tbuckley/cabot-search huggingface dataset:
Evaluating high-grade prostatic intraepithelial neoplasia as a predictor of outcome following radical prostatectomy
Authors: P. M. Pierorazio, S. M. Lambert, T. R. McCann, A. E. Katz, C. A. Olsson, M. C. Benson, J. M. McKiernan
Journal: Journal of Clinical Oncology (2006)

4612 Background: The presence of high-grade prostatic intraepithelial neoplasia (HGPIN) has been associated with future development of prostate cancer. High-grade intraepithelial neoplasia in other malignancies is associated with adverse outcome. This study examines the relationship between the presence of HGPIN in prostatectomy specimens, biochemical disease free survival (bDFS) and other cancer specific outcomes following radical retropubic prostatectomy (RRP). Methods: The Columbia University Urologic Oncology Database was reviewed and 2,522 were identified who had undergone radical prostatectomy from 1988 to 2005; 2,133 patients with or without HGPIN were included. Two-sample proportion analysis of means with 95% confidence intervals and ANOVA techniques were used to evaluate the relationship between HGPIN and pathologic stage, Gleason sum, perineural invasion, multifocality, extracapsular extension (ECE), margin status, and nodal status. Kaplan-Meier analysis with log-rank test and a multivariate Cox proportional hazard model controlling for preoperative PSA, Gleason sum and pathologic stage were used to assess differences in bDFS. Results: 1,885 of 2,133 (88.4%) patients demonstrated HGPIN. There was no significant difference in the distribution of pathologic stage or Gleason sum between the patients with and without HGPIN. The HGPIN-positive group had higher rates of perineural invasion (69.9 vs. 57.5%; p = 0.003), multifocality (63.0 vs. 38.4%; p = 0.000) and ECE (56.4% vs. 48.4%; p = 0.059). There was no statistically significant difference observed in nodal status or margin status between the two groups. Patients without HGPIN had an increased bDFS demonstrated by a predicted disease free survival of 73.6% versus 67.0% at 9 years (p = 0.045) with a median follow-up of 50 months. In the multivariate Cox hazard model HGPIN, PSA, Gleason sum and pathologic stage were validated as independent predictors of failure (p &lt; 0.001). The risk of failure was 1.9 × greater in the HGPIN-positive group than the HGPIN-negative group (p=0.006). Conclusions: The presence of HGPIN in the radical prostatectomy specimen denotes a significantly higher rate of tumor multifocality, perineural invasion, ECE, and ultimately biochemical recurrence. No significant financial relationships to disclose.
Identification and Purification of 115- and 125-Kilodalton Cell Surface Human Melanoma-Associated Antigens2
Authors: Joy Heaney-Kieras, Jean-Claude Bystryn
Journal: JNCI Journal of the National Cancer Institute (1986)

Surface macromolecules shed into culture medium by radioiodinated human melanoma cells were fractionated on Sepharose 6B and by sequential lectin-affinity chromatography. Radioactivity associated with melanoma-associated antigens (MAAs) was assayed by indirect immunoprecipitation with anti-melanoma serum. Two MAAs were separated and highly purified. Both antigens were single-chain glycoproteins expressed on many, but not all, melanoma cells but undetectable on normal melanocytes and a variety of unrelated normal, fetal, and malignant cells. One MAA, with a molecular mass of approximately 115 kd, eluted on Sepharose 6B in a lower molecular mass peak and had a high affinity for ricin lectin. The carbohydrate side chain of this antigen contained D-galactose. The other MAA, with a molecular mass of approximately 125 kd, eluted on Sepharose 6B in a peak of higher molecular mass and had a high affinity for wheat germ lectin. The carbohydrate side chain of this antigen contained sialic acid. Both antigens were highly purified. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, no contaminating proteins were present in the purified 115-kd MAA fraction, and only a single minor contaminant was present in the fraction containing the purified 125-kd MAA. These two antigens differed in their biochemical or immunological properties from other MAAs of similar size that have been previously described.
Investigating airway HMGB1 redox state in health and asthma
Authors: Leonarda Di Candia, Emilie Venereau, John R.A. Challiss, Ruth Saunders, Marco E. Bianchi, Christopher E. Brightling
Journal: European Respiratory Journal (2014)

Introduction: High mobility group box-1 (HMGB1) is released by damaged/stressed cells and activated immune cells, and is implicated in inflammatory disorders such as asthma. HMGB1 activity depends on its redox state with fully reduced HMGB1 mediating leukocyte chemotaxis (Venereau E. et al ., JEM 2012; 209:1519-1528). We hypothesised that sputum HMGB1 concentration and the proportion in the reduced form are elevated in asthma.

