Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased ...neuropathy risk and CYP2C8*3 genotype.
Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates.
In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status HR (per allele) = 1.93 (95% CI: 1.05–3.55), overall log-rank P = 0.006. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030).
The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.
The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is ...uncertainty about the benefit of chemotherapy for most patients, who have a midrange score.
We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death).
Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death endocrine vs. chemoendocrine therapy, 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.
Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).
The proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and programmed cell death, or ...apoptosis. In preclinical cancer models, proteasome inhibitors induce apoptosis, have in vivo antitumor efficacy, and sensitize malignant cells and tumors to the proapoptotic effects of conventional chemotherapeutics and radiation therapy. Interestingly, transformed cells display greater susceptibility to proteasome inhibition than nonmalignant cells. Therefore, proteasome inhibition holds promise as a novel approach to the treatment of cancer. Inhibitors of the proteasome impact on cells in part through down-regulation of nuclear factor kappaB, but also through modulation of cell cycle proteins and other pro- and antiapoptotic pathways. Bortezomib (VELCADE; formerly PS-341), the first such inhibitor to undergo clinical testing, has demonstrated impressive antitumor activity and manageable toxicities in Phase I and II trials both as a single agent, and in combination with other drugs. It has been approved recently by the Food and Drug Administration for therapy of patients with multiple myeloma who have received at least two prior regimens and progressed on the last of these. Ongoing preclinical evaluations of the mechanisms that underlie the antitumor effects of proteasome inhibitors, and clinical trials in a variety of tumor types, will allow additional refinement of the role these agents will play in cancer therapy. Below we discuss the rationale behind targeting the proteasome for cancer therapy, and review the preclinical and clinical data on proteasome inhibitors alone, and in combination with conventional chemotherapeutics.
Purpose
It is not known whether chemotherapy-related symptom experiences differ between Black and White women with early breast cancer (Stage I–III) receiving current chemotherapy regimens and, in ...turn, influences dose delay, dose reduction, early treatment discontinuation, or hospitalization.
Methods
Patients self-reported their race and provided symptom reports for 17 major side effects throughout chemotherapy. Toxicity and adverse events were analyzed separately for anthracycline and non-anthracycline regimens. Fisher’s exact tests and two-sample t-tests compared baseline patient characteristics. Modified Poisson regression estimated relative risks of moderate, severe, or very severe (MSVS) symptom severity, and chemotherapy-related adverse events.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.no changes
Results
In 294 patients accrued between 2014 and 2020, mean age was 58 (SD13) and 23% were Black. For anthracycline-based regimens, the only significant difference in MSVS symptoms was in lymphedema (41% Black vs 20% White,
p
= .04) after controlling for axillary surgery. For non-anthracycline regimens, the only significant difference was MSVS peripheral neuropathy (41% Blacks vs. 23% White) after controlling for taxane type (
p
= .05) and diabetes (
p
= .05). For all other symptoms, severity scores were similar. Dose reduction differed significantly for non-anthracycline regimens (49% Black vs. 25% White,
p
= .01), but not for anthracycline regimens or in dose delay, early treatment discontinuation, or hospitalization for either regimen.
Conclusion
Except for lymphedema and peripheral neuropathy, Black and White patients reported similar symptom severity during adjuvant chemotherapy. Dose reductions in Black patients were more common for non-anthracycline regimens. In this sample, there were minimal differences in patient-reported symptoms and other adverse outcomes in Black versus White patients.
Purpose
Ensuring and measuring adherence to prescribed exercise regimens are fundamental challenges in intervention studies to promote exercise in adults with cancer. This study reports exercise ...adherence in women who were asked to walk 150 min/week throughout chemotherapy treatment for early breast cancer. Participants were asked to wear a Fitbit
TM
throughout their waking hours, and Fitbit steps were uploaded directly into study computers.
Methods
Descriptive statistics are reported, and both unadjusted and multivariable linear regression models were used to assess associations between participant characteristics, breast cancer diagnosis, treatment, chemotherapy toxicities, and patient-reported symptoms with average Fitbit steps/week.
