tbuckley/cabot-search huggingface dataset:
Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.
Authors: J Weber, J C Yang, S L Topalian, D R Parkinson, D S Schwartzentruber, S E Ettinghausen, H Gunn, A Mixon, H Kim, D Cole
Journal: Journal of Clinical Oncology (1993)

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.
Does post-treatment surveillance imaging improve outcomes in patients with locally advanced rectal cancer?
Authors: Michael Wahl, Daphne A. Haas-Kogan, Moshiur Mekhail Anwar, Alan P. Venook
Journal: Journal of Clinical Oncology (2015)

548 Background: The optimal post-treatment surveillance strategy for pts with rectal cancer is undefined. Trials examining surveillance with serial CEA measurements and/or imaging for colorectal cancer have yielded conflicting results, and no prospective trials have been done specific to rectal cancer pts. In the absence of data, reputable guidelines advocate serial chest, abdomen and pelvic imaging, CEA and colonoscopy after definitive treatment of rectal cancer. The rationale is to identify recurrence before it is symptomatic: if local, to avoid morbidity and if distant, because of the possibility of curative therapy. However, frequent imaging raises concerns regarding radiation exposure, consequences from false-positive findings, and cost. Methods: We performed a retrospective cohort study of patients with stage II/III rectal cancer treated definitively with neoadjuvant chemoradiation followed by surgical resection over the past 10 years. CEA, imaging studies and colonoscopies were recorded for all pts with follow-up of at least 6 months, along with clinical endpoints of locoregional recurrence, development of distant metastases, nature of subsequent therapies, and survival. Results: 55 pts with complete follow-up data were identified (median follow-up, 3.2 years). Surveillance was performed with imaging, CEA and colonoscopy in 89%, 72% and 49% of pts, respectively. 6 local recurrences were identified (11%): two were diagnosed via surveillance imaging, 3 underwent surgery with curative intent, with one patient with no evidence of disease at last follow-up. In contrast, 13 pts (24%) developed distant metastases (6 liver, 5 lung, 2 diffuse metastases), of which 9 were detected on surveillance imaging, 7 underwent therapy with curative intent, and 6 had no evidence of disease at last follow-up. There were 8 false-positive imaging results, 2 of which resulted in unnecessary surgery. Conclusions: Our findings suggest that post-treatment surveillance imaging is useful for detecting oligometastatic disease amenable to curative therapy, but may be less so for locoregional recurrences. Prospective data is needed to further assess the utility of post-treatment imaging in this population.
Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control
Authors: Ayaka Ando, David Smallwood, Marcus McMahon, Louis Irving, Stuart B Mazzone, Michael J Farrell
Journal: Thorax (2016)

Chronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in patients with cough is an enhanced sensitivity of the respiratory system to stimuli that subsequently evoke excessive coughing. The aetiology of this 'cough hypersensitivity syndrome' is unclear but believed to involve hypersensitivity of the sensory neural pathways that innervate the airways and lungs.In the present study, we used functional brain imaging to compare central neural responses to airway stimulation using inhaled capsaicin in healthy people and patients with cough hypersensitivity.Hypersensitivity in response to inhaled capsaicin coincided with elevated neural activity in the midbrain in a region encompassing the nucleus cuneiformis (left: p<0.001; right: p<0.001) and periaqueductal gray (p=0.008) in comparison to normal sensitivity in controls. The enhanced activity noted in the midbrain is similar to that occurring in patients with chronic pain, thus providing empirical evidence to support the notion that cough and pain share neurobiological similarities. Furthermore, patients with cough hypersensitivity displayed difficulty controlling their cough, which manifested as a failure to suppress cough during capsaicin challenge (ie, reduced cough frequency) in controls compared with patients with cough hypersensitivity (p=0.046). Cough suppression was associated with reduced activity in a forebrain network that included the dorsomedial prefrontal and anterior mid-cingulate cortices. Additionally, cough frequency was correlated with activity in the right inferior frontal gyrus (R(2)=0.6, p<0.001) and right anterior insula (R(2)=0.6, p<0.001), regions previously implicated in voluntary cough suppression.These findings provide insight into the central neurobiology of cough hypersensitivity and suggest that both central amplification of cough sensory inputs and reduced capacity to suppress cough motor behaviours define patients with problematic cough.
Influence of Hormones on &lt;italic&gt;N&lt;/italic&gt;-2-Fluorenyldiacetamide-Induced Hyperplastic Hepatic Nodules in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Melvin D. Reuber
Journal: JNCI Journal of the National Cancer Institute (1969)

