tbuckley/cabot-search huggingface dataset:
Molecular profiling in patients (pts) with upper gastrointestinal (UGI) cancers correlated with clinical outcome
Authors: N. Virk, D. Yang, H. J. Lenz, A. B. El-Khoueiry, K. D. Danenberg, S. Iqbal
Journal: Journal of Clinical Oncology (2009)

e22042 Background: Recent efforts have expanded our understanding of the molecular pathogenesis of UGI cancers and how oncogenes and tumor suppressor genes play a role in both carcinogenic and metastatic processes. These markers may serve as prognostic and/or predictive factors for recurrence following resection and resistance to radiotherapy and chemotherapy. Gene expression levels of thymidylate synthase (TS), thymidylate phosphorylase (TP), epidermal growth factor receptor (EGFR) and excision repair cross complementing (ERCC-1) have been shown to be associated with outcomes in lung, gastric and colon cancer. We evaluated TS, ERCC-1, EGFR and TP gene expression levels in patients with UGI cancers. Methods: This was a retrospective study of 80 pts with UGI cancers evaluated at USC who underwent molecular profiling. The primary objective was to determine a correlation between TS, TP, ERCC1 and EGFR and correlate with clinical outcome. Characteristics of these 80 pts: (16 females, 64 males ); median age 61 years (range 34–85); tumor types evaluated - 32 (40%) esophageal, 24(30%) gastric, 24(30%) GE junction; stages- 53 % IV, 21% III, 12% II, 2% I were evaluated for intratumoral gene expression of TS, TP, ERCC-1, &amp; EGFR by real time quantitative PCR using Taqman technology from microdisected paraffin-embedded tumor sections. Results: High TS expression was associated with shorter OS (12.8 months vs. 23.7 months p=0.036). A significant correlation was found between TP &amp; ERCC-1 (p=0.0078, r=0.37); TP &amp; TS (p=0.0128, r=0.35); TP &amp; EGFR (p=0.0065, r=0.39); TS &amp; ERCC-1 (p=0.0004, r=0.39); ERCC-1 &amp; EGFR (p=0.025, r=0.30). No statistically significant relationship was found between TS &amp; EGFR (p=0.06,r=0.25). There was no correlation of ERCC-1, TP, &amp; EGFR with OS that reached statistical significance. Conclusions: TS mRNA levels were shown to be associated with OS in UGI tumors, consistent with data reported in colon cancer. TS gene expression was significantly associated with expression levels of ERCC-1. In addition, ERCC1 was associated with EGFR. These data show for the first time that molecular pathways of cytotoxic agents are linked to the EGFR pathway suggesting that sensitivity to fluoropyrimidines, oxaliplatin, and EGFR inhibitors may be associated. No significant financial relationships to disclose.
EGFR mutations (muts), IHC and FISH status, and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer (NSCLC) patients (pts) treated with gefitinib (GEF)
Authors: V. M. Villaflor, L. Buckingham, M. Gale, J. Coon, A. M. Mauer, T. Muzzafar, K. Kaiser, M. Shannon, L. Morrison, P. Bonomi
Journal: Journal of Clinical Oncology (2006)

7182 Background: EGFR and pAkt expression by immunohistochemistry (IHC), muts, and FISH status have been identified as possible molecular predictors for GEF efficacy in NSCLC (Cappuzzo, et. al, JNCI, 2005). The goal of this study was to independently evaluate these findings regarding survival (surv), and to assess the predictive value of mean chromosome 7 copy number/cell (C7). Methods: 150 consecutive Expanded Access Trial pts with &gt;1 week GEF therapy were included for analysis. IHC (present vs not detected) was performed for 87 pts, and 58 pts were analyzed for muts by SSCP, mut-specific PCR, and sequencing. Tissue from 81 pts was evaluated for EGFR and C7 gene copy numbers by fluorescence in situ hybridization (FISH). Results: 150 pts (77 female, 73 male; median (md) age 67; 85 adenocarcinoma) received GEF; md follow-up was 5.8 months (mo). Overall response was 8% (2 CR, 10 PR); 56 pts had stable disease. Md Kaplan-Meier surv was 5.9 mo. IHC revealed that 47/87 pts (54%) had EGFR + , and 36/75 pts (48%) had pAkt + tumors. pAkt + pts had significantly (sig) longer surv than pAkt − pts (11.4 vs 5.8 mo, p &lt; .05). High polysomy was seen in 36/81 pts (44%) who were designated FISH + ; 45 pts were FISH − . EGFR IHC and FISH positivity were not sig associated with surv. C7 was defined as low (&lt;3.6, 63 pts) or high (≥3.6, 18 pts); md surv was 6.6 and 17.1 mo, respectively, p &lt; .01. Muts were found in 17/58 tumors (29%). Md surv for pts with and without muts was 23.8 and 7.9 mo, respectively, p &lt; .07. EGFR IHC − pAkt − pts (18 pts) had sig shorter surv than 57 pts with any pos value (4.7 vs 8.8 mo, p &lt; .02). Double-positive pts had sig longer surv than pts with any neg value. Conclusions: These findings resemble but do not duplicate those reported by Cappuzzo, et al. Additionally, high C7, alone or combined with pAKT, may be an important predictor for GEF efficacy in NSCLC. Further studies of C7, a technically simple and reproducible FISH assay, are warranted. [Table: see text] [Table: see text]
Circulating plasma cells detected by flow cytometry as a predictor of survival in patients with newly diagnosed multiple myeloma
Authors: G. S. Nowakowski, T. E. Witzig, D. Dingli, M. J. Tracz, P. R. Greipp, S. V. Rajkumar
Journal: Journal of Clinical Oncology (2005)

