tbuckley/cabot-search huggingface dataset:
Capecitabine plus irinotecan (CAPIRI) as first-line treatment for patients (pts) with metastatic colorectal cancer (MCRC)
Authors: A. Laudani, B. Agostara, G. Savio, V. Leonardi, L. Salvagno, V. Palmisano, A. Usset
Journal: Journal of Clinical Oncology (2006)

13573 Background: Twice-daily oral capecitabine mimics 5-FU infusion and has superior efficacy, improved safety and convenience compared with 5-FU/LV in MCRC and early-stage colon cancer. Preclinical and phase I/II clinical data suggest supra-additive efficacy of X + irinotecan and no significant pharmacokinetic interactions. We evaluated the efficacy and safety of X plus weekly irinotecan (CAPIRI) in 3-week cycles as first-line treatment for MCRC. Methods: Pts with no prior treatment for MCRC received irinotecan 80 mg/m 2 i.v. infusion on d1&amp;8 + capecitabine 1000 mg/m 2 orally bid d1–14, q3w. Results: Baseline characteristics of the 39 enrolled pts (22 men/17 women) were: median age 59.9 years (range 38–76), ECOG PS 0–1, colon cancer (n=25), rectal cancer (n=14), metastatic sites (liver 74%, pelvis 20%, nodes 23%, lung 18%, peritoneum 10%, primary tumor 20%). Previous treatments were as follows: adjuvant chemotherapy (36%), radiotherapy (5%), neoadjuvant chemotherapy (3%). Pts received a total of 199 cycles (mean 5.1 per pt, range 1–13). All 39 pts were evaluable for safety and 38 for efficacy. The most common treatment-related grade 3/4 adverse events were nausea/vomiting (23% of pts), diarrhea (10%), and leucopenia (5%). The overall response rate was 45%, including 3 complete and 14 partial responses. A further 8 pts (21%) had stable disease. The duration of response in pts with a complete response was &gt;10 months. Conclusions: These early findings indicate that this combination is effective and well tolerated as first-line treatment for MCRC. Replacing 5-FU with capecitabine in XELIRI offers benefits to the pt in terms of efficacy, safety, convenience, reduced discomfort and avoidance of central venous access compared with infusional 5-FU/LV-based regimens (IFL and FOLFIRI). No significant financial relationships to disclose.
Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02)
Authors: H. I. Robins, P. Y. Wen, S. M. Chang, J. Kuhn, K. Lamborn, T. Cloughesy, M. R. Glibert, W. K. Yung, J. Dancey, M. D. Prados
Journal: Journal of Clinical Oncology (2007)

2057 Background: Glioblastomas (GBM) frequently have amplification/mutation of EGFR and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have only modest activity, there is a rationale for combinations of these agents. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor CCI-779 in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, &gt; 18 yrs old, KPS &gt; 60, adequate bone marrow reserve and organ function. Patients (pts) must not be receiving enzyme inducing antiepileptic drugs. The dose of erlotinib was fixed at 150 mg/d. Patients initially received CCI-779 50 mg intravenously once weekly and the dose was adjusted based on toxicities. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade (G) 4 hematologic toxicity except for G3 thrombocytopenia, and any G3 or unacceptable G2 non-hematologic toxicities. Escalation was performed in groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 pts. Results: To date 22 eligible pts have been enrolled (15 GBM; 7 AG). Patient characteristics were 12 male, 10 female; median age: 54 (26–74); median KPS 90 (70–100); median prior chemotherapy regimens 1 (0–3). Two of 3 pts receiving 50 mg of CCI-779 developed DLTs (intolerable G2 rash &amp; mucositis, &amp; G3 liver function abnormalities; G3 rash &amp; dehydration). Three of 6 pts receiving 25 mg of CCI-779 weekly experienced DLTs (G3 rash; G3 rash, diarrhea, dehydration; G3 mucositis &amp; infection). Two of 6 patients receiving weekly 15 mg of CCI-779 experienced G3 rash. The protocol was amended to define a DLT only if &gt; G3 toxicities persisted despite maximal therapy. Six additional pts were treated at 15 mg of CCI-779. One of 6 pts developed a G3 rash. Conclusions: The combination of erlotinib and CCI-779 was associated with a higher than expected incidence of rash and mucositis. The MTD for this combination is likely to be 150 mg/d of erlotinib and 15 mg/d of CCI-779. Final pharmacokinetics and response data will be presented. No significant financial relationships to disclose.
Accountable Health Communities — Addressing Social Needs through Medicare and Medicaid
Authors: Dawn E. Alley, Chisara N. Asomugha, Patrick H. Conway, Darshak M. Sanghavi
Journal: New England Journal of Medicine (2016)