Inbred A × C male rats 12 weeks old were given 0.025% N-2-Ruorenyldiacetamide in their diet for 4-week periods alternately with 1 week on the basal diet until the carcinogen was administered for 16 weeks. In a group of rats killed after 23 weeks, almost all had developed hyperplastic hepatic nodules. The hormonal status was altered in other groups of animals after 23 weeks to determine if the progression of the nodules to carcinomas was influenced. Intact control animals without changes in hormones developed carcinomas of the liver when killed at the end of 48 weeks. The lesions in adrenalectomized rats or those adrenalectomized and given either cortisone or deoxycorticosterone did not differ from the control animals. The incidence of carcinomas and metastases was decreased by hypophysectomy, adrenalectomy plus castration, castration, or thyroidectomy at 23 weeks. By contrast, the number of carcinomas per liver and the number of undifferentiated (as compared with differentiated) carcinomas were increased in castrated rats given testosterone or diethylstilbestrol. The changes in the progression of hyperplastic nodules to carcinomas, except for castrated rats given diethylstilbestrol or adrenalectomized rats given deoxycorticosterone, were similar to those observed previously in animals in which the hormones were altered simultaneously with administration of the carcinogen. It is concluded that this progression depends on hormones of the host, particularly testosterone.
Physician-Assisted Death for Patients With Mental Disorders—Reasons for Concern
Authors: Paul S. Appelbaum
Journal: JAMA Psychiatry (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 Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Psychiatry journal
Survival Analysis of Unresectable Gastric Cancer Patients Judged Resectable by Initial Ct
Authors: Yosuke Kumekawa, Keisho Chin, Izuma Nakayama, Takeru Wakatsuki, Mariko Ogura, Masato Ozaka, Mitsukuni Suenaga, Eiji Shinozaki, Nobuyuki Mizunuma
Journal: Annals of Oncology (2014)
In vitro evaluation of the PARP inhibitor ABT-888 in combination with temozolomide for the treatment of pediatric leukemia
Authors: T. M. Horton, L. Zhang, G. N. Jenkins, S. L. Berg, S. M. Blaney
Journal: Journal of Clinical Oncology (2007)

9528 Background: The alkylating agent temozolomide exerts its primary cytotoxic activity through the addition to O 6 methyl adducts to guanine residues in DNA, and temozolomide resistance results either from increased expression of methyl-guanine DNA methyltransferase (MGMT), which removes O 6 adducts, or from mutations in the mismatch repair system (MRS), which lead to microsatellite instability (MSI). Temozolomide also creates N 3 and N 7 methyl adducts that are efficiently removed by the base excision repair (BER) system. PARP inhibitors block BER and may potentiate the cytotoxic effects of temozolomide. Methods: The cytotoxicity of temozolomide in combination with the PARP inhibitor ABT-888 was evaluated in vitro in leukemia cell lines and primary leukemia cells using the MTT assay. PARP activity was measured using a commercially available PARP assay. Results: ABT-888 effectively enhanced temozolomide cytotoxicity in cell lines with elevated MGMT (Jurkat and HSB2 T-cell ALL cell lines) or MRS deficiencies (Jurkat and Molt-4 T cell ALL). The temozolomide IC 50 decreased from 450 μM to 35 μM at an ABT-888 concentration of 5 μM in the Jurkat T-cell ALL cell line and from 340 μM to 7.5 μM in the HSB2 T-cell line. ABT-888 also enhanced temozolomide cytotoxicity in non-T-cell leukemia subtypes, decreasing the IC 50 in the JM1 pre-B ALL cell line from 51 μM to 7.7 μM and decreasing the IC 50 from 316 μM to 22 μM in tumor cells obtained from a patient with pre-B ALL. PARP activity was also examined. In contrast, the sensitivity of U937 AML cells to temozolomide showed no effect of the addition of a PARP inhibitor. These results are consistent with the findings that these cells have low or undetectable MGMT and no MSI to suggest MRS mutations. Conclusion: These results suggest that ABT-888 may enhance the cytotoxic activity of temozolomide in leukemia patients whose tumors are resistant to temozolomide because of elevated MGMT expression and mismatch repair defects. No significant financial relationships to disclose.
Access to personalized medicine: Factors influencing the use and value of gene expression profiling in treatment decision making.
Authors: Yvonne Bombard, Linda Rozmovits, Maureen E. Trudeau, Natasha B. Leighl, Ken Deal, Deborah Marshall
Journal: Journal of Clinical Oncology (2013)