Methods: Subjects with asthma and healthy controls were recruited to a single centre. Sputum was induced and sputum HMGB1 concentration was measured by ELISA. HMGB1 redox state was assessed by Western blot under non-reducing conditions.

Results: The median (interquartile range) sputum HMGB1 concentration in subjects with moderate-to-severe asthma (GINA treatment steps 3-5, n=34) was significantly increased (429 (576) ng/mL) compared to mild asthma (122 (259) ng/mL) (GINA 1-2, n=8) and normal controls (123 (296) ng/mL, n=18) (p=0.003). Sputum HMGB1 concentration was positively correlated with sputum total cell number (r=0.51, p<0.001). Levels of both HMGB1 redox forms were higher in asthma (n=9) compared with normal controls (n=6) (p<0.05). Reduced HMGB1 relative expression in sputum was significantly higher in moderate-to-severe asthma (37±6% of total HMGB1, mean±SEM, n=16) compared to normal controls (11±7%, n=8) and mild asthma (13±8%, n=7) (p=0.015).

Conclusions: Sputum HMGB1 concentration is elevated in moderate-to-severe asthma and occurs increasingly in the reduced form. Whether this differential expression of HMGB1 between asthma and health has important clinical consequences requires further study.
Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia
Authors: Nicholas J. Short, Hagop M. Kantarjian, Elias J. Jabbour, Susan M. O'Brien, Stefan Faderl, Jan A. Burger, Rebecca Garris, Wei Qiao, Xuelin Huang, Nitin Jain, Marina Konopleva, Tapan M. Kadia, Naval Daver, Gautam Borthakur, Jorge E. Cortes, Farhad Ravandi
Journal: American Journal of Hematology (2016)

In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse-free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30-125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi-parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known.
Sexual Selection of Protamine 1 in Mammals
Authors: Lena Lüke, Maximiliano Tourmente, Eduardo R.S. Roldan
Journal: Molecular Biology and Evolution (2015)

Protamines have a crucial role in male fertility. They are involved in sperm chromatin packaging and influence the shape of the sperm head and, hence, are important for sperm performance. Protamine structure is basic with numerous arginine-rich DNA-binding domains. Postcopulatory sexual selection is thought to play an important role in protamine sequence evolution and expression. Here, we analyze patterns of evolution and sexual selection (in the form of sperm competition) acting on protamine 1 gene sequence in 237 mammalian species. We assessed common patterns as well as differences between the major mammalian subclasses (Eutheria, Metatheria) and clades. We found that a high arginine content in protamine 1 associates with a lower sperm head width, which may have an impact on sperm swimming velocity. Increase in arginine content in protamine 1 across mammals appears to take place in a way consistent with sexual selection. In metatherians, increase in sequence length correlates with sexual selection. Differences in selective pressures on sequences and codon sites were observed between mammalian clades. Our study revealed a complex evolutionary pattern of protamine 1, with different selective constraints, and effects of sexual selection, between mammalian groups. In contrast, the effect of arginine content on head shape, and the possible involvement of sperm competition, was identified across all mammals.
Phase I and pharmacokinetics (PK) study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors
Authors: K. P. Papadopoulos, Q. Chu, A. Patnaik, M. M. Mita, J. Cooper, R. Van Maanen, L. Lopez-Lazaro, C. Lebedinsky, E. K. Rowinsky, A. W. Tolcher
Journal: Journal of Clinical Oncology (2006)

