Hypersensitivity Reactions to Taxanes: A Multicenter Study for Outcomes and Safety of Rapid Drug Desensitization.

PURPOSE: Taxanes can cause hypersensitivity reactions (HSRs), which pose a significant challenge in the treatment of malignancies. Patients who are eligible for rapid drug desensitization (RDD) can continue treatment; however, some patients experience breakthrough reactions (BTRs). Data about risk factors for BTRs during RDDs in patients with HSRs to taxanes are limited. METHODS: This was a multicenter, retrospective study of patients with immediate-HSRs to taxanes. Initial HSRs were classified as grade 1, 2, or 3 based on severity. Prick/intradermal skin tests were performed with implicated taxanes. A 12-step protocol was used during RDD. RESULTS: The study comprised 75 patients (F/M: 63/12, mean age 49.92 ± 11.72 years, 43 HSRs to paclitaxel, 32 HSRs to docetaxel). The majority of reactions (86.7%) occurred during the first or second exposure. The prevalence of drug allergy history was higher in patients with paclitaxel HSR than in those with docetaxel HSR, although it was not statistically significant (23.3% vs. 6.3%). The initial HSRs were mostly grade 2 (n = 50, 66.7%) or grade 3 (n = 22, 29.3%). Skin tests with implicated taxanes were done on 48 patients, and the rate of positive response in patients with grade 1, 2, and 3 initial HSRs were 50%, 17.6%, and 16.7%, respectively. . A total of 255 RDDs were completely performed, although BTRs occurred in 27 (grade 1, 55.6%; grade 2, 40.7%; grade 3, 3.7%). There were no statistically significant correlations between the risk of BTR and age, drug cycle, gender, positivity of skin test or atopy. The step reduction was successfully done on 9 eligible patients with mild or moderate HSRs during the 12-step RDDs. CONCLUSIONS: Our experience demonstrates a 100% success rate in completing the 255 RDDs for taxanes, affirming the safety and efficacy of the RDD within the study population.

Quality evaluation of compounds in leaves of six Taxus species based on UPLC-MS/MS and chemometrics.

Introduction: Taxus species are used as medicinal plants all over the world. The leaves of Taxus species are sustainable medicinal resources that are rich in taxoids and flavonoids. However, traditional identification methods cannot effectively identify Taxus species on the basis of leaces used as raw medicinal materials, because their appearance and morphological characteristics are almost the same, and the probability of error identification increases in accordance with the subjective consciousness of the experimenter. Moreover, although the leaves of different Taxus species have been widely used, their chemical components are similar and lack systematic comparative research. Such a situation is challenging for quality assessment. Materials and methods: In this study, ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry combined with chemometrics was applied for the simultaneous determination of eight taxoids, four flavanols, five flavonols, two dihydroflavones, and five biflavones in the leaves of six Taxus species, namely, T. mairei, T. chinensis, T. yunnanensis, T. wallichiana, T. cuspidata, and T. media. Chemometric methods, including hierarchical cluster analysis, principal component analysis, orthogonal partial least squares-discriminate analysis, random forest iterative modeling, and fisher linear discriminant analysis, were utilized to differentiate and evaluate the six Taxus species. Results: This proposed method exhibited good linearity (R 2 = 0.9999-0.9972) with a lower quantification limits of 0.94-3.05 ng/mL for all analytes. The intra- and inter-day precisions were within 6.83%. Six compounds, namely, 7-xylosyl-10-deacetyltaxol, ginkgetin, rutin, aromadendrin, 10-deacetyl baccatin III, and epigallocatechin, were identified through chemometrics for the first time. These compounds can be used as important chemical markers to distinguish the above six Taxus species rapidly. Conclusion: This study established a method for determination of the leaves of six Taxus species, and revealing the differences in the chemical components of these six Taxus species.

Profiling of Taxoid Compounds in Plant Cell Cultures of Different Species of Yew (Taxus spp.).

