tbuckley/cabot-search huggingface dataset:
Randomized phase II trial comparing gemcitabine/cisplatin-based chemoradiotherapy (CRT) to 5-FU-based CRT in patients with locally advanced pancreatic cancer
Authors: R. Wilkowski, H. Rau, C. Bruns, A. Wagner, R. Sauer, W. Hohenberger, O. Koelbl, V. Heinemann
Journal: Journal of Clinical Oncology (2006)

4038 Background: CRT is a relevant treatment option for patients with unresectable pancreatic cancer. Up to now, 5-FU has been the drug of choice for concurrent CRT. Based on evidence that also gemcitabine may improve the antitumor activity of radiation, a randomized phase II trial was undertaken. Methods: Patients with locally advanced, non-metastatic and histologically proven pancreatic cancer were included into a three-arm trial. In arm treatment arm A, radiation (CTV I up to 50.0 Gy, conventional fractionation) was applied concurrently with protracted venous infusion of 5-FU (350 mg/m 2 /irradiation day). In treatment arm B, patients received radiotherapy together with gemcitabine (300 mg/m 2 /d 30 minute infusion) and cisplatin (30 mg/m 2 /d 60 minute infusion) applied on days 1, 8, 22, and 29. In treatment arm C, patients received an identical regimen of CRT as described for arm B which was followed by 4 cycles of chemotherapy with gemcitabine (1000mg/m 2 , 30 min iv) plus cisplatin (50mg/m 2 ) applied at 2-week intervals. Patients were stratified for Karnofsky performance status (KPS ≥80% vs. &lt;80%). The primary end-point of the trial was the 9-months survival rate. Results: Ninety-six patients with a median age of 63.5 years (range 40–75 years) were included into the trial from 01/02 until 06/05 (arm A: 32 patients, arm B: 33 patients, arm C: 31 patients). Two patients did not complete CRT. At the time of evaluation, 66 patients (70.2%) had died. 9-months survival rate was 60%, 58%, and 46% in treatment arms A, B, and C, respectively. Median overall survival in arm A was 9.6 mo (95% CI, 8.7–10.5 mo), in arm B 9.6 mo (95%CI, 7.4–11.8 mo), and in arm C 6.1 mo (95% CI, 1.6–10 mo). Secondary end-points such as treatment-related toxicity, response rate, secondary resectability, and time to progression are under evaluation. Conclusions: CRT with gemcitabine plus cisplatin is not superior to 5-FU-based CRT with regard to the primary end-point of 9-months survival rate. Updated results will be presented at the meeting. No significant financial relationships to disclose.
Thyroid function and growth hormone secretion in amitriptyline-treated depression
Authors: S B Leichter, L Kirstein, N D Martin
Journal: American Journal of Psychiatry (1977)

The authors studied changes in indices of thyroid function prospectively in a group of 11 patients given amitriptyline to treat depression. The drug caused no significant alteration in these indices, but scores on the Hamilton Depression Rating Scale improved significantly. In another group of subjects with depression, the stimulation of growth hormone secretion by L-dopa was unaffected by amitriptyline therapy.
Preclinical rationale for combination targeted therapy in advanced clear cell renal cell carcinoma (RCC): Abrogation of rapamycin-mediated induction of AKT phosphorylation by perifosine
Authors: W. S. Holland, P. C. Mack, D. R. Gandara, P. N. Lara
Journal: Journal of Clinical Oncology (2008)

