tbuckley/cabot-search huggingface dataset:
Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients.
Authors: W Dahut, N Harold, C Takimoto, C Allegra, A Chen, J M Hamilton, S Arbuck, M Sorensen, F Grollman, H Nakashima, R Lieberman, M Liang, W Corse, J Grem
Journal: Journal of Clinical Oncology (1996)

PURPOSE To conduct a phase I and pharmacologic study of the new topoisomerase I inhibitor, 9-aminocamptothecin (9-AC). PATIENTS AND MATERIALS A 72-hour infusion of 9-AC was administered every 14 days to 48 solid-tumor patients at doses of 5 to 59 microg/m2/h without granulocyte colony-stimulating factor (G-CSF) and 47 to 74 microg/m2/h with G-CSF. RESULTS Without G-CSF, two of eight patients who received 47 microg/m2/h had dose-limiting neutropenia in their initial cycle, as did both patients who received 59 microg/m2/h (with a platelet count &lt; 25,000/microL in one). With G-CSF, zero of seven patients treated with 47 microg/m2/h had dose-limiting neutropenia in their first cycle, while dose-limiting neutropenia occurred in six of 14 patients (with platelet count &lt; 25,000/microL in five) entered at 59 microg/m2/h. Among 39 patients entered at &gt; or = 25 microg/m2/h 9-AC with or without G-CSF, fatigue, diarrhea, and nausea/vomiting of grade 2 severity ultimately occurred in 54%, 30%, and 38%, respectively, while grade 3 toxicities of each type occurred in 8% of patients. Steady-state 9-AC lactone concentration (Css) increased linearly from 0.89 to 10.6 nmol/L, and correlated strongly with leukopenia ( r = .85). CONCLUSION The recommended phase II dose of 9-AC given by 72-hour infusion every 2 weeks is 35 microg/m2/h without G-CSF or 47 microg/m2/h with G-CSF support. Dose escalation in individual patients may be possible according to their tolerance.
European Cooperative Trial in Operable Breast Cancer (ECTO): Improved freedom from progression (FFP) from adding paclitaxel (T) to doxorubicin (A) followed by cyclophosphamide methotrexate and fluorouracil (CMF)
Authors: L. Gianni, J. Baselga, W. Eiermann, V. Guillem Porta, V. Semiglazov, A. Lluch, M. Zambetti, P. Valagussa, G. Bonadonna
Journal: Journal of Clinical Oncology (2005)

513 Background: In the mid 1990's data indicated that paclitaxel had marked antitumor activity in metastatic breast cancer, justifying the attempt at investigating whether the taxane could improve the therapeutic benefit of established regimens in early breast cancer Methods: From 1996 to 2002 a total of 1355 women with operable breast cancer (T>2cm) were randomized to adjuvant A (75 mg/m2 q21d x 4) followed by i.v. CMF (day 1&8 q28d x 4), or adjuvant A (60 mg/m2) and T (200 mg/m2 over 3 hrs q21d x 4) followed by CMF (AT→CMF), or AT→CMF as primary systemic therapy (PST). Results: Main patient characteristics (T-size, ER/PgR status, grade and age) were evenly distributed among arms. After median follow-up of 43 months, freedom from progression (FFP) was significantly better for women receiving adjuvant AT→CMF than A→CMF (HR 0.65, range 0.48–0.90, P=0.01). In a multivariate analysis, treatment inclusive of paclitaxel stood out as significantly associated with FFP (HR 0.66, P=0.012), together with clinical diameter <4 cm, positive PgR and negative nodal status. FFP was not statistically different between patients receiving AT→CMF as adjuvant or PST (HR 0.83, range 0.59–1.16, P=0.27). Total survival from randomization was not different between arms in the present analysis. As already reported (ASCO 2002, abstract 132) 23% of patients undergoing PST obtained eradication of invasive breast cancer (pCR). Women achieving pCR had a relapse-free survival at 43 months from surgery of 89% v. 74% in women who did not reach pCR (P=0.005). Incidence of local recurrence was low for women undergoing primary surgery (4%) or PST (4.1%). At the almost 5 years of follow up of the present analysis symptomatic cardiac toxicity (Common Toxicity Criteria grade 3) was 0.7% for women receiving A→CMF, and 0.4% for those receiving AT→CMF. Conclusions: The introduction of paclitaxel in the sequence of doxorubicin and CMF improved efficacy without increasing cardiac toxicity. No difference between adjuvant or primary systemic administration of AT→CMF was observed so far. Longer follow-up is needed for conclusive considerations on survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Dosing Long-Lasting Recombinant Factor VIII Fc Fusion Protein: Experience In The A-LONG Study
Authors: Amy Shapiro, Margaret V. Ragni, Roshni Kulkarni, Sarah Kulke, James Potts, Srividya Neelakantan, Ivan Nestorov, Jennifer A Dumont, Haiyan Jiang, Aoife Brennan, Glenn F Pierce
Journal: Blood (2013)
Nonrandomized single institutional comparison of radical prostatectomy, external beam radiotherapy, or permanent seed implantation in the management of localized prostate cancer
Authors: P. Kupelian, J. Ciezki, A. Mahadevan, A. Reuther, C. Reddy, E. Klein
Journal: Journal of Clinical Oncology (2004)