10 Background: Genomic information is increasingly used to personalize health care. One example is gene-expression profiling (GEP) tests that estimate recurrence risk to inform chemotherapy decisions in breast cancer treatment. Recently, GEP tests were publicly funded in Ontario. We assessed the clinical utility of GEP tests, exploring the factors facilitating their use and value in treatment decision-making. Methods: As part of a mixed-methods clinical utility study, we conducted interviews with oncologists (n=14), and focus groups and interviews with breast cancer patients (n=28) who underwent GEP, recruited through oncology clinics in Ontario. Data were analyzed using content analysis and constant comparison. Results: Various factors governing access to GEP have given rise to challenges for patients and oncologists. Oncologists are positioned as gatekeepers of GEP, providing access in medically appropriate cases. However, varying perceptions of appropriateness led to perceived inequities in access and negative impacts on the doctor-patient relationship. Media attention facilitated patient awareness of GEP but complicated gatekeeping. Additional administration burden and long waits for results led to increased patient anxiety and delayed treatment. Collectively, these factors inadvertently heightened GEP’s perceived value for patients relative to other prognostic indicators because of barriers to access. Conclusions: This study delineates the factors facilitating and restricting access to GEP, and highlights the roles of the media and organization of services in GEP’s perceived value and utilization. Results identify a need for administrative changes and practice guidelines to support streamlined and standardized utilization of the test.
Long-term safety assessment of a cohort of postmenopausal women treated with anastrozole as adjuvant treatment for hormone-dependent breast cancer: Baseline data
Authors: T. Delozier, J. P. Guastalla, E. C. Antoine, C. Roux, L. Mauriac, A. Fontana, E. Vicaut
Journal: Journal of Clinical Oncology (2008)

