tbuckley/cabot-search huggingface dataset:
IgG and IgA hypogammaglobulinemia is pervasive in Waldenstrom's macroglobulinemia (WM) and persists regardless of response or type of therapeutic intervention
Authors: Z. R. Hunter, K. O'Connor, J. Soumerai, A. Branagan, X. Leleu, E. Hatjiharissi, S. Treon
Journal: Journal of Clinical Oncology (2007)

8042 Background: IgG and IgA hypogammaglobulinemia (HG) is a commonly observed in patients with WM and has often been attributed to the extensive infiltration of lymphoplasmacytic cells in the bone marrow (BM). Methods: In this retrospective study we analyzed immunoglobulin and BM infiltration levels from 196 previously untreated patients at their first visit to our clinic who met the clinical and pathological criteria for WM. In addition, we also serially evaluated 65 WM patients who received various therapies for changes in IgA and IgG. All lab values and biopsies used were conducted at our clinic at the Dana-Farber Cancer Institute to insure consistency. Pre-therapy, end of therapy, and best Ig response post therapy were evaluated and patients were followed up to the point of their next treatment regimen. Results: Of the 197 previously untreated patients, 117 (59.7%) demonstrated abnormally low levels of IgG (&lt;700 mg/dl), whereas 131 (66.8%) had abnormally low levels of IgA (&lt;70 mg/dl), and 102 (52.0%) had abnormally low levels of both IgG and IgA. Median value for IgM was 2820 mg/dl (Range 179 - 12400), for IgG 623 mg/dl (Range 127–2770), for IgA 48.5 mg.dl (range 7 - 509), and for the 94 patients for whom BM biopsies were available, the median intratrabecular space involvement was 37.5% (range 5 - 95). No correlation was found between BM involvement and any Ig level. Results from each of the trials is summarized in the table below. Median follow up was 455 days. No correlation between degree of response and Ig recovery was observed. No Ig level that started abnormally low was ever restored to normal levels in this study despite the fact that some recovery is noted in the non-rituximab based trials. Conclusions: These studies indicate that there is no relationship between BM involvement HG in WM. Moreover, therapeutic intervention does not restore IgG or IgA levels indicating a possible constitutive Ig dysregulation problem in patients with WM. No significant financial relationships to disclose. [Table: see text]
Clinical, pharmacokinetic (PK), pharmacodynamic findings in a phase I trial of weekly (wkly) intravenous AZD4877 in patients with refractory solid tumors
Authors: J. R. Infante, J. L. Spratlin, R. Kurzrock, S. G. Eckhardt, H. A. Burris, T. A. Puchalski, J. Li, K. Wu, J. Ochs, R. S. Herbst
Journal: Journal of Clinical Oncology (2008)

2501 Background: AZD4877 is a specific, potent inhibitor of Eg5 (kinesin spindle protein). The sole function of Eg5 is to separate centrosomes during mitosis causing a bipolar spindle. Eg5 inhibition is thus specific for dividing cells, causing monoastral mitotic spindles (monoasters) and cell death. Methods: Eligibility included patients (pt) with refractory solid tumors, 0–1 PS, adequate organ function. Three successive wkly AZD4877 doses were followed by a 1 wk rest. Standard 3 to 6 pt per cohort were used, with 100% dose escalation until a grade (gr.) 2 adverse event and then escalation of 50 or 25%. Results: Twenty-nine pt received ≥1 dose. Three pt were evaluable for dose-limiting toxicity (DLT) at all doses except 30 mg (6 pt) and 45 mg (2 pt). Tumor types: colorectal (7), bladder (3), pancreas (3), other (16). No DLT at 5, 7.5, 10, 15, 20, 30 mg doses; at 45 mg and then 36 mg, 5 of 6 pt had neutropenic DLT (1 gr. 3 neutropenia/fever and 4 gr. 4 neutropenia ≥4 days with gr. 3 mucositis in 1 pt and gr. 3 thrombocytopenia/anemia in another pt after the first dose). Except for dose-related neutropenia, no significant dose or mechanism related gr. 3 or 4 toxicity occurred; neuropathy was not seen. Over the entire dosing range, PK appeared to be linear. For doses ≥20 mg, AZD4877 free plasma concentrations at 24 hr were above needed efficacy concentration in pre-clinical models. At doses <20 mg, only 2/14 pt stayed on study >8 weeks; at doses ≥20 mg at least 7/15 stayed on study > 8wk (longest on study now 24+ wk). Proof of mechanism was supported by the presence of monoasters in peripheral blood mononuclear cells after AZD4877 treatment. Conclusions: The maximum tolerated dose of weekly AZD4877 is likely to be 30 mg. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca Oncology AstraZeneca Oncology
Low dose Vidaza and thalidomide is an effective combination for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)
Authors: P. Westervelt, S. Amirifeli, M. Mehdi, M. Mumtaz, S. Alhomsi, S. Wang, P. Miron, C. Lata, N. Galili, A. Raza
Journal: Journal of Clinical Oncology (2006)