4653 Background: We review biochemical relapse-free survival (bRFS) rates after 125I permanent seed implantation (PI), external beam radiotherapy (EBRT), or radical prostatectomy (RP) for clinical stage T1-T3 prostate cancer in a large single center cohort. Methods: The study population was selected from 3074 consecutively treated patients with clinically localized disease treated between 1996–2001. Biochemical failure was defined as a confirmed PSA >0.2 ng/ml after RP and 3 consecutive rising PSA levels (ASTRO consensus definition) after EBRT or PI. RP patients receiving adjuvant radiotherapy and all patients receiving neoadjuvant or adjuvant androgen deprivation were excluded from analysis. To eliminate the time dependency of the ASTRO definition for failure, RP patients with < 24 month follow-up and EBRT and PI patients with <48 months of follow-up were also excluded, leaving 1056 patients in the study cohort. Clinical characteristics of the study population are summarized in the table. Results: The 5-year bRFS rates for PI vs EBRT vs RP were 86%, 81%, and 81%, respectively (p=0.56). Multivariate analysis identified PSA (p<0.001) and biopsy Gleason sum (p<0.001) as independent predictors of relapse, while treatment modality (p=0.42), clinical T stage (p=0.10), age (p=0.56), and race (p=0.11) were not predictors of failure. Conclusions: Even when allowing for longer follow-up times for patients treated with either EBRT or PI to manifest biochemical failure, bRFS rates were similar between PI, EBRT and RP as monotherapy for clinically localized prostate cancer in this contemporary cohort. Outcome in these predominantly low risk patients is determined by pretreatment PSA levels and biopsy Gleason score. No significant financial relationships to disclose.
Kaposi's Sarcoma in Los Angeles, California&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R K Ross, J T Casagrande, R L Dworsky, A Levine, T Mack
Journal: JNCI Journal of the National Cancer Institute (1985)

The demographic characteristics of "classic" Kaposi's sarcoma (KS) and of "epidemic" KS in Los Angeles, CA, were compared with the use of data from the Cancer Surveillance Program, the population-based tumor registry in Los Angeles County. The data obtained document the magnitude of the excess risk of classic KS for Jewish men of European (especially Eastern and Southern European) origin. The data also show in a systematic way the magnitude of the increase in acquired immune deficiency syndrome-related KS in one large urban area of the United States. In addition, they demonstrate that the demographic risk factors of religion and birthplace for classic KS are unrelated to epidemic KS and that the clinical presentation in terms of stage and primary site of classic KS is distinct from that of the epidemic form of the disease.
Results of spoligotyping of M. tuberculosis strains isolated in Belarus
Authors: Aksana Zalutskaya, Maria Wijkander, Alena Skrahina, Sven Hoffner
Journal: European Respiratory Journal (2011)

Introduction:  Multidrug resistant tuberculosis (MDR-TB) is a severe threat to effective TB-control as well as to successful treatment of the individual patients. The reported incidence of MDR-TB in Belarus is somewhat lower than in its neighboring countries, but the level of MDR-TB causes severe obstacles for the national TB program.   Objective:  To characterize MDR-TB and pan-susceptible M tuberculosis clinical isolates from TB patients in Belarus by molecular strain typing.   Methods:  The study totally comprised 163 clinical isolates from patients with pulmonary TB in Belarus, 81 isolates being MDR and 82 being pan-susceptible. The DST at the NRL in Minsk was externally quality assured by the WHO/IUATLD SRL in Stockholm. The molecular characterization of the isolates was carried out in Stockholm by spoligotyping according the protocol described by Kamerbeek et al using a commercial kit (Isogen Bioscience). The octal codes were analyzed using SITVIT2 database.   Results:  For both the MDR- and the susceptible group, most isolates were shown to belong to the Beijing family, seen in 33/81 (41%) and 26/82 (32%) respectively. In second place, in both groups, came the T1 family, identified in 30/81 (37%) and 16/82 (20%) of the cases. A statistical significant association to MDR-TB was demonstrated for the T1 type with the Fisher9s exact test (p-value 0.0151) but not for the Beijing family (p-value 0.2564).   Conclusions:  The result of this study demonstrated differences in the population structure of strains isolated from patients with MDR- and pan-susceptible TB, respectively. The major cause of MDR-TB is an ongoing transmission of resistant M tuberculosis strains, rather than to an independent development of MDR-TB.
KRAS mutational status and sensitivity to a reversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC) patients (pts).
Authors: Giulio Metro, Simona Duranti, Rita Chiari, Chiara Bennati, Carmen Molica, Maria Francesca Currà, Chiara Scafati, Annamaria Siggillino, Antonella Flacco, Luca Marcomigni, Vienna Ludovini, Vincenzo Minotti, Lucio Crinò
Journal: Journal of Clinical Oncology (2012)

