tbuckley/cabot-search huggingface dataset:
Glucagon-like peptide (GLP)-1 and the synthetic analogue exenatide: From novel therapy for diabetes to growth inhibition of breast cancer cells.
Authors: I. Wolf, H. Ligumsky, B. Kaufman, T. Rubinek
Journal: Journal of Clinical Oncology (2010)

e21035 Background: GLP-1 is a hormone secreted from endocrine L cells in the gut in response to food intake and promotes insulin secretion and satiety. These activities indicated GLP-1 as a potential therapy for type 2 diabetes. Exenatide is a long-acting GLP-1 receptor (GLP-1R) agonist approved for this indication. To date more than 10 million prescriptions for exenatide have been dispensed. Type 2 diabetes and breast cancer share common risk factors, namely obesity and older age, and commonly occur together. Thus, GLP-1 agonists are expected to be administered to patients who are at increased breast cancer risk. We aimed to explore the effects of GLP-1 and exenatide on breast cancer cell growth. Methods: The effects of GLP-1 and exenatide on proliferation of breast cancer cells were determined by MTT and colony assays and their in vivo effects were tested in athymic mice. Downstream signaling was determined using Western blotting and cAMP levels were determined using radio-immunoassay. Results: GLP-1 or exenatide reduced viability and enhanced apoptosis of breast cancer cells but did not affect viability of nontumorigenic mammary cells and human primary liver cells. Moreover, exenatide decreased the ability of MDA-MB-231 cells to form tumors in athymic mice. Either exenatide or GLP-1 elevated cAMP levels and phosphorylated its downstream target CREB in breast cancer cells. Surprisingly, treatment with exendin-(9-39), a GLP- 1R antagonist further increased cAMP levels; and infection of MCF-7 cells with the classic GLP-1R enhanced proliferation, suggesting the existence of a nonclassical GLP-1R in these cells. Finally, GLP-1, exenatide and exendin-9 activated p38 MAPK and AMP kinase. Conclusions: These data indicate GLP-1 and exenatide as potent inhibitors of breast cancer cells proliferation and suggest the existance of a unique signaling pathway for GLP-1 in breast cancer. This pathway may serve as a target for novel therapies. As GLP-1 levels are reduced in type 2 diabetes, GLP-1 may serve as a link between diabetes and breast cancer. Clinical studies are needed in order to determine if exenatide and other GLP-1R agonists have favorable effects on breast cancer progression. No significant financial relationships to disclose.
Patterns of adjuvant hormonal therapy (AHT) usage in early stage breast cancer (ESBC)
Authors: P. Cobb, L. S. Schwartzberg, K. Kulig, A. Johns, B. Fortner
Journal: Journal of Clinical Oncology (2006)

10695 Background: Aromatase inhibitors (AIs) are recommended as first line agents or after tamoxifen (T) as extended adjuvant therapy in hormone receptor positive ESBC. Little is known about adherence, adverse events, toxicity, duration of therapy, or change in agents in the community setting. Disparities between actual usage and clinical guideline recommendations could have a significant impact on outcomes. Methods: This retrospective observational study reviewed charts of 200 ESBC patients (pts) receiving AHT from 4 US community oncology clinics. To be eligible, each patient must have completed &gt;1 patient care monitor (PCM) survey, a validated electronic self-report measure that produces indices related to physical symptoms, psychological symptoms, functional status and overall health-related QOL. Baseline symptoms and toxicities prior to initiation of AHT and during and/or after are available on all evaluable patients. Pt charts were identified consecutively in reverse chronological order starting from 3/01/05. Results: Data are available on 42 pts. The mean age of the patients was 63.6 (range 43–86). First line AHT was T in 24 and AI in 18. Of available AIs, 14 pts received anastrozole, 3 letrozole and 1 exemestane. 18 pts continue AHT as per guidelines and 7 completed planned therapy (median duration, 58.8 months). Switching from 1 st line AHT to another agent occurred in 13 pts; 10 switched from TAM to an AI, mean duration of TAM 31.0 months and 3 pts to another AI. 8 pts (19%) changed for an adverse event (AE), and 5 changed due to MD/pt preference. AEs included eye problems (2), weight changes (2), GYN complaints (2), vasomotor symptoms (1), muscle/joint aches (2), and increased alkaline phosphatase (1). Of pts receiving 2 nd line AHT, 4 had discontinuation for an AE: muscle/joint aches (2), vasomotor symptoms (1), and eye problems (1). Conclusion: Switching of first line AHT is common for reasons of AEs or MD/pt decision. Pts with AEs to AHT often experience additional AEs after exposure to another agent. [Table: see text]
Secondary hematologic malignancies associated with temozolomide (TMZ) in patients with glioma.
Authors: H. Momota, Y. Narita, Y. Miyakita, S. Shibui
Journal: Journal of Clinical Oncology (2010)

