Impact of age,race and decade of treatment on overall survival in a critical population analysis of 40,000 multiple myeloma patients

With the availability of novel agents, the overall survival (OS) in patients diagnosed with multiple myeloma (MM) has improved over the last decade. Data on 40,294 MM patients in the years from 1973 to 2003 were obtained from the Surveillance, Epidemiology, and End Results Program (SEER) of the US National Cancer Institute. Statistical analyses evaluating gender, race, age, and year of diagnosis were performed using univariate and multivariate Cox regression models for the OS endpoint. The mean patient age at diagnosis was 68.3 years. Mean survival was 30 months (median = 19 months). Asian/Pacific Islander race was associated with an improved OS, HR 0.90 (CI 0.86–0.95, P < 0.001). American Indian/Alaska Native race was associated with a decreased OS, HR 1.18 (CI 1.01–1.38, P = 0.040). Multivariate analysis did not reveal statistically significant differences in OS between patients in the white and black race (P = 0.709). Younger age (age <65, and 65–75) was associated with improved OS when compared with patients >75 years of age (all P < 0.001). Recent treatment decades (1983–1992 and 1993–2003) were associated with improved OS on multivariate analysis with HR 0.88 (CI 0.88–0.89, P < 0.001) and HR 0.83 (CI 0.81–0.85, P < 0.001), respectively. As the largest population analysis to date, this study reveals a statistically significant improvement in OS for patients who were treated in more recent decades, even before the availability of novel agents. Patients who were <65 years of age and Asian/Pacific Islander race groups exhibited superior levels of OS, whereas American Indian/Alaska Native groups had decreased OS.     

How Long Will I Be Blue? Prolonged Skin Staining Following Sentinel Lymph Node Biopsy Using Intradermal Patent Blue Dye

Zusammenfassung

Hintergrund: Der für die Sentinel-Knoten-Biopsie bei Mammakarzinom-Patientinnen verwendete blaue Farbstoff kann längerfristige Hautverfärbungen im Injektionsbereich verursachen. Ziel dieser Studie war es, die Dauer derartiger Hautverfärbungen zu bestimmen. Patientinnen und Methoden: 236 aufeinanderfolgende Mammakarzinom-Patientinnen, bei denen eine brusterhaltende Operation und Sentinel-Knoten-Biopsie durchgeführt worden waren, wurden von Januar 2007 bis Dezember 2009 prospektiv untersucht. Ergebnisse: Bei 2 der 236 Patientinnen war eine bilaterale chirurgische Behandlung erfolgt, und 41 wurden im Rahmen jährlicher Nachuntersuchungen beurteilt. Blaue Verfärbungen im Injektionsbereich waren nach 12, 24 bzw. > 36 Monaten bei 36,5, 23,6 bzw. 8,6% der Patientinnen weiterhin sichtbar. Schlussfolgerung: Die Anwendung von Patentblau zur Identifikation des Sentinellymphknotens bei chirurgisch behandelten Mammakarzinom-Patientinnen kann zur längerfristigen Verfärbung der Haut im Injektionsbereich führen.     

In vitro evaluation of the metabolic stability of nine fragrance chemicals in trout and human hepatocytes

In vitro metabolic stability of nine fragrance chemicals: p-tolyl acetate, cashmeran, ethylene brassylate, celestolide, galaxolide, traseolide, ambretone, tonalide and pentadecanolide, was evaluated in trout and human hepatocytes. The compounds were incubated with trout hepatocytes at 12°C and human hepatocytes at 37°C. Quantification of compound disappearance with time was performed using gas chromatography/mass spectrometry. in vivo hepatic intrinsic clearance values were calculated from the in vitro data. Significant metabolism was observed with trout hepatocytes for five of the nine fragrance chemicals, while all nine were metabolized significantly with human hepatocytes. Previously published models were used to examine expected bioaccumulation and persistence in whole organisms. Calculated half-lives due to metabolism of the nine chemicals are significantly shorter for humans than trout: <1 hour and <1 day, respectively. For all chemicals with demonstrated hepatic metabolism, the models indicate a lack of accumulation. For those where metabolism was demonstrated in trout, calculated bioconcentration factors would not be classified as bioaccumulative under prevailing regulatory systems.     

