Notes

Addressing sustainability breaks.
1%) pembrolizumab-treated and 2 of 19 (10.5%) nivolumab-treated iPTOs. Post-immunotherapy cellular viability, in responding HGA organoids to pembrolizumab, decreased to less than 15% (
< 0.05). LGA iPTO treatment responses were observed in pembrolizumab and nivolumab, with an 8%-47.4% (
< 0.05) viability compared with controls. Ipilimumab showed no efficacy in the examined cohort.

Immunotherapy shows measurable efficacy in appendiceal cancer organoids. Information derived from immunocompetent organoids may be applied in selecting patients for clinical trial enrollment in rare diseases where preclinical models of disease are lacking.
Immunotherapy shows measurable efficacy in appendiceal cancer organoids. Information derived from immunocompetent organoids may be applied in selecting patients for clinical trial enrollment in rare diseases where preclinical models of disease are lacking.
M-protein is a well-established biomarker used for multiple myeloma (MM) monitoring. Current improvements in MM treatment created the need to monitor minimal residual disease (MRD) with high sensitivity. Measuring residual levels of M-protein in serum by mass spectrometry (MS) was established as a sensitive assay for disease monitoring. In this study we evaluated the performance of EasyM - a non-invasive, sensitive, MS-based assay for M-protein monitoring.

Twenty-six patients enrolled in MCRN-001 clinical trial of 2 high dose alkylating agents as conditioning followed by lenalidomide maintenance were selected for the study. All selected patients achieved CR during treatment, while 5 experienced progressive disease on study. The M-protein of each patient was first sequenced from the diagnostic serum using our
protein sequencing platform. The patient-specific M-protein peptides were then measured by targeted MS assay to monitor the response to treatment.

The M-protein doubling over 6 months measured by EasyM could predict the relapse in four out of five relapsed patients 2-11 months earlier than conventional testing. YM155 manufacturer In 21 disease-free patients, the M-protein was still detectable by EasyM despite normal FLC and MRD negativity. Importantly, out of 72 MRD negative samples with CR status, 62 were positive by EasyM. The best sensitivity achieved by EasyM, detecting 0.58 mg/L of M-protein, was 1000- and 200-fold higher compared to SPEP and IFE, respectively.

EasyM was demonstrated to be a non-invasive, sensitive assay with superior performance compared to other assays, making it ideal for MM monitoring and relapse prediction.
EasyM was demonstrated to be a non-invasive, sensitive assay with superior performance compared to other assays, making it ideal for MM monitoring and relapse prediction.
Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance.

We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a common high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance.

We identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Genetic cotargeting of the synergistic key regulator pair
and
associated athanogene 1 (
) significantly reduced leukemia cell viability
. Pharmacologic inhibition with dual small molecule inhibitor therapy targeting this pair of key nodes further demonstrated enhanced antileukemia efficacy of combining the BCL-2 inhibitor venetoclax with the tyrosine kinase inhibitors ruxolitinib or dasatinib
in human Ph-like ALL cell lines and
in multiple childhood Ph-like ALL patient-derived xenograft models. Consistent with network controllability theory, co-inhibitor treatment also shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated
-rearranged (Ph+) B-ALL and more similar to prognostically favorable childhood B-ALL subtypes.

Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.
Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.
Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) was tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study. Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens.

Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 11 to pembrolizumab 200 mg Q3W for less than or equal to24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200+IPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200+IPI100). Primary end points were incidence of grade 3-5 treatment-related adverse events (TRAEs) and objective response rate (ORR) per RECIST v1.1 by independent central review. Per protocol-defined thresholds, grade 3-5 TRAE incidence less than or equal to26% indicated meaningful toxicity reduction and ORR greater than or equal to48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumaboxicity.Sex hormones have been suggested as a contributor to gender disparity in incidence and mortality of colorectal cancer, but previous observational studies on endogenous sex hormones and colorectal cancer risk have led to contradictory results. Leveraging the large-scale UK biobank resource, Dimou and colleagues performed both observational and Mendelian randomization (MR) analyses to investigate the association of serum testosterone and sex hormone binding globulin concentrations with the risk of colorectal cancer. Although the findings provide little evidence for independent roles of the hormones in colorectal cancer, further interrogation of possible mediating effects of sex hormones on the causal pathways of colorectal cancer could deepen our understanding of colorectal cancer etiology and improve tailored prevention. While MR analysis is useful for inferring causality in observational studies, the current null results should be interpreted with caution because of insufficient statistical power and predefined assumptions of linearity. Moreover, given the widespread use of testosterone supplementation in older men to restore age-related decline of endogenous concentrations, large and long-term randomized controlled trials are required to clarify the effect of testosterone on colorectal cancer risk, which would provide critical evidence for health decision making.See related article by Dimou et al., p. 1336.In this issue of Cancer Epidemiology, Biomarkers & Prevention, Gallicchio and colleagues analyze recent rare-cancers research and suggest broad themes for accelerating progress in this important area. Whether the type of portfolio creation and portfolio management strategies that have worked for common cancers also work best for rare cancers warrants asking. This commentary argues for consideration of additional approaches. Incorporating principles and successes from large-scale network-based clinical trials and from advocacy-based research, and new ways to approach consortia, might accelerate the quantity and improve the quality of future rare-cancer research. Rare cancers significantly influence the overall cancer burden and cancer disparities. Creative community-based approaches to improve rare-cancers research should be considered.See related article by Gallichio et al., p. 1305.
This study was conducted to evaluate trends in survival, by race-ethnicity, for women diagnosed with breast cancer in Florida over a 26-year period.

This was a retrospective cohort study of women diagnosed with invasive breast cancer in Florida between 1990 and 2015. Data were obtained from the Florida Cancer Data System. Women in the study were categorized according to race (white/black) and Hispanic ethnicity (yes/no). Cumulative incidence estimates of 5- and 10-year breast cancer-related death with 95% confidence intervals (CI) were obtained by race-ethnicity, according to diagnosis year. Subdistribution hazard models were used to obtain subdistribution HRs (sHR) for the relative rate of breast cancer death accounting for competing causes.

Breast cancer mortality decreased for all racial-ethnic groups, and racial-ethnic minorities had greater absolute and relative improvement for nearly all metrics compared with non-Hispanic white (NHW) women. However, for the most recent time period (2010-2015), black women still experienced significant survival disparities with non-Hispanic black (NHB) women, having twice the rate of 5-year [sHR = 2.04; 95% confidence interval (CI), 1.91-2.19] and 10-year (sHR = 2.02; 95% CI, 1.89-2.16) breast cancer-related death. Adjustment for covariates substantially reduced the excess rate of breast cancer-related death for black women.

Despite efforts to improve disparities in breast cancer outcomes for underserved women in Florida, black women continue to experience significant survival disparities.

These results highlight the need for targeted approaches to eliminate disparities in breast cancer survival for black women.
These results highlight the need for targeted approaches to eliminate disparities in breast cancer survival for black women.
To evaluate the association of study design features and treatment effects in randomised controlled trials (RCTs) evaluating therapies for individuals with chronic medical conditions.

Meta-epidemiological study.

RCTs from meta-analyses published in the 10 general medical journals with the highest impact factor published between 1 January 2007 and 10 June 2019 and evaluated a drug, procedure or device treatment of chronic medical conditions.

The association between trial design features and the effect size, reporting a ratio of ORs (ROR) and 95% confidence interval (CI).

We included 1098 trials from 86 meta-analyses. The most common outcome in the trials was mortality (52%), followed by disease progression (16%) and adverse events (12%). Lack of blinding of patients and study personnel was associated with a larger treatment effect (ROR 1.12; 95% CI 1.00 to 1.25). There was no statistically significant association with random sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data, whether trials were stopped early, study funding, type of interventions or with type of outcomes (objective vs subjective).

The meta-epidemiological study did not demonstrate a clear pattern of association between risk of bias indicators and treatment effects in RCTs in chronic medical conditions. The unpredictability of the direction of bias emphasises the need to make every attempt to adhere to blinding, allocation concealment and reduce attrition bias.

Not applicable.
Not applicable.
Website: https://www.selleckchem.com/products/YM155.html