6570 Vidaza and thalidomide were administered to 29 patients with MDS or AML. Vidaza was given at a dose of 75mg/kg subq × 5 days q28 days and Thalidomide starting at 50mg/day and increasing to 100mg. Therapy was well tolerated. Median age was 70 years, and there were 16 males. Two patients had RA, 2 RARS, 9 RAEB, 4 CMMoL, 10 AML and 2 Unknowns. According to IPSS, 1 had low, 7 had Int-1, 5 had Int-2 and 4 had high risk disease, and 2 unclassified (10 had AML). Eleven patients had normal, 14 abnormal and 4 unknown for cytogenetics. Seven patients went off the study due to disease progression (5) or refused therapy (1), died within a week of treatment initiation (1) while 2 are on the first cycle and too early for evaluation. Twenty-five patients are evaluable for outcome. Ten patients received 5 or more cycles of Vidaza. HI was seen in 14/25 (56%), and stable disease in 6/25 (24%) while 5/25 (20%) had disease progression. Six patients experienced complete remission (CR) and are still receiving therapy (24%), 1 experienced HI-E, 2 HI-ANC, 3 HI-P, and 2 had a bilineage improvement (HI-P and ANC and HI-E and ANC). Of 10 AML patients, three went off study due to disease progression, 1 had stable disease, 6 responded with 4 complete remissions (CR), 1 HI-ANC and 1 HI-P. Interestingly, 6/10 AMLs had a history of prior MDS, 3/6 achieved CR, 2/6 had HI (ANC and platelets) and 1 has stable disease (continuing treatment). Among the 4 de novo AMLs, 1 had CR and 3 showed disease progression. We conclude that a combination of low dose Vidaza and thalidomide is well tolerated, and highly effective therapy for the treatment of patients with MDS as well as AML arising from a prior MDS. The ability to treat secondary MDS as out-patient and achieve such a high response rate represents a paradigm shift in AML therapy. No significant financial relationships to disclose.
Brain metastases as the initial site of failure in neoadjuvant chemotherapy patients (pts) with operable non-small cell lung cancer (NSCLC): Implications for prophylactic cranial irradiation (PCI)
Authors: M. Zukin, C. G. Ferreira, V. O. Santos, C. J. Andrade, R. G. Martins
Journal: Journal of Clinical Oncology (2005)

7327 Background: Between 25%–30% of all pts with NSCLC develop BM at some stage of their life, and this percentage is likely to increase with lengthening survival of pts with early stage of disease at presentation. The aim of the present study was to evaluate the pattern of recurrence after curative resection and identified potential pts for PCI. Methods: We reviewed the outcomes of 30 pts operated on for pathologic stage IB to IIIA NSCLC between Jan 2000 to Aug 2002. Pts received platinum doublet neoadjuvant chemotherapy(CT)in the context of phase II study. If considered operable, had a mediastinoscopy. Pts with negative mediastinal lymph nodes were operated with curative intent. Pts with involved mediastinum nodes were treated with xRT. The histologic type was squamous carcinoma (sqc) in 12, nonsquamous carcinoma (nsqc) (13 adenocarcinoma and 1 large cell carcinoma) and 4 nsclc. Mean follow up was 40 months. Survival was calculated by the actuarial method and compared by the log-rank test. Results: Twenty-three pts had thoracotomies. Complete surgical resection was achieved in 91% of pts taken to thoracotomy. All pts were evaluable for response. Recurrences were identified in 17 (56%) pts; distant metastasis (35%), distant and local recurrence (5%), local recurrence (60%). Five pts (16%) had BM and most of these pts (60%) were N2 prior the CT, and presented a nsqc subtype (80%).Brain relapse occured within 2 years of follow-up and all these pts developed BM as their initial site of failure. The actuarial progression free and overall survival were 71% and 84%, respectively After a median follow-up of 40 months, 12 pts have died. Conclusion: Our data indicate that BM have become a significant problem with the advent of combined modality therapy as the standard treatment in NSCLC and its potential impact on prolonging survival. Pathological stage and histologic type significantly influence recurrence after resection. Distant metastases especially (BM) were more common and late recurrences over follow-up of 2 years were more prominent in nsqc. These findings may have implications for PCI in this patient population. No significant financial relationships to disclose.
A Simple, General Result for the Variance of Substitution Number in Molecular Evolution
Authors: Bahram Houchmandzadeh, Marcel Vallade
Journal: Molecular Biology and Evolution (2016)

