tbuckley/cabot-search huggingface dataset:
Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure
Authors: M. C. Mueller, S. Branford, J. Radich, D. W. Kim, G. Martinelli, G. Saglio, T. Hughes, Y. Shou, A. Weitzman, M. Baccarani, A. Hochhaus
Journal: Journal of Clinical Oncology (2007)

7024 Background: Nilotinib (AMN107) is an oral, aminopyrimidine-derivative, selective inhibitor of the BCR-ABL tyrosine kinase with improved potency and specificity compared with imatinib. In preclinical models, activity of nilotinib was also demonstrated in 32/33 imatinib- resistant mutant cell lines. We sought to explore the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations associated with imatinib resistance. Methods: We have investigated peripheral blood samples from 101 chronic phase (CP) and 41 accelerated phase (AP) CML patients (pts) who had been enrolled in a phase II study investigating the efficacy and safety of 400mg nilotinib bid after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. The analysis covered amino acids 207–517 of the BCR-ABL tyrosine kinase domain. Results: Prior to nilotinib, 24 different BCR-ABL mutations involving 20 amino acids were detected affecting 44% CP and 61% AP pts. After 6 mo of therapy, complete hematologic response was achieved in 59%, major cytogenetic response (MCR) in 25% being complete (CCR) in 16% of pts with mutations vs 81%, 51% and 33% of pts without mutations, respectively. Response dynamics were associated with preclinical activity of nilotinib: MCR was reached in 10/18 pts with mutations associated with preclinical IC50 to nilotinib of &lt;100nM, 2/9 pts with IC 50 of 100–1,000 nM, and 0/4 pts with mutation T315I demonstrating virtual resistance to imatinib and nilotinib. In AP pts, hematologic response was achieved in 56% and 31%, MCR in 24% vs 19%, and CCR in 24% vs 13% of pts with or without mutations, respectively. Conclusions: Nilotinib is efficacious in pts with BCR-ABL mutations, except T315I, as well as in patients with BCR-ABL-independent resistance. Time to response may depend on the individual type of the mutation and correlates with the IC 50 to nilotinib. Thus, nilotinib may have an important therapeutic role in imatinib resistance as well as in frontline CML therapy to prevent emergence of resistant clones. [Table: see text]
Application of the International Germ Cell Consensus Classification (IGCCC) to the Nova Scotia population of patients with germ cell tumors (GCT)
Authors: E. Maydanski Murphy, J. Douglas, K. Thompson, L. A. Wood
Journal: Journal of Clinical Oncology (2006)

14625 Background: The IGCCC is the internationally accepted, clinically based, prognostic classification used to aid in the management of GCT. The goal of this study was to determine if the IGCCC is applicable to a population based cohort. Methods: A retrospective chart review of all patients diagnosed with GCT in NS between 1984–2004 was completed, and IGCCC classification (good, intermediate, poor) was assigned to each patient based on the site of the primary lesion, the presence or absence of non-pulmonary visceral metastases and pre-chemotherapy tumor marker values. Kaplan-Meier estimates of five year progression free survival (PFS) and overall survival (OS) were calculated for each IGCCC group, for both non-seminomatous GCT and seminomatous GCT. Results: The distribution, PFS and OS are shown below. Conclusions: The IGCCC seems applicable to a population-based cohort, with similar distribution of categories, as well as clear prognostic ability. This project was funded by a Norah Stephen Oncology Scholars Summer Studentship Grant from Cancer Care Nova Scotia. [Table: see text] [Table: see text]
Summary of treatment-emergent renal events from patients treated with single-agent carfilzomib from four phase II studies in relapsed and/or refractory multiple myeloma.
Authors: R Donald Harvey, Sagar Lonial, Priti Patel, Leanne McCulloch, Ruben Niesvizky, Jonathan L. Kaufman
Journal: Journal of Clinical Oncology (2012)

