tbuckley/cabot-search huggingface dataset:
Association of upregulated GATA-4 transcription factor colorectal adenocarcinoma with metastatic and primary tumors
Authors: E. C. Marginean, G. Torlakovic, H. Neufeld, E. Torlakovic
Journal: Journal of Clinical Oncology (2009)

e15093 Background: GATA-4 zinc finger transcription factor is involved in regulation of cellular development, proliferation, and differentiation and is important in embryonic development of gastrointestinal tract. However, GATA-4 is not expressed in normal adult colonic mucosa. Its protein expression in colonic adenocarcinoma has not been systematically evaluated and small number of samples was previously reported as negative. Nuclear factor-B (NF-B) activation was shown to promote the growth of the colon tumors in experimental models and was correlated with tumor angiogenesis and progression in human colorectal cancer. Methods: Forty cases of colorectal adenocarcinoma were evaluated. The benign colonic mucosa and the matching metastatic tumors of the same patients were also included in the study. TMAs which included 139 samples were evaluated by immunohistochemistry and nuclear and cytoplasmic GATA-4 expression was scored (0–3+). NF-B activation was detected as nuclear reactivity for p65. Results: GATA-4 was expressed in 32% of colorectal adenocarcinoma, but not in benign colonic mucosa (p=0.0001, Chi-Square). GATA-4 was also significantly more expressed in metastatic (41%) than in primary (21%) colorectal adenocarcinoma (p&lt;0.0001, Chi-Square). NF-B activation was not present in any of the samples of benign colonic mucosa, but it was detected in 64% adenocarcinomas (p&lt;0.0001, Chi-Square). While there was no difference in NF-B activation between primary vs. metastatic adenocarcinoma, a strong positive association between GATA-4 expression and NF-B activation (p&lt;0.0001, Linear-by- Linear) was found. Conclusions: GATA-4, a developmental transcription factor is not expressed by normal colonic mucosa, but is present in 1/5 of primary tumors that gave rise to distant metastases and in almost 1/2 of their respective metastases. GATA- 4 is also strongly positively associated with NF-B activation previously described to have a role in human cancer progression. GATA-4 may have a role in colorectal adenocarcinoma development and progression and it should be further evaluated in prospective studies as a putative adverse prognostic factor in colorectal adenocarcinoma. No significant financial relationships to disclose.
Hypofractionated radiation therapy for palliation of sarcoma metastases
Authors: O. Merimsky, V. Soyfer, B. Corn
Journal: Journal of Clinical Oncology (2009)

e21517 Background: RT is our preferred modality for local palliation of metastatic STS, regardless of systemic chemotherapy. While a protracted course of RT may be given as postoperative adjuvant treatment, a short and intense course of RT is usually needed for rapid palliation and local control of metastatic disease. Sarcomas are usually considered, at best, as moderately radio responsive tumors. RT doses within the range of 60 - 70 Gy are usually needed to be delivered in order to eradicate microscopic disease, while 50 Gy doses are needed for other malignancies such as breast or rectal cancer. Methods: Seventeen patients, 8 women and 9 men, at a median age of 61 years (range 53–95 years) had symptomatic metastatic sarcoma, and required rapid palliation. In total there were 20 sites of involvement by metastatic disease: trunk (chest wall, groin, axilla)- 13 cases, limb- 7 cases. The symptoms related to the metastases were either pain or discomfort in all the patients. In 15 cases the RT was the only modality for local palliation and in 5 cases RT was given following metastasectomy with close or involved margins. All the patients were treated by a short and intensive course of administration: 39 Gy were given in 13 fractions of 3 Gy/day, 5 times a week. Results: Median follow-up period was 25 weeks. The treatment was well tolerated. Acute side effects included first-degree burn (skin redness) and mild superficial pain in all the cases. No wound complications were noted among those undergoing surgery. Late side effects included skin pigmentation and induration of irradiated soft tissues. Durable pain control was achieved in 12 out 15 cases treated for gross metastases. Tumor progression was seen in the 3 other cases within a period of 2 to 9 months. Among 5 lesions which were irradiated as an adjunctive treatment following resection, no local recurrence was observed. Conclusions: The results of this series, although limited in size, point to the safety and feasibility of hypofractionated RT for palliation of musculoskeletal metastases from sarcoma. No significant financial relationships to disclose.
Combined administration of imatinib mesylate and ionizing radiation leads to increased radiosensitivity in the human glioblastoma cell line RuSi RS1
Authors: M. Holdhoff, K. A. Kreuzer, C. Appelt, R. Scholz, A. Jordan, B. Hildebrandt, C. A. Schmidt, R. A. Van Etten, B. Dörken, P. Le Coutre
Journal: Journal of Clinical Oncology (2004)