632 Background: Clinical studies have shown that anastrozole offers some tolerability advantages over tamoxifen. Fewer gynecologic problems and fewer vascular events were noted, but higher rates of musculo-skeletal adverse events were associated with anastrozole. Methods: A French prospective, multicenter, longitudinal survey is ongoing in postmenopausal women treated for 5 years with anastrozole for hormone-dependent early breast cancer. The aim of this study is to describe long-term tolerability of anastrozole in clinical practice. Safety data are collected at routine consultations, through a self-questionnaire and a yearly phone interview during the five years of adjuvant treatment with anastrozole. Characteristics of the study population at baseline prior treatment with anastrozole are presented below. Results: 1,567 subjects have been recruited (mean age 63.6 ± 8.5 years and mean time since menopause 14.1 ± 9.7 years) by 117 specialists. Lymph node status is N0, N1, N2, N3 for 70.2%, 25.3%, 3.6% and 0.9% respectively. Estrogen and progesterone receptors are positive in 98.9% and 77.4% of subjects. At baseline, hypertension and dyslipidemia were present in 35.3% and 29.3% of subjects. Bone mineral density, performed in 42.6% of subjects, exhibited spine and hip T scores of -0.8 ± 1.5 and -0.8 ± 1.2. Risk factors for osteoporosis were present in 27.6%.of subjects; 6.1% of them presented with known osteoporosis and 7.6% had documented osteopenia; 47.4% presented with musculo-skeletal pathology. Current osteoarticular symptoms were reported by investigators in 46% of subjects (median history of 1 year). Through the self-questionnaire assessment, 67% of subjects reported pre-existing osteoarticular pain before the intake of anastrozole. Conclusions: A high percentage of patients showed osteoarticular symptoms, osteoporosis and cardiovascular risk factors at baseline prior to receiving anastrozole. These data should be taken into account when interpreting the long term tolerability of treatment during the 5-year follow-up. No significant financial relationships to disclose.
Prognostic significance of mutations of nucleophosmin (NPM1) gene and internal tandem duplication of FLT3 gene (FLT3 ITD) in acute myeloid leukemia (AML) with normal karyotype
Authors: S. Brunet, J. Esteve, J. Nomdedéu, J. M. Ribera, A. Llorente, R. Duarte, M. Tormo, R. Guardia, E. Montserrat, J. Sierra
Journal: Journal of Clinical Oncology (2008)

7024 Background: Mutations of NPM1 gene are present in half of patients (pat) with adult AML and normal karyotype and mutated cases have favorable outcome. NPM1 mutations frequently associate to FLT3 ITD, an adverse factor, so it is of interest to perform analyses considering both molecular markers. Methods: We analyzed the impact of NPM1 gene mutations and FLT3 ITD on complete remission (CR) achievement, event free survival (EFS), and overall survival (OS) of AML patients with normal karyotype, included in AML-03 protocol. Between Dec.03-and Ap.07, 130 pat (median age: 50) <70 years-old in the mentioned trial had a normal karyotype. Induction therapy consisted in 1or 2 courses of idarubicin, intermediate ara-C (IDAC) and etoposide plus G-CSF priming. Post-consolidation was risk-adapted: a) one course to CR and no adverse features: autologous stem-cell transplant (autoSCT); b) Two courses to CR, leukocyte count >50x109/L or FLT3 ITD: Allotransplant (alloSCT) if HLA-identical sibling available. Results: NPM1 gene mutations were detected in 61 pat (47%) and FLT3 ITD in 52 (40%). According to molecular status, 3 subgroups were considered: 1) pat with mutated NPM1 (NPM1+) without FLT3 ITD (FLT3 ITD-) (n=34, 26%); 2) pat unmutated NPM1 (NPM1-) and FLT3 ITD- (n=44, 34%) and 3) pat FLT3 ITD+ regardless of NPM1 mutational status (n=52, 40%). Overall, 98 (75%) of the 130 pat achieved a CR, with no differences in NPM1+ and NPM- cases. In contrast, pat of the three molecular subgroups had different CR rates: NPM1+/FLT3 ITD-, 94%; NPM-/FLT3 ITD-, 82%; FLT3 ITD+, 60% (p=0.001). OS at 3 years of pat from the three groups were 60+10%, 60+10% and 20+10% (p=0.001), respectively. Of note, FLT3 ITD- pat who achieved CR after 1 course and received an autoSCT (n=20) had an OS of 86+13% if NMP1+ and 67+16% if NPM1- (p=ns); EFS had a similar pattern. Conclusions: In AML with a normal karyotype, FLT3 ITD+ is the molecular marker with strongest predictive value. In this series, NPM1 mutational status had no significant impact in OS of FLT3 ITD- pat. The analysis of a higher number of pat will be helpful to confirm or not the favorable results observed in the NMP1+/FLT3 ITD- group in terms of CR, and regarding OS and EFS of low risk pat treated with autoSCT. No significant financial relationships to disclose.
Natural History of Body Weight Gain, Survival, and Neoplasia in the F344 Rat
Authors: H A Solleveld, J K Haseman, E E McConnell
Journal: JNCI Journal of the National Cancer Institute (1984)