The number of substitutions (of nucleotides, amino acids, etc.) that take place during the evolution of a sequence is a stochastic variable of fundamental importance in the field of molecular evolution. Although the mean number of substitutions during molecular evolution of a sequence can be estimated for a given substitution model, no simple solution exists for the variance of this random variable. We show in this article that the computation of the variance is as simple as that of the mean number of substitutions for both short and long times. Apart from its fundamental importance, this result can be used to investigate the dispersion index R, that is, the ratio of the variance to the mean substitution number, which is of prime importance in the neutral theory of molecular evolution. By investigating large classes of substitution models, we demonstrate that although R≥1⁠, to obtain R significantly larger than unity necessitates in general additional hypotheses on the structure of the substitution model.
Increased DNA Methylation and Reduced Expression of Transcription Factors in Human Osteoarthritis Cartilage
Authors: Oscar Alvarez‐Garcia, Kathleen M. Fisch, Nathan E. Wineinger, Ryuichiro Akagi, Masahiko Saito, Takahisa Sasho, Andrew I. Su, Martin K. Lotz
Journal: Arthritis & Rheumatology (2016)

To analyze the methylome of normal and osteoarthritic (OA) knee articular cartilage and to determine the role of DNA methylation in the regulation of gene expression in vitro.DNA was isolated from human normal (n = 11) and OA (n = 12) knee articular cartilage and analyzed using the Infinium HumanMethylation450 BeadChip array. To integrate methylation and transcription, RNA sequencing was performed on normal and OA cartilage and validated by quantitative polymerase chain reaction. Functional validation was performed in the human TC28 cell line and primary chondrocytes that were treated with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC).DNA methylation profiling revealed 929 differentially methylated sites between normal and OA cartilage, comprising a total of 500 individual genes. Among these, 45 transcription factors that harbored differentially methylated sites were identified. Integrative analysis and subsequent validation showed a subset of 6 transcription factors that were significantly hypermethylated and down-regulated in OA cartilage (ATOH8, MAFF, NCOR2, TBX4, ZBTB16, and ZHX2). Upon 5-aza-dC treatment, TC28 cells showed a significant increase in gene expression for all 6 transcription factors. In primary chondrocytes, ATOH8 and TBX4 were increased after 5-aza-dC treatment.Our findings reveal that normal and OA knee articular cartilage have significantly different methylomes. The identification of a subset of epigenetically regulated transcription factors with reduced expression in OA may represent an important mechanism to explain changes in the chondrocyte transcriptome and function during OA pathogenesis.
Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial
Authors: R Stupp, J Bauer, O Pagani, B Gerard, T Cerny, C Sessa, G Bastian, M Sarkany, J Schläpfer, B Giroux, S Leyvraz
Journal: Annals of Oncology (1998)
Late-breaking abstract: Non specific IgG replacement in lung transplantation recipients with low IgG plasma levels: Effects on survival and bronchiolitis obliterans syndrome occurrence
Authors: Christophe Pison, Hubert Roth, Chrystel Saint Raymond, Johanna Claustre, Boubou Camara, Sébastien Quétant
Journal: European Respiratory Journal (2011)