1564 Background: The selective tyrosine kinase inhibitor imatinib mesylate (Gleevec) effectively inhibits the activity of the abl, PDGF receptor (PDGFR) and c-kit tyrosine kinases. Because of the specific target profile of this orally available and generally well tolerated drug, imatinib is under intensive investigation for the potential treatment of other diseases. Malignant gliomas frequently show a high expression of PDGF receptor which is involved in tumorigenesis by formation of an autocrine loop. A role in DNA repair carried out through c-abl and c-kit was previously described both for c-abl and c-kit. In this study we address the potential use of imatinib mesylate and concomitant ionizing radiation (IR) to improve the radiosensitivity of the glioblastoma cell line RuSi RS1. Methods: Cells of the primary glioblastoma cell line RuSi RS1, as well as of the colon cancer cell line WiDr and of BT20, a human breast cancer cell line, were incubated with different concentrations of imatinib mesylate 30 minutes prior to irradiation (doses between 0 and 16 Gy). Western blots were done comparing the different expression of c-abl, PDGFR alpha and beta, and c-kit in the different cell lines. Immunoprecipitation was performed to assess inhibition of the different kinases by imatinib mesylate. Results: Under combined treatment with imatinib and IR a significant shift of the IC50 (dose needed to reduce the survival fraction by 50%) was detected in RuSi RS1 compared to IR alone. This effect was not seen in WiDr or BT20. RuSi RS1 showed an overexpression of PDGFR beta. Inhibition of tyrosine kinase phosphorylation by imatinib could be shown for PDGFR beta and c-abl (the IP failed for c-kit). Conclusion: Concomitant administration of imatinib mesylate and ionizing radiation increases the radiosensitivity of the glioblastoma cell line RuSi RS1. This effect might partly be due to disruption of an autocrine loop of the PDGF/PDGFR system. Inhibition of DNA repair mechanisms in which the tyrosine kinase activity of c-abl and c-kit is involved might be important causes of this observed phenomenon as well. No significant financial relationships to disclose.
Trend and geographic variations in the incidence of mantle cell lymphoma in the United States from 1975 to 2003
Authors: Y. Zhou, H. Wang, Y. Zhang, X. Du, L. Kwak, J. Romaguera, M. Wang
Journal: Journal of Clinical Oncology (2007)

8091 Background: Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin's lymphoma (NHL). To better understand the incidence and epidemiological features of MCL in the United States, we conducted a population-based study with 3943 patients (pts) of MCL identified from the Surveillance, Epidemiology, and End Results (SEER) tumor registries over 28 years. Methods: From SEER public database, we identified 157,035 pts of all ages diagnosed with NHL between 1975 and 2003 in 9 SEER areas. Of these pts, 3,943 (2.5%) had histologically confirmed MCL, acccounting for 2.51% of NHL. The incidence with 95% confidence intervals were generated from SEER*Stat Software. Incidence was age-adjusted to the U.S. 2000 standard population. Annual percent change (APC) for the incidence was calculated and considered to be statistically significant if P&lt;0.05. The crude 1-year survival rate was calculated as the ratio of the number of pts who survived over 1 year and the number of pts diagnosed with MCL. Results: Of 3,943 pts with MCL, 69.4% were late-stages (stages III IV), 24.2% were early-stages (stages I-II), and 7.1% were unstaged. Median age at diagnosis for MCL was 68.0. Overall incidence was 0.380/100,000/year, which increased by age from 0.02 in pts aged &lt;40 to 2.02 for 70–79 and 1.81 in pts aged 80 or older. The age-adjusted incidence increased from 0.077 in 1975 to 0.641 in 2003. APC was 4.71% (P&lt;0.001). Incidence of MCL was higher in men (0.555) than in women (0.250) (P&lt;0.001). Annual increase was greater in men (5.84%) than in women (2.82%). There were also substantial geographic variations (P&lt;0.001) in the incidence of MCL. The age-adjusted incidence was highest in Seattle (0.455) and the lowest in Hawaii (0.314). The incidence appeared to be higher in Caucasians (0.405) than in African-Americans (0.235) and other races (0.238). Annual increase was 5.1% in Caucasians, and 1.1% in African-Americans and other races. The 1-year survival rate was 85.0% for pts diagnosed in 1975–84, and increased to 90.4% for pts diagnosed in 1985–1994 and 82.0% for pts diagnosed in 1995–2003. Conclusions: The incidence of MCL increased progressively from 1975 to 2003, and was significantly higher in males and in Caucasians. There were substantial geographical variations in the incidence of MCL. No significant financial relationships to disclose.
Clinical response to targeted radionuclide therapy with multiple 500 mCi doses of <sup>111</sup>In-pentetreotide in patients with progressive neuroendocrine tumors
Authors: E. S. Delpassand, J. Sims-Mourtada, A. Azhdarinia, F. Ashoori, W. Sureshbabu, J. Hernandez, F. Torabi, G. Espenan, E. A. Woltering, L. B. Anthony
Journal: Journal of Clinical Oncology (2007)