2046 Background: Temozolomide (TMZ) is a widely used alkylating agent in the treatment of gliomas. Although reports of treatment-related myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) associated with TMZ are accumulating, it remains unclear whether TMZ has the same leukemogenic potential as other alkylating agents. Methods: A single institution retrospective analysis was made using a database of 359 glioma patients treated with either nimustine (ACNU)-based, TMZ-based, or combination therapy and followed for a minimum of 2 months between January 1990 and December 2009 at the National Cancer Center Hospital in Japan. The objectives of this study were to characterize secondary hematological malignancies associated with TMZ and to estimate the rate of TMZ-related MDS/AML and ALL by comparing ACNU-based therapy. Results: Of the 359 patients, 225 patients received the therapy with ACNU alone or ACNU plus other chemotherapeutic drugs (ACNU-based group, median follow-up period: 31.4 months), 63 patients received ACNU-based therapy followed by TMZ therapy (ACNU/TMZ group, median follow-up period: 19.1 months), and 71 patients received the therapy with TMZ alone or TMZ plus other chemotherapeutic drugs (TMZ-based group, median follow-up period: 16.9 months). Three patients in ACNU-based group developed MDS/AMLs (1.33%, mean person year of MDS/AML: 6.4 years), two patients in ACNU/TMZ group developed MDS/AMLs (3.17%, mean person year of MDS/AML: 2.4 years), and one patient in TMZ-based group developed ALL (1.41%, mean person year of ALL: 1.1 years). Conclusions: Although retrospective analysis, relatively short follow-up period and small sample size in this study limit the strength of our conclusions, TMZ may increase the incidence of secondary hematologic malignancies and shorten their latency in combination with other chemotherapeutic agents. It is noteworthy that ALL occurs only in TMZ-based group with a relatively short latency in this series. No significant financial relationships to disclose.
A systematic review and meta-analysis of the role of p53 as measured by immunohistochemistry in the prognosis of colorectal cancer
Authors: S. A. Grumett
Journal: Journal of Clinical Oncology (2005)

3611 Background: There exists controversy regarding the role of p53 expression in the prognosis of colorectal cancer. More than twenty papers have been published in the last ten years with conflicting Results: An individual patient data systematic review and meta-analysis of the role of immunohistochemistry has not been attempted before Methods: A comprehensive literature search identified 45 papers which fulfilled the inclusion criteria, using disease-specific survival as an endpoint. Data was collected, standardised and analysed using hazard ratios as outcome measures and inverse variance weighting. Results: 18 groups submitted a total of 6246 patients’ data. The pooled hazard ratio was 1.137 (95% CI 1.062–1.218). This result was positive by random and fixed-effects models. Conclusions: Over-expression of p53 as measured by immunohistochemistry worsens disease-specific survival. There was however, evidence of heterogeneity and publication bias. Corrections were made for missing data. No significant financial relationships to disclose.
No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques.
Authors: A J Nixon, J Manola, R Gelman, B Bornstein, A Abner, S Hetelekidis, A Recht, J R Harris
Journal: Journal of Clinical Oncology (1998)

PURPOSE To determine whether left-breast irradiation using modern techniques after breast-conserving surgery leads to an increased risk of cardiac-related mortality. METHODS Between 1968 and 1986, 1,624 patients were treated for unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA, with conservative surgery and breast irradiation. Seven hundred forty-five patients with a potential follow-up of at least 12 years were analyzed. Clinical, pathologic, and treatment characteristics were compared between the 365 patients (49%) who received left-sided irradiation and the 380 patients (51%) who received right-sided irradiation. The relationship between left-sided breast irradiation and the risk of nonbreast cancer- and cardiac-related mortality was examined. RESULTS There was no significant difference in the distribution of clinical, pathologic, or treatment characteristics between the two groups, with the exception of a small difference in pathologic tumor size (medians, left, 2.0 cm, right, 1.5 cm; P = .007). At 12 years, a majority of patients still were alive. Slightly more patients with left-sided tumors had died of breast cancer (31% v 27%; P = NS). Equivalent proportions from each group died of nonbreast cancer causes (11%), including nine patients (2%) from each group who died from cardiac causes. The risk of cardiac mortality did not increase as time after treatment increased for patients who received left-sided irradiation compared with right-sided irradiation. A model that controlled for clinical, pathologic, and treatment differences showed no significant increase in any category of cause of death (breast, cardiac, or other) for patients who received left-sided irradiation. CONCLUSION These results suggest that modern breast radiotherapy is not associated with an increased risk of cardiac-related mortality within at least the first 12 years after treatment.
Quality of life (QOL) of patients (pts) with metastatic hormone refractory prostate cancer (mHRPC) following treatment with docetaxel or mitoxantrone in the TAX-327 study
Authors: G. R. Pond, D. R. Berthold, R. Dewit, M. Eisenberger, I. F. Tannock
Journal: Journal of Clinical Oncology (2006)

