tbuckley/cabot-search huggingface dataset:
Anti-angiogenic therapy in combination with hypoxia-inducible factor-1α (HIF-1α) modulation
Authors: G. S. Falchook, E. F. Jackson, J. J. Wheler, S. L. Moulder, D. S. Hong, A. Naing, N. M. Tannir, K. N. Lawhorn, C. S. Ng, R. Kurzrock
Journal: Journal of Clinical Oncology (2008)

14604 Background: HIF-1α mediates adaptive responses to hypoxic conditions induced by anti-angiogenic therapy. Bortezomib has demonstrated the ability to inhibit transcriptional activity of HIF-1α. We hypothesized that the addition of bortezomib to bevacizumab would augment response, and we performed a phase I trial of bortezomib and bevacizumab to assess safety, maximum tolerated dose (MTD), and correlative studies of anti-angiogenic activity. Methods: Patients with advanced malignancy refractory to standard therapy were eligible. Cohorts of 6 patients received bevacizumab and bortezomib on a 3-week cycle, with a stair-step dose escalation design. Pharmacodynamic assessment included plasma VEGF, soluble VEGFR2, 20S proteasome inhibition activity, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Additional patients will be treated at the MTD to further evaluate safety and expression of HIF- 1α, VEGF, and VEGFR2 in tumor specimens at baseline and after cycle 1. Results: 45 patients have been treated, and the MTD has not yet been identified. Dose escalation continues with current doses of bevacizumab 12.5 mg/kg and bortezomib 1.3 mg/m2. One PR was confirmed in a patient with renal cell carcinoma (RCC) and 5 minor responses in RCC, breast cancer, neuroendocrine carcinoma, leiomyosarcoma, and nasopharyngeal carcinoma. 21 patients (47%) experienced no drug-related toxicities greater than grade 1. The most common drug-related toxicities observed include fatigue, myalgia, and thrombocytopenia. Plasma VEGF levels demonstrated decreases at 1 and 4 hours post-infusion, followed by increases on days 2, 3, and at the end of cycle 1. DCE-MRI analysis demonstrated decreases in Ktrans in the acute phase after treatment with bevacizumab and bortezomib. Soluble VEGFR2 and 20S proteasome inhibition activity will be analyzed and available at the time of presentation. Conclusion: Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated, advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved. HIF1α expression will be evaluated in biopsy specimens at baseline and after cycle 1 in an expansion cohort after the MTD is identified. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech
Association between Oncotype DX and receipt of chemotherapy in early-stage breast cancer within the Medicare population from 2004 to 2007.
Authors: Michaela Ann Dinan, Xiaojuan Mi, Shelby D. Reed, Gary H. Lyman, Lesley H Curtis
Journal: Journal of Clinical Oncology (2014)

309 Background: In 2004, the Oncotype DX (ODX) multigene assay became available to help guide physicians in their decision to recommend adjuvant chemotherapy in patients with early stage estrogen receptor (ER) positive breast cancer. ODX utilization within a non-academic, nationally representative breast cancer population has not been previously examined. Methods: Retrospective analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data of the association between ODX testing and receipt of chemotherapy in patients diagnosed with invasive, non-metastatic, ER-positive breast cancer between 2004 and 2007. Results: A total of 28,760 Medicare beneficiaries met study criteria. NCCN guidelines were used to stratify patients on the basis of clinical and pathologic features into low (&lt;1 cm tumors, 24.4%), intermediate (≥ 1 cm tumors, 52.0%), and high (node positive, 23.7%) risk disease. In patients with low or intermediate risk disease, receipt of ODX was associated with increased chemotherapy utilization (13% vs. 1% and 19% vs. 8%, respectively; both P &lt; 0.001), but not in high risk patients (30% vs. 39%, P= 0.34). Conclusions: Randomized trials have previously suggested the ability of ODX to decrease chemotherapy utilization. In this study, we observed increased chemotherapy utilization associated with receipt of ODX in patients with low and intermediate NCCN risk disease. Association between ODX and chemotherapy utilization in observational studies may be impacted by preferential administration of ODX testing to patients being considered for chemotherapy. [Table: see text]
Effect of cytogenetics at diagnosis on outcome of CML: Results from the randomized German CML Study IV.
Authors: A. Leitner, S. Saussele, C. Haferlach, G. Goehring, B. Schlegelberger, S. Jung-Munkwitz, U. Proetel, M. Lauseker, M. Pfirrmann, J. Hasford, A. Hochhaus, R. Hehlmann
Journal: Journal of Clinical Oncology (2011)