16083 Background: RCCs are highly vascularized tumors characterized by VHL abnormalities resulting in the upregulation of hypoxia inducible factor (HIF). Inhibition of mTOR, an upstream modulator of HIF, is an established therapeutic strategy in advanced RCC. One proposed resistance mechanism for mTOR inhibition is the compensatory upregulation of AKT, a promoter of cell growth and proliferation. Perifosine, an orally bioavailable AKT inhibitor, has clinical activity against RCC. We sought to determine whether treatment with perifosine and an mTOR-inhibitor (rapamycin) would synergistically inhibit RCC in preclinical models. Methods: Four clear cell RCC cell lines were studied: A498, CAKI-1, 769-P, and 786-O. Dose curves of single-agent and combination perifosine + rapamycin were performed by MTT. Combination studies were designed for median-effect. Status of pAKT (S473), pmTOR (S2481) and HIF-2alpha was assessed by Western blot. Cell lines had low basal levels of pAKT and VHL, moderate levels of pmTOR and HIF-2alpha, and no detectable HIF-1alpha. Results: CAKI-1, 769-P, and 786-O were sensitive to perifosine with an IC50 between 5–10 uM, while the IC50 of A498 was > 20 uM. Growth inhibition by rapamycin plateaued by 0.5–1 nM with none of the lines achieving an IC50. Combination treatments were essentially additive at lower doses of perifosine, becoming sub-additive or antagonistic at higher doses. Perifosine blocked phosphorylation of AKT induced by rapamycin. As a single agent and in combination, perifosine inhibited HIF-2alpha expression in the 769-P and CAKI-1 cell lines. Conclusions: Perifosine has high single-agent activity in select RCC lines and can abrogate the induction of AKT phosphorylation mediated by mTOR inhibition. Perifosine + rapamycin was at best additive, suggesting that pAKT is not the sole mechanism of resistance. Studies to explore the roles of VHL and HIF in response to this combination are ongoing. A Southwest Oncology Group trial in RCC patients testing the rational combination of perifosine and the mTOR inhibitor temsirolimus is now under development. No significant financial relationships to disclose.
Validity, reliability and responsiveness of Euroqol (EQ5D) in patients (Pts) receiving palliative care (PC)
Authors: Q. Xia, S. S. Hwang, V. T. Chang, P. Osenenko, Y. Alejandro, H. Yan, K. Toomey, S. Srinivas
Journal: Journal of Clinical Oncology (2005)

8082 Background: Measurement of utility (U) in PC is important and has not been reported. The EQ5D has five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) that can be converted into an U and a health VAS (H). We report the validity, reliability of EQ5D and its responsiveness in capturing change over time. Methods: 103 advanced cancer pts completed the EQ5D, FACT-G, EFAT and MSAS-SF every 4 weeks from the start of palliative care to death. The KPS was determined at each time point. We defined four time points - 6, 3, 2 and 1 month (m) prior to death (PTD) and performed the following analyses: (1) Spearman correlation, linear mixed model and MANOVA to examine the convergent and discriminant validity; (2) intraclass correlation coefficients (ICC) to assess the reliability; (3) mixed-effect models to assess patterns of changes over time. Results: The median survival time was 3.7 m (range 1.3–38.2) with median of 3 interviews (range 1–19). (1) Validity. At each time point, each EQ5D dimension correlated significantly with comparable measures and discriminated among comparable criterion variable sets significantly by MANOVA (all p<0.0001); FACT-G SUMQOL correlated significantly with U (all p<0.0001) and H (all p<0.0001). The independent predictors of U included EFAT (p<0.0001), FACT-G PWB (p=0.0002), MSAS-SF PSYCH (p=0.004) and GDI (p=0.03), while H depended on MSAS-SF number of symptoms (p=0.04) only. (2) Reliability. Longitudinal ICC of EQ5D U was 0.41 and similar to the comparable variables studied. (3) Responsiveness. Each EQ5D dimension (pain/discomfort p=0.006; anxiety/depression p=0.0001; mobility <0.0001; self-care p<0.0001; usual activity p<0.000) and U (p<0.0001) worsened significantly but no change in H (p=0.5) over time. There was a gradual decline in U (-0.05/m) from 6m PTD with accelerated deterioration at 1 m PTD (-0.25). Conclusions: The EQ5D is valid, reliable and responsive to change over time for advanced cancer pts and can serve as an outcome measure in PC settings. The U reflects multidimensional measures and declines significantly over time; the perception of H is only predicted by number of symptoms and remains steady. Supported by PDIA and NJCCR Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NJCCR, PDIA
Clinical experience with different dosing schedules of decitabine in patients with myelodysplastic syndromes (MDS)
Authors: D. Steensma, H. Kantarjian, P. Wijermans
Journal: Journal of Clinical Oncology (2009)