4557 Background: The TAX-327 study compared 3-weekly docetaxel (D3), weekly docetaxel (D1) or mitoxantrone (M), each with prednisone (P) for 1006 pts with mHRPC. Survival and symptom control were superior for treatment with D3+P as compared to M+P (Tannock et al, NEJM 2004;351;1502–12). Here we investigate QOL and its relation to pain, and effects of treatment on QOL in pts with minimal symptoms. Methods: Pts were assessable for pain response if Present Pain Intensity (PPI) ≥ 2 (range 0–5) or Analgesic Score (AS) ≥ 10. QOL was measured by the FACT-Prostate (FACT-P) self-report score (range 0–156, higher scores indicate better QOL). QOL response required a 16-point increase in FACT-P score maintained on 2 occasions; here deterioration of QOL was defined by a 16-point decrease from baseline in FACT-P score. Pts with minimal symptoms were defined at baseline by a FACT-P score &gt; 128 or by PPI &lt; 2 and AS &lt; 10. Results: QOL was substantially impaired at baseline (FACT-P score ≤128) in 92% and 75% of pts who were and were not assessable for pain (p &lt; 0.001). Correlation of FACT-P score with PPI and AS will be presented. QOL response and deterioration for all assessable pts, and for those with minimal symptoms are shown in the table (p-values compared with M+P). Time-dependent analysis of QOL and its relation to duration of treatment will be presented at the meeting. Conclusions: Most pts had impaired QOL at baseline regardless of pain. There was greater improvement in QOL following treatment with D+P compared to M+P for all pts and for pts with minimal symptoms. With the caveat that unequal withdrawal of pts might bias the data, there was greater probability of decline in QOL for pts receiving weekly docetaxel. [Table: see text] [Table: see text]
Evaluation of a MAb-PAM4-defined MUC1 immunoassay as a potentially new diagnostic test for pancreatic cancer
Authors: D. V. Gold, G. Newsome, D. E. Modrak, Z. Ying, T. M. Cardillo, I. Horak, D. M. Goldenberg, R. M. Sharkey
Journal: Journal of Clinical Oncology (2005)

4102 Background: At the present time there are no reliable methods for the early detection and diagnosis of pancreatic cancer. Since the PAM4 MAb identifies an epitope that is more restricted to pancreatic cancer than other MUC1-producing forms of cancer, we developed an immunoassay to quantitate this antigen in serum specimens. Methods: The immunoassay consists of MAb-PAM4 as the capture reagent and an IgG fraction derived from a polyclonal, anti-MUC1 antiserum as the probe. The former reagent provides specificity and the latter a high signal output. Results: At a cutoff value of 10.2 units/ml, 41 of 53 (77%) pancreatic cancer patients were positive, with a median value of 31.7 units/ml, while none of the 20 normal specimens and only 2 of 32 (6%) pancreatitis sera were positive. ROC analyses for discrimination of pancreatic cancer from normal and pancreatitis specimens provided an area under the curve (AUC) of 0.88 (95% CI, 0.81 - 0.95), with a specificity of 96% and a positive likelihood ratio of 20.5. Of the 53 pancreatic cancer specimens, 41 were assessable for both PAM4-MUC1 and CA19–9. Of these, 24 (59%) were considered positive for CA19–9 (at a cutoff of 35 units/ml). As with the PAM4-MUC1 assay, none of the normal specimens was positive. However, of the 32 pancreatitis samples, CA19–9 was positive in 38%. ROC analyses for discrimination of pancreatic cancer from normal and pancreatitis serum specimens provided an AUC of 0.74 (95% CI, 0.63 - 0.84), with a specificity of 77% and a positive likelihood ratio of 2.59. Statistical analyses for PAM4-MUC1 in this same subset of pancreatic cancer sera differed little from the group analyses discussed above; sensitivity for this subset was slightly reduced (71%), but specificity remained high (96%), as did the positive likelihood ratio (18.7). Conclusions: These initial data suggest that the PAM4-MUC1 assay may offer a significant improvement over the CA19–9 assay for the discrimination of pancreatic cancer from normal and pancreatitis populations. (Supported in part by grants CA92723 and CA98488 from the NIH.) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Immunomedics Immunomedics
Liposarcoma treatment: Role of radiotherapy and chemotherapy
Authors: A. Longhi, S. Neri, C. Speranza, M. Alberghini, C. Ferrari, M. Abate, M. Cesari, S. Ferrari, E. Palmerini, M. Mercuri
Journal: Journal of Clinical Oncology (2008)

