tbuckley/cabot-search huggingface dataset:
Neutrophil to lymphocyte ratio (NLR) as a predictive marker of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC).
Authors: Gayatri Vaidyanathan, Grace K. Dy, Petr Starostik, Shiva Dibaj
Journal: Journal of Clinical Oncology (2014)

e19117 Background: NLR has prognostic value in different types of cancers including NSCLC. EGFR TKI’s have conferred survival benefit to patients (pts) with advanced NSCLC harboring EGFR TK mutations (EGFRm+), although response and duration of clinical benefit varies. The predictive value of NLR in this setting is unknown. Methods: We conducted a retrospective study on 42 pts with EGFR TKI-naive advanced EGFRm+ NSCLC. The objective of the study was to explore the correlation between NLR with response to EGFR TKI therapy. Pretreatment NLR was calculated from complete blood count (CBC) before the pts were started on Erlotinib and post treatment NLR was calculated from CBC after being on Erlotinib at the end of 2 months (mo) and 4 mo. Pts were classified into two groups, High NLR ≥ 5 or Low NLR < 5 . Response evaluation using RECIST 1.1 was based on imaging done at the end of 4 months of therapy. Fisher exact test was used for analysis. Results: The mean age of pts was 65y. Male: Female ratio was 1:2. 23 pts were smokers. Majority were Caucasians with only 2 pts of Asian ethnicity. 93% of EGFR mutations were in Exon's 19 or 21. 2 patients were excluded from analysis as they did not reach 4mo time point limit. NLR at 2mo was significantly associated with response to treatment. Low NLR pts at 2 mo had clinical benefit (CR/PR/SD) at 4 mo while high NLR pts had more disease progression. NLR at 4 mo showed the same results. Conclusions: NLR after 2mo EGFR TKI therapy may potentially predict the likelihood of response/disease progression among EGFRm+ NSCLC patients. Further investigation is warranted to confirm these observations and identify the biological mechanism to tailor therapies in the future. Correlation between NLR and Tumor response. Response at 4 mo CR (%) PR (%) SD (%) PD (%) P value Total N 2 (5) 7 (17.5) 24 (60) 7 (17.5) Pretreatment NLR Low NLR 2 (100) 6 (85.7) 20 (83.3) 4 (57.1) 0.482 High NLR 1 (14.3) 4 (16.7) 3 (42.9) Post-treatment NLR at 2months Low NLR 2 (100) 5 (71.4) 22 (91.7) 3 (42.9) 0.026 High NLR 2 (28.6) 2 (8.3) 4 (57.1) Post-treatment NLR at 4 months Low NLR 2 (100) 4 (57.1) 21(87.5) 3 (42.9) 0.039 High NLR 3 (42.9) 3 (12.5) 4 (57.1)
The effect of adjuvant chemotherapy for patients with adverse pathology after neoadjuvant chemotherapy for muscle invasive bladder cancer.
Authors: William P. Parker, Elizabeth B. Habermann, Courtney N. Day, Harras B. Zaid, Igor Frank, Robert Houston Thompson, Matthew K. Tollefson, Stephen A. Boorjian, Lance C. Pagliaro, Jeffrey Karnes
Journal: Journal of Clinical Oncology (2017)