e18023 Background: Treatment with a reversible EGFR-TKI may benefit pts with EGFR WT advanced NSCLC, though to a much lesser extent than pts carrying an activating mutation in the EGFR gene. We assessed whether KRAS mutational status would help predict sensitivity to gefitinib or erlotinib in EGFR WT advanced NSCLC pts. Methods: Sixty-seven EGFR WT, advanced NSCLC pts treated with a reversible EGFR-TKI in any line setting were included. Pts were treated from May 2005 to March 2011 at the Medical Oncology of the Perugia Hospital. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results: Median age was 60 years (39-84); 52 pts (77.6%) were PS 0 or 1; 58 pts (86.6%) belonged to the non-squamous subtype and 22 pts (32.8%) were never-smokers. Eighteen pts (26.8%) were KRAS mutant (MUT), of which 14 pts at codon 12 (COD 12 MUT) and 4 pts at codon 13 (COD 13 MUT). Overall, 11 pts (16.4%) responded to treatment and 8 pts (11.9%) achieved stable disease, for a disease control rate of 28.3%. At a median follow-up of 25.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.9 and 29.5 months, respectively. When analyzed according to KRAS status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (N=18) compared with the EGFR WT/KRAS WT population (N=49) (1.6 vs. 3.0 months, respectively, p=0.04). However, no significant difference was observed between the two groups in terms of OS (18.0 vs. 34.8 months, respectively, p=0.42). Within the EGFR WT/KRAS MUT subrgoup a significantly longer PFS was reported for COD 12 MUT pts compared with COD 13 MUT pts (1.7 vs 0.7 months, respectively, p=0.04). Similarly, KRAS COD 12 MUT pts experienced a statistically significant superior OS compared with COD 13 MUT pts (36.2 vs 7.4 months, respectively, p=0.003). Conclusions: EGFR WT/KRAS MUT pts appear to be more resistant to treatment with a reversible EGFR-TKI, the greatest resistance occurring in COD 13 MUT pts. KRAS COD 12 MUT pts may represent a clinically distinct subgroup of KRAS mutants with a particularly favorable prognosis.
Design, Optimization, and Pre-Clinical Evaluation of Direct, Mechanism-Based STAT3 Inhibitors for Treating Myeloid Disorders
Authors: William L. Heaton, Anna M. Eiring, Nadeem A. Vellore, Diana Resetca, Sina Haftchenary, David Rosa, Ahmed M. Ali, Anna V. Senina, Anthony D. Pomicter, Brent D.G. Page, Ira L. Kraft, Kimberly R. Reynolds, Derek J. Wilson, Riccardo Baron, Thomas O'Hare, Patrick T. Gunning, Michael W. Deininger
Journal: Blood (2014)
Vascularization of Premalignant Lesions in Carcinogen-Treated Hamster Cheek Pouch&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J W Ferguson, A C Smillie
Journal: JNCI Journal of the National Cancer Institute (1979)

Of 27 lesions induced in Syrian golden hamsters by 12 applications of 0.5% 7,12-dimethylbenz[a]anthracene in liquid paraffin, 14 showed a static phase of at least 28 days' duration in their life history. Ten static lesions resumed growth, and this was accompanied by clinically obvious vascularization in 8 cases, 7 of which culminated in carcinomas by the end of the study. Because the wall of the normal hamster cheek pouch possesses small nodules whose histologic structure closely resembles that of hyperplastic epithelium, they could be misinterpreted as a product of carcinogenesis.
The Research on Adverse Drug Events and Reports (RADAR) evaluation of the quality of reports to the FDA’s MedWatch system for oncology related adverse drug reactions (ADRs): Extensive improvements are needed
Authors: C. L. Bennett, R. E. Morse, K. R. Carson, S. Belknap, D. Raisch
Journal: Journal of Clinical Oncology (2005)