2029 Background: Trabectedin (ET-743) is a DNA minor-groove intercalating agent that blocks transcription factor activity, elicits G2/M cell cycle arrest, and induces apoptosis. Single agent activity has been demonstrated in soft tissue sarcoma (STS), breast, prostate and ovarian cancer. In preclinical studies sequential exposure of paclitaxel (P) followed by trabectedin (T) 24 hrs later resulted in synergy. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RD) of sequential P and T administered every 2 weeks in patients with advanced solid tumors. Methods: Escalating doses of P (80–120 mg/m 2 ) over 1hr iv on day 1 and T ( 525–775 μg/m 2 ) as 3 hrs iv day 2 every 2 weeks were administered. To evaluate drug:drug interactions, P was administered alone on day -7 in course 1 and PK studies performed courses 1 &amp; 2. MTD was defined as ≥ 2/3 pts with dose limiting toxicity (DLT) in the 1 st 2 courses. Results: 29 pts were enrolled and 27 were evaluable: median age was 48 yrs (19–82). M/F 16/13. Pts were treated over 5 dose levels: I 80/525 (n = 3), II 80/580 (n = 3), III 120/580 (n = 6), IV 120/650 (n = 11), V 120/775 (n = 4). A total of 213 courses of therapy were given, median number of course was 4 (range 1–28). There were 4 DLTs due to neutropenia delaying therapy &gt; 1 week; one each at 120/580 (Grade 2) and 120/650 (Grade 4) and 2 at the MTD of 120/775 (Grade 4). Most common toxicities observed for P+T were neutropenia (24%), nausea (51%), vomiting (24%), transaminitis (23%), myalgia (24%) and alopecia (20%). One pt with PNET has an ongoing CR 16 months, one breast cancer pt (prior P failure) has PR 12 mo+ and 8 pts (6 STS) had SD &gt; 3 mo (range 4–15 mo). There appear to be no marked drug:drug interactions for P and T. Preliminary non-compartmental PK results [geometric mean (CV%)] for T include t 1/2 52.4 hr (43.6%); Cl l/hr/m 2 31.6 (57.3%); V ss l/m 2 1382 (69%) and for P are t 1/2 , 29.2 hr (39.1%); Cl l/hr/m 2 15.3 (44.1%); V ss 213 l/m 2 (72%). Conclusions: The recommended dose for this combination is paclitaxel 120 mg/m 2 day 1 and trabectedin 650 μg/m 2 day 2 administered every 2 weeks. Antitumor activity in STS and breast cancer, predictable PK parameters, and tolerable toxicity warrants further study of this combination. [Table: see text]
A Risk Score Integrating BAALC, ERG and WT1 Expression Can Be Used To Improve Risk Stratification In Acute Promyelocytic Leukemia
Authors: Anna Hecht, Florian Nolte, Daniel Nowak, Verena Nowak, Benjamin Hanfstein, Thomas Büchner, Karsten Spiekermann, Wolf-Karsten Hofmann, Eva Lengfelder
Journal: Blood (2013)
A phase II study of oral phenoxodiol in castrate and noncastrate prostate cancer patients with associated cytokine changes.
Authors: G. Gibney, A. Elfiky, S. Bussom, C. J. Hoimes, A. Burns, J. A. McDonough, E. Rowen, Y. C. Cheng, W. K. Kelly
Journal: Journal of Clinical Oncology (2010)

4661 Background: Phenoxodiol is a synthetic isoflavone compound with broad anti-tumor activity that inhibits in vitro prostate cancer (PC) growth and in a prior phase II study has demonstrated the potential for treatment efficacy in advanced hormone refractory disease. This study assessed phenoxodiol treatment in castrate and noncastrate PC patients and assessed the levels of 14 cytokines prior to and during therapy to correlate with clinical outcomes. Methods: Patients with progressive PC that were 1) chemotherapy-naïve castrate-resistant (Group A) or 2) noncastrate with rising PSA and without bone metastasis (Group B) were enrolled. Patients received oral phenoxodiol 400mg TID continuously. One cycle was 28 days. The primary endpoint was post-therapy changes in PSA. Partial response (PR) was ≥ 50% PSA decline within 12 weeks. Progression of disease (PD) was a PSA ≥ 25% rise above baseline or nadir. Stable disease (SD) was a PSA level that met neither PR nor PD criteria. Serum cytokine levels were measured with BD CBA flex kits using the BD FACS Array, along with PSA every 4 weeks. Results: 13 patients in Group A and 11 patients in Group B were enrolled. PSA PR occurred in 1 patient in Group A. 10 patients had SD while 12 patients had PD (8 in Group A; 4 in Group B). Preliminary analysis showed baseline cytokine levels for each group were not statistically different. Phenoxodiol did not clearly correlate with changes in cytokine levels. Patients with metastatic bone disease had greater overall interferon-γ inducible protein (IP-10) levels. During treatment, interferon- γ (IFN-γ) increased from baseline levels in patients with PSA PR or SD while monocyte chemotactic protein-1 (MCP-1) levels increased from baseline levels in patients with PSA PD. No consistent changes were observed for other cytokines including IL-8, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). Conclusions: In this small population, phenoxodiol showed modest activity with a third of the patients demonstrating stable disease. Larger studies evaluating the relationship between IFN-γ and MCP-1 levels and disease progression are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Marshall-Edwards
Phase I trial of concurrent paclitaxel (P), carboplatin (C), and external beam chest irradiation with glutamine (G), in patients with locally advanced non-small cell lung cancer
Authors: A. Younas, K. Redmond, J. Howington, B. Kleykamp, A. R. Jazieh
Journal: Journal of Clinical Oncology (2004)