7011 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients using two dosing regimens: 15 mg/m 2 intravenous (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days q 6 weeks (wks) and 20 mg/m 2 IV over 1 hr once daily for 5 consecutive days q 4 wks. Methods: Results were reviewed from two randomized phase 3 studies comparing the 3-day dosing schedule of decitabine with supportive care, D-0007 and EORTC-06011, and two phase 2 studies with the 5-day dosing schedule, DACO-020 and ID03–0180. Data from each clinical trial supporting overall improvement, duration of improvement, time to AML or death, progression-free survival (PFS), and transfusion independence was assessed. Results: Patients had IPSS classification scores of intermediate-2 or high-risk (D-0007, 70%; EORTC-06011, 93%; ID03–0180, 66%; DACO-020, 46%) and de novo MDS (D-0007, 87%; EORTC-06011, 88%; ID03–0180, 70%; DACO-020, 89%). Comparable overall improvement (complete response [CR] + partial response [PR] + hematologic improvement [HI]), time to AML or death, and PFS was observed across all trials (Table). The duration of improvement ranged between 9.2 and 11.3 months. A trend was observed for improved outcomes with an increased number of decitabine treatment cycles. Conclusions: Overall improvement rates by IWG criteria exceeded 30% in all 4 studies. Higher overall improvement rates corresponded to increased median number of treatment cycles. Increasing the number of decitabine treatment cycles administered may provide additional benefit to MDS patients. [Table: see text] [Table: see text]
HPV and base of tongue cancer: Reason for the increased incidence?
Authors: P. Attner
Journal: Journal of Clinical Oncology (2010)

e16014 Background: We have earlier shown an increase in the incidence of tonsillar cancer and the role of HPV as a risk factor. HPV prevalence in tonsillar cancer is approaching the same numbers as cervical cancer, where almost all tumors are HPV-associated. The second most common cancer of the oropharynx, base of tongue cancer, is not as well investigated regarding incidence trends and HPV prevalence. Following our previous research on tonsillar cancer, we assessed the increase in incidence of base of tongue cancer and the prevalence of HPV in this disease. Methods: Incidence data for base of tongue cancer in Sweden from 1970 to 2007 was obtained from the Swedish Cancer Registry. All patients diagnosed with base of tongue cancer in Stockholm County between 1998-2007 (109 individuals) were identified. From 95 patients, paraffin-embedded, pretreatment biopsies were obtained and tested for HPV both by general HPV PCR and HPV-16/HPV-33 type specific PCR. Expression of HPV-16 RNA was analyzed to confirm E6 and/or E7 expression. Results: We found an overall increase in the incidence of base of tongue cancer from 0.15/100,000 person years 1970-1974 to 0.47/100,000 person years during 2005-2007 in Sweden. From 1998 to 2007, the prevalence of HPV in base of tongue cancer increased from 58% 1998-2001 to 84% 2004-2007 (p<0.05). In the HPV-positive tumors, HPV-16 dominated (86%) but interestingly, HPV33 was detected in as many as 10%. E6 and/or E7 RNA were found in 85 % of the samples tested. No age difference was observed in HPV-positive and HPV-negative groups, respectively. Conclusions: The incidence of base of tongue cancer is increasing and today over 80% of all base of tongue SCC in the County of Stockholm is HPV positive, which mimics the development for tonsillar cancer in the Stockholm area. This suggests that HPV contributes to the increase of the incidence. There are differences between tonsillar and base of tongue cancer patient, no age difference could be observed between HPV positive and HPV negative patients in the base of tongue group. If, in parallel with tonsillar cancer, this results in better prognosis for patients with HPV-positive base of tongue cancer as compared to patients with HPV-negative cancer, remains to be investigated. No significant financial relationships to disclose.
Induction of the cancer-testis antigen MAGE-A3 in myeloma cell lines by 5’azacitidine and MGCD0103
Authors: A. Moreno, S. Szmania, J. Shi, B. Barlogie, G. Prentice, F. van Rhee
Journal: Journal of Clinical Oncology (2008)