367 Background: While neoadjuvant chemotherapy (NAC) for muscle−invasive bladder cancer (MIBC) is recognized as the standard of care, the management of patients with locally advanced and/or nodal disease after NAC and radical cystectomy (RC) is not well defined. We sought to evaluate the association of adjuvant chemotherapy (AC) and overall survival (OS) among patients with adverse pathology after NAC and RC. Methods: The National Cancer Database was reviewed to identify patients with adverse pathology (pT3N0, pT4N0, or pTanyN1−3) at RC following NAC from 2006−2012. Patients were stratified by receipt of AC. Clinical and pathologic variables were abstracted. OS was the primary end−point and differences on the basis of AC were assessed by the Kaplan−Meier method and log−rank test. Multivariable Cox proportional hazards regression was used to assess the association of AC with OS controlling for age, sex, race, Charlson score, year of diagnosis, pathologic stage, and receipt of adjuvant radiotherapy. Results: Adverse pathology following NAC and RC was identified in 1,361 patients from 2006−2012, of whom 328 (24.1%) received AC. Staging was pT3N0 in 444 (32.6%), pT4N0 in 162 (11.9%), and pTanyN1−3 in 755 (55.5%). Median OS for the entire cohort was 22.9 months, which differed by pathologic stage: 34.6 months (pT3N0), 21.4 months (pT4N0), and 19.3 months (pTanyN1-3)(p &lt; 0.01). No difference in OS was noted by receipt of AC in the overall cohort (median OS 24.6 months with AC vs 22.0 months without AC; p = 0.18), or when stratified by pathologic stage. On multivariable analysis, receipt of AC was not significantly associated with overall mortality (HR 0.86; 95%CI 0.74−1.01; p = 0.06) for all patients. When stratified by stage, AC was associated with a significantly decreased risk of mortality among patients with pT4N0 disease (HR 0.56; 95%CI 0.33−0.97; p = 0.04), but not pT3N0 or pTanyN1−3 (p &gt; 0.05). Conclusions: Patients with adverse pathology at RC after NAC have a median OS of approximately 2 years. AC was not associated with improved survival, except in the subgroup with pT4N0 disease. Clinical trials with newer systemic therapies are warranted for patients in this setting.
Psychosocial outcomes in cancer survivors treated at a comprehensive cancer center or a minority-serving institution.
Authors: Debra L. Friedman, Maureen Sanderson, Pamela Hull, Debra Wujcik, Dira R Ashworth, Amaka Okafor, Jane Kennedy, Paula Hill, Nalini Conner, David Shen Miller, Steven N. Wolff
Journal: Journal of Clinical Oncology (2013)

e20523 Background: Cancer health disparities are well described for incidence, diagnosis and treatment. Little is known about disparities among long-term survivors. Methods: At Vanderbilt-Ingram Cancer Center (VICC), an NCI-designated comprehensive cancer center and Meharry Medical College (MMC), minority serving institutional partner, we evaluated quality of life (QOL) using the FACT-G, FACT-B, FACT-L, and FACT-P; posttraumatic stress disorder (PTSD) using the PTSD Checklist (PCL); and posttraumatic growth (PTG) using the PTG Inventory (PTGI) among breast, lung or prostate cancer survivors. We used linear regression to compare the scale mean values by institution while adjusting for confounding variables. Results: Among 111 breast, 53 lung and 68 prostate cancer survivors, mean age was 62 years, 61% were female, 33% were black, 65% were married, 22% and 67% respectively had a high school degree or some college/higher education, 36% were employed and 94% were insured. MMC survivors were younger (p = 0.0005), more likely to be black (p &lt;0.0001), less likely to be married (p &lt; 0.0001), less educated (p&lt;0.0001) and more likely to be uninsured (p &lt; 0.0001). After adjusting for race, insurance status and educational level, there were no significant differences in cancer-related QOL between VICC and MMC survivors. MMC survivors did score significantly higher than VICC survivors on the PCL (33.9 vs. 28.3; p = 0.01) and the PTGI (75.9 vs. 62.5; p = 0.002). A total of 19 (8.3%) survivors met criteria for PTSD with a score of 50 or more (18.1% MMC, 3.8% VICC, p =0.003). Scores were significantly increased for MMC survivors relative to VICC survivors on all PTG subscales, especially the appreciation for life subscale (p = 0.0005). Conclusions: Cancer health disparities extend into the survivorship period. Although overall QOL did not differ, survivors treated at an underserved institution had significantly higher PTSD than those treated at a comprehensive cancer center. Underserved survivors also exhibited higher degrees of PTG. Further evaluation will identify the most significant sources of stress and resilience in order to design interventions to improve psychosocial wellbeing and decrease disparities.
Effect of MiR-501-5p on CYLD expression and cell proliferation in human hepatocellular carcinoma.
Authors: Dan-yun Ruan, Yang Li, Nan Jiang
Journal: Journal of Clinical Oncology (2015)