6580 Background: The presence of circulating plasma cells (PC) detected by immunofluorescence in patients with multiple myeloma (MM) has been associated with a worse prognosis (Blood, 1996;88:1780–1787). However, PC detection by immunofluorescence, is complex and not readily available in most clinical laboratories. Therefore, we investigated the prognostic significance of circulating PC detected by flow cytometry (FC) in patients with newly diagnosed MM. Methods: FC was performed in patients with newly diagnosed MM within the first week of diagnosis prior to the initiation of treatment. Mononuclear cells were isolated by density gradient centrifugation. The number of circulating PC was measured by gating on CD38 +, CD45- cells. 50,000 events were analyzed per patient and the number of PC detected among these events was recorded. Study endpoint was an overall survival(OS). Results: Between 5/1998 and 1/2003 FC was performed on 303 patients with newly diagnosed MM (123 females, 180 males). Median age was 65 yrs (range 29–94), median follow up was 24.5 mos (range 1–76). According to the International Staging System (ISS), 69 (23%), 128 (42%) and 78 (26%) patients had stage 1,2 and 3 disease respectively. In 28 patients(9%)ISS could not be determined. In 80 patients (26%) no circulating PC were seen; 163 (53%) patients had 0–5,104 (35%) patients had 6–10 circulating PC. 36 (12%) patients had > 10 circulating PC. The median OS for the whole cohort was 46 months. Patients with ≤ 5 circulating PC had median OS of 59 mo, patients with > 5 circulating PC had a median OS of 40 mo (p=0.0014). On multivariate analysis (Cox proportional hazard model), the prognostic value of circulating PC was independent of β2-microglobulin (p=0.0422), lactate dehydrogenase (p=0.0058) and C-reactive protein (p=0.0246). In patients with ISS 2 or 3, the median survival was 26 mo if there were > 5 circulating PC. Median survival was 48 mo if the circulating PC number was ≤ 5 (p=0.0244). There was no difference in survival in ISS 1 patients, however, the median OS in this group has not been reached. Conclusion: The number of circulating PC measured by flow cytometry in patients with newly diagnosed MM is an independent predictor of survival. No significant financial relationships to disclose.
Obesity and microvascular invasion in HCC
Authors: A. B. Siegel, J. C. Yu, J. Moss, S. Wang, J. S. Jacobson, E. Lim, V. Khungar, L. Ferrante, S. Scrudato, R. S. Brown, A. I. Neugut
Journal: Journal of Clinical Oncology (2008)