14008 Background: MAGE-A3 is an immunogenic cancer testis antigen that is frequently expressed in high-risk multiple myeloma. We tested whether the demethylating agent 5’azacitidine (5’aza) and the histone deacetylase inhibitor MGCD0103 could modulate MAGE-A3 expression in MM cell lines. Methods: Myeloma cell lines ANBL-6, LP-1, RPMI 8226, OCI-MY5, OCI-MY1 and ARK were treated with 5’aza for 72 hrs followed by 24 hrs of normal media or MGCD0103. Fold change in MAGE-A3 RNA expression levels was assessed by real-time PCR using the ddCT method normalized to the internal control GAPDH. Cell viability was assessed by flow cytometry and methylation status of the MAGE-A3 promoter was determined by methylation specific PCR (MS-PCR). Results: MM cell lines positive for MAGE-A3 prior to treatment (RPMI 8226, OCI-MY5, OCI-MY1, and ARK) did not have appreciably increased MAGE-A3 expression after treatment, whereas MAGE-A3 expression was induced in previously negative lines ANBL-6 and LP1. Treatment with 500nM 5’aza increased MAGE-A3 transcripts an average of 73 fold (ANBL-6) and 24 fold (LP-1). A higher concentration of 1μM 5’aza led to greater MAGE-A3 expression but was also highly cytotoxic. MGCD0103 alone did not appreciably increase MAGE-A3 expression, however the addition of MGCD0103 for 24hrs after 5’aza led to a further 3.1 fold on average (ANBL6) and 2.2 fold on average (LP-1) increase in MAGE-A3 expression over 5’aza alone. MS-PCRindicated that the MAGE-A3 promoters in both ANBL-6 and LP-1 were hypermethylated prior to treatment and hypomethylated after treatment. The MM cell lines that were MAGE-A3 positive at baseline had hypomethylated promoters prior to treatment. Conclusions: The cancer testis antigen MAGE-A3 can be induced in MAGE-A3 negative myeloma by 5’aza and further increased by MGCD0103. Demethylating agents and histone deacetylase inhibitors may play a role in enhancing the efficacy of immunotherapy strategies targeting MAGE-A3. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion Pharmion Pharmion
Ifosfamide based neoadjuvant chemotherapy in locoregionally advanced head &amp; neck squamous cell carcinoma (HNSCC): A retrospective analysis of 718 cases
Authors: V. R. Pai, P. S. Kulkarni, A. T. Mazumdar, G. Biswas, P. M. Parikh, K. A. Pathak, A. K. D'Cruz
Journal: Journal of Clinical Oncology (2004)