This study involved the fact that knowledge of the natural incidence of neoplastic lesions is essential for interpretation of experiments designed to reveal the effects of potential carcinogens. Although the F344 rat is widely used in chronic (2-yr) testing programs, the natural history of neoplasia after 24 months is not known; thus this study, with 529 male and 529 female inbred F344 rats, was designed to deal with this aspect. This report also included information on growth and longevity. In addition, the tumor rates found in this study were compared with 2-year historic control tumor rates; results revealed the following. 1) Maximum mean body weights were 468 and 330 g for males and females, respectively. Peak weight in males was reached at 77 weeks of age and in females, at 107 weeks of age. 2) There was no clear sex difference in longevity; a median life-span (50% survival age) or 28 months was recorded in both sexes. 3) Variety of neoplastic lesions in animals that were allowed to live out their life-span was not greater than that in animals that were killed between 110 and 116 weeks of age; thus older age was not characterized by unique neoplasms. 4) The incidence of certain neoplasms increased markedly after 110-116 weeks. The data indicated that life-span studies in F344 rats had no advantages over 2-year studies. However, availability of life-span data is essential for interpretation of the 2-year studies.
Baseline and recurrence levels of soluble HER2 (sHER2) in early-stage HER2-neu positive breast cancer (HER2+BC) from the NCCTG adjuvant Intergroup trial N9831
Authors: A. Moreno-Aspitia, D. W. Hillman, A. C. Dueck, W. P. Carney, W. L. Lingle, K. S. Tenner, J. M. Lafky, M. M. Reinholz, L. A. Kutteh, E. A. Perez
Journal: Journal of Clinical Oncology (2009)

539 Background: An increased baseline sHER-2 concentration is an indicator of poor prognosis in the metastatic and adjuvant settings of HER-2+BC. This study evaluated the levels of sHER-2 during treatment and at time of recurrence in N9831. Methods: Aims were to describe sHER-2 levels during treatment and at time of recurrence in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab). Baseline serum samples of 1506 pts from both arms along with 86 recurrence serum samples were analyzed for sHER-2 (ng/mL). In addition, 556 serial samples were obtained in 148 patients over the treatment period. Median follow up was 4.5 years. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models. Results: Analyzing serial sHER-2 levels during treatment, mean log sHER-2 remained constant in Arm C (estimated slope = 0.004, p = 0.44) while the estimated increase per month was 0.026 (on log e scale) for Arm A (p = 0.0003). Based on the linear model at 18 months, the mean log sHER-2 was 2.98 (95% CI: 2.87–3.09) and 2.55 (95% CI: 2.40–2.70) for Arms A and C, respectively. Among pts with disease recurrence, sHER-2 levels increased in Arm A from baseline to time of recurrence (mean = 72.9, median = 1.7, p =0.005) while sHER-2 levels remained unchanged in Arm C (mean = 9.2, median = -0.9, p = 0.65). While all 86 recurrence patients had baseline sHER2 levels &lt;50, 24% (15/63) of Arm A patients had very high recurrence sHER-2 levels (≥50) as compared to 9% (2/23) on Arm C (p=0.10). Patients with recurrence sHER-2 levels ≥15 had shorter survival time following recurrence with 3 year overall survival of 51% compared to 76% for the &lt;15 sHER-2 group (HR = 2.77; 95% CI: 1.20–6.43, p = 0.02). Conclusions: Based on serial specimens during treatment, the concurrent trastuzumab arm (C) had constant sHER-2 levels, whereas the standard chemotherapy arm (A) had increasing sHER-2 levels. In arm A, recurrence sHER-2 levels increased significantly from baseline while recurrence sHER-2 levels did not change in arm C. Additionally, pts with high sHER-2 levels at recurrence had shorter overall survival following recurrence. Partial support: CA25224, CA114740 , Genentech, Siemens, and the BCRF. [Table: see text]