Plant cell cultures of various yew species are a profitable source of taxoids (taxane diterpenoids) with antitumor activity. So far, despite intensive studies, the principles of the formation of different groups of taxoids in cultured in vitro plant cells have not been fully revealed. In this study, the qualitative composition of taxoids of different structural groups was assessed in callus and suspension cell cultures of three yew species (Taxus baccata, T. canadensis, and T. wallichiana) and two T. × media hybrids. For the first time, 14-hydroxylated taxoids were isolated from the biomass of the suspension culture of T. baccata cells, and their structures were identified by high-resolution mass spectrometry and NMR spectroscopy as 7ß-hydroxy-taxuyunnanin C, sinenxane C, taxuyunnanine C, 2α,5α,9α,10ß,14ß-pentaacetoxy-4(20), 11-taxadiene, and yunnanxane. UPLC-ESI-MS screening of taxoids was performed in more than 20 callus and suspension cell lines originating from different explants and grown in over 20 formulations of nutrient media. Regardless of the species, cell line origin, and conditions, most of the investigated cell cultures retained the ability to form taxane diterpenoids. Nonpolar 14-hydroxylated taxoids (in the form of polyesters) were predominant under in vitro culture conditions in all cell lines. These results, together with the literature data, suggest that dedifferentiated cell cultures of various yew species retain the ability to synthesize taxoids, but predominantly of the 14-OH taxoid group compared to the 13-OH taxoids found in plants.

[Peripheral neuropathy, onycholysis and health-related quality of life in womens with breast cancer treated with taxanes. Prospective longitudinal study.] / Neuropatía periférica, onicólisis y calidad de vida en mujeres con cáncer de mama en tratamiento con taxanos. Estudio longitudinal prospectivo.

OBJECTIVE: Peripheral neuropathy and onycholysis are adverse events produced by taxanes in breast cancer that persist even after the end of treatment and negatively influence quality of life. The objectives of the study were to describe these side effects and the degree of involvement and relating them to the drug doses received. METHODS: Prospective, cross-sectional study of in 50 womens dignosed of breast cancer, treated with docetaxel and paclitaxel in Hospital Universitario Miguel Servet in Zaragoza (Aragón, Spain). CTCAE v.5.0 scale and Semes Weinsten test were used to evaluate peripheral neuropathy and onycholysis. ECOG scale was performed to measure the health-related quality of life. Study variables were evaluated before-during treatment and 1 and 6 months after finish treatment. Statistical analysis was performed using Jamovi 1.2®. For the relationship of the qualitative variables, the chi-square, Fisher's exact test, Mc's test were used. Nemar and the Odds Ratio test. Effects were considered significant if p<0.05. RESULTS: 43 subjects were included. During treatment the 9.8 presented motor neuropathy and 12.2% sensitive neuropathy, 37.2% onycholisis in upper extremities and 39.5% in lower extremities (χ2=11.3; p<0.001 / χ2=13.0; p<0.001) and 38.1% a health related quality of live limited in excessive activities (χ2=10.3; p=0.001). Post-treatment evaluation the 20.9% presented motor neuropathy and 32.6% sensitive neuropathy (χ2=3.57; p=0.059 / χ2=6.23; p=0.013), the 86% onycholisis in upper extremities and lower extremities (χ2=6.07; p=0.048 / χ2=10.1; p=0.006) and 58.5% a health related quality of live limited in excessive activities (χ2=8.47; p=0.014). 6 month later, the initials parameters were not recuperated. CONCLUSIONS: Taxanes have a negative impact on the health-related quality of life in patients, even 6 months after finishing treatment due to the peripheral neuropathy and onycholysis that they cause.

OBJETIVO: La neuropatía periférica y la onicólisis son eventos adversos producidos por los taxanos en el cáncer de mama, que perduran incluso habiendo finalizado el tratamiento e influyendo negativamente en la calidad de vida. Los objetivos del estudio fueron describir estos efectos secundarios, midiendo el grado de afectación, y relacionarlos con las dosis de fármaco recibidas. METODOS: Se realizó un estudio observacional, longitudinal prospectivo con muestreo consecutivo inicial de concuenta mujeres con cáncer de mama en tratamiento con docetaxel y/o paclitaxel en el Hospital Universitario Miguel Servet de Zaragoza (Aragón, España). Para la valoración de la neuropatía periférica (motora y sensitiva) se utilizó la escala CTCAE v.5.0 y el test de Semmes Weinsten. La valoración de la calidad de vida relacionada con la salud se midió mediante la escala ECOG. Se realizaron valoraciones previo-durante-post y a los 6 meses de haber finalizado el tratamiento. El análisis estadístico se realizó mediante Jamovi 1.2®. Para la relación de las variables cualitativas se utilizó la chi-cuadrado, el test exacto de Fisher, el test de Mc.Nemar y el test de Odds Ratio. Los efectos se consideraron significativos si p<0,05. RESULTADOS: Se incluyeron finalmente 43 mujeres. Durante el tratamiento, el 9,8% presentó neuropatía motora y el 12,2% neuropatía sensitiva, el 37,2% onicólisis en extremidades superiores y el 39,5% en inferiores (χ2=11,3; p<0,001 / χ2=13,0; p<0,001), y el 38,1% una calidad de vida restringida a actividad exagerada (χ2=10,3; p=0,001). En la valoración postratamiento, el 20,9% presentó neuropatía motora y el 32,6% neuropatía sensitiva (χ2=3,57; p=0,059 / χ2=6,23; p=0,013), el 86% onicólisis en extremidades superiores y el 90,7% en inferiores (χ2=6,07; p=0,048 / χ2=10,1; p=0,006) y el 58,5% al menos una calidad de vida restringida a actividad exagerada (χ2=8,47; p=0,014). A los seis meses no se recuperaron los valores iniciales de evaluación. CONCLUSIONES: Los taxanos repercuten negativamente en la calidad de vida de las mujeres incluso a los seis meses tras finalizar el tratamiento debido a la neuropatía periférica y la onicólisis que provocan.