e18569 Background: Patients (pts) with multiple myeloma (MM) are vulnerable to renal injury and impairment both from their disease and treatment-related adverse events (AEs). Carfilzomib (CFZ) is a selective proteasome inhibitor with proven efficacy in MM. Safety data have been compiled from over 700 pts who have received single-agent CFZ. All were pretreated and included individuals with varying degrees of renal function, including hemodialysis pts. Herein we present an analysis of the incidence and severity of CFZ treatment-emergent renal events from 526 pts in four phase 2 trials. Methods: Pts from the 003-A0, 003-A1, 004, and 005 trials were included in this analysis. In all studies, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m 2 in C1 for all studies escalating to 27 mg/m 2 in C2 per individual protocol, except 005 (15 mg/m 2 in C1, 20 mg/m 2 in C2, and 27 mg/m 2 in C3). Renal AEs—the incidence, frequency, and resolution of episodes of worsening renal function, defined minimally as a doubling of serum creatinine from baseline—and shifts in other laboratory parameters were tabulated and summarized based on NCI CTCAE v.3 criteria. Results: The majority of pts (71%) had renal dysfunction (CrCl &lt;50 mL/min) at baseline. Overall, 87% experienced no significant worsening of renal function during the course of treatment. Transient worsening was reported in 31 pts (6%) with a median duration of 1.4 weeks and a median of 1.0 episode per patient; non-transient worsening was reported in 37 pts (7%) with 8 (2%) of those permanently discontinuing treatment due to a renal dysfunction AE. 38 patients (7.2%) experienced Grade 3/4 acute renal failure, of which 31 were Grade 3. The percentage of patients in 003-A0, 003-A1, and 004 whose creatinine levels shifted to Grade 3 or 4 from any lower grade was &lt;5%. Results from 005 showed no major PK differences in pts with a wide range of renal function. Conclusions: Treatment-emergent renal events resulting in CFZ discontinuation were uncommon. Based on the findings from this cross trial analysis, CFZ dose and schedule need not be adjusted in pts with baseline renal dysfunction, including pts on hemodialysis.
Ablative chemotherapy and stem cell transplant in patients with breast cancer. Thirteen years of follow-up
Authors: U. Bohn, J. Aguiar Morales, D. Aguiar Bujanda, S. Saura, C. A. Rodríguez
Journal: Journal of Clinical Oncology (2008)

11570 Background: High-dose chemotherapy followed by stem cell autotransplant was used in the 1990s to treat patients with high-risk breast cancer. Methods: Retrospective review of the high-risk breast cancer patients on stage II-III who received ablative chemotherapy and stem cell procedure as part of the treatment. A total of 18 patients were treated between November 1994 and February 1998. The median age was 41 years (range 30–50y). AJCC 4th edition (1993–97): Stage II: 8p: 3 pN2 (4–9) and 5 N2>10). Stage IIIA: 4 : 1 (pN4 −9) and 3 (pN>10). Stage IIIB: 6 (LABC: 5 and Inflamatory: 1). Histologic grade: G3: 12 and G2: 6. Eight patients on stage II with conservative surgery (CS) and lymphadenectomy and four on stage IIIA with radical modified mastectomy (RMM) received FE75C day 1/3w/ 6 cycles (5FU: 600 mg/m2; 4Epi: 75 mg/m2 and cyclophosphamide 600 mg/m2), followed by STAMP-V (cyclophosphamide 1.5 gr/m2 days 1–4; carboplatin 200 mg/m2 days 1–4 and thiotepa 125 mg/m2 days 1–4) and reinfusion of stem cell. Six patients on stage IIIB were treated with neoadjuvant chemotherapy with three cycles of FE75C - Surgery - three FE75C cycles, STAMP-5 and stem cell reinfusion. Radiotherapy was given to all patients and tamoxifen 20 mg/daily during 5 years if they were positive receptors. Results: The 18 patients were evaluable for the statistical analysis. There were found 12/18 (66%) recurrences (Stage II-IIIA: 7/12 [58%]; Stage IIIB: 5/6 [83%]) and 10/18 (55.5%) deaths (Stage II-III: 6/12 [50%] and Stage IIIB: 4/6 [66%]). The most common sites of recurrences were SNC + bone: 3; SNC: 3; bone: 2; liver: 1. Once over 13 years, the median disease-free survival (DFS) was 49 months (range 9–155 m. 95%CI: 48–104) and the median overall survival (OS) was 82 months (range 16–155 m. 95%CI: 73–125). The confidence interval is so wide because of the reduced number of patients. The DFS and OS at 5, 10 and 13 years were 44%, 33%, 33% and 72%, 50%, 44%, respectively. No relevant side effects and no toxic death related to the procedures were observed. Conclusions: Thirteen years after beginning treatment, 8 (44.4%) patients are still alive without disease. The most common site of metastases were CNS and bone. No significant financial relationships to disclose.
MMP-mediated regulation of EnaC channel in pleural mesothelium
Authors: Eleni Apostolidou, Foteini Malli, Efrosini Paraskeva, Konstantinos Gourgoulianis, Paschalis-Adam Molyvdas, Chrissi Hatzoglou
Journal: European Respiratory Journal (2011)