4520 Background: Obesity is a risk factor for worsened outcomes in hepatocellular carcinoma (HCC). Adipokines such as leptin are known to be angiogenic, and are increased in those with obesity. We hypothesized that tumor specimens from obese patients would be more likely than those from non-obese patients to show microvascular invasion, a known predictor of poor survival in HCC. Methods: 164 consecutive patients who underwent surgery (resection or transplantation) at Columbia University Medical Center from 1/1/2002–12/31/2006 with available pathology were evaluated retrospectively for clinical and pathological characteristics and overall survival. Results: The median age of our patients was 58 years. 49%, 27% and 24% were Child-Pugh class A, B, and C respectively. At surgery, 34% had a BMI >30 kg/m2, 42% had a BMI of 25–30 kg/m2, and 24% had a BMI <25 mg/m2. 33% had microvascular invasion on pathology. Table 1 shows the positive association between BMI and presence of microvascular invasion in our cohort. A Cochran- Armitage test for trend showed a significant association between microvascular invasion and BMI (p = 0.002). The presence of microvascular invasion on pathology was associated with significantly worsened overall survival in our dataset, as expected. BMI tertile was not associated with overall survival in univariate and multivariable analyses. Conclusions: We showed a significant association between obesity and increased microvascular invasion in a cohort of patients who received surgery for HCC. The association remained when we adjusted for Child- Pugh score to control for potential confounding with ascites. This analysis suggests that increased body mass may have a dose-response relationship with microvascular invasion, perhaps mediated by adipokines such as leptin. A larger prospective study is planned. Association between BMI and microvascular invasion Crude Adjusted for Child-Pugh BMI (kg/m2) OR (95% CI) OR (95% CI) <25 1.0 Referent 1.0 Referent 25–30 3.2 (0.8–19.1) 3.3 (0.6–17.9) >30 6.8 (1.6–39.9)* 6.7 (1.2–36.9)* * = p < 0.05 No significant financial relationships to disclose.
Chemical Carcinogenesis and Immunity: Immunologic Status of Rats Treated With Methylnitrosourea&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B S Zwilling, J A Filppi, F W Chorpenning, A Koestner, M S Rheins
Journal: JNCI Journal of the National Cancer Institute (1978)

During the treatment of outbred Sprague-Dawley rats with methylnitrosourea (MNU) or the noncarcinogenic analog diphenylnitrosamine, antibody levels to teichoic acid as well as several parameters of lymphocyte and macrophage function were assessed in animals not overtly stimulated with antigen. Treatment with MNU did not appear to alter most immunologic parameters studied. Some alterations occurred in natural antibody levels, in spleen weight, and in peripheral blood differentials of rats that had received the highest carcinogen dose (4.5 mg/kg). These alterations, however, appeared to coincide with the development of tumors and were not observed in animals with premalignant lesions. Levels of chemical carcinogens that were capable of inducing tumors did not necessarily suppress the immune response.
Single versus sequential high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ-cell tumors (GCT)
Authors: A. Lorch, O. Rick, J. T. Hartmann, C. Kollmannsberger, B. Metzner, I. Schmidt-Wolf, W. E. Berdel, R. Schirren, J. Beyer, C. Bokemeyer
Journal: Journal of Clinical Oncology (2006)

4511 Background: Patients (pts) with relapsed or refractory GCT may be cured by HDCT. It is unknown whether single or sequential HDCT is superior. Methods: Between 11/99 and 11/04, 216 pts with relapsed or refractory GTC were treated in a prospective, randomized, multicenter phase III trial with either one cycle of cisplatin 100 mg/m 2 , etoposide 375 mg/m 2 and ifosfamide 6 g/m 2 (VIP) plus three cycles of high-dose carboplatin 1500 mg/m 2 and etoposide 1500 mg/m 2 (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2200 mg/m 2 , etoposide 1800 mg/m 2 and cyclophosphamide 6400 mg/m 2 (CEC, arm B) followed by reinfusion of autologous peripheral blood progenitor cells. Primary study endpoint was the event-free survival (EFS) one year after randomization. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicities. An event was defined as any deviation from the planned treatment, relapse, progression or death from any cause. The planned study size was 230 pts to detect a difference of 15% with an alpha error of 5% and a power of 80%. Results: The study was stopped after recruitment of 216 pts due to excess treatment-related mortality in arm B: 111 pts were randomized in arm A and 105 pts in arm B. Due to non-GCT histologies at review 5/216 pts had to be excluded from further analysis. With a median follow-up of 36 months, 109/211 (52%) evaluable pts are still alive and 91/211 (43%) are progression-free. At one year EFS; PFS and OS are 40%, 55% and 80% in arm A as compared to 37%, 49% and 61% in arm B. Treatment-related deaths mainly due to sepsis and cardiac toxicity were less frequent in arm A (4/111 pts, 4%) as compared to arm B (15/105 pts, 14%) (p = 0.01). Severe non-hematologic organ toxicities were also less frequent in arm A. Conclusions: Treatment with sequential high-dose carboplatin and etoposide is at least as effective but less toxic than single HDCT with carboplatin, etoposide and cyclophosphamide. No significant financial relationships to disclose.
Docetaxel (D) and cisplatin (C) induction chemotherapy followed by bi-weekly D with concurrent thoracic radiotherapy for stage III non-small cell lung cancer (NSCLC): A Galician Lung Cancer Group study
Authors: G. Huidobro, S. Vázquez, M. Lázaro, J. R. Mel, J. Casal, J. Castellanos, Y. Vidal, J. L. Fírvida, M. Amenedo
Journal: Journal of Clinical Oncology (2008)