After lung transplantation, IgG plasma levels < 6 gr/L are recorded in more than 50% of cases resulting in adverse events (JHLT 2001;71:242; Transplantation 2005;79:1723). We conducted an open study with non specific IgG, Tegelines® in all patients with IgG plasma < 6 g/L post transplantation since 1991 in 59 out of 119 consecutive recipients who survived more than 3 months in Grenoble. Both groups had similar donor and recipient characteristics and events during a mean follow-up of 4.14±3.4 years except for a shorter duration of ventilation in donors, a longer first hospitalization stay and more acute rejection/TBB performed 0.32±1.2 ( vs 0.11±0.18) in non-substituted group. IgG substitution started 4.5 [0-76] and lasted 5 [0-115] months, mean cumulative doses were 53±48 gr. In multivariate Cox regression model, IgG substitution conferred a net benefit in terms of survival at 5 years HR: 0.40 [0.18-0.88] 95%CI, p:0.022 taking in account age of recipients and donors, annualized number of treated infection and rejection episodes, and BOS free survival at 5 years HR: 0.50 [0.25-1.03] 95%CI, p:0.06 taking in account age of recipients and donors, type IC vs EC preservation solution, use of cardiopulmonary by-pass, annualized number of treated infection and rejection episodes. We conclude that replacement therapy with non specific IgG in lung transplant recipients with low IgG plasma levels resulted in a better survival and BOS free survival at 5 years post-transplantation as compared to non-substituted group. Limitation: non randomized design. A prospective controlled multicentre study is warranted. Funds from LFB, France.
Applying Principles of Instructional Design to a Medical School Course in Psychiatry
Authors: WARNER JOHNSON, JOHN SNIBBE, JOHN E. CROWDER, HARRY ZALL, GEORGE H. WOLKON
Journal: American Journal of Psychiatry (1974)

Modern principles of instructional design were applied by the authors to an undergraduate medical school course in psychiatry with extremely promising results. The authors presented a description of the program design and instructional techniques to second-year medical students, emphasizing in a specific way the development and implementation of learning objectives. It was found that these instructional methods led both to increased perceived learning and greater actual learning.
Three Cases of Fatal Intracranial Hemorrhage with Metastasis of Gastric Cancer to the Bone/Bone Marrow
Authors: Yusuke Kimura, Teruhisa Azuma, Yuki Aiyama, Miyako Imanaka, Maho Nakahara, Shunjiro Noguchi, Akira Tsujimura, Yukio Tsugihashi, Hiroyasu Ishimaru, Kazuhiro Hatta
Journal: Annals of Oncology (2014)
Extra osseous Ewing's tumors: Which is the most appropriate treatment? Experience of the French and International Societies of Pediatric Oncology (SFOP and SIOP)
Authors: O. Oberlin, M. P. Castex, H. Rubie, O. Delattre, C. Calvo Escribano, A. Rey, M. Stevens
Journal: Journal of Clinical Oncology (2004)

9038 Background: The best treatment for Extra-Osseous Ewing Sarcoma (EOE) is still matter of debate Methods: Between 1989 and 1999, according to countries, patients (pts) with EOE were treated either in SIOP MMT 89 study (32 pts) or SFOP osseous Ewing's tumor (OE) study (31 pts). Briefly, MMT strategy included chemotherapy (IVA: Ifosfamide-Vincristine-Actinomycine, 6 to 9 courses), surgical resection in pts with incomplete response to chemotherapy (CT) and local irradiation in case of post-operative residue. OE protocol included CT (Cyclophosphamide-Doxorubicin, CPM-DXR, 5 courses), surgical resection; then, treatment was stratified on histological response: good responders (< 10% viable cells) received alternating courses of CPM-DXR and Vincristine-Actino during 6 months. Four poor responders were given intensified chemotherapy (Ifosfamide-VP16) before high-dose chemotherapy (Bu-Mel) followed by local irradiation for 3 of them. Results: Characteristics of pts treated in both protocols were similar in terms of age and sites. Five-year OS and EFS of the pts treated with OE protocol were 83 and 75% respectively, which was significantly better than OS and EFS of the pts treated with MMT strategy (59 and 44%) (p=0.04 and 0.008 respectively). Although local treatment was more intensive in OE strategy (96% resections vs 75%, 71% irradiations vs 50%), the difference in the outcome is explained by a higher rate of metastatic relapses in pts treated with MMT protocol (Metastasis-free survival of 82 vs 54%). Univariate analysis for overall survival showed that age < 10 years, and OE protocol were favourable predictive factors. Univariate analysis for disease-free survival showed that size < 5 cm and OE protocol were favourable predictive factors. However, in multivariate analysis, only type of protocol remained significant for overall and disease-free survivals. Conclusions: Our study suggests that patients with EOE should be treated with bony targeted regimen, probably because they contain anthracyclins No significant financial relationships to disclose.
Genetic variants of kinases suppressors of ras in <i>KRAS</i>-<i>BRAF</i> wild-type metastatic colorectal cancer patients treated with cetuximab and irinotecan.
Authors: Leonor Benhaim, Fotios Loupakis, Wu Zhang, Armin Gerger, Pierre Oliver Bohanes, David Páez, Chiara Cremolini, Takeru Wakatsuki, Dongyun Yang, Yan Ning, Rita El-Khoueiry, Hua Zhang, Lisa Salvatore, Marta Schirripa, Alfredo Falcone, Georgios Giamas, Justin Stebbing, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2012)