Introduction-aim: The epithelial sodium channel (ENaC), which participates in sodium reabsorption across the apical membrane of mesothelial cells, has been recently identified in pleura with molecular techniques. MMP2 and MMP9 are two matrix metalloproteinases (MMPs) that have been found elevated in exudative pleural effusions. The aim of this study was to investigate if MMP2 and MMP9 influence functionally ENaC activity.

Methods: Intact sheets of parietal sheep pleura were obtained and the short-circuit current (Isc) was recorded in Ussing chambers. MMP2 (0.1 ng/ml or 20 ng/ml) or MMP9 (0.1 ng/ml or 20 ng/ml) were added on the apical solution of the pleura. After a 40-min incubation, amiloride (10-4 M) was added to the apical compartment of all experiments in order to calculate the ENaC-mediated current. This current was defined as the difference between the Isc value just before amiloride addition and the Isc value 5 min after amiloride addition. The amiloride-sensitive Isc was compared between control tissues (having received only PBS) and tissues treated with MMP2 or MMP9.

Results: A statistically significant decrease in amiloride-sensitive Isc occurred when 20 ng/ml MMP2 were added to the pleura (p<0.05). When the pleura was incubated with 0,1 ng/ml MMP2 or MMP9, an increase in amiloride-sensitive Isc occurred but this was not statistically significant.

Conclusions: According to the above results, MMP2 regulates ENaC activity by decreasing the sodium current which is produced by ENaC. A same effect for MMP9 was not confirmed. Previous studies have shown a serine-peptidase mediated regulation of ENaC activity. This is the first study that suggests a matrix metalloproteinase-mediated downregulation of ENaC current.
Favorable treatment outcome of children with early stage large B-cell and anaplastic large cell lymphomas
Authors: M. P. Link, M. Devidas, S. B. Murphy, F. G. Behm, R. Hutchison
Journal: Journal of Clinical Oncology (2004)

8500 Background: The non-Hodgkin lymphomas (NHL) of childhood are heterogeneous. Large cell lymphomas (LCL) are relatively rare in children and sub-divided among diffuse large B-cell lymphomas (DLBCL), anaplastic large cell lymphomas (ALCL), peripheral T (PT) and other rare subtypes. Methods: We conducted a trial (POG 9219) for stage I and II NHL which accrued 396 children between 1992 and 1999. One hundred fifty-six (40%) had large cell lymphoma. All patients received nine weeks of chemotherapy including vincristine 1.5mg/m2 weekly for seven doses; doxorubicin 40mg/m2 and cyclophosphamide 750mg/m2 on days 1, 22 and 43; and prednisone 40mg/m2 daily for 28 days during the first 4 weeks and on days 43–47. None received radiotherapy. Results: Material for further study was available from 111 patients with LCL. Forty-six (42%) had DLBCL, 58 (52%) had ALCL, and 7 (6%) had PT. Among children with DLBCL, primary sites included lymph nodes (13), GI tract (8), bone (8), tonsil (8), testis (3), and other (6). Among children with ALCL, primary sites included lymph node (36), skin (11), bone (6), and other (5). Only one patient with DLBCL developed recurrent disease and died. The remaining 45 patients are all event free survivors. At 5 years, the projected event-free survival (EFS) is 98 % (SE 3%), and the overall survival (OS), 98 % (SE 3%). Thirty-five children with ALCL (60%) had T cell markers, and the remainder had null cell markers. Nine patients with ALCL (T=5; null=4) failed treatment: three failed induction, and six relapsed from complete remission, but were effectively salvaged. No patient with ALCL died. The projected 5 year EFS for early stage ALCL is 84 % (SE 7%) (DLBCL versus ALCL, p-value 0.02); the OS, 100%. Among seven patients with PT, two failed to achieve complete remission, one of whom has died. The remaining five are event-free survivors. Conclusions: Nine weeks of modest intensity chemotherapy are sufficient for children with early stage DLBCL. The outcome for ALCL and PT is less favorable than DLBCL, but most such children become long-term survivors. No significant financial relationships to disclose.
Lineage-affiliated transcription factors bind the Gata3 Tce1 enhancer to mediate lineage-specific programs
Authors: Sakie Ohmura, Seiya Mizuno, Hisashi Oishi, Chia-Jui Ku, Mary Hermann, Tomonori Hosoya, Satoru Takahashi, James Douglas Engel
Journal: Journal of Clinical Investigation (2016)