14027 Background: Patients with advanced stage neuroendocrine tumors have limited therapeutic options. Previous treatments with doses up to 360 mCi per fraction have shown promising results in stabilizing progressive disease. The intent of this study was to evaluate the efficacy and safety of 2 consecutive 500 mCi doses of 111 In-pentetreotide in patients with progressive neuroendocrine tumors. This study was performed according to an FDA approved IND application. Methods: In a non-randomized study, 18 patients (13 men, 5 women) with an average age of 59 (ranging from 41–83 yr.) received 2 cycles of 500 mCi 111 In-pentetreotide infused over 3 to 6 hours (avg. cumulative dose range: 955–1006.1 mCi). All patients had progressive neuroendocrine tumors and failed first line therapy. All patients had grade 3 to 5 uptake in the tumors in the pre-therapy diagnostic 111 In-pentetreotide scan. The primary endpoint was clinical, metabolic and imaging response using RECIST criteria. Early and long term hematological, renal and hepatic toxicities during the average follow up period of 9.87 months (range 3.93 to 17.23 months) was performed using NCI Common Toxicities criteria. Results: Sixteen out of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. Metabolic response defined as 25% or more decline in Chromogranin or other markers was achieved in 72% of the patients. Clinical response defined by Functional Living Index (FLI) questionnaire and physical exam was achieved in 84% of the patients. Ten patients (55%) had grade I or II hematological toxicities, one patient had grade III thrombocytopenia, with nadir mean of 5 weeks after therapy. None of the patients required supportive therapy. Duration of hematological toxicities ranged from 1–6 weeks). One patient had grade II liver toxicity which appeared 4 weeks after therapy and resolved on week 5. No renal toxicity was observed during the follow-up period. Conclusions: Multiple 500 mCi doses of 111 In-pentetreotide therapy are effective in patients with progressive disseminated neuroendocrine tumors. Safety profile of this regimen suggests the opportunity for non-myeloablative dose escalation. No significant financial relationships to disclose.
Pharmacology of high-dose methotrexate in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG #20 trial.
Authors: A. J. Ferreri, M. Joerger, A. D. Huitema, S. Krähenbühl, J. H. Schellens, T. Cerny, M. Reni, E. Zucca, F. Cavalli
Journal: Journal of Clinical Oncology (2010)

2566
Survival update on a subset of peritoneal mesothelioma (PM) patients in an expanded access program (EAP) of pemetrexed (P) alone or combined with cisplatin in the treatment of malignant mesothelioma (MM)
Authors: J. Bloss, T. F. Wozniak, P. A. Janne, C. P. Belani, M. L. Keohan, H. J. Ross, J. Polikoff, D. M. Mintzer, L. Taylor, C. K. Obasaju
Journal: Journal of Clinical Oncology (2005)

7174 Background: A phase III trial of mesothelioma pts showed improved efficacy for P with cisplatin versus cisplatin alone, leading to a demand for patient access to P prior to regulatory approval. In order to gather additional efficacy and safety data, an Eli Lilly and Company EAP was opened to allow access to P for all eligible pts with MM. Methods: Patients were treated once every 21 days with P 500mg/m2 alone or with cisplatin 75mg/m2, for a maximum of 6 cycles. Chemotherapy naïve pts received the combination of cisplatin plus P, while pre-treated pts received P alone. All pts were supplemented with folic acid, vitamin B12, and received steroid prophylaxis. Results: There were 1056 pts with MM that received at least one dose of study drug at 462 sites in the United States. Of the 98 pts with PM there were 38 chemotherapy naïve pts (M 74%, F 26%; Median age: 65), 57 previously treated pts (M 56%, F 42%; Median age: 58), and 3 missing. The most commonly reported serious adverse events in the EAP regardless of causality were: dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). In seventy-three pts evaluated for response there were: 4 CRs (5.5%), 15 PRs (20.5%), 33 SDs (45.2%), and 21 PDs (28.8%) for an objective response rate of 26.0% (95% CI 16.5–37.6%). Median survival has not been reached for chemotherapy naïve pts (95% CI=7.6, –; 81.6% censorship) and median survival is 13.1 months for previously treated pts (95% CI=7.8, 13.1; 77.2% censorship). Conclusions: The toxicity observed for all pts enrolled in the EAP group is acceptable. The disease control rate (CRs+PRs+SDs) of 71.2% in the subset of pts with peritoneal mesothelioma indicates activity in this patient population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly Eli Lilly
Long-term outcomes after laparoscopic splenectomy for splenomegaly
Authors: S. A. Brethauer, S. Chalikonda, A. Dan, V. Nfonsam, C. Goncalves, S. Rosenblatt, A. Lichtin, R. M. Walsh
Journal: Journal of Clinical Oncology (2006)