Statistics for X‐chromosome associations

In a genome‐wide association study (GWAS), association between genotype and phenotype at autosomal loci is generally tested by regression models. However, X‐chromosome data are often excluded from published analyses of autosomes because of the difference between males and females in number of X chromosomes. Failure to analyze X‐chromosome data at all is obviously less than ideal, and can lead to missed discoveries. Even when X‐chromosome data are included, they are often analyzed with suboptimal statistics. Several mathematically sensible statistics for X‐chromosome association have been proposed. The optimality of these statistics, however, is based on very specific simple genetic models. In addition, while previous simulation studies of these statistics have been informative, they have focused on single‐marker tests and have not considered the types of error that occur even under the null hypothesis when the entire X chromosome is scanned. In this study, we comprehensively tested several X‐chromosome association statistics using simulation studies that include the entire chromosome. We also considered a wide range of trait models for sex differences and phenotypic effects of X inactivation. We found that models that do not incorporate a sex effect can have large type I error in some cases. We also found that many of the best statistics perform well even when there are modest deviations, such as trait variance differences between the sexes or small sex differences in allele frequencies, from assumptions.     

Steroid-sparing maintenance immunosuppression is safe and effective after simultaneous liver-kidney transplantation

Optimization of maintenance immunosuppression (mIS) regimens in the transplant recipient requires a balance between sufficient potency to prevent rejection and avoidance of excessive immunosuppression to prevent toxicities and complications. The optimal regimen after simultaneous liver-kidney (SLK) transplantation remains unclear, but small single-center reports have shown success with steroid-sparing regimens. We studied 4184 adult SLK recipients using the Scientific Registry of Transplant Recipients, from March 1, 2002, to February 28, 2017, on tacrolimus-based regimens at 1 year post-transplant. We determined the association between mIS regimen and mortality and graft failure using Cox proportional hazard models. The use of steroid-sparing regimens increased post-transplant, from 16.1% at discharge to 88.0% at 5 years. Using multi-level logistic regression modeling, we found center-level variation to be the major contributor to choice of mIS regimen (ICC 44.5%; 95% CI: 36.2%-53.0%). In multivariate analysis, use of a steroid-sparing regimen at 1 year was associated with a 21% decreased risk of mortality compared to steroid-containing regimens (aHR 0.79, P = .01) and 20% decreased risk of liver graft failure (aHR 0.80, P = .01), without differences in kidney graft loss risk (aHR 0.92, P = .6). Among SLK recipients, the use of a steroid-sparing regimen appears to be safe and effective without adverse effects on patient or graft survival.     

Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ

Purpose

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods

We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results

Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion

We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.     

The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells

Multiple signal transduction cascades, consisting of multiple interacting proteins, are activated following stimulation through most cell surface receptors, including the immunoglobulin receptor of B lymphocytes. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, resulting in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a lipid kinase that consists of an 85-kD regulatory subunit, bound to a 110-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that contains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 120-kD protein that is expressed in early B-lineage cells and in myeloid cells and is phosphorylated on tyrosine following receptor-mediated signaling in T and B lymphocytes. We demonstrate here that phosphorylated c-cbl complexes with CD19 and with PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active PI3K in anti-Ig- stimulated cells. Although we cannot differentiate between a three- component, c-cbl/CD19/p85 complex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct signal transduction pathways.     

Protein-tyrosine kinase p72syk in Fc gamma RI receptor signaling

In this report we show that gamma-interferon (IFN) induces the expression of the nonreceptor protein tyrosine kinase, p72syk, and that cross-linking the Fc gamma RI receptor in IFN-differentiated U937 cells (U937IF cells) results in the activation of syk kinase. We show that syk is tyrosine phosphorylated (12-fold increase) after Fc gamma RI cross-linking. In vitro kinase assays demonstrate that the specific kinase activity of syk increased eightfold after Fc gamma RI cross- linking. The activation of signal transduction through the Fc gamma RI receptor, as measured by the respiratory burst, is associated with the tyrosine phosphorylation and catalytic activation of the syk kinase. We show that syk coprecipitates with the gamma subunit of the Fc gamma RI, Fc gamma RI gamma. The data suggest that p72syk is involved in signal transduction through the Fc gamma RI receptor, involving the Fc gamma RI gamma subunit.