tbuckley/cabot-search huggingface dataset:
First-line therapy with bortezomib (formerly PS-341) in patients with multiple myeloma (MM)
Authors: S. Jagannath, B. Durie, J. Wolf, E. Camacho, D. Irwin, J. Lutzky, M. McKinley, E. Gabayan, J. Crowley, D. P. Schenkein
Journal: Journal of Clinical Oncology (2004)

6551 Background: Preclinical evidence has suggested that the proteasome is an effective therapeutic target in MM. Clinical trials have since demonstrated the durable efficacy and safety of bortezomib (Velcade), a potent reversible proteasome inhibitor, recently approved for the treatment of pts with refractory and relapsed MM. Preliminary results of an ongoing phase 2 trial of bortezomib administered to pts with newly diagnosed MM are reported here. Methods: Pts received bortezomib 1.3 mg/m2 2x/wk x2 q3 wk for a maximum of 6 cycles. Dexamethasone 40 mg the day of and after each bortezomib dose was allowed after 2 cycles for pts with < PR, and after 4 cycles for pts with < CR. Response criteria were based on modified EBMT criteria, with the addition of a near CR category (disappearance of all M protein by electrophoresis, but positive immunofixation, with normal bone marrow). Stem cells could be harvested at the discretion of the physician. Neurologic tests are being performed before and after bortezomib. Results: Nineteen pts (47% males, median age 63 yrs) have been accrued. Pts presented with IgG (58%), IgA (32%), or light chain (10%) disease, with a median KPS of 90 (50 - 100). The majority of pts were Durie-Salmon Stage III (55%). As of November 2003, 12 pts have completed 6 cycles and were evaluable for response: there were 4 (33%) near CR, 5 (42%) PR, 1 (8%) MR, and 2 (17%) PD. One pt has undergone stem cell transplant with complete hematologic recovery. The most common adverse events (grades 1 –3) were fatigue (67%), diarrhea (58%), constipation (42%), nausea (42%), peripheral neuropathy (33%), and vomiting (33%). One episode of each of the following grade 3 events occurred: abdominal pain, diarrhea, dizziness, dyspnea, fever, neuropathic pain, neutropenia, syncope, and vomiting. One pt required dose modification. No grade 4 toxicity was observed. Conclusions: In this study, bortezomib appeared to be promising as initial therapy in patients with newly diagnosed MM and had manageable toxicities. Major responses (near CR and PR) were seen in 75% of the patients by 6 cycles. Study accrual is ongoing, and the full complement of 42 pts is expected to be recruited quickly. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc.
Phase I and Pharmacologic Study of PN401 and Fluorouracil in Patients With Advanced Solid Malignancies
Authors: Manuel Hidalgo, Miguel A. Villalona-Calero, S. Gail Eckhardt, Ronald L. Drengler, Gladys Rodriguez, Lisa A. Hammond, Sami G. Diab, Geoffrey Weiss, Allison M. Garner, Elizabeth Campbell, Karen Davidson, Arthur Louie, James D. O’Neil, Reid von Borstel, Daniel D. Von Hoff, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To assess the feasibility of administering PN401, an oral uridine prodrug, as a rescue agent for the toxic effects of fluorouracil (5-FU), and to determine the maximum-tolerated dose of 5-FU when given with PN401, with an 8-hour treatment interval between these agents. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of 5-FU, given as a rapid intravenous infusion weekly for 3 consecutive weeks every 4 weeks. PN401 was administered orally 8 hours after 5-FU administration, to achieve sustained plasma uridine concentrations of at least 50 μmol/L. Initially, patients received 6 g of PN401 orally every 8 hours for eight doses (schedule 1). When dose-limiting toxicity (DLT) was consistently noted, patients then received 6 g of PN401 every 2 hours for three doses and every 6 hours thereafter for 15 doses (schedule 2). RESULTS: Twenty-three patients received 50 courses of 5-FU and PN401. Among patients on schedule 1, DLT (grade 4 neutropenia complicated by fever and diarrhea) occurred in those receiving 5-FU 1,250 mg/m 2 /wk. Among patients on schedule 2, 5-FU 1,250 mg/m 2 /wk was well tolerated, but grade 4, protracted (&gt; 5 days) neutropenia was consistently noted in those treated with higher doses of the drugs. Nonhematologic effects were uncommon and rarely severe. The pharmacokinetics of 5-FU, assessed in 12 patients on schedule 2, were nonlinear, with the mean area under the time-versus-concentration curve (AUC) increasing from 298 ± 44 to 962 ± 23 μmol/L and mean clearance decreasing from 34 ± 4 to 15.6 ± 0.38 L/h/m 2 as the dose of 5-FU was increased from 1,250 to 1,950 mg/m 2 /wk. 5-FU AUCs achieved with 5-FU 1,250 mg/m 2 /wk for 6 weeks along with the intensified PN401 dose schedule were approximately five-fold higher than those achieved with 5-FU alone. Plasma uridine concentrations increased with each of the three PN401 doses given every 2 hours, and uridine steady-state concentrations were greater than 50 μmol/L. CONCLUSION: Treatment with oral PN401 beginning 8 hours after 5-FU administration is well tolerated and results in sustained plasma uridine concentrations above therapeutic-relevant levels. The recommended 5-FU dosage for phase II evaluations is 1,250 mg/m 2 /wk for 3 weeks every 4 weeks with the intensified PN401 dose schedule (schedule 2). At this dose, systemic exposure to 5-FU as measured by AUC was five-fold higher than that observed after administration of a conventional 5-FU bolus.
PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts
Authors: Mogher Khamaisi, Sayaka Katagiri, Hillary Keenan, Kyoungmin Park, Yasutaka Maeda, Qian Li, Weier Qi, Thomas Thomou, Danielle Eschuk, Ana Tellechea, Aris Veves, Chenyu Huang, Dennis Paul Orgill, Amy Wagers, George L. King
Journal: Journal of Clinical Investigation (2016)