6553 Background: The prognostic impact of cytogenetic findings in addition to the standard t(9;22) at diagnosis of chronic myeloid leukemia (CML) is conflicting. Methods: We used baseline and outcome data of 1028 patients (607 male, 421 female, median age 53, range 16-88) with chronic phase CML randomized to the German CML-Study IV (imatinib [IM] 800 mg [n=264] vs IM 400 mg [n=253] vs IM 400 mg + IFN [n=281] vs IM 400 mg after IFN failure [n=108] vs IM 400 mg + AraC [n=122]) to investigate the impact of additional clonal cytogenetic findings at diagnosis on time to complete cytogenetic remission (CCR), an accepted prognostic marker. Cytogenetic analysis was performed after 24- and/or 48 h culture on G-banded metaphases. If appropriate, fluorescent-in-situ-hybridization was used in addition. Results: In total, at diagnosis 905/1028 patients (88%) solely had the standard t(9;22), 123/1028 patients (12%) had additional clonal cytogenetic findings: 52/1028 patients (5.1%) had variants of the t(9;22), 33/1028 patients (3.2%) lacked the Y chromosome (-Y), and 38/1028 patients (3.7%) had additional numerical or structural aberrations except -Y. Median age, sex and treatment were similarly distributed except for –Y patients who were older and only male. For patients with standard t(9;22), with variant t(9;22), with variant t(9;22) and other clonal chromosomal findings other than –Y, and standard with additional clonal chromosomal findings other than -Y and variant t(9;22), median time (years) to CCR was 0.98, 0.84, 1.08 and 1.34. There were differences regarding time to CCR at distinct time points when comparing variant t(9;22) and standard (variant t(9;22) better) and when comparing standard and additional chromosomal findings other than -Y (standard better). When comparing variant t(9;22) and additional chromosomal findings other than -Y, time to CCR was significantly shorter with variant t(9;22) ( p < 0.001). No difference regarding time to CCR was seen when comparing standard and –Y. Conclusions: We conclude that some additional clonal cytogenetic findings at diagnosis have an impact on time to CCR and possibly on prognosis. Due to the retrospective nature of the analysis the data are hypothesis generating only.
Persistence of microvesicle-induced gene expression changes in murine marrow cells using an in vitro and in vivo model.
Authors: M. Pereira, J. M. Aliotta, A. Amaral, M. Dooner, L. Goldberg, P. J. Quesenberry
Journal: Journal of Clinical Oncology (2011)

e21086 Background: Microvesicles are subcellular entities that are derived from a variety of cells and contain DNA, RNA and protein. We have previously shown that microvesicles isolated from murine lung tissue (lung-derived microvesicles, LDMV) enter murine whole bone marrow cells (WBM) in culture and WBM that has consumed LDMV produce lung-specific mRNA and protein up to three weeks later. We wished to determine the persistence of these phenotypic changes in a long-term in vitro culture and an in vivo transplant model. Methods: In vivo study: cell-free conditioned media (CM) was made using murine lungs. WBM cells were then co-cultured with either LDMV, minced lung fragments (separated from WBM by a 0.4 micron, cell-impermeable membrane) or neither. One week later, cultured WBM was transplanted into cohorts of lethally-irradiated C57BL/6 mice. Recipient mice were sacrificed six weeks post transplant and WBM isolated from each recipient was lysed and examined for the presence of lung-specific genes, including surfactants A, B, C and D (Sp-A, B, C, D), aquaporin-5 (Aq-5), and clara cell specific protein (CCSP), via real-time PCR. In vitro study: CM was made in same fashion as with the in vivo study. One week later cells were washed and placed into a secondary culture, without lung. WBM was harvested at two week intervals and RNA and protein was extracted for real-time PCR and Western Blot analysis. Results: In vivo study: Mice transplanted with WBM exposed to LDMV express pulmonary epithelial cell genes in the cells of their bone marrow, liver, spleen and thymus 6 weeks after transplantation. In vitro study: WBM maintains expression of pulmonary epithelial cell genes and proteins in vitro up to 12 weeks after exposure to soluble factors released by lung cells. Conclusions: These findings suggest that LDMV-induced phenotypic alteration of marrow cells is not a transient phenomenon and that a lung cell-derived transcriptional agent is transferred to marrow cells in culture and responsible for these stable phenotypic changes.
Preresectional endoscopic third ventriculostomy in the management of pediatric posterior fossa tumors.
Authors: T. B. Rabiu
Journal: Journal of Clinical Oncology (2011)