5550 Background: Advanced head and neck cancer is a major therapeutic problem in India. Despite the advances in the surgical & radiotherapeutic techniques, the prognosis of these patients remains poor. Ifosfamide, Cisplatin & Taxanes have shown activity as single agents in HNSCC. Methods: 718 patients with previously untreated locoregionally advanced head and neck cancer at Tata Memorial Hospital who received Ifosfamide based neoadjuvant chemotherapy were studied. The regimens used were: 1) A: Ifosfamide 1.5-gm/ m2 2) B: Ifosfamide 1.5-gm/ m2 with cisplatin (I+P) 3) C: Ifosfamide 2.2gm/ m2 with cisplatin. 4) D: Paclitaxel 175mg/m2 day 1 with I+P 5) E: Docetaxel 75mg/m2 Day 1 with I+P. Ifosfamide with mesna & Cisplatin (15-mg/ m2/day) were given for 5 days. All the patients received 2 cycles of chemotherapy with an interval of 4 weeks. Results: There were 58 patients on regimen A, 207 on B, 270 on C, 122 on D & 61 patients on regimen E. The median age was 52 years with male: female ratio of 6.5: 1. Group A had overall response rate (ORR) of 54.44 % with median time to tumor progression (TTP) of 2 months. The ORR in B was 66.6 % & TTP 5.5 months. In C, the ORR was 79.9 % & TTP 8 months. In D, the ORR was 74.59 % & 70.4% in E. The TTP for D & E was 10 months (p=0.05). 0.9 % patients in B & 2.5 % in C suffered from grade III neutropenia. 48.3% patients on D & 49.1 % patients on E had grade III & IV neutropenia. Conclusion: Ifosfamide is effective neoadjuvant chemotherapy in previously untreated locoregionally advanced HNSCC. Addition of the cisplatin to Ifosfamide (I+P) improves the ORR by 13.22 %. Dose escalation of Ifosfamide in the I+P combination improves the response rate further by 13.33 %. Addition of the taxanes to the I+P combination does not increase the response rates but resulted in increased time to progression (TTP). No significant financial relationships to disclose.
African-American women with breast cancer treated with preoperative chemotherapy have reduced pathologic complete response rates
Authors: H. A. Zaren, E. Sciupokiene, A. Mackeviciute, X. Gao, K. Ferrer, Y. Wang, S. Zhang, M. Sekosan, K. A. Dookeran
Journal: Journal of Clinical Oncology (2004)

876 Background: African-American (AA) women with breast cancer have an increased risk of death, compared with white women. Biologic differences may contribute to outcome disparities for AA women. Response to preoperative (preop) chemotherapy in AA women may provide useful information on tumor biology. Methods: We retrospectively reviewed 442 consecutive minority-underserved women treated for breast cancer at the MBCCOP, Stroger Hospital of Cook County, in Chicago. Results: Preop therapy was given to 63 (23%) women and 42 had records for review. Of these, 50% (21) were AA. Preop clinical stage distribution for AAs showed 1 with 2A, 5 with 2B, 12 with 3A and 3 with 3B disease; for non-AAs the distribution was 1 with 2A, 8 with 2B, 4 with 3A and 7 with 3B disease. Although more AAs had 3B disease and more non-AAs had 2B disease, this was not significant. Preop node positive status was 17 AAs vs. 14 non-AAs. AC only was used almost equally for both groups (6 AA vs. 7 non-AA), and the addition of Taxane was similar (15 AA vs. 13 non-AA). Equal numbers from both groups were non-compliant with preop therapy (2 AA & 2 non-AA), or had disease progression (2 AA & 2 non-AA). Pathologic residual invasive disease was found in 91% AAs and 76% non-AAs. Pathologic microscopic invasive disease was found in 10% AAs and 5% non-AAs. Pathologic complete response (pCR) was not found in AAs, but 19% non-AAs had a pCR. Node positive status post surgery was similar for both groups (N1: 4 AA vs. 3 non-AA; N2: 7 AA vs. 8 non-AA). For non-AAs, 3 of 4 pCRs occurred in patients with preop clinical stage 3B, and 1 in stage 2B; in this group, pathologic down staging was seen in 63% of 2B, 50% of 3A, & 72% of 3B disease. For AA women, pathologic down staging was comparable, with 60% of 2B, 67% of 3A, & 100% of 3B disease, but pCR did not occur. Conclusions: These results indicate that AA women with breast cancer treated with preop therapy have reduced pCR rates compared to non-AAs. It is unlikely that these results are due to differences in stage distribution, type of therapy or compliance issues. Further investigation of potential differences in tumor biology is required. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration This research was funded in part by the NCI (MBCCOP Grant CA95867), Aventis Pharmaceuticals Inc. & the Avon Foundation
The economic burden of chemotherapy-induced nausea and vomiting and its impact on the quality of life of Italian cancer patients
Authors: R. R. Deuson, E. Ballatori, B. Ruggeri, F. Roila, S. Sarti, G. Soru, G. Cruciani, M. Di Maio, C. Locatelli
Journal: Journal of Clinical Oncology (2004)