e15169 Background: Analysis using publicly available algorithms has found that cylindromatosis (turban tumor syndrome) (CYLD) is a potential target of miR-501-5p. Some studies have shown that both miR-501-5p and CYLD are associated with cancer development. We examined the possible relationship between miR-501-5p and CYLD in the development of hepatocellular carcinoma (HCC). Methods: We assessed miR-501-5p expression in HCC specimens and cell lines(QGY-7703, BEL-7402, MHCC97H, Huh7, HepG2, MHC97L, HCCC-9810, and Hep3B) using RT-PCR, HepG2 cell line was selected for further study. Luciferase reporter assay was used to confirm the target associations. The effect of miR-501-5p on cell proliferation was confirmed with tetrazolium and colony formation assays. Gene and protein expression were examined using RT-PCR and western blotting, respectively. Results: miR-501-5p was significantly upregulated in eight pairs of cancerous tissues and cell lines compared with the adjacent noncancerous liver tissues and hepatocyte cell line Lo2 (P < 0.001). The MTT assay showed that ectopic expression of miR-501-5p increased the cell growth rate significantly(P < 0.001), the colony formation assay and anchorage-independent growth ability assayyielded similar results, suggest that miR-501-5p upregulation increases HCC cell proliferation. Then the HepG2 cells were transfected with miR-501-5p inhibitor had the opposite results. Western blotting revealed that CYLD expression was decreased in miR-501-5p overexpression HepG2 cells and increased in HepG2 cells transfected with miR-501-5p inhibitor, MiR-501-5p overexpression reduced the luciferase reporter activity of the CYLD 3′ UTR consistently and dose-dependently; miR-501-5p inhibition had the opposite effect, suggest that MiR-501-5p targeted the 3′ untranslated region of CYLD directly. RT-PCR and western blotting results showed that miR-501-5p overexpression increased Cyclin D1 and c-myc expression significantly, which subsequently promoted HCC cell proliferation. Conclusions: Our findings suggest that miR-501-5p plays an important role by promoting HCC cell proliferation, and may identify new targets for anti-cancer treatment.
Results of reduction of treatment intensity based on response to a novel induction therapy in stage III and IV head and neck cancer
Authors: M. R. Kudrimoti, G. W. Warren, J. Valentino, P. M. Spring, M. Mohiuddin, W. H. St. Clair, Y. Brill, C. Given, W. F. Regine, S. M. Arnold
Journal: Journal of Clinical Oncology (2006)

5561 Background: Concurrent cisplatinum based chemotherapy and qd radiotherapy (RT) to 70 Gy is standard therapy for stage III-IV head and neck (H/N) SCCA. Presented is a prospective IRB approved study tailoring the definitive therapy based on response to induction therapy. Methods: 25 patients with Stage III-IV H/N SCCA were treated with 2 cycles of induction therapy every 21 days comprised of carboplatin (AUC 6 day 1), paclitaxel (75 mg/m 2 days 1, 8, and 15), and low dose RT (0.5 Gy BID days 1, 2, 8, and 15) for chemosensitization. The response rates of this mode of induction therapy have been presented previously (ASCO 2005 #3184). Patients with complete response (CR) to induction were treated with reduced dose RT at the primary site (reduced from 70 to 60–66 Gy) and 2 cycles of IV cisplatin (100 mg/m 2 ) instead of 3. Those with partial response (PR) or stable disease (SD) were treated with surgery and adjuvant therapy or with altered fractionation regimens. The impact of dose reduction on survival (OS and DFS), failure patterns, compliance and toxicity (according to NCI CTCAE) were used as end points for the study. Results: Patients included 9 with tonsil, 5-L, 3-HP, 3-OC, and 5-BOT. There were 4-T1,9-T2,9-T3,and 3-T4 tumors. The nodal involvement was N0–5, N1–3, N2–13, N3–4. Patients presented with Stage III (28%), IVA (52%), and IVB (20%). Sixty percent had a CR, 32% had a PR, and 8% had SD after induction therapy. Two patients with CR were non-compliant after induction therapy and not further evaluated. With a median FU of 20.5 months (range 11–36 mo) the OS and DFS is 100% (13/13) in the dose reduced group (CR) and 60% (6/10) in the PR/SD treated with more aggressive regimens. The incidence of distant failure is 40% (4/10) in the PR vs 0% (0/13) in the CR. No patients in the dose reduced group required feeding tubes; however 30% (3/10) were required in patients with PR. Compliance with chemotherapy was 79% (10/13) in the CR vs 80% (8/10) in the PR. Conclusions: Our early results show that the patients showing a CR to induction chemotherapy are a favorable group of patients and they may be treated with reduced treatment intensity. This report provides strong evidence that RT dose deescalation for head and neck cancers may be feasible following assessment after induction therapy. [Table: see text]
Outcome of an advanced anaplastic astrocytoma patient treated with Newcastle disease viral (NDV) oncolytic therapy.
Authors: Arnold Freeman, Tibor Bakacs, Ralph W Moss
Journal: Journal of Clinical Oncology (2013)

