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.
Targeted Agent Use in Cancer Patients at the End of Life Hui, David, MD, MSc, FRCPC; Karuturi, Meghan Sri, MD; Tanco, Kimberson Cochien, MD ...
Journal of pain and symptom management,
07/2013, Letnik:
46, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract Context The use of targeted therapy at the end of life has not been well characterized. Objectives To determine the frequency and predictors of targeted therapy use in the last days of life. ...Methods All adult patients residing in the Houston area who died of advanced cancer between September 1, 2009 and February 28, 2010 and had contact with our institution within the last three months of life were included. We collected baseline demographics and data on chemotherapy and targeted agents. Results Eight hundred sixteen patients were included: average age 62 years (range 21–97), female 48% and white 61%. The median interval between the last treatment and death was 47 (interquartile range IQR 21–97) days for targeted agents and 57 (IQR 26–118) days for chemotherapeutic agents. Within the last 30 days of life, 116 (14%) patients received targeted agents and 147 (18%) received chemotherapy. Regimens given in the last 30 days of life included a median of one (IQR 1–2) chemotherapeutic or targeted agent and 43 (5%) patients receiving targeted agents had concurrent chemotherapy. The most common targeted agents in the last 30 days of life were erlotinib ( n = 25), bevacizumab ( n = 20), rituximab ( n = 11), gemtuzumab ( n = 8), and temsirolimus ( n = 8). On multivariate analysis, younger age (odds ratio OR 0.98 per year, P = 0.01), hematologic malignancy (OR = 6.1, P < 0.001), and lung malignancy (OR = 2.6, P = 0.05) were associated with increased targeted agent use in the last 30 days of life. Conclusion Targeted agents were used as often as chemotherapy at the end of life, particularly among younger patients and those with hematologic malignancies. Guidelines on targeted therapy use at the end of life are needed.
Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight ...breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer.
The maintenance of pluripotency and specification of cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets of genes ...through both activation and repression. The transcriptional repressor RE1-silencing transcription factor (REST) plays important but distinct regulatory roles in embryonic (ESC) and neural (NSC) stem cells. We investigated how these distinct biological roles are effected at a genomic level. We present integrated, comparative genome- and transcriptome-wide analyses of transcriptional networks governed by REST in mouse ESC and NSC. The REST recruitment profile has dual components: a developmentally independent core that is common to ESC, NSC, and differentiated cells; and a large, ESC-specific set of target genes. In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog. We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype.
A major question in systems biology is how to identify the core gene regulatory circuit that governs the decision-making of a biological process. Here, we develop a computational platform, named ...NetAct, for constructing core transcription factor regulatory networks using both transcriptomics data and literature-based transcription factor-target databases. NetAct robustly infers regulators' activity using target expression, constructs networks based on transcriptional activity, and integrates mathematical modeling for validation. Our in silico benchmark test shows that NetAct outperforms existing algorithms in inferring transcriptional activity and gene networks. We illustrate the application of NetAct to model networks driving TGF-β-induced epithelial-mesenchymal transition and macrophage polarization.
The evolutionally conserved MAPK Sty1 and bZIP transcriptional activator Atf1 are known to play a pivotal role in response to the reactive oxygen species in S. pombe. However, it is unclear whether ...all of the H(2)O(2)-induced genes are directly regulated by the Sty1-Atf1 pathway and involved in growth fitness under H(2)O(2)-induced stress conditions.
Here we present the study on ChIP-chip mapping of the genomic binding sites for Sty1, Atf1, and the Atf1's binding partner Pcr1; the genome-wide transcriptional profiling of the atf1 and pcr1 strains in response to H(2)O(2); and the phenotypic assessment of approximately 90 Atf1/Pcr1-bound or unbound genes for growth fitness under H(2)O(2) conditions. ChIP-chip analysis shows that Atf1 and Pcr1 binding sites are overlapped in the genome and constitutively present before H(2)O(2) stress. On the other hand, Sty1 recruitment primarily occurs at the Atf1/Pcr1 binding sites and is induced by H(2)O(2). We found that Atf1/Pcr1 is clearly responsible for the high-level transcriptional response to H(2)O(2). Furthermore, phenotypic assessment indicates that among the H(2)O(2)-induced genes, Atf1/Pcr1-bound genes exhibit a higher likelihood of functional requirement for growth fitness under the stress condition than the Atf1/Pcr1-unbound genes do. Notably, we found that the Atf1/Pcr1-bound genes regardless of their responsiveness to H(2)O(2) show a high probability of requirement for growth fitness.
