, age, smoking status, or stage. FGFR1 amplification is common in SQCLCs.
Computer-aided lung cancer screening with CT: A clinically usable nodule detection and assessment system.
Authors: Lo Pechin , Brown Matthew S. , Goldin Jonathan , Barnoy Eran , Kim Hyun J. , McNitt-Gray Michael F. , Aberle Denise R.
Published: March 2020

7562

Background: The National Lung Screening Trial (NLST) recently demonstrated that lung cancer screening with low-dose CT reduces mortality. Current protocols use 4–8 mm nodules as positive screens. While there are some computer-aided nodule detection (CAD) systems currently available, they are rarely used in clinical practice because they generate too many false positives and lack reliable measurement tools. The purpose of this work is to develop a new CAD system to overcome these limitations and evaluate it against an expert panel of radiologists. Methods: The CAD system developed for lung nodule detection and measurement incorporates computer vision techniques including intensity thresholding, Euclidean Distance Transformation, and watershed segmentation. Rules pertaining to volume and shape were applied to automatically discriminate between nodules and bronchovascular anatomy. CAD system performance was assessed using 108 consecutive cases from the publically available Lung Imaging Database Consortium (LIDC), in which four radiologists reviewed each case. CT slice thickness ranged from 0.6–3.0 mm. Nodules were included that were: (a) ≥ 4mm, and (b) marked by a majority of the LIDC readers, and (c) ≥ 4 x CT slice thickness (to ensure adequate spatial resolution). Results: 44 of 108 subjects had one or more nodules meeting criteria. Median CAD sensitivity per subject for these 44 cases is reported for all nodules ≥ 4mm and the subset of nodules ≥ 8mm. The false positive (FP) rate per subject is reported for all 108 cases. The overall concordance correlation coefficient (CCC) between the CAD volume of each nodule and the LIDC reference volume was measured. Conclusions: Based on clinical CT screening protocols, a CAD system has been developed with high nodule sensitivity and a much lower false positive rate than previously reported systems. Automated volume measurements show strong agreement with the reference standard, providing a comprehensive detection and assessment workflow for lung cancer screening. [Table: see text]
Impact of environmental tobacco smoke (ETS) on ALK rearrangements in never smokers (NS) with non-small cell lung cancer (NSCLC): Analyses on a prospective multinational ETS registry.
Authors: Kubo Akihito , Ando Masahiko , Soo Ross A. , Kawaguchi Tomoya , Ou Sai-Hong Ignatius , Ahn Myung-Ju
Published: March 2020

7565

Background: EGFR and ALK are important driver mutations in NS. While we reported the significant association of increased ETS with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), ETS association with ALK has not been reported. Methods: ETS exposure on NS with NSCLC was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood and in adulthood, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3). Results: From March 2008 to December 2012, 498 NS with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/female, 114/384; age <65/>=65, 286/212. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319). Conclusions: Increased ETS exposure was closely associated with EGFR mutations in NS with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in NS with NSCLC was not significant.