e13029 Background: Oncolytic viruses are increasingly recognized for their potential promise of lasting impact on our cancer treatment repertoire. The use of attenuated Newcastle Disease Virus (NDV) against cancer was pioneered more than 40 years ago by Laszlo Csatary, a Virginia physician, who died March 20, 2012 at age 88. In 1968, Csatary used attenuated NDV as a cancer treatment. NDV, an RNA virus, shows tumor selectivity in its replication behavior in mammalian cells, including humans. Methods: A.G., a 14-year-old boy, presented in September 1994 with a large left fronto-temporal mass. The tumor was debulked and he then received 56 Gy of radiation to the brain. Pathology indicated the tumor was a glioblastoma multiforme (GBM). By November1995 there was local recurrence. Despite various chemotherapies, the cancer progressed. In May 1996 patient started on attenuated intravenous NDV in Budapest, Hungary. This was the only agent he received for the next 8 years. Results: There was progressive shrinkage of the GBM resulting in complete disappearance at 1 year. The patient remains well with no evidence of tumor 16 years after the start of NDV. Conclusions: NDV was able to eradicate GBM in this seemingly hopeless situation and merits further evaluation in this and other cancers.
The outcomes of allogeneic stem cell transplantation in AML patients with monosomal karyotypes.
Authors: Sang Kyun Sohn, Soo Jung Lee, Jong Gwang Kim, Yee Soo Chae, Byung Woog Kang, Joon Ho Moon, Jin Ho Baek
Journal: Journal of Clinical Oncology (2012)

6538 Background: The prognosis of acute myeloid leukemia (AML) with monosomal karyotype (MK) was reported extremely poor. We investigated the role of allogeneic stem cell transplantation (allo-SCT) for those with MK. Methods: A total of 114 patients who received allo-SCT for treatment of AML were retrospectively analyzed. All patients were treated with standard induction chemotherapy with anthracycline and cytarabine. Cytogenetic abnormalties were grouped according to recently published MRC criteria and MK was defined as at least two autosomal monosomies or one monosomy plus one or more structural abnormality. Results: Thirteen patients had favorable cytogenetic risk, 78 intermediate, 11 adverse without MK, and 12 adverse with MK at the time of diagnosis. Among 12 patients with MK, 5 (41.7%) achieved CR after induction therapy, 1 (8.3%) relapsed and 6 (50.0%) refractory at the time of allo-SCT. The 2-year overall survival (OS) was significantly lower for patients with MK (17.5%) compared to favorable (76.9%), intermediate (61.0%), and adverse without MK (36.4%, p=0.017). In the multivariate analysis, those with MK was related with extremely poor outcomes (HR 6.02, p=0.008), which was independent risk factor for OS. Survival benefit was observed in MK group with chronic GVHD compared to those without chronic GVHD. The median survival was 272 days with chronic GVHD (95% CI 204-339 days) compared to 159 days (95% CI 76-172 days) without chronic GVHD (p=0.010). Conclusions: The prognosis remained poor in patients with MK despite of allo-SCT. Innovative approaches to induce GLV effects are needed to improve SCT outcomes in patients with MK.
Trends in the costs and utilization of targeted cancer therapies for the privately insured non-elderly: 2001-2011.
Authors: Fabrice Smieliauskas, Ya-Chen T. Shih, Daniel M. Geynisman, Ronan Joseph Kelly, Thomas J. Smith
Journal: Journal of Clinical Oncology (2015)