17527 Background: Numerous studies have demonstrated the feasibility of laparoscopic splenectomy (LS) for splenomegaly. There is little published data on the long-term efficacy of LS. The aim of this study is to determine long-term outcomes following LS for splenomegaly. Methods: Retrospective review of patients undergoing LS between 8/95 and 5/05. Splenomegaly was defined by CT criteria of craniocaudal length &gt; 17 cm. Preoperative diagnoses included lymphoma in 13 patients (20%), leukemia in 15 (23%), autoimmune hemolytic anemia in 3 (5%) and other hematologic disorders in 8 (12%). 26 patients (40%) had no definitive diagnosis prior to splenectomy. Patients with ITP were excluded. Patient demographics, operative indications, operative morbidity and mortality, pathology, pre- and postoperative hematological indices were collected. Follow-up was obtained from patient records and telephone interviews. Results: 311 patients underwent LS during the study period. 65 patients underwent LS for splenomegaly. The mean age was 59 and 62% were male. There were no operative deaths. 7 patients (11%) were converted from LS to open. There were 9 (14%) major complications including 4 re-operations (3 for bleeding), 3 portal vein thromboses, 1 intra-abdominal abscess and 1 postoperative hemorrhage managed non-operatively. Thirty-two patients underwent LS primarily for diagnostic purposes. Nine had an existing hematologic disease and LS was performed to evaluate splenic involvement. LS confirmed a diagnosis in 19 (59%) patients including 11 lymphomas (34%). Thirty-three patients underwent LS primarily for treatment of either symptoms (33%) or cytopenias (66%). LS effectively treated mass symptoms in all patients. Among all patients 33 (51%) had associated cytopenias. At median f/u of 20 months 15 (45%) patients had no recurrence of cytopenias, 15 (45%) patients required further treatment and 3 were lost to follow up. One responder (7%) died of lymphoma 3 months after surgery without recurrence of cytopenia. The 15 non-responders had progression of disease requiring chemotherapy and transfusions and 9 (60%) died a median of 6 months after LS. Conclusions: LS is a valuable diagnostic and therapeutic tool for patients with splenomegaly and provides durable treatment for splenomegaly-associated cytopenias. No significant financial relationships to disclose.
A phase II open-label study of vandetanib in patients with locally advanced or metastatic hereditary medullary thyroid cancer
Authors: R. I. Haddad, A. D. Krebs, J. Vasselli, L. G. Paz-Ares, B. Robinson
Journal: Journal of Clinical Oncology (2008)

6024 Background: Medullary thyroid cancer (MTC) is the most common cause of death in patients with hereditary syndromes caused by activating mutations in the RET protooncogene. RET activation is the initial oncogenic event, with the activity of other receptor tyrosine kinases, including VEGFR and EGFR, likely to contribute to tumor growth and metastasis. Vandetanib (ZACTIMA™) is a once- daily oral agent that selectively targets RET, VEGFR and EGFR. A previous study has demonstrated the activity of vandetanib 300 mg in patients with hereditary MTC. In this study, the activity of vandetanib 100 mg was evaluated in patients with hereditary MTC. Methods: Eligible patients with unresectable, measurable, locally advanced or metastatic hereditary MTC received vandetanib 100 mg. Upon disease progression, eligible patients could enter post-progression treatment with vandetanib 300 mg until a withdrawal criterion was met. The primary objective was to assess the objective tumor response rate (RECIST). Secondary assessments included progression-free survival and safety and tolerability. Results: This study has completed accrual. Nineteen patients (13 male/6 female; median age 45 years, range 23–80) entered the study and received initial treatment with vandetanib 100 mg. Of these, 15/19 (78.9%) patients had a confirmed RET germline mutation; the mutation status of the other 4 patients was unknown. As of 18 December 2007, the median duration of treatment was 274 days (range 1–456); 14 patients are currently ongoing on vandetanib 100 mg and 2 patients have entered post-progression treatment with vandetanib 300 mg. Three patients have discontinued treatment (1 due to adverse event, 1 withdrawal of consent, 1 death). Preliminary objective tumor assessments have demonstrated partial responses in 2 patients, stable disease ≥24 weeks in 6 patients and progressive disease in 2 patients, yielding an objective response rate of 10.5% (2/19) and a disease control rate of 42.1% (8/19). Conclusions: These preliminary results suggest that vandetanib 100 mg also has activity in patients with hereditary MTC. A final analysis will be performed in April 2008. A randomized, placebo-controlled, international phase III study of vandetanib 300 mg in MTC is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology AstraZeneca Oncology
Prognostic value of metastasis pattern for morbidity in prostate cancer measured by quantitative bone scintigraphy.
Authors: M. Hoejgaard, B. Zerahn, K. Avogdilan, B. Kristensen, K. J. Mikines
Journal: Journal of Clinical Oncology (2010)

