Lenalidomide in the Treatment of Young Patients with Multiple Myeloma: From Induction to Consolidation/Maintenance Therapy

Multiple myeloma is the second most common hematologic malignancy. It accounts for 20,580 new cancer cases in the USA in 2009, including 11,680 cases in men, 8,900 cases in women, and 10,580 deaths overall. Although the disease remains still incurable, outcomes have improved substantially over recent years thanks to the use of high-dose therapy and the availability of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Various trials have shown the advantages linked to the use of novel agents in the transplant and not-transplant settings. In particular, this paper will present an overview of the results achieved with lenalidomide-containing combinations in patients eligible for high-dose therapies, namely, young patients. The advantages obtained should always be outweighed with the toxicity profile associated with the regimen used. Therefore, here, we will also provide a description of the main adverse events associated with lenalidomide and its combination

Rebound effects caused by withdrawal of MET Kinase inhibitor are quenched by a MET Therapeutic antibody

Abstract MET oncogene amplification is emerging as a major mechanism of acquired resistance to EGFR-directed therapy in lung and colorectal cancers. Furthermore, MET amplification predicts responsiveness to MET inhibitors currently in clinical trials. Among the anti-MET drugs available, ATP-competitive small-molecule kinase inhibitors abrogate receptor autophosphorylation and downstream activation of ERK1/2 and AKT, resulting in cell-cycle arrest. However, this antiproliferative effect allows persistence of a pool of cancer cells that are quiescent but alive. Once the inhibition is removed, rebound activation of MET-driven cell proliferative pathways and tumor growth may occur, an adverse event observed frequently in clinical settings after drug discontinuation. Here we show that inhibitor withdrawal prompts receptor phosphorylation to levels higher than those displayed at steady-state and generates a rebound effect pushing quiescent cancer cells back into the cell cycle, both in vitro and in experimental tumor models in vivo. Mechanistically, we found that inhibitor treatment blocks MET endocytosis, causing a local increase in the number of receptors at the plasma membrane. Upon inhibitor washout, the receptor is readily rephosphorylated. The initial phosphorylation is not only increased but also prolonged in duration due to downmodulation of a phosphatase-mediated MET-negative feedback loop, which accompanies receptor internalization. Notably, treatment with a MET therapeutic antibody that induces proteolytic cleavage of the receptor at the cell surface substantially prevents this rebound effect, providing a rationale to combine or alternate these mechanistically different types of MET-targeted therapy. Cancer Res; 76(17); 5019–29. ©2016 AACR.</jats:p

Tankyrase inhibition impairs directional migration and invasion of lung cancer cells by affecting microtubule dynamics and polarity signals

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Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity

Background: Transcriptional classification has been used to stratify colorectal cancer (CRC) into molecular subtypes with distinct biological and clinical features. However, it is not clear whether such subtypes represent discrete, mutually exclusive entities or molecular/phenotypic states with potential overlap. Therefore, we focused on the CRC Intrinsic Subtype (CRIS) classifier and evaluated whether assigning multiple CRIS subtypes to the same sample provides additional clinically and biologically relevant information. Methods: A multi-label version of the CRIS classifier (multiCRIS) was applied to newly generated RNA-seq profiles from 606 CRC patient-derived xenografts (PDXs), together with human CRC bulk and single-cell RNA-seq datasets. Biological and clinical associations of single- and multi-label CRIS were compared. Finally, a machine learning-based multi-label CRIS predictor (ML2CRIS) was developed for single-sample classification. Results: Surprisingly, about half of the CRC cases could be significantly assigned to more than one CRIS subtype. Single-cell RNA-seq analysis revealed that multiple CRIS membership can be a consequence of the concomitant presence of cells of different CRIS class or, less frequently, of cells with hybrid phenotype. Multi-label assignments were found to improve prediction of CRC prognosis and response to treatment. Finally, the ML2CRIS classifier was validated for retaining the same biological and clinical associations also in the context of single-sample classification. Conclusions: These results show that CRIS subtypes retain their biological and clinical features even when concomitantly assigned to the same CRC sample. This approach could be potentially extended to other cancer types and classification systems

Adverse Birth Outcomes of adolescent and Young adult Women Diagnosed With Cancer During Pregnancy