7561 Background: Concurrent chemoradiotherapy (CChRT) is the preferred treatment for patients (p) with locally advanced NSCLC. Limited safety information is available on the use of CChRT with bi-weekly D after induction chemotherapy with D-C. Methods: 71 p with inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), were included in a phase II study with induction chemotherapy consisting of three cycles of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1–2 every 3 weeks and, if no surgery, then received CChRT with D 30 mg/m2 every 2 weeks for four courses, during thoracic conformal radiotherapy (60–66 Gys, 180 cGy/day). Median follow-up: 13.4 months. Results: The p characteristics were as follows: mean age 62.4 years (43–74); male/female 66/5; ECOG PS 0/1 in 19/52 p; stage IIIAN2 21 p (29.6%) and stage IIIB 50 p (70.4%). 66 p were evaluable for response and 68 p for toxicity. Induction D-C response: 1 CR and 39 PR (RR 60.6%; CI95%:49–72), 19 SD (28.6%) and 7 PD (8.9%). 9 p went to surgery: 5 pPR, 1 pSD, 1 pPD and 2 unresectable. 46 p completed CChRT (1 p no evaluable) with 8 CR, 27 PR, 4 SD and 6 PD (RR 77.7%; CI95%:66–90). The median to PFS was 13 months and median OS was 21 months. The PFS and OS at 1/2 years was 51/26% and 65/34% respectively. A total of 193 cycles of D-C were administered (2.8 per p), with the main toxicity (NCI-CTC) per p Grade (g) 1–2/3–4 (%) was as follows: neutropenia 17.6/28; anemia 42.6/1.4; nausea/vomiting 41.2/2.9; fatigue 36.7/1.4; diarrhea 26.4/0; allergy 11.2/1.4; there were 1 treatment-related death. The main toxicities (RTOG) per p in CChRT (D doses: 176, 3.8 per p) were g1–2 neutropenia/anemia 28/39%; g1–2/3 esophagitis in 45.6/2.1% and g1–2/3 pneumonitis in 28.2/2.1 %; hospitalization was necessary in 4 p with 1 toxic death. Conclusions: Induction chemotherapy with D-C followed by bi-weekly D with concurrent thoracic radiotherapy is a feasible treatment option for locally advanced NSCLC, showing good clinical activity and tolerability, with acceptable long-term survival. No significant financial relationships to disclose.
Comparison of serum levels of CEA and CA 15–3 in triple-negative breast cancer at the time of metastases and serum levels at the time of first diagnosis
Authors: D. Sener Dede, S. Aksoy, N. Bulut, O. Dizdar, Z. Arik, I. Gullu, Y. Ozisik, K. Altundag
Journal: Journal of Clinical Oncology (2009)

e12017 Background: Cancer antigen 15–3 (CA 15–3) and carcinoembryonic antigen (CEA), are often used in follow up care of breast cancer and provide important clues to the clinicians for disease progression in metastatic and recurrent breast cancer. Triple-negative breast cancers are frequently defined as a single group identifiable using routine clinical tests. They are negative for estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), the so-called triple-negative breast cancers. In this study we compared the tumor markers of triple negative breast cancer and non-triple negative patients. Methods: We retrospectively analyzed serum CEA and CA 15–3 levels of both triple negative and non-triple negative breast cancer patients at the time of first diagnosis and when they developed metastatic disease. Results: 544 consecutive nonmetastatic breast cancer patients presenting at Hacettepe University Institute of Oncology, Ankara, Turkey, with a median age of 49 were evaluated. 15.1% of the patients were triple negative breast cancer. At the time of diagnosis triple negative group had lower serum CEA (2.5 ± 5.9 vs 4.0 ±16.4 p = 0.35) and CA 15–3 (23.7 ± 14.6 vs 37.1 ± 117; p = 0.021) levels compared to non-triple negative group. In patients who developed metastasis during follow up; the CEA (3.2 ± 3.8 vs 29.6 ± 106.4 p = 0.022) and CA15–3 (46.9 ± 46.3 vs 203.2 ± 534 p = 0.008) levels were also significantly lower in triple negative breast cancer group compared to non-triple negative group.In non-triple negative breast cancer patients who developed metastasis, mean serum levels of CEA and CA15–3 significantly increased compared to baseline, whereas in triple negative group who developed metastasis CEA and CA 15–3 levels did not differ significantly. Conclusions: While being a good laboratory parameter in the follow-up of patients with breast cancer metastases, tumor markers may not show the increased tumor burden in the triple-negative breast cancer patients. No significant financial relationships to disclose.
Evaluation of indibulin, a novel tubulin targeting-agent, in combination with capecitabine, with mathematically optimized dose scheduling
Authors: J. J. Lewis, M. D. Galsky, L. H. Camacho, D. M. Loesch, P. B. Komarnitsky, L. Norton
Journal: Journal of Clinical Oncology (2009)

