tbuckley/cabot-search huggingface dataset:
Effect of gefitinib on the bioavailability of oral irinotecan in children with refractory solid tumors
Authors: K. R. Crews, W. L. Furman, J. C. Panetta, B. B. Freeman, L. C. Iacono, P. J. Houghton, C. F. Stewart
Journal: Journal of Clinical Oncology (2004)

2012 Background: Gefitinib (ZD1839, Iressa), an oral EGFR tyrosine kinase inhibitor, significantly increased the oral bioavailability of irinotecan in preclinical murine pharmacokinetic studies. Based on this observation, we are conducting a study of the combination of gefitinib and irinotecan in children with refractory solid tumors with the objective to evaluate the effect of gefitinib on irinotecan bioavailability. Methods: Patients receive gefitinib orally continuously at a dose of 112.5 mg/m2/d or 150 mg/m2/d. On day 21 of gefitinib, patients receive intravenous (IV) irinotecan (15 mg/m2) and on day 22 of gefitinib, patients receive the same dose of the IV formulation of irinotecan orally in Cran-Grape juice. Serial plasma samples were collected on day 21 and day 22, and concentrations of irinotecan, SN-38 and SN-38 glucuronide lactone were measured using a validated HPLC assay. Pharmacokinetic analysis was performed using non-linear mixed effects modeling (NONMEM). Included in the analysis were IV and oral pharmacokinetic data from 4 patients receiving the combination of irinotecan and gefitinib, along with IV and oral data from 31 children receiving irinotecan alone at doses of 15–75 mg/m2 in a previously reported Phase I study (POCPT). Results: The bioavailability of irinotecan lactone increased significantly (p<0.001) from a population average (range) of 8% (1–34%) without gefitinib (n=31) to 56% (25–72%) with gefitinib (n=4). Furthermore, the SN-38 AUC following an oral irinotecan dose of 15 mg/m2 in patients receiving gefitinib was significantly higher [median (range) AUC 83.9 ng*h/mL (64.8–189.4 ng*h/mL) vs 4.0 ng*h/mL (3.9–20.3 ng*h/mL), p<0.05] when compared to those of 3 patients on POCPT receiving the same oral irinotecan dose. Conclusion: These data suggest that gefitinib increases the bioavailability of irinotecan, resulting in an increased systemic exposure to SN-38, the active metabolite. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; NIH; Amer Lebanese Syrian Associated Charities
Trends in paediatric asthma hospitalisations – differences between neighbouring countries
Authors: Juho E Kivistö, Jennifer L P Protudjer, Jussi Karjalainen, Anna Bergström, Matti Korppi
Journal: Thorax (2017)

Paediatric asthma hospitalisation trends in Finland and Sweden over the past 10 years are unclear. We investigated the incidence of paediatric asthma hospitalisations in both countries from 2005 to 2014, using Finland's National Hospital Discharge Register and Sweden's National Patient Register which cover all hospitalisations in the respective countries. During the study period, the incidence of paediatric asthma hospitalisations decreased by 51% in Finland, but remained stable in Sweden. In both countries, asthma hospitalisations decreased over time among children aged 0–4 years, with unclear trends for older ages. The reasons for these intercountry differences are unclear, thus warranting future research.
WNT inhibitory factor-1 (WIF-1): A new role in carcinogenesis?
Authors: Tan Wei Chow, Ming Thong Ong, Shaharum Shamsuddin
Journal: Journal of Clinical Oncology (2014)