10578 Background: The best adjuvant treatment for soft tissue sarcomas is still unclear. Soft tissue sarcomas is an eterogenous group of several different hystotypes. The aim of this retrospective study is to evaluate prognostic factors and treatments. Methods: All liposarcoma cases evaluated in our Pathology from Jan 1985 to December 2005 were reviewed: 299 cases of liposarcoma were found of these only 155 were treated at Rizzoli since their first diagnosis. Metastatic since diagnosis and pediatric cases were excluded. Of these 155 pts only 122 had localized liposarcoma of soft tissue and adequate informations and follow up. Results: Male were 71 and female 51, Median age 47 (15–85). Histology was as follows: mixoid 62, round cell 33, pleomorphic 27. Grading according to FNCCL was G1=18, G2=51, G3=53. Median tumor volume was 183 cm3 (8–3,800), mean 401. Surgical margins were adequate in 84 patients (66.4%) unadequate in 34 (27.9%), 4 missing. Treatment received were: 18 no treatment besides surgery, presurgery radiotherapy (PRE-RT) alone in 52 pts, postsurgery RT (POST- RT) alone in 30 pts, chemotherapy ± RT in 22 patients. Chemotherapy was based on anthracyclin and ifosfamide scheme (3–5 cycles), RT was ranging from 4,000–4,500 cGy. Five years DFS was 50 months for all group (range 1–230) and 5 yrs OS was 64 ms (10–230). Positive prognostic factors were grading, adequate margins and mixoid histology. Then excluding 18 pts who were G1 we evaluate on the remaining 104 patients, all G 2 an 3, the 5 yrs DFS and OS according to the treatment received. 5 yr DFS was 64% for those who received no-Tx, 56.5% for those who received PRE-RT and 82% for those who received POST RT, and 55.4 for those who received chemotherapy. 5-yr OS was 80% for no-Tx group, 81% for PRE-RT, 92% for POST-RT and 79% for chemo group. OS according to histology (on 104 pts, excluding G1) was 90% for mixoid, 82.8% for round cells and 74% for pleomorphic. At multivariate analysis grading and therapy (RT POST) maintain positive significance. Conclusions: From this retrospective study POST -RT seems to be the best treatment for localized liposarcoma. No significant financial relationships to disclose.
Phase 1 study of carboplatin in patients with advanced cancer, intermittent intravenous bolus, and 24-hour infusion.
Authors: S Leyvraz, T Ohnuma, M Lassus, J F Holland
Journal: Journal of Clinical Oncology (1985)

We undertook a phase 1 study of Carboplatin (CBDCA) on an intermittent single intravenous (IV) bolus (schedule A) and a 24-hour continuous infusion schedule (schedule B). Hydration and forced diuresis were not performed. Patients were not premedicated for anticipated vomiting. Thirty-eight adult patients with solid tumors received a total of 71 courses. In schedule A, doses were escalated from 20 to 600 mg/m2. The dose-limiting toxicity was myelosuppression. At doses of 270 mg/m2 and higher, leukopenia and thrombocytopenia were reproducibly seen. The dose of 600 mg/m2 was the maximally tolerated dose, producing severe thrombocytopenia (platelet counts less than 30,000/microL). Other toxicities included a fall in hemoglobin levels and tolerable nausea and vomiting. Schedule B produced comparable hematologic and emetogenic toxicities to those in schedule A. In three patients audiograms became abnormal with high-frequency hearing loss without overt deafness. Two patients developed hypomagnesemia without irreversible renal dysfunction. Patients with poor performance status, preexisting renal dysfunction, a third fluid space, or bone metastases seemed to develop increased hematologic toxicity. The recommended phase 2 dose for good risk patients is 400 mg/m2 IV bolus and for poor risk patients 270 mg/m2 IV bolus. Responses were seen in one patient each with head and neck carcinoma (partial response), small cell lung cancer (minor response), and breast cancer (minor response).
High-dose Allovectin-7 in patients with advanced metastatic melanoma: final phase 2 data and design of phase 3 registration trial
Authors: J. M. Richards, A. Bedikian, R. Gonzalez, M. B. Atkins, E. Whitman, J. Lutzky, M. A. Morse, T. Amatruda, E. Galanis, J. Thompson
Journal: Journal of Clinical Oncology (2005)