The transcription factor GATA3 is essential for the genesis and maturation of the T cell lineage, and GATA3 dysregulation has pathological consequences. Previous studies have shown that GATA3 function in T cell development is regulated by multiple signaling pathways and that the Notch nuclear effector, RBP-J, binds specifically to the Gata3 promoter. We previously identified a T cell–specific Gata3 enhancer (Tce1) lying 280 kb downstream from the structural gene and demonstrated in transgenic mice that Tce1 promoted T lymphocyte–specific transcription of reporter genes throughout T cell development; however, it was not clear if Tce1 is required for Gata3 transcription in vivo. Here, we determined that the canonical Gata3 promoter is insufficient for Gata3 transcriptional activation in T cells in vivo, precluding the possibility that promoter binding by a host of previously implicated transcription factors alone is responsible for Gata3 expression in T cells. Instead, we demonstrated that multiple lineage-affiliated transcription factors bind to Tce1 and that this enhancer confers T lymphocyte–specific Gata3 activation in vivo, as targeted deletion of Tce1 in a mouse model abrogated critical functions of this T cell–regulatory element. Together, our data show that Tce1 is both necessary and sufficient for critical aspects of Gata3 T cell–specific transcriptional activity.
Use of unnecessary medications by terminally ill cancer patients.
Authors: R. Riechelmann, A. B. Fede, M. C. Miranda, D. V. Antonangelo, H. L. Schaffhausser, L. Trevizan, B. Hamermesz, C. Zimmermann, A. Del Giglio
Journal: Journal of Clinical Oncology (2010)

9073 Background: Cancer patients at the end of life take many medications but the proportion who take unnecessary medications(UnM) is unknown. Methods: Cross-sectional survey of medications utilized by terminally ill ambulatory patients with solid tumors. Categorization of the medications as necessary or unnecessary as per criteria developed by the authors, summarized in the Table. Results: Among 87 patients taking a median of 4 (range: 1-13) medications, 21 (24%, 95% CI 15.6–34.5%) were taking at least one UnM, with the most common being gastric protectors (11 instances). Most UnM had been prescribed by physicians, did not determine either cost or adverse events to patients and their median time of use was 240 days (one month to 15 years); the median time of use of necessary medications was 180 days. In multivariable analyses, patients with Charlson Comobidity Index ≤1 (OR: 4.49, CI95% 1.32–15.26; p = 0.01) and those whose medication list had not been reconciled by physicians in the last visit (OR: 6.38, CI95% 1.21–33.40; p = 0.02) were significantly more likely to use an UnM. Conclusions: Patients with terminal cancer take many medications considered unnecessary. Medication reconciliation should be routinely performed by health professionals involved in the care of these patients. Criteria to define UnM Drug class Clinical situation Rational Statins Indication: hypercholesterolemia, but no cardiovascular event in the prior 12 months. The long-term benefit of statins not likely to be seen within 6 months of expected survival Gastric protectors No medical history of gastrointestinal bleeding, peptic ulcer, gastritis or known chronic use (more than 30 days) of anti-inflammatory agents None of the widely accepted indications Antihypertensives Arterial blood pressure < 90 × 60 mmHg at the time of last consultation and symptoms of hypotension Considered dangerous to patients Antidiabetic Either a single measure of fasting glucose < 50 mg/dl within 4 weeks of consultation or reported symptoms of hypoglycemia and a fasting glucose test below lower limit of normal Considered dangerous to patients Any medication No clear medical indication identified Unknown No significant financial relationships to disclose.
Cancer statistics in China, 2015
Authors: Wanqing Chen, Rongshou Zheng, Peter D. Baade, Siwei Zhang, Hongmei Zeng, Freddie Bray, Ahmedin Jemal, Xue Qin Yu, Jie He
Journal: CA A Cancer Journal for Clinicians (2016)