11124 Background: Carcinogenesis is an orchestrated expression and depression of oncogenes and tumor suppressor genes at cellular level. The early involvement of epidermal growth factor receptor (EGFR) and wingless and integration site growth factor (WNT) signaling pathways in cell development has attracted much interest among researchers and clinicians. Aberrant activity in both signaling pathways may contribute to cancer formation. By tackling the potential key players in the study of cancer cell signaling pathways, alternative cancer treatment could be promoted in current cancer context. WIF-1 is a physiological inhibitor for WNT signaling pathway used to prevent carcinogenesis resulted from the activation of WNT signaling pathway. The structure of WIF domain is known to have a binding site that interacts with WNT molecules while the function(s) of its EGF-like domain is still unknown. Methods: To study the potential involvement of WIF-1 in EGFR signaling pathway, in silico protein-protein docking between WIF-1 and EGFR was carried out. Co-immunoprecipitation and western blot were designed to study the in vitro binding of EGFR/WIF1 and the potential resulting activation of EGFR downstream signaling pathways. Results: In vitro and in silico experimental results suggested that WIF-1 might play additional role in EGFR signaling pathway via its EGF-like domain. The binding energy of WIF-1/EGFR (-616.40 kcal/mol) was comparative to that of EGF/EGFR binding (-627.18 kcal/mol). Further results indicated that WIF-1 was bound to, and hence was co-immunoprecipitated with, EGFR. Downstream key factors in EGFR signaling pathway were found to be activated following the binding of WIF-1 to EGFR. In addition, the results obtained showed a prominent activation of downstream WNT signaling pathway via crosstalk from WIF-1 activated EGFR signaling pathway. Conclusions: As EGFR signaling pathway plays a crucial role in carcinogenesis, and the possibility to activate WNT signaling pathway via crosstalk between the WIF-1 activated EGFR signaling pathway and downstream of WNT signaling pathway, the use of WIF-1 in the treatment of cancer probably need to be reviewed for the safety of patients undergoing the treatment and prevent undesired outcomes from happening.
Methotrexate and cetuximab for metastatic advanced head and neck squamous cell carcinoma: A retrospective study.
Authors: Bassel Atassi, Khaled Alsibai, George H. Yoo, Ho-Sheng Lin, Gregory Dyson, Harold Kim, John Robert Jacobs, Omer Kucuk, Ammar Sukari
Journal: Journal of Clinical Oncology (2012)

e16019 Background: After the failure of first line palliative chemotherapy in recurrent non-resectable or metastatic head and neck squamous-cell carcinoma (HNSCC), there is no standard of care treatment that improves survival or quality of life. Both, methotrexate and cetuximab have single agent activity in metastatic HNSCC. We are presenting our institutional experience in using unique combination chemotherapy with methotrexate plus cetuximab (MC). Methods: Retrospectively, single institution’s charts were reviewed from 2004-2010, all patients have documented recurrent non-resectable or metastatic HNSCC. Patients received weekly IV methotrexate 25 mg/m 2 plus IV cetuximab 250 mg/m 2 . Each cycle is 4 weeks treatments. Patients who completed at least 2 cycles were included. Patients can receive MC as first line if they have poor performance status. Treatment was continued until progression. Results: Total of 39 patients were included, 27 male and 12 female. Median patients’ age was 57 years old. 35 patients received methotrexate plus cetuximab (MC) after failure of prior line of palliative chemotherapy. 17, 10 and 8 patients received MC as second, third and fourth line therapy, respectively. 4 patients received MC as 1st line because they were not candidate for more aggressive therapy. The average received number of weekly treatments was 31 (8-95) and average number of cycles was 7 (2-23). Prior chemotherapy regimens include taxanes, platinum, 5-flurouracil, and gemcitabin. 13 patients received prior cetuximab as single agent or in combination. Median progression free survival was 7.1 months and overall survival was 9.8 months. Considering the line of therapy, the median survival was 6.9, 10.1, 13.5 and 9.9 months for patients received MC as 1st, 2nd , 3rd and 4th line of therapy respectively (P= 0.356). Grade 1 and 2 skin rash and hypomagnesimia were observed in 47% and 36% of patients. Conclusions: Methotrexate plus cetuximab is a well tolerated regimen with a significant survival benefit. Prospective well designed studies are warranted in order to evaluate this regimen as a second line palliative therapy for patients with advanced non-curable head and neck squamous cell carcinoma.
Novel functional assessment techniques for geriatric lymphoma patients
Authors: A. B. Siegel, J. M. Fiore, J. C. Ketas, R. R. Furman, C. P. Sison, M. L. Ashe, L. M. Mathews, M. Lachs, M. Coleman, J. P. Leonard
Journal: Journal of Clinical Oncology (2004)