Together, our analyses on global mapping of protein binding sites, genome-wide transcriptional profiling, and phenotypic assessment provide insight into mechanisms for global transcriptional regulation by the Sty1-Atf1 pathway in response to H(2)O(2)-induced reactive oxygen species.
Background
This study explores the incidence of patient‐reported major toxicity—symptoms rated “moderate,” “severe,” or “very severe”—for chemotherapy regimens commonly used in early breast cancer.
...Patients and Methods
Female patients aged 21 years or older completed a validated Patient‐Reported Symptom Monitoring instrument and rated 17 symptoms throughout adjuvant or neoadjuvant chemotherapy. Fisher's exact tests compared differences in percentages in symptom ratings, and general linear regression was used to model the incidence of patient‐reported major toxicity.
Results
In 152 patients, the mean age was 54 years (range, 24–77), and 112 (74%) were white; 51% received an anthracycline‐based regimen. The proportion of patients rating fatigue, constipation, myalgia, diarrhea, nausea, peripheral neuropathy, and swelling of arms or legs as a major toxicity at any time during chemotherapy varied significantly among four chemotherapy regimens (p < .05). The mean (SD) number of symptoms rated major toxicities was 6.3 (3.6) for anthracycline‐based and 4.4 (3.5) for non‐anthracycline‐based regimens (p = .001; possible range, 0–17 symptoms). Baseline higher body mass index (p = .03), patient‐reported Karnofsky performance status ≤80 (p = .0003), and anthracycline‐based regimens (p = .0003) were associated with greater total number of symptoms rated major toxicities (alternative model: chemotherapy duration, p < .0001). Twenty‐six percent of dose reductions (26 of 40), 75% of hospitalizations (15 of 20), and 94% of treatment discontinuations (15 of 16) were in anthracycline‐based regimens.
Conclusion
Capturing multiple toxicity outcomes throughout chemotherapy enables oncologists and patients to understand the range of side effects as they discuss treatment efficacies. Continuous symptom monitoring may aid in the timely development of interventions that minimize toxicity and improve outcomes.
Implications for Practice
This study investigated patient‐reported toxicities for 17 symptoms recorded prospectively during adjuvant and neoadjuvant chemotherapy regimens for early breast cancer. An analysis of four commonly used chemotherapy regimens identified significant differences among regimens in both individual symptoms and total number of symptoms rated moderate, severe, or very severe. Longer chemotherapy regimens, such as anthracycline‐based regimens followed by paclitaxel, had higher proportions of symptoms rated major toxicities. The inclusion of patient perspectives on multiple toxicity outcomes at the same time at multiple time points during chemotherapy has the potential for improving patient‐provider communication regarding symptom management, patient satisfaction, and long‐term clinical outcomes.
摘要
背景。本研究探索了在常用于治疗早期乳腺癌的化疗方案中患者报告的主要毒性(即被评为“中度”、“重度”或“极重度”的症状)的发生率。
患者和方法。年满 21 岁或以上的女性患者填写一份经验证的患者报告的症状监测文件并对辅助或新辅助化疗期间的 17 个症状进行评级。Fisher's精确检验对症状评级百分比之间的差异进行比较，一般线性回归用于模拟患者报告的主要毒性的发生率。
结果。在 152 名患者中，平均年龄为 54 岁(范围介于 24–77 岁之间)，112 名患者 (74%) 为白种人；51% 的患者接受蒽环类方案治疗。在化疗期间的任何时间将疲劳、便秘、肌痛、腹泻、恶心、周围神经病变以及手臂或腿部肿胀评为主要毒性的患者的比例在 4 个化疗方案中显著不同 (p < 0.05)。在蒽环类方案和非蒽环类方案中，被评为主要毒性的症状的平均数 (SD) 分别为 6.3 (3.6) 和 4.4 (3.5)(p = 0.001；可能的范围，0–17 个症状)。基线较高的体质量指数 (p = 0.03)、患者报告的 Karnofsky 体力状态 ≤80 (p = 0.000 3) 以及蒽环类方案 (p = 0.000 3) 与被评为主要毒性的症状的总数较高相关(替代模式:化疗持续时间，p < 0.000 1)。在蒽环类方案中，剂量减少占 26%(40 名患者中的 26 名患者)，住院治疗占 75%(20 名患者中的 15 名患者)，治疗中断占 94%(16 名患者中的 15 名患者)。
结论。获取化疗过程中的多种毒性结果，可令肿瘤学家和患者在讨论治疗有效性时了解副作用的范围。持续的症状监测可能有助于及时地制定可以最大限度地减少毒性并改进预后的干预措施。
《肿瘤学家》
实践意义:本研究调查了患者报告的早期乳腺癌辅助和新辅助化疗方案中前瞻性记录的 17 个症状的毒性。针对 4 个常用化疗方案的分析在单项症状和被评为“中度”、“重度”或“极重度”的症状的总数方面确定了方案之间的显著差异。在较长的化疗方案中，如后续采用紫杉醇治疗的蒽环类方案，被评为主要毒性的症状占有较高的比例。同时，在化疗期间的多个时间点加入患者关于多种毒性结果的看法，这可能会改进患者和医疗服务提供者之间有关症状管理、患者满意度以及长期临床预后的沟通。
This article focuses on the incidence of patient‐reported major toxicity for chemotherapy regimens commonly used in breast cancer, especially considering the need for patient‐centered assessments of treatment tolerability as an important complement to the NCI's CTCAE.