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high‐quality data from an additional number of population‐based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population‐based cancer registries (2009‐2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000‐2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age‐standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P = .1), whereas they increased significantly (+2.2% per year; P &lt; .05) among females. In contrast, the mortality rates since 2006 have decreased significantly for both males (−1.4% per year; P &lt; .05) and females (−1.1% per year; P &lt; .05). Many of the estimated cancer cases and deaths can be prevented through reducing the prevalence of risk factors, while increasing the effectiveness of clinical care delivery, particularly for those living in rural areas and in disadvantaged populations. CA Cancer J Clin 2016;66:115–132. © 2016 American Cancer Society.
Propofol sedation for flexible bronchoscopy: A large randomized, controlled, non-inferiority trial
Authors: Peter Grendelmeier, Eric Pflimlin, Michael Tamm, Daiana Stolz
Journal: European Respiratory Journal (2012)

BACKGROUND: 

Propofol is a feasible and safe method for sedation in patients undergoing flexible bronchoscopy. However, there are no data comparing bolus administration versus continuous infusion of propofol for flexible bronchoscopy.

METHODS: 

702 consecutive patients undergoing flexible bronchoscopy were randomly allocated to receive intravenous propofol using either a continuous infusion or an intermittent bolus technique. The primary endpoint was the number of any adverse event (SaO2 ≤ 90 %; need for oro- or nasopharyngeal airway insertion; systolic BP < 90 mmHg, minor or major bleeding, pneumothorax, need to abort bronchoscopy, ICU, intubation or death) assessed by the end of FB and at 24 hours.

RESULTS: 

The number of any adverse event was similar in both randomized groups (Bolus group 219 vs. 211 Infusion group, p = 0.810). There were complications in 8 (1.1%) cases (6 major bleedings, 2 intubations). There was no death. As compared to the Bolus group, the amount of propofol required was significantly higher in the infusion group (226mg ± 147 versus vs. 308 mg ± 204.8, p < 0.0001). In a linear multivariate regression model, this difference remained significant independently of duration and the interventions (e.g. TBB, EBUS) performed during flexible bronchoscopy. The duration of bronchoscopy was significantly longer in the infusion group (14 [9 - 24] versus 17 [12 - 27] minutes, p < 0.0001).

CONCLUSION: 

Although propofol continuous infusion is as feasible and safe as bolus administration, it is associated with higher propofol requirements and a longer duration of the bronchoscopy.
Expression of Bax and Bcl2 proteins in small cell lung cancer (SCLC)
Authors: A. Badzio, M. Krajewska, H. Elsaleh, A. Kowalczyk, K. Kurowski, J. Jassem
Journal: Journal of Clinical Oncology (2007)

18189 Background: Bax and Bcl2 proteins are members of Bcl-2 family which plays a critical role in the regulation of apoptosis. There are few data on the occurrence and clinical relevance of these proteins in SCLC. Methods: We have analyzed expression of Bax and Bcl2 in 86 SCLC patients. All patients had limited disease and were treated with surgery followed by chemotherapy between 1982 and 2001 (median follow up 2 years). In all cases the diagnosis of SCLC was established only after the examination of surgical specimen. This series included 59 males and 22 females, 11 T1, 46 T2, 13 T3 and 11 T4 tumors, 41 N0, 15 N1, 24 N2 and 1 N3. Expression of both proteins was evaluated by immunohistochemistry and scored, taking into account proportion of cells with positive staining and staining intensity. H-score was calculated as a proportion of positive cells times staining intensity. Continues data on H-score were used to assess relationships with clinical data. Results: Median H-scores for Bax and Bcl2 were 70 (range 0–300) and 90 (range 0–300) respectively. The positive immunostaining rates (cut-off point of 10%) for Bax and Bcl-2 in the entire group were 81% and 79% respectively. Bax and Bcl-2 expression did not correlate with any clinicopathological parameters such as age, tumor size, lymph node involvement and stage of the disease. Survival was not influenced by expression of Bax (p=0.6) or Bcl2 (p=0.86). There was a significant positive correlation between Bax and Bcl2 expression rates (p=0.018, regression coefficient 0.23). Conclusions: Bax an Bcl2 proteins are commonly overexpressed in SCLC, with tendency for co-expression. Clinical relevance of these markers is questionable in this patient cohort. No significant financial relationships to disclose.