6028 Background: MedWatch, the Adverse Event Reporting System for the FDA has been the main source of drug safety information since its introduction in 1993. It is especially important for cancer drugs, which have a low therapeutic index. Herein, we evaluated the quality of oncology-associated ADR reports contained in MedWatch and two other data sources. Methods: For new cancer drugs, we evaluated: 1) the completeness of ADR reports from MedWatch, clinical trials, and the published literature, 2) frequency with which ADRs submitted to MedWatch were subsequently retrievable from external queries. Mean frequency of reporting of > 8 ADR-related clinical variables for each ADR such as drug dose & schedule, clinical & laboratory findings, days to ADR onset, and outcomes were calculated. Results: For three oncology-related ADRs, mean completeness scores were best for ADRs described in published case reports (Lit), intermediate for ADRs which occurred in clinical trials (RCT), and poorest for ADRs which occurred outside of the clinical trial setting and were submitted to MedWatch (Table). Several ADR reports which described bisphosphonate-associated osteonecrosis and gemtuzumab-associated veno-occlusive disease were submitted by physicians to the FDA, but were not retrievable when RADAR investigators queried the MedWatch database. Conclusions: ADR reports for cancer drugs contained in the MedWatch database are frequently of poor quality, and in some instances, are not retrievable. Policy-makers should consider establishing an independent pharmaceutical safety monitoring board. Moreover, policy-makers should also consider establishing an on-line source for MedWatch reports, similar to the on-line database established by the FDA for devices. No significant financial relationships to disclose.
British Thoracic Society guidelines for the investigation and management of pulmonary nodules: accredited by NICE
Authors: M E J Callister, D R Baldwin, A R Akram, S Barnard, P Cane, J Draffan, K Franks, F Gleeson, R Graham, P Malhotra, M Prokop, K Rodger, M Subesinghe, D Waller, I Woolhouse
Journal: Thorax (2015)

This guideline is based on a comprehensive review of the literature on pulmonary nodules and expert opinion. Although the management pathway for the majority of nodules detected is straightforward it is sometimes more complex and this is helped by the inclusion of detailed and specific recommendations and the 4 management algorithms below. The Guideline Development Group (GDG) wanted to highlight the new research evidence which has led to significant changes in management recommendations from previously published guidelines. These include the use of two malignancy prediction calculators (section ‘Initial assessment of the probability of malignancy in pulmonary nodules’, algorithm 1) to better characterise risk of malignancy. There are recommendations for a higher nodule size threshold for follow-up (≥5 mm or ≥80 mm3) and a reduction of the follow-up period to 1 year for solid pulmonary nodules; both of these will reduce the number of follow-up CT scans (sections ‘Initial assessment of the probability of malignancy in pulmonary nodules’ and ‘Imaging follow-up’, algorithms 1 and 2). Volumetry is recommended as the preferred measurement method and there are recommendations for the management of nodules with extended volume doubling times (section ‘Imaging follow-up’, algorithm 2). Acknowledging the good prognosis of sub-solid nodules (SSNs), there are recommendations for less aggressive options for their management (section ‘Management of SSNs’, algorithm 3).

The guidelines provide more clarity in the use of further imaging, with ordinal scale reporting for PET-CT recommended to facilitate incorporation into risk models (section ‘Further imaging in management of pulmonary nodules’) and more clarity about the place of biopsy (section ‘Non-imaging tests and non-surgical biopsy’, algorithm 4). There are recommendations for the threshold for treatment without histological confirmation (sections ‘Surgical excision biopsy’ and ‘Non-surgical treatment without pathological confirmation of malignancy’, algorithm 4).

Finally, and possibly most importantly, there are evidence-based recommendations about the information that people …
Phase III trial of irinotecan plus oxaliplatin (IROX) versus irinotecan plus 5-FU/folinic acid (FOLFIRI) as first-line treatment of metastatic colorectal cancer (CRC): The FIRE-Trial
Authors: A. Schalhorn, F. W. Ludwig, D. Quietzsch, P. A. Maubach, G. Schlimok, H. Lambertz, K. Weigang-Koehler, M. Schulze, R. Schlag, M. Grundeis, V. Heinemann
Journal: Journal of Clinical Oncology (2005)