Neuropatía periférica, onicólisis y calidad de vida en mujeres con cáncer de mama en tratamiento con taxanos. Estudio longitudinal prospectivo / Peripheral neuropathy, onycholysis and health-related quality of life in womens with breast cancer treated with taxanes. Prospective longitudinal study

FUNDAMENTOS: La neuropatía periférica y la onicólisis son eventos adversos producidos por los taxanos en el cáncer de mama, que perduran incluso habiendo finalizado el tratamiento e influyendo negativamente en la calidad de vida. Los objetivos del estudio fueron describir estos efectos secundarios, midiendo el grado de afectación, y relacionarlos con las dosis de fármaco recibidas. MÉTODOS: Se realizó un estudio observacional, longitudinal prospectivo con muestreo consecutivo inicial de concuenta mujeres con cáncer de mama en tratamiento con docetaxel y/o paclitaxel en el Hospital Universitario Miguel Servet de Zaragoza (Aragón, España). Para la valoración de la neuropatía periférica (motora y sensitiva) se utilizó la escala CTCAE v.5.0 y el test de Semmes Weinsten. La valoración de la calidad de vida relacionada con la salud se midió mediante la escala ECOG. Se realizaron valoraciones previo-durante-post y a los 6 meses de haber finalizado el tratamiento. El análisis estadístico se realizó mediante Jamovi 1.2 ®. Para la relación de las variables cualitativas se utilizó la chi-cuadrado, el test exacto de Fisher, el test de Mc.Nemar y el test de Odds Ratio. Los efectos se consideraron significativos si p<0,05. RESULTADOS: Se incluyeron finalmente 43 mujeres. Durante el tratamiento, el 9,8% presentó neuropatía motora y el 12,2% neuropatía sensitiva, el 37,2% onicólisis en extremidades superiores y el 39,5% en inferiores (χ2 =11,3; p<0,001 / χ2 =13,0; p<0,001), y el 38,1% una calidad de vida restringida a actividad exagerada (χ2 =10,3; p=0,001). En la valoración postratamiento, el 20,9% presentó neuropatía motora y el 32,6% neuropatía sensitiva (χ2 =3,57; p=0,059 / χ2 =6,23; p=0,013), el 86% onicólisis en extremidades superiores y el 90,7% en inferiores (χ2 =6,07; p=0,048 / χ2 =10,1; p=0,006) y el 58,5% al menos una calidad de vida restringida a actividad exagerada(χ2=8,47; p=0,014). A los seis meses no se recuperaron los valores iniciales...(AU)

BACKGROUND: Peripheral neuropathy and onycholysis are adverse events produced by taxanes in breast cancer that persist even after the end of treatment and negatively influence quality of life. The objectives of the study were to describe these side effects and the degree of involvement and relating them to the drug doses received. METHODS: Prospective, cross-sectional study of in 50 womens dignosed of breast cancer, treated with docetaxel and paclitaxel in Hospital Universitario Miguel Servet in Zaragoza (Aragón, Spain). CTCAE v.5.0 scale and Semes Weinsten test were used to evaluate peripheral neuropathy and onycholysis. ECOG scale was performed to measure the health-related quality of life. Study variables were evaluated before-during treatment and 1 and 6 months after finish treatment. Statistical analysis was performed using Jamovi 1.2® . For the relationship of the qualitative variables, the chi-square, Fisher’s exact test, Mc’s test were used. Nemar and the Odds Ratio test. Effects were considered significant if p<0.05. RESULTS: 43 subjects were included. During treatment the 9.8 presented motor neuropathy and 12.2% sensitive neuropathy, 37.2% onycholisis in upper extremities and 39.5% in lower extremities (χ2 =11.3; p<0.001 / χ2 =13.0; p<0.001) and 38.1% a health related quality of live limited in excessive activities (χ2 =10.3; p=0.001). Post-treatment evaluation the 20.9% presented motor neuropathy and 32.6% sensitive neuropathy (χ2 =3.57; p=0.059 / χ2 =6.23; p=0.013), the 86% onycholisis in upper extremities and lower extremities (χ2 =6.07; p=0.048 / χ2 =10.1; p=0.006) and 58.5% a health related quality of live limited in excessive activities (χ2 =8.47; p=0.014). 6 month later, the initials parameters were not recuperated. CONCLUSIONS: Taxanes have a negative impact on the health-related quality of life in patients, even 6 months after finishing treatment due to the peripheral neuropathy and onycholysis that they cause.(AU)