3597 Background: Scaffold proteins kinase suppressor of ras (KSRs) have emerged as critical modulators of the EGFR pathway that binds to RAS promoting ERK activation. KSR1 and KSR2 have been shown to be over expressed in various solid tumours including colon cancer. In-vitro, the down-regulation of KSR results in reduction of cells proliferation and tumour growth independently to KRAS status. Moving from this biological rational we investigated the correlation between functional polymorphisms in the KSR genes and clinical outcomes in patients with KRAS and BRAF wild-type mCRC treated with cetuximab and irinotecan. Methods: Germline DNA was obtained from peripheral blood of patients with mCRC KRAS and BRAF wild- type resistant to irinotecan treated with a combination of cetuximab and irinotecan. Seven functionally relevant SNP were selected on the basis of public literature resources and databases, 4 in the KSR1 and 3 in the KSR2 genes and analyzed by PCR followed by direct sequencing. All candidate SNPs were evaluated for association with response rate, PFS and OS. Results: A total of 66 patients were included.After a median follow-up of 13.3 months, median PFS and OS were 4.7 and 11.3 months respectively. Seventeen out of 66 patients (26%) achieved a RECIST response. In univariate analysis, KSR2 rs11068551 any G(AG/GG) genotype was significantly associated with shorter PFS compared to that of A/A carriers (median 3.5 vs. 7.4 months, HR=1.74 [95%CI: 1-3.04] p=0.049, log-rank test). This result remained significant in a multivariate model (HR=2.13 [95%CI: 1.15-3.95], p=0.017, log-rank test). None of the other tested SNPs were significantly associated with outcomes. Conclusions: Beyond KRAS and BRAF, some proteins including KSR are involved in modulating the level of activation of the EGFR pathway. Our results show that the functionally relevant KSR2 rs11068551 could affect PFS in advanced mCRC patients treated with cetuximab and irinotecan. Preclinical studies to confirm and further explain these preliminary findings are ongoing.
High Levels of Antibody that Neutralize B-cell Infection of Epstein–Barr Virus and that Bind EBV gp350 Are Associated with a Lower Risk of Nasopharyngeal Carcinoma
Authors: Anna E. Coghill, Wei Bu, Hanh Nguyen, Wan-Lun Hsu, Kelly J. Yu, Pei-Jen Lou, Cheng-Ping Wang, Chien-Jen Chen, Allan Hildesheim, Jeffrey I. Cohen
Journal: Clinical Cancer Research (2016)

Elevated IgA antibodies indicative of ongoing exposure to Epstein-Barr virus (EBV) are high-risk biomarkers for nasopharyngeal carcinoma (NPC), an EBV-related epithelial tumor. However, protective biomarkers that limit exposure to the virus have not been defined. We evaluated whether antibodies that can neutralize EBV infection by targeting glycoproteins involved in viral cell entry, including EBV vaccine candidate glycoprotein 350 (gp350), were associated with lower NPC risk.In a prospective cohort of 2,557 individuals from 358 high-risk NPC multiplex families in Taiwan, we identified 21 incident NPC cases and 50 disease-free controls. To complement data from high-risk families, we further identified 30 prevalent NPC cases and 50 healthy controls from the general Taiwanese population. We quantified EBV-neutralizing antibody, antibodies against EBV glycoproteins involved in B-cell and epithelial cell entry, and anti-EBNA1 IgA, a high-risk NPC biomarker.EBV-neutralizing antibodies blocking B-cell infection and anti-gp350 antibodies were present at significantly higher levels in disease-free controls compared with incident NPC cases (P < 0.03). Family members with both low EBV-neutralizing potential and elevated EBNA1 IgA had a 7-fold increased risk of NPC (95% CI, 1.9-28.7). Neutralizing antibodies against epithelial cell infection did not differ between incident cases and disease-free controls. Anti-glycoprotein antibody levels measured at diagnosis (prevalent NPC) were significantly higher than levels measured prior to diagnosis (P < 0.01).Elevated titers of EBV-neutralizing antibody and anti-gp350 antibody were low-risk biomarkers for NPC. These data suggest that a vaccine that induces potent EBV gp350 and B-cell-neutralizing antibodies could reduce the risk of EBV-related cancers such as NPC. Clin Cancer Res; 22(14); 3451-7. ©2016 AACR.