3516 Objective: This randomised cross-over study compares the 1st-line efficacy and toxicity of infusional 5-FU/FA (AIO regimen) plus irinotecan (FOLFIRI) to the combination of irinotecan plus oxaliplatin (IROX). Methods: 488 patients (pts) from 56 centres were enrolled between July 2000 and the end of study in September 2004. In the FOLFIRI arm, pts received FA 500mg/m2 plus 5-FU 2000 mg/m2 (24h) and irinotecan 80mg/m2 given weekly for 6 times. In the IROX arm pts were treated with oxaliplatin 85mg/m2 (d1, 15, 29) and irinotecan 80mg/m2 weekly times 6. Treatment cycles were repeated on day 50 in both treatment arms. Patients were stratified according to LDH, adjuvant pretreatment, and Karnofsky performance status (KPS) showing LDH >240 U/ml in 42% vs 39%, adjuvant pretreatment in 31% vs 29%, and a KPS=100% in 48% vs 47%, in the FOLFIRI- and IROX-arm respectively. The primary end-point of the trial was progression-free survival. At disease progression, pts were offered to switch to the comparator regimen. Results: At the time of analysis, treatment efficacy was evaluable in 299 pts (157 FOLFIRI, 142 IROX). The complete remission rate (CR) was 8% in both arms, the partial remission rate (PR) 38% vs 42% for an overall remission rate (CR+PR) of 46% vs 50%. Stable disease (SD) was documented in 47% vs 33% resulting in a disease control rate (CR+PR+SD) of 92% vs 83%. In the FOLFIRI- and the IROX-arm respectively, median progression-free survival was 8.7 months (95% CI, 7.3–9,6) vs 7.3 months (95% CI, 6.4–8.2) (p=0.15), while median overall survival was 21.1 months (95% CI, 18.8–27.2) vs 18.6 months (95% CI, 16.3–22.8) (p=0.23). Treatment was stopped due to toxicity in 8.5% vs 16.5%, and 60-day mortality was 5.5% and 3.4% (FOLFIRI vs IROX). Conclusions: FOLFIRI and IROX are comparably effective with regard to response, progression-free survival, and overall survival. Toxicity is similarly acceptable in both treatment arms. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharma Germany
A Molecular Analysis of the Shared Epitope Hypothesis: Binding of Arthritogenic Peptides to DRB1*04 Alleles
Authors: Kirsten M. Anderson, Christina L. Roark, Mary Portas, Michael T. Aubrey, Edward F. Rosloniec, Brian M. Freed
Journal: Arthritis & Rheumatology (2016)

The shared epitope hypothesis posits that amino acids QR/KRAA in positions 70-74 of the DRΒ1 chain are responsible for rheumatoid arthritis susceptibility. However, even DRB1*04 alleles containing the shared epitope vary greatly with respect to degrees of susceptibility. This study was undertaken to conduct a molecular examination of the shared epitope hypothesis by measuring binding of arthritogenic peptides to susceptibility and resistance alleles.We measured binding of native and citrullinated forms of vimentin(66-78) and α-enolase(11-25) and noncitrullinated type II collagen(258-272) to 88 class II alleles on Luminex beads (which includes alleles of many varying degrees of susceptibility and resistance). We expressed DRΒ1*04:01, *04:02, and *08:01 in T2 cells and mutated DRΒ1*04:01 at positions 67, 70, 71, 74, and 86 to corresponding residues in DRB1*04:02, *04:03, *04:04, *04:05, and *08:01. Finally, we measured responses of 4 DRΒ1*04:01 restricted collagen(258-272) T cell hybridomas against wild-type DRΒ1*04:01, *04:02, and all mutated alleles.The most susceptible allele, DRΒ1*04:01, preferentially bound citrullinated vimentin(66-78) and citrullinated α-enolase(11-25) over the native forms. DRΒ1*04:02 exhibited no preference for citrullinated peptides, and *08:01 preferred native peptides. Similarly, DRB1*04:01 bound collagen(258-272) , but *04:02 and *08:01 did not. Mutating DRΒ1*04:01 at positions 70, 71, 74, and 86 to the corresponding residues in DRΒ1*04:02 or *08:01 dramatically reduced the specificity for citrullinated peptides and collagen(258-272) binding.These observations demonstrate that while amino acids at positions 70, 71, and 74 within the shared epitope in DRΒ1 mediate binding and T cell responses of arthritogenic peptides, position 86 outside the shared epitope also plays a critical role.
The dangers of ad hoc protocols.
Authors: G E Hanks
Journal: Journal of Clinical Oncology (1984)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1984.2.10.1177 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 6491700 The dangers of ad hoc protocols. G E HanksxG E HanksSearch for articles by this author https://doi.org/10.1200/JCO.1984.2.10.1177 PDF "The dangers of ad hoc protocols.." Journal of Clinical Oncology, 2(10), pp. 1177–1178© 1984 by American Society of Clinical Oncology