2538 Background: Indibulin (IDB) is a novel, orally available tubulin-targeting molecule that perturbs cancer cell migration and mitosis. It is active against taxane-resistant cell lines and is synergistic with 5-FU in vitro and in vivo. Two translational studies have been conducted: a Phase IB study of IDB in combination with capecitabine (CAP) in patients with advanced solid tumors, and mathematical modeling applying Norton-Simon models to breast carcinoma MX-1 xenografts to further develop Phase II dose. Methods: IDB is administered continuously starting at 400 mg BID. CAP is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID. IDB and CAP are escalated to MTD: IDB 600 mg BID &amp; CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks using RECIST. In the xenograft model indibulin is administered at dose levels from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma. Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the efficacy/toxicity ratio. Results: To date, 7 patients have been treated and are evaluable for safety. Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are evaluable for efficacy and all have stable disease (3 for 6 cycles, 1 for 3 cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, anorexia, and headache. Neither DLTs nor grade ≥3 AEs have been observed. In MX-1 xenografts, indibulin demonstrates linear dose-efficacy relationship over the range of 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser effects over the next 5 days to a peak of efficacy at day 10 Conclusions: IDB + CAP is well tolerated, without neurotoxicity. There is preliminary evidence of clinical activity even with this sub-optimal, continuous schedule of IDB. Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug-induced toxicity. Pre- clinical evaluation in a breast cancer model supports an intermittent dosing schedule to further increase the activity of IDB. [Table: see text]
Utility of decreased FDG SUV as a response and prognostic indicator in multiple myeloma therapy with BiRD
Authors: S. Goldsmith, S. M. Philips, D. S. Jayabalan, M. Coleman, R. Niesvizky
Journal: Journal of Clinical Oncology (2008)

8607 Background: To assess the utility of post-treatment [Rx] FDG SUV decrease from pre-Rx SUV as an indicator of response and prognosis [RPI] in Multiple Myeloma [MM] patients [pts] receiving BiRD therapy. Methods: 11 pts [6 M; 5 F] with active clinical and serologic MM [Salmon-Dury Class IIa (4), IIIa (6), III (1)] had FDG PET/CT pre and post BiRD Rx. Iliac crest [IC] and Index Lesion [IL] SUV obtained from images 60 min post 12–15 mCi FDG pre & post BiRD [Biaxin, lenalidomide (R) & Dexamethasone [D], 40 mg on day 1, 2,3,8,15 and 22]. BiRD is an innovative 23 day immunomodulator regimen in clinical trials for MM treatment. Pre and post Rx interval varied from 3–12 months depending upon pts ability to tolerate protocol. Results: 4 pts had CR; 4 PR; 3 minimal Respnse [mR]. Mean pre Rx SUV for CR: Rt IC/Lt IC/IL =3.9, 3.9, 6.7; PR = 5.1, 3.9, 9.3; mR = 3.5, 3.7, 3.6. Mean Post-Rx SUV: CR = 2.1, 2.2, 2.5; PR = 2.2, 2.1, 5.2; mR = 2.9, 2.4, 1.7. % Change SUV for CR = 46, 41, 44; PR = 50, 46, 54; mR = 0, 37, 49. Zero value due to 1 outlier; otherwise average 36%. Conclusions: Whereas post Rx SUV change is a promising RPI in many tumors, it was not useful in MM pts Rx with BiRD. 41–54% SUV decrease was seen regardless of clinical response. BiRD involves high doses of D which inhibits tumor glucose utilization. Effect of D dose and interval to FDG PET is undetermined in MM. Steroid administration may be another variable affecting FDG SUV. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene Celgene
CIRCULATING NEUTROPHIL GRANULE SUBSET RELEASE IN RESPONSE TO BACTERIAL STIMULUS IS AUGMENTED IN PATIENTS WITH ALCOHOL-RELATED LIVER DISEASE AND MAY CONTRIBUTE TO ORGAN BYSTANDER DAMAGE
Authors: Troy Tranah, Godhev Manakkat Vijay, Jennifer Ryan, Daniel Abeles, L. J. Markwick, P. J. Chana, Debbie Shawcross
Journal: Gut (2013)