7296 Background: Esophagitis is a common and often the dose limiting toxicity of the combined chemo-radiation therapy in patients with locally advanced lung cancer. Our study aimed to minimize this complication by using G in an attempt to escalate the dose of chemotherapy. Methods: This is a phase I trial of escalating dose of weekly P, (Taxol, Bristol-Myers Squibb, New York, NY) by 10 mg/m2 increments starting at 50 mg/m2, and weekly C, (Paraplatin, Bristol-Myers Squibb, New York, NY) using auc of 2, 2.5, 3 mg/ml/min for seven weeks. G, (Sympt-X, Baxter, Deerfield, IL) was given at a dose of 10 gm. p.o tid for nine weeks. Radiation therapy dose was 6300 cGy in 34 daily fractions. Consolidation therapy consisted of C auc = 6 mg/ml/min, and P, 100 mg weekly times 3 every 28 days for 2 cycles. Results: 10 patients were enrolled, with median age 63 years (59–78), 9 males and 1 female, 7 patients were Caucasian and 3 African Americans. At the dose level of C auc = 2, and P 60 mg/m2, grade three esophagitis and one death due to sepsis were encountered. Therefore, the maximum tolerated dose (MTD) was determined to be C auc = 2 and P 50 mg/m2. Toxicities in the induction phase included grade three hypersensitivity reaction to P (1), grade one esophagitis (5), grade two constipation (2), grade one nausea (1), grade two emesis (2), grade one cough (3), grade two neutropenia (4), and grade two anemia (2). Consolidation treatment was given to four patients; toxicities encountered were grade one nausea (1), grade one emesis (2), grade two neutropenia (1) and grade two anemia (2). No significant thrombocytopenia or renal impairment resulted in induction or consolidation. Conclusion: The MTD of the above regimen is C = auc 2, P 50 mg/m2, and G 10 gm. p.o tid. Addition of G did not facilitate the escalation of the concomitant chemotherapy. Phase II trial of this combination at the recommended doses is in progress. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia.
Authors: A M Carella, I Cunningham, E Lerma, A Dejana, F Benvenuto, M Podestà, L Celesti, F Chimirri, M Abote, F Vassallo, O Figari, C Parodi, M Sessarego, M Valbonesi, P Carlier, E Prencipe, A M Gatti, D van den Berg, R Hoffman, F Frassoni
Journal: Journal of Clinical Oncology (1997)