To accelerate the development of a scalable delivery model for addressing upstream determinants of health, the Centers for Medicare and Medicaid Services recently announced a 5-year, $157 million test of a payment model called Accountable Health Communities.
HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis
Authors: Seo-Hyun Choi, Jae-Kyung Nam, Bu-Yeo Kim, Junho Jang, Young-Bae Jin, Hae-June Lee, Seungwoo Park, Young Hoon Ji, Jaeho Cho, Yoon-Jin Lee
Journal: Cancer Research (2016)

The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFβ or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non-small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases.
Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis
Authors: Anass Bouchnita, Nathalie Eymard, Tamara K. Moyo, Mark J. Koury, Vitaly Volpert
Journal: American Journal of Hematology (2016)

Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients.
Sulfation of 4-hydroxytamoxifen is a novel pathway of tamoxifen-induced apoptosis in breast cancer cell lines
Authors: Susan A. Nowell, Goncalo Gamboa de Costa, Yue Wu, Lisa Carter, Jeremy Hemiup, Norman Glenister, Warren Davis
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5323 

For the past thirty years, tamoxifen therapy for estrogen receptor positive breast cancer has been the gold standard of therapy and has been a major factor in increasing overall survival from this disease. The primary mechanism of action of tamoxifen’s effect has been thought to be mediated by binding of the active metabolite, 4-hydroxytamoxifen, to the estrogen receptor, thus blocking estrogen-stimulated cellular proliferation. However, it is known that tamoxifen exerts many effects on tumor cells, including the induction of apoptosis. 4-Hydroxytamoxifen is sulfated to form 4-sulfoxytamoxifen (4-SO4TAM) in a reaction catalyzed by human sulfotransferase 1A1 (SULT 1A1). SULT1A1 is a member of the sulfotransferase superfamily of Phase II detoxification enzymes. The net result of catalysis by SULT1A1 is generally to produce a metabolite that is more polar, and thus, more easily excretable from the organism. A single nucleotide polymorphism in exon 7 of the SULT 1A1 ( SULT 1A1*2 ) gene produces a less thermostable enzyme with approximately two-fold lower activity than that of the common allele SULT 1A1*1 . We have shown previously that the SULT1A1*2 low activity allele is associated with significantly poorer overall survival in woman treated with tamoxifen for breast cancer. Since this finding was converse to what one would expect if sulfation were an elimination step for this active metabolite, we investigated the hypothesis that 4-SO4TAM plays an important role in the anti-carcinogenic mechanism of tamoxifen through a pathway independent of detoxification. We synthesized 4-SO4TAM and compared the potential of TAM, 4-OHTAM and 4-SO4TAM to initiate DNA damage and apoptosis in various breast cancer cell lines. Comet assays revealed that at equimolar concentrations, significantly more DNA damage was evident in ZR75-1 cells exposed to 4-SO4TAM compared to the other compounds. Average olive tail moments (a measure of DNA breakage) were 3.3, 2.5 and 2.3 for 4-SO4TAM, 4-OHTAM and TAM, respectively. Cytoxicity assays showed that 4-SO4TAM had no cytotoxic properties. Subsequent flow cytometry analysis demonstrated the presence of significant numbers of apoptotic cells when ZR75-1 (ER positive) and MDA-MB231 (ER negative) cells were exposed to 4-SO4TAM. This is the first study to show that 4-SO4TAM can cause apoptosis and therefore it may play a significant role in the efficacy of tamoxifen as an anti-carcinogenic treatment.
A randomized phase II trial comparing pulsed erlotinib before or after carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer
Authors: G. J. Riely, C. M. Rudin, M. G. Kris, E. Senturk, C. G. Azzoli, J. Brahmer, M. Fogle, M. Ginsberg, V. A. Miller, N. A. Rizvi
Journal: Journal of Clinical Oncology (2007)