Abnormal fibroblast function underlies poor wound healing in patients with diabetes; however, the mechanisms that impair wound healing are poorly defined. Here, we evaluated fibroblasts from individuals who had type 1 diabetes (T1D) for 50 years or more (Medalists, n = 26) and from age-matched controls (n = 7). Compared with those from controls, Medalist fibroblasts demonstrated a reduced migration response to insulin, lower VEGF expression, and less phosphorylated AKT (p-AKT), but not p-ERK, activation. Medalist fibroblasts were also functionally less effective at wound closure in nude mice. Activation of the δ isoform of protein kinase C (PKCδ) was increased in postmortem fibroblasts from Medalists, fibroblasts from living T1D subjects, biopsies of active wounds of living T1D subjects, and granulation tissues from mice with streptozotocin-induced diabetes. Diabetes-induced PKCD mRNA expression was related to a 2-fold increase in the mRNA half-life. Pharmacologic inhibition and siRNA-mediated knockdown of PKCδ or expression of a dominant-negative isoform restored insulin signaling of p-AKT and VEGF expression in vitro and improved wound healing in vivo. Additionally, increasing PKCδ expression in control fibroblasts produced the same abnormalities as those seen in Medalist fibroblasts. Our results indicate that persistent PKCδ elevation in fibroblasts from diabetic patients inhibits insulin signaling and function to impair wound healing and suggest PKCδ inhibition as a potential therapy to improve wound healing in diabetic patients.
Accounting for Missing Data in Clinical Research
Authors: John R. Stevens, Anvar Suyundikov, Martha L. Slattery
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Gene expression profiling of BRCA1-mutant human breast cancer cells after exposure to tamoxifen plus estrogen
Authors: C. D. Murphy, A. B. Olshen, S. Chuai, A. Viale, S.-W. Kim, P. I. Borgen, C. Hudis, J. Boyd
Journal: Journal of Clinical Oncology (2004)