8166 Background: Age over 60 and impaired “performance status” (PS) are adverse prognostic features in the International Prognostic Index (IPI) for lymphoma. However, patients over 60 comprise a heterogeneous population, and commonly used PS measures in oncology are subjective and incomplete. More discriminative tools may provide prognostic information that identify subgroups of older lymphoma patients with differing abilities to tolerate disease and treatment. Methods: Geriatricians have validated several tests which predict mortality and functional decline. We evaluated the performance of NHL outpatients aged 60 or older on 4 of these assessments. The timed “up and go” (UG) measures the time (seconds) needed to stand, walk 3 meters, and sit down. The “functional reach” (FR) measures the distance one can reach forward with a fixed base of support. The Tinetti scale (TGB) measures aspects of gait and balance. The hand grip (HG) measures grip strength with a hand-held meter. The primary objective of this pilot study is to establish the range of scores on these examinations in this patient population. Secondary objectives include correlation of scores with survival, treatment tolerance, and quality of life. Results: The mean age of subjects (N=25) was 70, 13 male (M) and 12 female (F). Five were newly-diagnosed, with 15 having aggressive, and 10 having indolent lymphoma. Twenty had an ECOG PS=1, 2 had PS=0, and 3 had PS=3. Within the largest (PS=1) group, the 4 tests each provided further discriminatory ability to differentiate among subjects. The IRQ/Median (higher values reflect greater variance) was 73.1 for HG, 42.3 for UG, 1.8 for TGB, and 16.8 for FR). M and F differed significantly in both the hand grip (M >F) and TGB (F>M). The HG and UG tests showed the most variability, even when stratified by sex. Conclusions: All of the tests demonstrated a range of scores within the ECOG PS=1 measure, and could be completed in about 5 minutes. Given the potential utility of these measures to discriminate among patients, we plan to prospectively study a larger cohort of older lymphoma patients to determine the ability of these assessments to predict survival, tolerability of therapy, and quality of life. No significant financial relationships to disclose.
Contact investigation after a fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an aircraft, Germany, July 2013
Authors: Maria an der Heiden, Barbara Hauer, Lena Fiebig, Gisela Glaser-Paschke, Markus Stemmler, Claudia Simon, Sabine Rüsch-Gerdes, Andreas Gilsdorf, Walter Haas
Journal: Eurosurveillance (2017)

In July 2013, a passenger died of infectious extensively drug-resistant tuberculosis (XDR-TB) on board of an aircraft after a 3-hour flight from Turkey to Germany. Initial information indicated the patient had moved about the aircraft coughing blood. We thus aimed to contact and inform all persons exposed within the aircraft and to test them for newly acquired TB infection. Two-stage testing within 8 weeks from exposure and at least 8 weeks after exposure was suggested, using either interferon gamma release assays (IGRAs) or tuberculin skin test (TST). The TST cut-off was defined at a diameter > 10 mm; for differentiation between conversion and boosting, conversion was defined as increase of skin induration > 5 mm. Overall, 155 passengers and seven crew members were included in the investigation: the questionnaire response rate was 83%; 112 (69%) persons were tested at least once for TB infection. In one passenger, who sat next to the area where the patient died, a test conversion was registered. As of March 2017, no secondary active TB cases have been reported. We describe an unusual situation in which we applied contact tracing beyond existing European guidelines; we found one latent tuberculosis infection in a passenger, which we consider probably newly acquired.
A phase 2 study of IPI-926, an oral hedgehog inhibitor, in patients with myelofibrosis.
Authors: Koji Sasaki, Jason R. Gotlib, Ruben A. Mesa, Farhad Ravandi, Jorge E. Cortes, Patrick Francis Kelly, Jeffrey Lorne Kutok, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2014)