4644 Background: Quantification of bone metastases in the skeleton expressed as Bone Scan Index (BSI) and location of these are prognostic factors for mortality and morbidity in prostate cancer (PC). The purpose of this study was to identify prognostic factors for morbidity in PC based on location and extent of metastases derived from quantified bone scintigraphies (BS). Methods: Data from 107 consecutive patients with noncurable hormone-naive PC with available pretreatment 99mTc-MBP BS from the period 2003-2007 were retrospectively analyzed. BSI and location of metastases were measured from the BS using Exini Bone 1.0 (Exini AB, Sweden). Observed BSI for 8 regions was compared to the expected BSI calculated from the red bone marrow distribution. A logistic regression model for having skeletal events (SE), defined as external beam radiation for bone pain, spinal cord compression or pathological fracture at any location in the skeleton based on pre-treatment BSI, metastases distribution and PSA, was made. Results: The average BSI for the 72 patients with metastases at diagnosis was 1.063. Metastatic distribution expressed as the average BSI in these patients for each region was compared to the expected BSI of the same regions (Table). Patients with metastases to the skull had increased risk of SEs with OR: 4.2 (95% CL: 1.1-16.4, p<0.036) compared to the baseline patient with no metastases. No other regions, nor total BSI or PSA reached significance. Conclusions: PC does not metastasize randomly to the skeleton but clusters in the regions closest to the primary tumor. Patients with skull metastases have a higher risk of SEs throughout the skeleton. Very few SEs actually occurred in the skull region but skull metastases may indicate an atypical pattern of dissemination with a more aggressive phenotype of PC with more SEs. Observed and expected average BSI Skull Cervical spine Thoracic spine Lumbar spine Pelvis Upper limbs Lower limbs Thorax Observed BSI 0.057 0.012 0,129 0.127 0.471 0.041 0.079 0.147 Expected BSI 0.139* 0.036* 0,150 0.116 0.385* 0.088* 0.041* 0.108* * Different from corresponding average BSI, same region, p<0.05 t-test. No significant financial relationships to disclose.
Mild Traumatic Brain Injury in U.S. Soldiers Returning from Iraq
Authors: Rohit R Das
Journal: New England Journal of Medicine (2008)

To the Editor: We wish to express a number of concerns about the methods used in the study of mild traumatic brain injury by Hoge et al. (Jan. 31 issue).1 We learned through firsthand experi­ ence in the combat zone that immediately after a concussion, the soldier’s reported account is most accurate during the initial 24 hours after the blast incident.2 We therefore would be con­ cerned about recall bias introduced 3 to 4 months after a return from deployment. In addition, unlike perforation of the tympan­ ic membrane, a transient neurologic event (e.g., a “split­second” loss of consciousness) after a blast incident is not a sentinel finding of direct­ blast overpressure.2 Rather, it is a combination of at least three biodynamic variables: bodily displacement, direct­blast overpressure (involving intrinsic neural­tissue strains), and cardiopulmo­ nary insufficiency.3-5 The adverse effects of cardiopulmonary­ induced transient neurologic events (e.g., vasode­ pressor presyncope) are neither necessarily per­ manent nor cumulative, as a result of biologic restorative processes. Thus, we are concerned that the assessment methods used do not properly reflect the dimen­ sions of mild traumatic brain injury. Further­ more, we believe that the diagnosis of mild trau­ matic brain injury can be made only over time.