9620 Background: Tamoxifen has been shown to reduce the risk of estrogen receptor (ER)-positive breast cancer in high-risk patients, including BRCA mutation carriers. However, as tumors in BRCA mutation carriers are largely ER-negative, tamoxifen efficacy in this high-risk population remains controversial. Toward that end, we hypothesized that acute tamoxifen exposure may induce similar changes in the gene expression profiles of ER-negative, BRCA1-mutant cells and ER-positive, BRCA1 wild-type cells, which may account for a chemoprotective effect of tamoxifen in both these populations. Methods: ER-positive (MCF7, T-47D, ZR-75–1), ER-negative (MDA-MB-436, SK-BR-3), and BRCA1-mutant, ER-negative (HCC1937) human breast cancer cells were cultured in steroid hormone-free media for 5 days followed by treatment with 10 nM 17-beta estradiol plus 100 nM 5-hydroxytamoxifen or vehicle alone for 8 hours. Total RNA from each cell line was isolated and subjected to gene expression profiling using the Affymetrix U133A Gene Chip oligonucleotide array. Results: The impact of tamoxifen plus estrogen exposure on gene expression was estimated, on a gene by gene basis, by taking the difference between the expression of treated cells and the average expression of the untreated cells. For each gene, confidence intervals (CI) were determined for the mean difference in expression between HCC1937 and ER-positive cells and HCC1937 and ER-negative cells. Genes were identified for which the CI included zero for ER-positive cells and for which the CIs did not overlap. 334 genes were identified which followed this pattern. Over-represented groups of genes included those involved in tumor suppression such as MAPK9 and FAF1 and cell cycle arrest genes including CDKN1B and TSG101. Conclusions: We have identified genes for which the influence of tamoxifen plus estrogen in BRCA1-mutant, ER-negative cells is more similar to its influence in wild-type BRCA1, ER-positive cells than wild-type BRCA1, ER-negative cells. Investigation of these genes may present insight into the molecular mechanism through which tamoxifen may prevent breast cancer in BRCA1 mutation carriers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Assessment of tissue velocity imaging of both ventricules in vasoreactive patients
Authors: Ekaterina Kobal, M. Saidova, N. Danilov, O. Arkhipova, T. Martynyuk, I. Chazova
Journal: European Respiratory Journal (2012)

The purpose: To estimate dynamics of right and left ventricular systolic and diastolic function by estimation Sa, Ea of the lateral tricuspid and mitral valve annulus during acute pharmacological testing (APhT)with inhaled nitric oxide (iNO)in patients with idiopathic pulmonary arterial hypertension (IPAH).Materials and methods:In the study we included 11 pts (11 females)with IPAH aged 31-51 (mean age 39,8± 7,4years). All pts were performed right heart catheterization (RHC)with APhT and noninvasive vasodilator testing with iNO (20ppm for 10min)before two hours to RHC. The estimation of SPAP was performed initially at rest and then at 10min of nitric oxide Inhalation. All pts were responders. Echo included routing parameters and TVI was used for the estimation of systolic and diastolic function of RV/LV before and after APhT. Results: In pts with IPAH (functional class II-III, WHO)the mean value of tricuspid regurgitation (TR) gradient was 64,8±11,5mmHg. In all pts included in the study the degree of TR was at least III. Taking into account right atrial pressure levels mean SPAP was 75±11,6mmHg by Transthoracic Doppler Echocardiography(TDEcho.)before APhT. Mean SPAP was 47,5±6,2mmHg. by echo after APhT. According to RHC data mean SPAP was 76,8±16,6mmHg. before test and 46,6±7,9mmHg after iNO. We found no significant dynamic of routine echo parameters.To 10'of iNO there was significant improvement Sa,Ea of RV during APhT with iNO. There was improvement Sa,Ea of LV but not significant. Conclusion: TDEcho. may be used for an accurate assessment of vasodilator response as compared to RHC data. During APht with iNO only Sa, Ea of RV may be used for detecting vasoreactive patients.
Prognostic impact of cancer-testis antigen expression in primary cutaneous melanoma
Authors: J. S. Cebon, S. Svobodova, J. Browning, I. D. Davis, R. Scolyer, R. Murali, J. F. Thompson, S. Deb, A. Azad, D. MacGregor
Journal: Journal of Clinical Oncology (2009)