7111 Background: Aberrant expression of the Hedgehog (Hh) signaling pathway initiates cancer, promotes tumor survival, and is related to the development of desmoplastic tumor stroma. We conducted a phase 2 study of IPI-926, an oral Hh inhibitor, in patients (pts) with myelofibrosis (MF); NCT01371617. Methods: Pts with performance status ≤2, adequate organ function, no active infection, and a life expectancy of at least 3 months, received 160 mg IPI-926 orally daily in continuous 28-day cycles. Response was defined by IWG consensus criteria. Using a Simon 2-Stage method to differentiate a response rate of ≤10% and >30%: ≈12 evaluable pts with MF were to be enrolled; if at least 2 responses occurred, up to 35 pts were to be enrolled. Results: 14 pts were treated for a median of 5.1 months (range, 0.7-7.3). Their age was 71 years (range 55-82), with a median of 5.8 years since diagnosis; 4 had palpable spleen of median 10.5 cm (range 6-23), 6 (43%) were transfusion dependent, 8 (57%) had primary MF, and all had ≥ intermediate-2 MF. While several pts had reduction in spleen size by palpation (<50%), no pt had significant improvement in symptoms. One pt had clinical improvement with transfusion independence for 6 months. Two patients progressed to acute leukemia, and 11 were taken off therapy due to no response and/or side effects. Adverse events of any grade (in >30% of patients) included elevated AST or ALT in 11 pts, nausea in 8, increased conjugated bilirubin in 7 (3 with gr 3 toxicity), decreased appetite in 6 (1 with gr 3 toxicity), and constipation or vomiting in 5 pts each. Correlative studies on samples after >3 months on therapy were analyzed: 2/8 pts had reduction in GLI1 mRNA in bone marrow (BM) aspirate cells; 3/10 pts had reductions in GLI1 protein by immunohistochemistry in BM biopsies by 3 months; 4/10 pts had minimal to modest decreases in fiber-length density in BM biopsies at 3 months. Serum cytokine levels measured at baseline and after 4 weeks of treatment were not qualitatively different. Conclusions: The safety and clinical activity (ORR ≤ 10%) of IPI-926 did not support continued evaluation as a monotherapy in MF. The preliminary biologic activity suggests Hh pathway inhibitors in combination with other novel agents in MF should be considered. Clinical trial information: NCT01371617.
Vascular endothelial growth factor expression in hepatitis C virus (HCV)-related advanced hepatocellular carcinoma (HCC) compared with hepatitis B virus (HBV)-related advanced HCC.
Authors: Yu Yun Shao, Min-Shu Hsieh, Chung-Yi Huang, Yung-Ling Chang, Chih-Hung Hsu, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2013)

4115 Background: HCC with different etiologic factors may result in activation of different signaling pathways. This study aimed to clarify if HBV-related HCC (HBV-HCC) and HCV-related HCC (HCV-HCC) may have difference in the expression of key molecules that are relevant to contemporary molecular targeted therapy. Methods: We enrolled patients diagnosed with advanced HCC from 2001 to 2011 who had tumor tissues obtained upon the diagnosis of advanced HCC at our center. Tumor slides were immunohistochemically stained for phosphorylated extracellular signal-regulated kinases (p-ERK), Raf kinase inhibitory protein (RKIP), and vascular endothelial growth factor (VEGF). The expressions of p-ERK and RKIP were evaluated according to percentages of positive-staining cells and graded as: 0: 0; 1+: 1-10%; 2+: 11-50%; 3+: &gt; 50%. Grades 0 and 1 were considered negative, and grades 2 and 3 positive. VEGF staining was evaluated as strong or weak according to staining intensity. The staining results of VEGF were further recorded as H scores, defined as intensity (0, 1, 2, or 3) × percentages of positive staining. Results: In total, 131 patients were enrolled in this study; 94 (72%) patients had HBV-HCC, and 37 (28%) patients had HCV-HCC. HBV-HCC and HCV-HCC had similar expression of p-ERK (positive: 45% vs. 51%, p = 0.491) and RKIP (positive: 83% vs. 84%, p = 0.912). HCV-HCC was more likely to have strong VEGF staining than HBV-HCC (95% vs. 72%, p = 0.005) and higher H scores for VEGF staining (289.5 vs. 248.8, p&lt; 0.001). In multivariate analysis adjusting for age, sex, macrovascular invasion, extrahepatic metastasis, and α-fetoprotein level, HCV-HCC remained an independent factor associated with strong VEGF staining. VEGF staining intensity was not associated with age, sex, macrovascular invasion, extrahepatic metastasis, and α-fetoprotein level. Conclusions: HCV-HCC has stronger VEGF expression than HBV-HCC. (This study was supported by the grant of NSC101-2314-B-002-141, 100CAP1020-2, and NTUH.101-N1965.)
Influence of comorbidity and ECOG on efficacy and safety in irinotecan-refractory elderly patients (&gt;65 years) with metastatic colorectal cancer (mCRC) treated with cetuximab plus irinotecan.
Authors: Christian Jehn, L. Böning, Hendrik Kröning, Kurt Possinger, Antonio Pezzutto, Diana Lueftner
Journal: Journal of Clinical Oncology (2012)