6071 Background: In Italy, the economic burden of chemotherapy-induced nausea and vomiting (CINV) and its impact on a patient's daily life have received little attention. Methods: Prospective observational study in 7 oncology centers. Cancer patients receiving cisplatin-containing regimens reported the incidence and intensity of CINV for 8 consecutive days in a diary and completed a Functional Living Index for Emesis (FLIE) questionnaire. Costs related to emesis (direct medical and non-medical costs and indirect costs, including adverse events) and costs of antiemetic therapy were recorded from the perspectives of the hospital, the patient, and the National Health Service (NHS). Costs from the patient's perspective were obtained using a validated questionnaire. The endpoint “No or minimum Impact on Daily Life” (NIDL) is defined as a total score of 108 FLIE points (average item score >6 on a 7-point scale). Results: 62 of 169 enrolled patients (36.7%) had at least one emetic episode and 102/169 (60.4%) experienced mild nausea. Mean costs per patient of acute and delayed emesis are shown in the table. The impact of CINV on a patient's ability to carry out daily activities was evaluated in 155 patients. Impact on patients' daily life occurred because of nausea (77/155; 49.7%) and vomiting (64/155, 41.3%). Conclusions: 60% of cisplatin-treated patients suffered from nausea and 33% from vomiting. CINV affected patients' daily life in more than 40% of the cases. Costs for prophylaxis and management of emesis are high and variable. The economic burden of CINV and its impact on patients' daily life (especially in the delayed phase) is still considerable despite current antiemetic prophylaxis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck & Co., Inc. Ballatori Partnership, LLC, Merck & Co., Inc.
Regulatory Approvals of Pediatric Oncology Drugs: Previous Experience and New Initiatives
Authors: Steven Hirschfeld, Peter T.C. Ho, Malcolm Smith, Richard Pazdur
Journal: Journal of Clinical Oncology (2003)

To review the Food and Drug Administration (FDA) experience with approvals of new drugs for pediatric oncology and to discuss new regulatory initiatives directed at pediatric oncology.A retrospective review of FDA archival documents and the published literature.More than 100 drugs have been approved by the Division of Oncology Drug Products of the FDA for the treatment of malignancies. Only 15 have pediatric use information in their labeling, which is less than 50% of the drugs commonly used in the treatment of pediatric malignancies. In the past 20 years, there have been six submissions to the FDA for pediatric oncology indications. To illustrate principles of the approval process, each submission is discussed.Potential reasons for a lack of New Drug Application submissions for pediatric oncology include the small pediatric oncology market compared with the adult oncology market and perceived barriers to performing studies in children. Reasons for failure to approve pediatric indications include small numbers of patients, lack of appropriate controls, and failure to demonstrate patient benefit. Approval criteria include the use of controlled trials, prospective data collection, and disease-appropriate end points. Regulatory initiatives to promote pediatric therapeutic development and product labeling are discussed.
Multispectral imaging of T and B cells in murine tissue
Authors: Zipei Feng, Mohammad Farhad, Bernard A Fox, Shawn Jensen
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Assessment of patterns of immune infiltrates has been shown to be highly prognostic and diagnostic in many types of cancers. The clinical impact of such analysis is most notably shown in colon cancer, where objective quantification of CD3+ and CD8+ T cells densities in the primary