9004 Background: Cancer-testis antigens (CTAg) are epigenetically regulated molecules expressed in many cancers including melanoma. Although functional studies are limited, they are often immunogenic making them attractive targets for immunotherapy. In normal tissues expression is restricted to germ cells and a small range of other tissues such as trophoblast. Previous studies have shown that CTAg expression increases with disease progression. We investigated whether the expression of three CTAgs, against which vaccines have been developed, may have prognostic significance in early stage melanoma. Methods: 233 AJCC Stage II melanomas were analyzed for expression of MAGE-A1, MAGE-A4 and NY-ESO-1 by immunohistochemistry. The relationship between CTAg expression, clinico-pathological features and relapse free survival (RFS) from initial diagnosis were correlated. Mutivariate analysis using known prognostic factors and CT Ag expression in the model were used to calculate hazard ratios. Results: All three CTAg were significantly co-expressed with each other (P=0.0001). RFS was reduced if tumors expressed any of these CTAgs (CTAg+ve). Median RFS for patients with CTAg+ve tumors was 45m versus 72m for those with CTAg-ve tumors (P=0.008, logrank test). Univariate analysis demonstrated that the impact of CTAg expression on RFS was comparable in magnitude to ulceration, Breslow thickness and mitotic rate, currently accepted prognostic factors. Multivariate analysis demonstrated CTAg expression, ulceration and thickness but not mitotic rate were independently associated with poorer RFS ( Table ). Conclusions: CTAg expression in cutaneous primary melanoma has impact on prognosis comparable to Breslow thickness ulceration and mitotic rate. Further study into their function and the impact of clinical targeting is warranted. [Table: see text] No significant financial relationships to disclose.
A phase II study of orzel (UFT+leucovorin) in elderly (≥75 years old) patients with colorectal cancer: Results of ECOG 1299
Authors: E. C. Popa, W. Luo, H. Hochster, B. Lyman, M. Mulcahy, P. Beatty, A. B. Benson
Journal: Journal of Clinical Oncology (2005)

3608 Background: UFT, an oral fluoropyrimidine consisting of Tegafur plus uracil (1:4 molar ratio), constitutes a readily absorbed combination agent inhibiting DPD and is reliably converted to 5FU. LV has been added to each dose in order to potentiate 5FU activity (Orzel). Phase III trials in metastatic colorectal cancer showed activity comparable to intravenous 5-FU/LV with reduced gastrointestinal and dermatologic toxicity (tox). In this study we evaluate the response rate (RR) and tox profile in the elderly defined as those ≥ 75 years of age. Methods: Elderly pts ≥75 years, with measurable disease, PS≤2 and no prior chemotherapy for metastatic disease were enrolled. Adjuvant therapy if completed ≥ 6 months prior was permitted. Treatment was administered as UFT 100 mg/m2 plus leucovorin 30 mg q8 hours for 28 days with 7 days of rest. CT scans were performed every two cycles. Results: 58 pts were enrolled between June 2000 and July 2001. Twenty-seven (46%) were women; median age was 81 (range 75–89) yrs, with PS 0 =14, 1=31, 2=13. Median number of cycles given was 4. 57 pts are evaluable for tox with Grade 3–4 tox as follows: gastrointestinal 20 (34%), neutropenia 4 (7%), no hand-foot syndrome. There was only one grade 4 diarrhea reported. Six (10%) required dose reductions for GI toxicity. There were 2 fatalities with GI bleed and CVA. RR is as follows: CR: 2 (3.5%), PR: 9 (15.5%), SD: 20 (34%), PD: 13 (23%) and 14 (24%) not evaluable (7 withdrew, 3 deaths, 1 tox, 1 no rx, 2 no data available). Median time to progression was 19 weeks and overall survival 11.8 months. Conclusions: UFT +LV is well tolerated in the elderly with an incidence of grade 3–4 toxicity similar to phase III reports in younger patients. Activity in this study was comparable to intravenous 5FU/LV. This oral fluoropyrimidine is well tolerated and very active in elderly patients. It is an excellent alternative to intravenous 5FU/LV. Supported by NIH grants CA23318, 66636, 21115, 11083, 17145, 21076, 16087. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Culturally appropriate surrogates for vulnerable patients perspectives of participation in randomized clinical trials
Authors: H. M. Linden, A. Hart, J. C. Jackson, L. Reisch, C. Nakano, M. Harrington, J. G. Elmore
Journal: Journal of Clinical Oncology (2004)