7619 Background: A randomized phase 3 trial failed to show any improvement in response rate (RR) or overall survival (OS) when erlotinib was added to carboplatin and paclitaxel (TRIBUTE). However, preclinical data suggested that administration of erlotinib before or after chemotherapy may improve efficacy of chemotherapy [Gumerlock et al ASCO 2003, Solit et al Clin Can Res 2005]. We designed this trial to test the hypothesis that administration of pulsed erlotinib prior to or following chemotherapy would improve the response rate in patients with advanced NSCLC. Methods: All patients had chemotherapy naive, stage IIIB or IV NSCLC and were former or current smokers. All patients received carboplatin (AUC 6) and paclitaxel (200 mg/m 2 ). Patients were randomly assigned to one of three arms: erlotinib 150 mg days 1,2, and chemotherapy on day 3; erlotinib 1500 mg days 1, 2 and chemotherapy on day 3; or chemotherapy on day 1 and erlotinib 1500 mg on days 2,3. Patients received up to six 21-day cycles of treatment. The primary endpoint was overall RR (CR+PR) using RECIST. We planned to enroll 29 patients to each arm in a “pick the winner” design comparing arms to the chemotherapy alone arm of TRIBUTE (RR 19%) with a desirable RR of 50%. Results: Eighty-seven patients were randomized to 3 arms. Accrual is complete. The most common grade 3/4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3/4 rash or diarrhea were uncommon. Conclusions: Treatment with erlotinib before (150 mg on days 1 and 2 or 1500 mg on days 1 and 2) or after (1500 mg on days 2 and 3) administration of carboplatin and paclitaxel failed to improve response rates compared to TRIBUTE. The benefit of pulsatile administration of erlotinib predicted by preclinical models was not evident in this clinical trial. Supported by Genentech, Inc. [Table: see text] [Table: see text]
Abstract 17558: Age-Dependent Effects of Renal Denervation Therapy on Diastolic Blood Pressure and Pulse Pressure in Office and Home Blood Pressure Monitoring
Authors: Christian Fatum, Klaas Franzen, Kai Mortensen, Michael Reppel, Caroline Gisbertz, Ansgar Leidinger, Frank Himmel, Tobias Graf, Frank Bode, Heribert Schunkert, Joachim Weil
Journal: Circulation (2012)

Background: Percutaneous renal sympathetic denervation (RDN) significantly decreases blood pressure in patients with resistant hypertension. High pulse pressure (PP) has been shown to be related to increased cardiovascular events. In assessing the efficancy of antihypertensive treatment, it may therefore be important to determine changes in PP systolic BP and diastolic BP. However, the long-term effect of RDN on SBP, DBP and PP in young vs. elderly patients has never been studied. Methods: 24 Patients were selected according to the SIMPLICITY criteria (SBP ≥ 160 mmHg and ≥ 150 mmHg in diabetics, treated with three or more antihypertensive drugs). 11 were ≤ 65 years and 13 were above this age. 33% were women, and 29% were diabetic. BP testing was performed via office BP measurements (OMRON™device) and confirmed via home BP monitoring. Patients were advised to measure 3x daily BP at home (hBP) according to ESH guidelines. Out of these measurements the mean hBP was calculated for each week before baseline an...
Number and percentage of pathologically involved lymph nodes (pLN) in patients (pts) with pancreatic adenocarcinoma (PA) predicts for overall survival (OS) in pts treated with postoperative adjuvant chemoradiotherapy (CRT)
Authors: P. Salmon, D. Moghanaki, R. Mick, E. E. Furth, A. Behbehani, A. Morgans, J. Drebin, E. F. Rosato, R. Whittington, B. J. Giantonio
Journal: Journal of Clinical Oncology (2008)