e12520 Background: Most children with posterior fossa tumors have clinically-important hydrocephalus at presentation. Traditionally, many of them are treated with ventriculo-peritoneal (VP) shunting prior to tumor resection. There are on-going debates about the efficacy of pre-resectional endoscopic third ventriculostomy (ETV) in the care of these patients. This study evaluates the usefulness of ETV in this category of children as presented in current global literature. Methods: A PUBMED search was performed for studies reporting the use of ETV in the management of hydrocephalus prior to tumor resection in children with posterior fossa tumors. Data on the success rates of ETV as well as its complications were collated and analyzed. Results: Nine studies from diverse geographical areas were identified. A total of 224 children were studied. The average reported success rate was 89.7%(range: 65.0% - 100.0%). The reported complications were meningitis, intraventricular hemorrhage, CSF leak, reversed herniation and orbital emphysema in 2, 4, 1, 1, and 1 patient(s) respectively. There was no reported mortality. Conclusions: ETV is useful in the treatment of hydrocephalus prior to tumour resection in children with posterior fossa tumor. Its high sucess rates and extremely low morbidity rates make it ideal for symptomatic control before definitive tumor surgery in the pediatric population.
Recurrence pattern after neoadjuvant chemotherapy compared to surgery alone in patients with muscle-invasive bladder cancer.
Authors: Takuya Koie, Chikara Ohyama, Atsushi Imai, Shingo Hatakeyama, Takahiro Yoneyama, Yasuhiro Hashimoto
Journal: Journal of Clinical Oncology (2016)

374 Background: Neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer (MIBC) has better survival benefit than radical cystectomy (RC) alone. However, recurrences still occur in many cases and recurrent disease is the most lethal factor associated with death in MIBC. On the other hand, the rate and pattern of recurrences after neoadjuvant chemotherapy in MIBC patients remains unclear. Methods: Eligible patients had histologically confirmed stage T2-T4a muscle-invasive urothelial carcinoma of the bladder without lymph node or distant metastasis in this study. The cohort of neoadjuvant group consists of 130 patients with MIBC. The cohort of RC alone group includes 135 patients with MIBC treated with RC and bilateral pelvic lymph node dissection between May 1994 and July 2007. Propensity score matching was used to adjust for potential selection biases associated with treatment type. Recurrence site was defined as local, LN (lymph nodes), and distant metastases. Results: Propensity score-matched analysis indicated 130 matched pairs from both groups. The 5-year overall survival rate was 91% for neoadjuvant GCarbo versus 49% for RC alone group (P &lt; 0.0001). The disease-free survival rate was 87% for neoadjuvant GCarbo versus 57% for surgery alone (P &lt; 0.0001). The distant metastases were comparable in both groups. The total number of local recurrences or LN mets was markedly decreased in neoadjuvant GCarbo compared with RC alone cohort. Conclusions: The MIBC patients treated with neoadjuvant GCarbo achieved an improved oncological outcome with a different recurrence pattern compared to RC alone.
A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.
Authors: Sang Joon Shin, Jeeyun Lee, Ik-Joo Chung, Tae Won Kim, Hoo Geun Chun, Dongbok Shin, Yeul Hong Kim, Hong-Suk Song, Sae-Won Han, Jong Gwang Kim, Sun Young Kim, Young Jin Choi, Hyun Cheol Chung
Journal: Journal of Clinical Oncology (2013)