PURPOSE Mobilization of Philadelphia (Ph) chromosome-negative progenitors is now possible in many Ph1-positive chronic myelogenous leukemia (CML) patients who had received interferon alfa (IFN-alpha) with no cytogenetic response. In this pilot study, we used this approach in patients without prior IFN-alpha therapy to determine if the number and quality of mobilized progenitors would be increased and to evaluate the potential effect of these cells as autografts. PATIENTS AND METHODS Twenty-two untreated patients were mobilized within 12 months of diagnosis. The treatment regimen consisted of the mini-ICE protocol. Beginning on day +8, granulocyte colony-stimulating factor (G-CSF) was used in all patients. Leukophoresis was performed as the patients were recovering from aplasia, when WBC count exceeded 0.8 x 10(9)/L. RESULTS In 14 patients, (63%) the leukophoresis product was entirely Ph1-negative and in four patients the Ph1-positive cell rate was &lt; or = 7%. Significant numbers of long-term culture-initiating cells (LTC-IC) and CD34+ Thy1+Lin- cells were found in most of the Ph1-negative collections that were tested. Twelve patients underwent autografting with their mobilized peripheral-blood progenitor cells (PBPC) (Ph1-negative collections, 10 patients; major cytogenetic response, two patients). All patients engrafted and are alive; six have Ph1-negative marrow 7 to 15 months after autografting. Posttransplant treatment was IFN-alpha combined with interleukin (IL)-2 because of the recent demonstration of synergistic activity in augmenting cytolytic activity. CONCLUSION Intensive chemotherapy given in early chronic phase of CML is well tolerated and results in high numbers of circulating Ph1-negative precursor cells.
Chance acquaintanceship with long-term consequences
Authors: Folke Brinkmann, Helga Heykes-Uden, Claudia Tombois, Olga Kordonouri, Gesine Hansen
Journal: European Respiratory Journal (2014)

Introduction:  Tuberculosis (TB) in childhood has become rare in Germany. About 80% of the infected children have a migration background. Children living in a household with a smear positive adult are at high risk of TB infection (60-80%). Infants suffer more often from rapid progression and disseminated TB disease. Therefore chemoprophylaxis in exposed infants is recommended. Rapid and thorough contract tracing is essential to identify e.g. resistant TB strains.  Case report:  A three month old girl presented with fever and failure to thrive. She was from a family with migration background and was diagnosed with complicated and disseminated pulmonary tuberculosis. Contact tracing in the family and surrounding was performed immediately but yielded no results. Genetic fingerprinting finally identified the baby9s strain as identical to a woman9s who died of pulmonary TB at that time. The girls9 family had lived in the same block of flats for a few weeks. The infected girl9s family did not recall any contact with the deceased women apart from a very brief encounter in the corridor just after the girl was born.  Conclusion:  TB infection in infants can develop even if the contact with the index case is very short. This stresses the importance of chemoprophylaxis with isoniazide in all exposed children under the age of five. Contact tracing is essential to identify the index person and resistance pattern of the TB strain. New molecular methods can improve contact tracing and clarify the chain of infection.
Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial.
Authors: Carlos Fernandez-Martos, Rafael Estevan, Antonia Salud, Carles Pericay, Manuel Gallen, Enrique Sierra, Javier Serra, Miguel Pera, Juan Maurel, Salvadora Delgado, M. José Safont, Jose Vicente Roig, Jorge Aparicio, Jaime Feliu, Damian Garcia, Ruth Vera, Javier Suarez, Vicente Alonso, Marta Martin-Richard, Gina Brown
Journal: Journal of Clinical Oncology (2012)

3586 Background: Retrospective data suggest that RT might not be needed in all patients with stage II/III RC. Modern systemic therapy might have local efficacy similar to chemoradiation (CRT). Methods: A multicenter phase II trial was undertaken to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with T3 middle third rectal adenocarcinoma. Eligible patients (pts) had measurable disease at the baseline and candidate for R0 total mesorectal escision (TME) with intermediate-risk defined by pelvic MR a) T3 with distal border of tumor &gt; 5 cm from the anal verge and below the sacral promontory. b) tumor ≥2 mm from the mesorectal fascia. Pts received 4 cycles of Cap 2000 mg/m2 (d1-14), Ox 130 mg/m2 (d1) and B 7.5 mg/kg (d1) every 3 weeks (last cycle without B). Pts undergo re-staging with MR. One radiologist reviewed all pre- and post-treatment MR scans independently. Pts without progression proceed to TME 4-6 weeks from the last cycle. If progression, pts were to be referred for pre-op cap/RT followed by TME. 1º Endpoint: Tumor Response (RECIST). Design: Simon 2-stage; 28 pts 1st stage and 46 pts 2nd stage. We report data on the planned analysis of pts included for 1st stage. Results: 28 eligible pts (10F/18M) were enrolled from 7/09-5/11. Tumor response, compliance and toxicity details are shown in table below. Two pN2 pts received postop Cap/RT. Conclusions: Neoadjuvant CAPOX-B is active and safe. Early parameters of efficacy are encouraging and seem similar to those observed with CRT. [Table: see text]