15509 Background: pLN status may predict OS in pts following resection for PA. However, among pts treated with postoperative CRT at our institution, pN0 vs pN1 status as defined by AJCC criteria was not predictive in univariate analysis. We hypothesize the degree of locoregional metastatic pLN burden may better predict outcome to adjuvant CRT following resection. Methods: We identified 92 pts with PA between 1981–2005 who completed adjuvant 5-FU based CRT. Nodal data collected included # of LNs sampled and # positive (pos). Median and 5-yr OS rates were estimated by the Kaplan-Meier method. In previous analysis, resection status was the strongest independent predictor of OS (complete vs. microscopic or gross disease, HR = 1.8 and 6.8, p<0.001). Predictive significance of LN variables were evaluated by univariate and multivariate analysis, adjusting for resection status, with the Cox proportional hazards model. Results: Median and 5-yr OS for all pts was 27.1 months and 27% (SE ± 5%), respectively. Conclusions: Locoregional metastatic burden as measured by percent positive LN and/or absolute # number of positive pLNs are significantly associated with OS following adjuvant CRT. After adjusting for resection status, absolute # pLNs remained significantly associated with OS. These findings support further stratification of resected pts with PA and nodal metastasis in future prospective trials. # pts 5-yr OS ± SE HR 95% CI P P * AJCC N-Stage N0 43 34.9% ± 8.7% 1.0 N1 49 15.4% ± 6.3% 1.5 0.9-2.5 0.09 0.32 Percent pos LN 0% 43 34.9% ± 8.7% 1.0 1-25% 36 22.2% ± 8.3% 1.3 0.7-2.2 >25% 13 0% 2.6 1.3-5.2 0.03 0.14 Number pos LN 0 43 34.9% ± 8.7% 1.0 1-4 43 17.8% ± 7.2% 1.3 0.8-2.3 5+ 6 0% 5.1 2.0-12.7 0.002 0.01 * adjusted for resection status by Cox regression analysis No significant financial relationships to disclose.
Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation given as a 24-hour continuous infusion weekly times four every 5 weeks.
Authors: L L Siu, A M Oza, E A Eisenhauer, P S Firby, J J Thiessen, M Michael, N Wainman, J Manzo, R Feld, R A Goldberg, M J Moore
Journal: Journal of Clinical Oncology (1998)