492 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free survival (PFS). Results: We randomized 105 patients (52 patients, group A and 53 patients, group B). Median PFS was 7.0 months in group A (hazard ratio [HR], 1.057) and 7.2 months in group B (P = 0.8401). The most frequent grade 3/4 events were thrombocytopenia (9.6% vs 26.4%), neutropenia (13.5% vs 15.1%), and anemia (3.8% vs 13.2%). We observed a difference between the 2 groups in all grades of anemia (15.4% vs 32.1%), diarrhea (30.8% vs 47.2%), vomiting (50.0% vs 26.4%), and chromaturia (23.1% vs 0.0%). Analysis using a COX proportional hazard model showed that baseline interleukin 6 (IL-6) level was associated with survival benefit of TSU-68 (P = 0.012). Conclusions: TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy. Further biomarker analysis is being performed to determine the efficacy of this treatment. Clinical trial information: JapicCTI-111403.
Influence of systemic and local immune response on overall survival after hepatic resection of colorectal liver metastasis.
Authors: Takeomi Hamada, Hidenobu Ishizaki, Yukihiro Haruyama, Rouko Hamada, Takuto Ikeda, Kazuhiro Otani, Yoshiro Fujii, Hiroaki Kataoka, Kazuhiro Kondo
Journal: Journal of Clinical Oncology (2015)

756 Background: Colorectal cancer progression is dependent on complex interactions between the tumor and the host. Tumor infiltrating lymphocytes (TIL) have been reported as a prognostic factor in colorectal cancer. The aim of this study was to assess the prognostic value of pre-operative systemic immune biomarkers and TIL in patients with resectable colorectal liver metastases (CLM). Methods: Clinicopathological data were reviewed for patients (n=31) who underwent hepatic resections for CLM between 2000 and 2008. Prognostic variables from the primary lesion, metastatic lesion, and host inflammatory biomarkers measured as routine pre-operative blood tests (modified Glasgow Prognostic Score and neutrophil to lymphocyte ratio [NLR]) were evaluated by univariate and multivariate analyses. To evaluate the local immune responses of resected metastatic lesion, immunohistochemical analysis was performed. The immune subsets were CD8+ T cells, CD45RO+ T cells, Fork head box p3+ (FOXP3+) T cells, and CD66b+ neutrophils. We also evaluated PD-L1 expression in the metastatic lesion. Results: The number of metastases ≥ 4, extrahepatic metastasis, adjuvant chemotherapy, and NLR &gt; 4.1 were correlated with cancer-specific survival in univariate analysis. On multivariate analysis, the number of metastases (HR: 0.09, CI: 0.01-0.56, p=0.0102), adjuvant chemotherapy (HR: 0.08, CI: 0.01-0.39, p=0.0025), and raised NLR (HR: 0.11, CI: 0.01-0.99, p=0.0494) remained independent prognostic indicators. Accumulation of CD45RO+ memory T cells in the metastatic tumors was significantly associated with favorable survival in patients with resectable CLM (p=0.020). Interestingly, increased neutrophils in peripheral blood showed significant correlation with reduced accumulation of CD45RO+ memory T cells in metastatic lesion (p=0.023). Conclusions: Based on the present results and the existing validation literature, systemic immune response including NLR and local immune response including CD45RO+ memory T cells may be promising prognostic factor of patients with resectable CLM. Further functional analysis of neutrophils in CLM patient will be needed.
Relevance of germ-line genetic variations for treatment response in pediatric osteosarcoma patients.
Authors: M. Hagleitner, P. Hoogerbrugge, B. W. B. Schreuder, U. E. Flucke, M. J. Coenen, D. M. W. Te Loo
Journal: Journal of Clinical Oncology (2011)