The diameter of biodegradable particles used to coencapsulate immunostimulants and subunit vaccines affects the magnitude of memory CD8+ T cells generated by systemic immunization. Possible effects ...on the magnitude of CD8+ T cells generated by mucosal immunization or memory subsets that potentially correlate more strongly with protection against certain pathogens, however, are unknown. In this study, we conjugated our novel host-derived mucosal immunostimulant, EP67, to the protective MCMV CTL epitope, pp89, through a lysosomal protease-labile double arginine linker (pp89-RR-EP67) and encapsulated in PLGA 50:50 micro- or nanoparticles. We then compared total magnitude, effector/central memory (CD127/KRLG1/CD62L), and IFN-γ/TNF-α/IL-2 secreting subsets of pp89-specific CD8+ T cells as well as protection of naive female BALB/c mice against primary respiratory infection with MCMV 21 days after respiratory immunization. We found that decreasing the diameter of encapsulating particle from ∼5.4 μm to ∼350 nm (i) increased the magnitude of pp89-specific CD8+ T cells in the lungs and spleen; (ii) partially changed CD127/KLRG1 effector memory subsets in the lungs but not the spleen; (iii) changed CD127/KRLG1/CD62L effector/central memory subsets in the spleen; (iv) changed pp89-responsive IFN-γ/TNF-α/IL-2 secreting subsets in the lungs and spleen; (v) did not affect the extent to which encapsulation increased efficacy against primary MCMV respiratory infection over unencapsulated pp89-RR-EP67. Thus, although not observed under our current experimental conditions with MCMV, varying the diameter of nanoscale biodegradable particles may increase the efficacy of mucosal immunization with coencapsulated immunostimulant/subunit vaccines against certain pathogens by selectively increasing memory subset(s) of CD8+ T cells that correlate the strongest with protection.
Immunotherapy has revolutionized the treatment of patients with advanced melanoma as well as other cancers. Most studies, whether of interleukin-2 or checkpoint inhibitor therapies, have limited ...follow-up after 5 years, making the incidence of late relapses uncertain. In addition, the incidence of second primary melanomas in patients with stage IV melanoma treated with immunotherapy has rarely been reported.
We performed a single-institution retrospective study of stage IV melanoma patients treated with interleukin-2 or checkpoint inhibitors over the period from 1992 to 2013. We found 59 patients alive and in remission 5 years after the beginning of immunotherapy and reviewed their subsequent clinical course.
This 59-patient cohort had a median follow-up of 13.1 years, with 36 patients followed up for at least 10 years. Four patients (6.8%) had relapses of their metastatic melanoma at 5, 8, 15, and 17 years after starting the successful immunotherapy. Three of the four are still alive. Only one patient in 690 patient-years of observation had a second primary invasive melanoma.
Although late relapses after immunotherapy for melanoma do occur, we can conclude that the prognosis of stage IV melanoma patients in continuous remission 5 years after starting immunotherapy is excellent, with a progression-free survival of approximately 85% and a melanoma-specific survival of approximately 95% at 20 years in our series. Our incidence of second primary melanomas is lower than usually reported. These results have important implications regarding the follow-up of stage IV melanoma patients successfully treated with immunotherapy.
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