Results
Of 127 women consented to the study, 100 had analyzable Fitbit data (79%); mean age was 48 and 31% were non-white. Mean walking steps were 3956 per day. Nineteen percent were fully adherent with the target of 6686 steps/day and an additional 24% were moderately adherent. In unadjusted analysis, baseline variables associated with
fewer
Fitbit steps were: non-white race (
p
= 0.012), high school education or less (
p
= 0.0005), higher body mass index (
p
= 0.0024), and never/almost never drinking alcohol (
p
= 0.0048). Physical activity variables associated with
greater
Fitbit steps were: pre-chemotherapy history of vigorous physical activity (
p
= 0.0091) and higher self-reported walking minutes/week (
p
< 0.001), and higher outcome expectations from exercise (
p
= 0.014). Higher baseline anxiety (
p
= 0.03) and higher number of chemotherapy-related symptoms rates “severe/very severe” (
p
= 0.012) were associated with fewer steps. In multivariable analysis, white race was associated with 12,146 greater Fitbit steps per week (
p
= 0.004), as was self-reported walking minutes prior to start of chemotherapy (
p
< 0.0001).
Conclusions
Inexpensive commercial-grade activity trackers, with data uploaded directly into research computers, enable objective monitoring of home-based exercise interventions in adults diagnosed with cancer. Analysis of the association of walking steps with participant characteristics at baseline and toxicities during chemotherapy can identify reasons for low/non-adherence with prescribed exercise regimens.
The observation of neutrons turning into antineutrons would constitute a discovery of fundamental importance for particle physics and cosmology. Observing the n–n̄ transition would show that baryon ...number (B) is violated by two units and that matter containing neutrons is unstable. It would provide a clue to how the matter in our universe might have evolved from the B=0 early universe. If seen at rates observable in foreseeable next-generation experiments, it might well help us understand the observed baryon asymmetry of the universe. A demonstration of the violation of B–L by 2 units would have a profound impact on our understanding of phenomena beyond the Standard Model of particle physics.
Slow neutrons have kinetic energies of a few meV. By exploiting new slow neutron sources and optics technology developed for materials research, an optimized search for oscillations using free neutrons from a slow neutron moderator could improve existing limits on the free oscillation probability by at least three orders of magnitude. Such an experiment would deliver a slow neutron beam through a magnetically-shielded vacuum chamber to a thin annihilation target surrounded by a low-background antineutron annihilation detector. Antineutron annihilation in a target downstream of a free neutron beam is such a spectacular experimental signature that an essentially background-free search is possible. An authentic positive signal can be extinguished by a very small change in the ambient magnetic field in such an experiment. It is also possible to improve the sensitivity of neutron oscillation searches in nuclei using large underground detectors built mainly to search for proton decay and detect neutrinos.
This paper summarizes the relevant theoretical developments, outlines some ideas to improve experimental searches for free neutron oscillations, and suggests avenues both for theoretical investigation and for future improvement in the experimental sensitivity.
Background Ductal carcinoma in situ (DCIS) has a generally favorable overall prognosis, with a systemic recurrence rate of approximately 1%, a local recurrence rate after mastectomy of 1%, and a ...local recurrence rate after breast-conserving treatment of less than 10%. Preliminary studies have suggested that women with DCIS may overestimate their risk of disease recurrence. Few data exist regarding psychosocial outcomes for women with DCIS. Methods Women in Eastern Massachusetts with newly diagnosed DCIS were asked to participate in a longitudinal study of risk perceptions, psychosocial concerns, and health behaviors. Psychosocial outcomes after DCIS diagnosis and risk perceptions were evaluated at enrollment and at 9 and 18 months. All statistical tests were two-sided. Results Four hundred eighty-seven women with DCIS (64% of eligible participants) completed the enrollment survey. Overall quality of life was good among the women surveyed, and the substantial anxiety at enrollment decreased with time (P < .001). At enrollment, 54% perceived at least a moderate risk for DCIS recurrence in the next 5 years, 68% in their lifetime; 39% perceived at least a moderate risk for invasive cancer in the next 5 years, 53% in their lifetime; and 28% perceived at least a moderate likelihood of DCIS spreading to other places in their body. At 18 months after enrollment, perceived risks had not statistically significantly changed from those at enrollment (P = .38). Anxiety at enrollment was the factor that was most consistently and strongly associated with overestimation of future breast cancer–related risks (perceived moderate or greater risk vs less than moderate risk of DCIS recurring within 5 years: odds ratio OR = 4.0, 95% confidence interval CI = 1.6 to 9.9, P = .003; of invasive breast cancer within 5 years: OR = 4.3, 95% CI = 1.9 to 9.9, P < .001; and of invasive breast cancer during lifetime: OR = 5.3, 95% CI = 2.0 to 14.3, P < .001). Conclusions Many women with newly diagnosed DCIS have inaccurate perceptions of the breast cancer risks that they face, and anxiety is particularly associated with these inaccurate perceptions.
To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this ...complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17-516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman's rho, 0.42; P < 10
) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease.
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