7543 Background: Allovectin-7, a bicistronic plasmid formulated with a cationic lipid system and encoding HLA-B7 and β-2 microglobulin, is an immunotherapeutic designed to induce a pro-inflammatory response and express allogenic MHC-class I antigen upon intralesional administration. Methods: We have conducted a Phase 2 dose-escalation trial to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy; injectable lesion(s); ECOG PS 0–1 and adequate organ function. Patients with brain or visceral (except lung) metastases, abnormal LDH, or any lesion ≥100 cm2 were excluded. Patients with 2 or more injectable lesions were randomized to receive injections of 2 mg Allovectin-7 divided for injection for up to 5 lesions. Patients received weekly intratumoral injections of a total of 2 mg of Allovectin-7 for 6 weeks followed by 3 weeks of observation and evaluation. Overall Response (OR) was assessed using RECIST guidelines two weeks following the last injection of each cycle. Patients with stable or responding disease received additional cycles of Allovectin-7. Results: Final, audited data are presented for the 133 patients enrolled. All patients were evaluated for safety (6 patients in the dose-escalation stage and 127 patients in the 2 mg efficacy stage), and 127 patients were evaluated for efficacy. Fifteen patients (11.8%, 95% CI: 6.2–17.4) achieved an objective response lasting a median duration of 12.7 months (95% CI: 8.3 - ongoing). The responders include two patients who had lesions resected and found no evidence of melanoma. Median time to progression was 1.6 months and median overall survival was 21.3 months (95% CI: 14.8–33.4). There were no reported Grade 3 or Grade 4 adverse events associated with Allovectin-7. Conclusions: Results indicate that high-dose Allovectin-7 is an active, well-tolerated treatment for Stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions. The details of the Phase 3, follow-up clinical trial design will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vical Vical
Overall survival trends in pediatric osteosarcoma patients over the past three decades
Authors: R. van Schie, M. Hagleitner, P. Hoogerbrugge, U. Flucke, H. Schreuder, M. te Loo
Journal: Journal of Clinical Oncology (2009)

10041 Background: In the late seventies, the combination of chemotherapy and surgery, significantly improved survival of osteosarcoma patients. However, the chemotherapeutic drugs used for treatment of osteosarcoma patients has not significantly changed since then although surgery clearly improved further and adjuvant chemotherapy have been added. In this study, we retrospectively evaluated, whether after the introduction of neoadjuvant chemotherapy in the late seventies, further improvement in outcome of pediatric osteosarcoma patients was achieved. Methods: Since 1978 and 2008, 54 previously untreated pediatric patients with osteosarcoma were enrolled in six consecutive regimens of different agents and intensity. The main difference between the treatment protocols is the addition of either methothrexate or ifosfamide. Overall survival (OS) and event free survival (EFS) in relationship to the different treatment regimens was calculated using the Kaplan-Meier method. Significance of difference in outcome were calculated using the log rank test. Results: The 5-year EFS and OS of the whole group was 54.7% and 61.1%, respectively. There was no significant difference in outcome in patients treated between 1978 and 1993 (n = 18), as compared to patients treated after 1993 (n = 36, OS 47.1% vs 69.4%, p = 0.34). Of all treatment regimens used, OS was the highest in patients treated with cisplatin, doxorubicin, and methotrexate (OS after 5 year 70%). Multivariate analysis showed that EFS and OS significantly correlated with the histological response but not with one of the treatment regimens used. Conclusions: No significant improvement in overall survival has been accomplished in pediatric osteosarcoma patients during the past thirty years. Histological response after neoadjuvant chemotherapy was the most important prognostic factor. No significant financial relationships to disclose.