6597 Background: Studies documenting high costs of cancer drugs often focus on targeted therapies as a whole without differentiating between oral and intravenous agents; such distinction is important because they differ in insurance design. Our study examined recent trends on targeted oral anticancer medications (tOAMs), and targeted IV anticancer medications (tIVAMs) and explored the cost drivers. Methods: We classified cancer drugs as tOAMs, tIVAMs, and non-targeted agents. Using the 2002-2011 LifeLink Health Plan Claims Database, we described trends in utilization and in insurance payments and out-of-pocket (OOP) costs per patient per month (PPPM) and during the first year of systemic therapy among privately insured non-elderly cancer patients. We performed Cochran-Armitage tests and generalized linear models to test the statistical significance of utilization and cost trends, respectively, and conducted decomposition analysis to disaggregate the cost trend into the increase driven by therapeutic substitution to more expensive classes of drugs vs. increases in drug prices over time. Results: Targeted therapies accounted for 11% of all systemic therapy utilization and 22% of systemic therapy expenditures in 2001, increasing to 42% (28% tIVAMs and 14% tOAMs) of utilization but 63% (38% tIVAMs, 25% tOAMs) of expenditures in 2011. Insurance payments PPPM for tOAMs more than doubled in ten years, growing from $3,381 PPPM in 2001 to $7,370 in 2011 (P < 0.001), whereas PPPM for tIVAMs remained fairly constant (around $7,000) throughout. Decomposition analyses of two time periods (2001-2005 and 2005-2010) showed that switching to more expensive classes of drugs accounted for the large majority of cost increase. Post-launch price increases contributed a 10-11% of spend increases during the two periods, while the increase in launch price accounted for 6% and 15% of spending growth, respectively, for each period. Conclusions: Payers should consider more aggressive management of pharmacy benefits for tOAMs and payment reforms for injectable drugs to contain the rising costs of cancer care.
Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain
Authors: Nadine Dandachi, Neil J. Kelly, John P. Wood, Christine L. Burton, Josiah E. Radder, Adriana S. Leme, Alyssa D. Gregory, Steven D. Shapiro
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Macrophage elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD).To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer.We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non-small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and KrasLSL/G12D mouse models of lung cancer.We show that SR20 triggers tumor apoptosis by up-regulation of gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4, sensitizing cells to an autocrine loop of TRAIL-mediated cell death. We then demonstrate the therapeutic efficacy of SR20 against two murine models of lung cancer.The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.
Perifosine (P) as an active agent in the treatment of patients with advanced sarcoma
Authors: R. Birch, S. Chawla, J. Nemunaitis, P. Savage, P. Kaiser, A. Spira, A. Cervera, E. Middleman, E. Sausville, M. Knowling, I. Henderson
Journal: Journal of Clinical Oncology (2007)

10059 Background: Clinical benefit rate (CBR), defined as complete or partial responses (RECIST) or stable disease &gt; 4 months, has been taken as evidence for the activity of mTOR inhibitors in sarcomas, (Chawla ASCO 2006). P is a novel oral alkylphosphocholine that targets the PI3K pathway upstream from mTOR by inhibiting the phosphorylation of Akt. (Kondapaka, Mol Cancer Ther 2003). P's activity against sarcomas has now been evaluated in 121 patients enrolled in one of 3 phase (ph) I trials or 4 ph II studies. Five of these studies have been published. All of the data are in the Keryx database from which this analysis was performed. Methods: Dose-schedules in the ph I trials were weekly (wkly) 100–800 mg; loading dose (LD) 300 - 1,800 following by daily (d) 50 - 21 every 21 days; LD 400 - 900 &amp; d 50 - 100 continuously. In the ph II trials doses were LD 900 &amp; d 150 every 21 days, LD 900 and d 100 continuously, d 50 mg continuously; wkly 900, wkly1200 &amp; wkly 1,500. Regimens that included a wkly or LD of 1,200 mg or more or a d dose of ≥ 150 mg were more toxic and are defined as “higher dose” for this analysis. Results: 121 pts with sarcoma were entered on studies prior to 9/1/2006 and could be assessed for CBR. CBR is shown in the table below. Toxicities were mainly gastrointestinal and/or fatigue. The percentage of pts with grade 0 nausea (N), vomiting (V), diarrhea (D) and fatigue (F) for lower dose P was 40, 60, 45 and 57% respectively compared to 29, 38, 24 and 66% for higher dose P. The proportion of patients with grade 2+ N, V, D and F was 19, 15, 17 and 21% for lower dose P and 46, 31, 40 and 21% for higher dose P. Conclusions: In the ph I/II studies of P the CBR was 50%. This compares favorably with the activity of the mTOR inhibitors. There was no suggestion of greater activity in those given higher doses of P, but there was substantially more toxicity and greater earlier withdrawal from therapy with the higher doses. [Table: see text] No significant financial relationships to disclose.