9518 Background: Osteosarcoma comprises 5% of all pediatric malignancies and only 50% of the patients will survive. A poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can help to understand the mechanism of drug response in these patients and offers the possibility to optimise treatment and improve outcome. Therefore, we applied a pathway-based approach to evaluate the cumulative effect of genes involved in the transport and metabolism of cisplatin and doxorubicin in relationship to clinical outcome of patients with osteosarcoma. Methods: We used a two stage approach to comprehensively evaluate the role of polymorphisms in genes involved in the cisplatinum and doxorubicin pathway. For the first stage we included 107 patients with osteosarcoma, 31 with good histologic respons (huvos III/IV) following neoadjuvant treatment and 76 patients with bad histologic respons (huvos I/II). A total of 54 candidate genes were selected by a pathway-driven approach based on literature, using databases from NCBI (PubMed, Gene, and SNP) and the Pharmacogenomics Knowledge Base. In order to comprehensively assess common genetic variation in the genes selected, a linkage disequilibrium (LD) based tag-SNP strategy was employed. A final set of 384 SNPs were typed using Illumina Beadarray platform. Results: Of the 384 SNPs genotyped, 353 SNPs passed our initial quality control criteria, and of these, two were excluded by PLINK default thresholds. Another 20 SNPs of the remaining 351 SNPs failed to meet Hardy-Weinberg equilibrium (HWE) criteria (PHWE<0.05). Of the remaining 331 SNPs analyzed in the discovery stage, a total of 24 SNPs with PTrend<0.05 in the cisplatina doxorubicine pathway were associated with histological response. In addition, a clear associations betweenthe development of acute cardiotoxicity and the presence of SNPs in the doxorubicine pathway were observed. Conclusions: This pharmacogenetic results might be useful to stratify treatment of patients immediately after diagnosis and offer the possibility to improve treatment and disease free survival of pediatric patients with osteosarcoma.
ErbB/PI3K/Akt/NF-kappaB pathway analysis in prostate cancer tissues by hierarchical clustering analysis (HCA)
Authors: I. H. Koumakpayi, C. Le Page, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2008)

22087 Background: The PI3K/Akt/NF-κB pathway activation is central to prostate cancer progression and therefore an attractive therapeutic target. There is in vitro evidence that the ErbB family of epidermal growth factor receptors are involved in the constitutive activation of the PI3K/Akt/NF-κB pathway, while activated PTEN can inhibit the activation of Akt by PI3K. However, the in vivo mechanismsby which ErbB family receptors activate the PI3K/Akt/NF-κB pathway in prostate cancer cells is still unknown. A preliminary investigation of pathway markers was undertaken to identify patterns of expression in prostate cancer tissues using immunohistochemistry (IHC). Furthermore, marker expression was correlated with clinical outcomes. Methods: IHC was done on an in-house prostate tissue array containing 368 cores from 63 cancer patients. We investigated the correlation of the clinicopathological parameters predicting outcome for native and appropriate activated phospho isoforms for EGFR, phospho-EGFR, Her2, phospho-Her2, ErbB3, PI3K, phospho-Akt, PTEN, phospho-PTEN and p65 NF-κB and phospho-p65. HCA was used to organize score data and to identify the best protein profile associated with biochemical recurrence (BCR). Results: Phospho-EGFR and phospho-Her2 expression were significantly increased in Gleason 6 and correlated with the activation of Akt (r=0.728, p<0.0001) and p65 NF-κB (p=0.012). No correlation was observed between PTEN or phospho-PTEN and Akt activation. Interestingly, Kaplan-Meier analyses of several proteins including ErbB3, p65 NF-κB, phospho-Akt were associated with BCR, with the activated forms of EGFR and Her2 having the best predictive values (p<0.001). HCA categorized 4 groups of patients primarily based on EGFR activation status. We observed a strong statistically significant difference in the BCR between the 4 groups, which confirmed the observation of the strong association between activation of EGFR, Her2 and Akt with BCR. Conclusions: Our in vivo study support the in vitro evidence that activated EGFR and activated Her2 are involved in the activation of the PI3K/Akt/NF-κB pathway. In addition our results suggest that in vivo PTEN-independent mechanisms are also involved in the activation of Akt in prostate cancer. No significant financial relationships to disclose.