e14140 Background: In clinical practice elderly patients (pts) with comorbidities may not be treated appropriately based on perceptions about their life expectancy and ability to tolerate potential side effects of chemotherapy. We investigated the influence of comorbidity, ECOG status and age on the efficacy and safety profile of cetuximab and irinotecan in irinotecan pretreated mCRC patients aged &lt; 65 and &gt; 65 years. Methods: 497 irinotecan-pretreated pts with mCRC were entered in the database of this noninterventional study. Comorbid conditions were recorded and scored according to the Charlson Comorbidity Index (CCI). Descriptive statistics, χ²-or Fishers exact test and multivariate analysis were applied. Results: A total of 247 and 250 pts aged &lt; 65 (median:59) and &gt; 65 (median:70) years, respectively, were documented. 79% of the pts showed a reduced ECOG status of 1–2, with no difference the age groups (p=0.65). Grade III/IV toxicities occurred in 18 % of pts without any difference between age groups although older pts had more comorbidities, with a higher CCI (p=0.002). The duration of any grade of skin reaction was in pts age &lt; 65 significant longer (42 d), than in patients aged &gt; 65 (31 d); (p=0.04). However, there was a trend towards higher grade (≥2) skin toxicity in pts aged &gt; 65. A total of 71% of the pts developed skin rash, which was strongly related to response (P=0.006). Age, line of therapy, ECOG, gender, CCI had no influence on response in multiple regression analysis. The objective response rates were similar for both groups: 38.1% for age &lt; 65 vs. 36.4% for age &gt; 65 (p=0.57). Progression-free survival (PFS) did not differ between pts 18–65 years old (6.0 months) in comparison with pts &gt;65 years (6.1 months) (p=0.99; log-rank test). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,499; 95% Cl, 0.34–0.72; p=0.002), but not CCI, age or gender. Conclusions: Only ECOG had a negative influence on PFS. There were no significant differences in response rate and safety profile for patients aged &lt; 65 and &gt; 65 years when treated with cetuximab and irinotecan. Comorbidities had no influence on efficacy or toxicity.
Update on the phase II trial and correlative studies of depsipeptide in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma
Authors: R. Piekarz, R. Frye, M. Turner, J. Wright, J. Leonard, S. Allen, S. Bates
Journal: Journal of Clinical Oncology (2004)

3028 Background: Depsipeptide, FK228 (Fujisawa Pharmaceuticals), is the first of a new generation of histone deacetylase inhibitors to demonstrate consistent clinical activity in a specific tumor type. As a result, we are currently conducting a multi-institutional phase II trial in patients with CTCL, PTCL, or other mature T cell lymphomas. Methods: This trial is accruing patients into 4 separate arms based on histology and prior therapy. Depsipeptide is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle. Results: Thirty-nine patients have been enrolled. In Arm 1, comprised of patients with CTCL who had not previously received more than 2 cytotoxic chemotherapy regimens, objective responses were observed in 7 of 14 patients, including 3 patients with complete response and 4 patients with partial response, for a response rate of 50%. Duration of response ranged from 6 to continuing over 34 months. Of the 17 patients with PTCL enrolled, 4 (24%) achieved a PR lasting 9 and 12 months in 2 patients, and ongoing over 4 months in 2 patients. Overall the drug is well tolerated, with observed toxicities including nausea, vomiting, fatigue, neutropenia, thrombocytopenia, and hypocalcemia. Non-specific ST-T wave changes are noted by ECG, without changes in cardiac function. Six patients, all with objective responses, have received depsipeptide for 12 to 34 months without evidence of cumulative toxicity. Molecular endpoints have been studied in patient normal and malignant cells. Increased acetylation of histone H3 has been observed in patient samples obtained 4 hr after initiation of the depsipeptide infusion. Inductions ranging from 2 to 24-fold were observed in 19 out of 24 paired samples obtained from individual patients, with 13 patients demonstrating a greater than 4-fold induction. Changes in gene expression have also been noted. Conclusions: These results suggest that histone deacetylase inhibitors such as depsipeptide are active in patients with T cell lymphoma. All 4 arms remain open to accrual at the NCI and extramural sites. Molecular effects can be assayed in patients treated with HDIs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fujisawa Pharmaceutical Company