PURPOSE 9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin (CMP) derivative that inhibits normal topoisomerase I function. Schedule dependency was noted, with the greatest activity seen in the setting of greater than 24 hours exposure to lactone (L) concentrations &gt; or = 10 nmol/L. In this phase I study, 9-AC was given by a continuous intravenous infusion over 24 hours once weekly times four every 5 weeks. PATIENTS AND METHODS Twenty patients, of whom 16 had fluorouracil-refractory colorectal cancer (CRC), entered the study. Dose levels were 0.7 mg/m2 (n = 4), 1.4 mg/m2 (n = 3), 1.9 mg/m2 (n = 6), and 1.65 mg/m2 (n = 7). Detailed pharmacokinetic (PK) measurements of 9-AC L and carboxylate (C) were performed on day 1 of cycles 1 and 2. RESULTS At 1.9 mg/m2, dose-limiting toxicity (DLT) was reached, with three of six patients having grade 4 neutropenia. At 1.65 mg/m2, one of seven patients had grade 4 neutropenia. Nonhematologic toxicity was modest, with diarrhea &gt; or = grade 3 in two patients and lethargy &gt; or = grade 3 in eight. PK/pharmacodynamic (PD) analyses showed marked interpatient variability. Steady-state concentrations (Css) of 9-AC L &gt; or = 10 nmol/L (3.6 microg/L) were seen in five of seven patients at 1.65 mg/m2 and five of six patients at 1.9 mg/m2. Using the sigmoidal maximal effect (Emax) model, 9-AC L area under the concentration-time curve (AUC) and Css correlated with day 15 decrease in neutrophils (R2 = .47), but not platelets. CONCLUSION The recommended phase II dose of 9-AC colloidal dispersion (CD) given as a 24-hour continuous infusion weekly for 4 of every 5 weeks is 1.65 mg/m2.
Two phase I, pharmacokinetic (PK) and pharmacodynamic (PD) studies of TAS-109, a novel nucleoside analogue with 14 days and 7 days continuous infusion (CI) schedules
Authors: K. K. Sankhala, C. H. Takimoto, A. C. Mita, H. Xiong, J. Rodon, R. Adinin, K. Burns, T. Toko, K. Arakawa, S. Kopetz
Journal: Journal of Clinical Oncology (2008)

2577 Background: TAS-109 is a novel deoxycitidine analogue with unique mechanism of action. Brief exposure to high concentrations of TAS-109 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to TAS-109 at low concentration causes DNA fragmentation, G2/M phase arrest and apoptosis. TAS-109 demonstrated activity in tumor xenografts resistant to other deoxycitidine analogs. Methods: Two phase I studies assessed the safety, PK, PD and preliminary efficacy of TAS-109. Patients (pts) with refractory solid tumors received TAS-109 CI 14 days on/7 days off (study-1) and 7 days on/7 days off (study-2). Enrollment required age > 18 yrs, ECOG Performance Status 0–2 and adequate organ function. Tumor response was assessed by RECIST criteria. Plasma was sampled for PK. PD studies utilized the Comet assay for study-2, allowing quantification of DNA strand breaks. Results: 29 pts were dosed in both studies. In study-1 (15 pts), dose limiting toxicities (DLT) consisting of febrile neutropenia (2 pts) and thrombocytopenia (1 pt) occurred at 4.0 mg/m²/day. At 3.0 mg/m²/day, 3 pts experienced neutropenia on day 8 of cycle 2. Therefore 2 mg/m²/day was explored and was well tolerated in 6 pts. In study-2 (14 pts), grade 4 neutropenia was DLT at 4 mg/m²/day. The maximum tolerated dose was 3 mg/m²/day. Other toxicities included nausea (18 pts), emesis (8 pts), diarrhea (10 pts), neutropenia (15 pts), thrombocytopenia (5 pts) and alopecia (10 pts). In study-1, 5 pts had stable disease (SD) for >12 wks; one pt with colon carcinoma had 25% decrease in target lesions and decrease in CEA levels (1153ng/ml to 179ng/ml) after 4 cycles. In study-2, 3 pts had SD for 32, 16 and 14 wks respectively. Paired comet assays performed for 7 pts showed increase in DNA strand breaks at day 8 (p=0.01). PK data for study-1 showed dose-proportionality for steady state concentration and AUC of TAS-109 and its primary metabolite. Conclusions: CI of TAS-109 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2 mg/m²/day and 3 mg/m²/day on the 14-day and 7-day CI schedules respectively. Preliminary activity was suggested. PD data demonstrate biological activity at the tested doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Taiho Taiho
Oral antifungal is associated with increased risk of miscarriage
Authors: Jacqui Wise
Journal: BMJ (2016)

Use of the oral antifungal drug fluconazole during pregnancy was associated with an increased risk of miscarriage in an analysis of 1.4 million pregnancies in Denmark published in JAMA .1

Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are the first line treatment for pregnant women, oral fluconazole is often used in cases of recurrence or severe symptoms or when topical treatment has failed.

The researchers used a nationwide register …