BACKGROUND: We examined adverse birth outcomes among adolescent and young adult women diagnosed with cancer (AYA women, ages 15-39 years) during pregnancy. METHODS: We linked data from the Texas Cancer Registry, vital records, and Texas Birth Defects Registry to identify all singleton births to AYA women diagnosed during pregnancy from January 1999 to December 2016. We compared prevalence of adverse live birth outcomes between AYA women and women without cancer (matched 1:4 on age, race and ethnicity, and year). Among AYA women, we used log-binomial regression to identify factors associated with these outcomes. Statistical tests were 2-sided. RESULTS: AYA women had 1271 singleton live births and 20 stillbirths. AYA women (n = 1291) were 33.3% Hispanic and 9.8% non-Hispanic Black and most commonly had breast (22.5%), thyroid (19.8%), and gynecologic (13.3%) cancers. Among live births, AYA women had a higher prevalence of low birth weight offspring (30.1% vs 9.0%), very preterm (5.7% vs 1.2%), and preterm birth (25.1% vs 7.2%); cesarean delivery (44.3% vs 35.2%); and low Apgar score (2.7% vs 1.5%), compared with women without cancer (n = 5084) (all P \u3c .05). Prevalence of any birth defect by age 12 months did not statistically differ (5.2% vs 4.7%; P = .48), but live births to AYA women more often had heart and circulatory system defects (2.2% vs 1.3%; P = .01). In adjusted models, cancer type and chemotherapy were associated with adverse live birth outcomes. CONCLUSIONS: AYA women diagnosed during pregnancy have higher prevalence of adverse birth outcomes and face difficult decisions in balancing treatment risks and benefits

CPOD en gestantes atendidas en el centro de salud Campo Marte, Arequipa 2017 - 2021

El objetivo de la presente investigación fue estimar el CPOD en gestantes atendidas en el Centro de Salud Campo Marte, Arequipa 2017 – 2021. El estudio es de tipo básico, un diseño no experimental, presenta un alcance de investigación de nivel descriptivo, transversal, retrospectivo, observacional. La técnica de muestreo usada fue muestreo no probabilístico, por conveniencia, mediante la técnica de observación, utilizando como instrumento la Ficha de recolección de CPOD. La población está constituida por la cantidad de historias clínicas generadas en los años 2017-2021 del Centro de Salud Campo Marte, en la ciudad de Arequipa, y la muestra constituida por 150 historias clínicas, que cumplieron los criterios de selección. Como resultados se encontró, a través del programa IBM SPSS Statistics versión 25, con una estandarización sugerida a un coeficiente de Kappa >85%, un CPOD de 10.57 de porcentaje, considerando como rango de edad frecuente la edad entre los 18 a 25 años de edad, con una frecuencia de 76 y un porcentaje de 50.7, el valor más frecuente es moderado con una frecuencia de 78 y un porcentaje de 52, considerando el tercer trimestre de edad gestacional más frecuente como grado moderado en un porcentaje de 64.3, y según número de partos las mujeres con un parto presenta su valor moderado más frecuente con un porcentaje de 54.1. Concluyendo que el índice de CPOD en madres gestantes es alto siendo de 10.57, en base a la recolección de historias clínicas de data entre 2017- 2021

Stillbirth after adolescent and Young adult Cancer: a Population-Based Study

BACKGROUND: Gonadotoxic effects of cancer treatment may increase risk of adverse birth outcomes in adolescent and young adult (AYA, aged 15-39 years) women diagnosed with cancer. We estimated risk of stillbirth (fetal death of gestational age ≥20 weeks or weighing ≥350 grams) in a population-based sample of AYA women. METHODS: AYA women diagnosed with cancer between January 1, 1995, and December 31, 2015, were identified using the Texas Cancer Registry and linked to live birth and fetal death certificates through December 31, 2016. Among AYA women, cumulative incidence of stillbirth was estimated by gestational age, and Poisson regression models identified factors associated with stillbirth. Standardized fetal mortality ratios (SMR) compared the observed fetal mortality rate in AYA women with the expected fetal mortality rate in the general population. RESULTS: A total of 11 628 live births and 68 stillbirths occurred to 8402 AYA women after diagnosis. Cumulative incidence of stillbirth in AYA women was 0.70% (95% confidence interval [CI] = 0.51% to 0.96%) at 40 weeks of gestation. Risk of stillbirth was higher among Hispanic (risk ratio [RR] = 2.64, 95% CI = 1.29 to 5.41) and non-Hispanic Black (RR = 4.13, 95% CI = 1.68 to 10.16) women compared with non-Hispanic White women; there was no association with receipt of chemotherapy or time since diagnosis. Age- and race and ethnicity-adjusted fetal mortality rate in AYA women was similar to the general population (SMR = 0.99, 95% CI = 0.77 to 1.26). CONCLUSIONS: AYA women may be counseled that overall risk of stillbirth is low, and for most, cancer does not appear to confer additional risk