869 Background: Low health literacy may preclude adequate consent for clinical trial participation in vulnerable populations. Understanding the patient perspective is essential to understand low participation rates, and the conditions under which researchers have a duty to exclude particular patients. A qualitative study was conducted to explore willingness and comprehension of randomized clinical trial participation in African American and immigrant communities. Methods: Twelve focus groups of 7–11 individuals (N=111) were recruited from African American churches (6 groups), and professional association for Medical Interpreters (MIs) (6 groups, including Asian, African, Russian/Ukranian, and Spanish languages) to serve as proxy voices for patients. Focus groups involved a 2-hour audio-taped discussion co-facilitated by two moderators, wherein a detailed breast cancer randomized clinical trial was discussed. Results: Several themes describe vulnerable patients' willingness to participate in research studies, and understanding of randomized clinical trial participation. African American church-going women were enthusiastic about breast cancer research, but were reluctant to be personally randomized, and expressed mistrust for research. MIs noted that some immigrant patients struggled to understand the indications for screening and treatment . As such MIs expressed strong concern that it is inappropriate to further burden such patients with education regarding the option to participate in clinical trials. Conclusions: Interest and enthusiasm for clinical trials is strong in a selected population of African American women, yet some immigrants may not understand the cultural context of a clinical trial, meriting possible exemption from consideration for participation. Medical clinics and researchers providing breast cancer screening and treatment options to women can benefit greatly by enhanced cultural awareness and sensitivity to the cultural context of vulnerable populations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Avon Foundation
Checklist can help avoid CT chest scans in a third of blunt trauma cases
Authors: Susan Mayor
Journal: BMJ (2015)

Using a simple checklist can help to avoid computed tomography (CT) scans of the chest in a third of people admitted to emergency departments with blunt trauma without increasing the risk of missing major injury, a US study has shown.

The study, published in PLOS Medicine ,1 investigated more than 11 000 patients aged 15 or over who were treated at eight major US trauma centres. The patients all had blunt trauma injuries generally resulting from road accidents and falls, which account for most trauma cases seen in hospital emergency departments.

The researchers used data collected on 6002 patients in the first part of their study …
CALGB 9761: A prospective analysis of IHC and PCR based detection of occult metastatic disease in stage I NSCLC
Authors: M. A. Maddaus, X. Wang, R. T. Vollmer, N. Z. Abraham, J. D’Cunha, D. L. Herzan, A. Patterson, L. J. Kohman, M. R. Green, R. A. Kratzke
Journal: Journal of Clinical Oncology (2006)

7030 Background: CALGB 9761 was a prospective trial of tumor and lymph node collection during planned surgical resection in patients with clinical stage I NSCLC. The primary objective was to determine if occult micrometastases (OM) detected by immunohistochemistry (IHC) or real time PCR of CEA in histologically negative lymph nodes is associated with poorer survival. Methods: 502 patients with clinical stage I NSCLC were accrued. 302 (60%) were eligible for analysis. 200 were ineligible due to postoperative stage change or change in diagnosis. At surgical resection samples of primary tumor and N2 and N1 lymph nodes were harvested. Lymph nodes were split in half, one half was sent for standard surgical pathologic analysis and the other half snap frozen and sent for IHC analysis using a polyclonal anticytokeratin antibody cocktail. Results: Of 302 eligible patients, 173 were T1N0 and 129 T2N0 by routine postoperative pathology. The median follow-up time for eligible patients is 5.25 years. Overall survival at 5 years is 63.22%. Median survival is not yet estimable. 14% of patients had IHC positive tissue in lymph nodes, a rate lower than expected compared to published single institution studies. Overall survival for this group at 5 years is 55.96% compared to 65.65% for the IHC negative group (p=0.38). The failure free survival at 5 years is 41.74% for the IHC positive group and 60.25% for the IHC negative group (p=0.16). RT-PCR data is currently being analyzed. Data on the first 50 patients analyzed demonstrated presence of CEA in nodal tissues and potential upstaging in approximately 50% of the patients. Conclusions: In a multi-institutional setting, IHC detection of OM by use of a polyclonal cytokeratin cocktail in stage I NSCLC has limited capacity to detect OM and poorly predicts recurrence and survival. No significant financial relationships to disclose.