Taxoids-rich extract from Taxus wallichiana alleviates high-fat diet-induced insulin resistance in C57BL/6 mice through inhibition of low-grade inflammation.

The needle powder of Taxus wallichiana is in use for the management of diabetes and inflammation-related complications in the Indian and Chinese Systems of Traditional Medicine but the lack of proper pharmacological intervention has prompted us to investigate the pharmacological mechanism against inflammation-induced insulin resistance in high-fat diet-fed C57BL/6 mice. Hexane (Tw-H), chloroform (Tw-C), and ethyl acetate (Tw-EA) extracts were prepared from a needle of T. wallichiana and its effect on glucose uptake against TNF-α-induced insulin resistance in skeletal muscle cells was studied. Among all, Tw-EA extract has shown promising glucose uptake potential. Tw-EA treatment is also able to decrease the lipid accumulation in adipocytes. Chemical signature of Tw-EA using HPLC showed the presence of taxoids. Efficacy of taxoids-rich extract from T. wallichiana (Tw-EA) was further validated in in vivo system against high-fat diet (HFD)-induced insulin resistance in C57BL/6 mice. Oral treatment of Tw-EA showed significant reduction in blood glucose, pro-inflammatory cytokine production and body weight gain when compared with vehicle-treated HFD-induced insulin resistance in C57BL/6 mice. Histopathology and immunohistochemistry study in skeletal muscle and adipose tissue revealed that oral treatment of Tw-EA is able to reduce the infiltration of inflammatory cells in skeletal muscles, ameliorate the hypertrophy in adipose tissue and upregulate the GLUT4 protein expression. Treatment with Tw-EA significantly up-regulated mRNA expression of insulin signaling pathway (IRS-1, PI3K, AKT, GLUT 4). This study suggested the beneficial effect of taxoids-rich extract from Taxus wallichiana against the inflammation-associated insulin resistance condition.

Identification of genes associated with biosynthesis of bioactive flavonoids and taxoids in Taxus cuspidata Sieb. et Zucc. plantlets exposed to UV-B radiation.

UV-B radiation is a typical environmental stressor that can promote phytochemical accumulation in plants. Taxus species are highly appreciated due to the existence of bioactive taxoids (especially paclitaxel) and flavonoids. However, the effect of UV-B radiation on taxoid and flavonoid biosynthesis in Taxus cuspidata Sieb. et Zucc. is largely unknown. In the present work, the accumulation of taxoids and flavonoids in T. cuspidata plantlets was significantly induced by 12 and 24 h of UV-B radiation (3 W/m2), and a large number of significantly differentially expressed genes were obtained via transcriptomic analysis. The significant up-regulation of antioxidant enzyme- and flavonoid biosynthesis-related genes (phenylalanine ammonia lyase 1, chalcone synthase 2, flavonol synthase 1, and flavonoid 3', 5'-hydroxylase 2), suggested that UV-B might cause the oxidative stress thus promoting flavonoid accumulation in T. cuspidata. Moreover, the expression of some genes related to jasmonate metabolism and taxoid biosynthesis (taxadiene synthase, baccatin III-3-amino 3-phenylpropanoyltransferase 1, taxadiene-5α-hydroxylase, and ethylene response factors 15) was significantly activated, which indicated that UV-B might initiate jasmonate signaling pathway that contributed to taxoid enhancement in T. cuspidata. Additionally, the identification of some up-regulated genes involved in lignin biosynthesis pathway indicated that the lignification process in T. cuspidata might be stimulated for defense against UV-B radiation. Overall, our findings provided a better understanding of some potential key genes associated with flavonoid and taxoid biosynthesis in T. cuspidata exposed to UV-B radiation.

Potent antitumor activity of novel taxoids in anaplastic thyroid cancer.

PURPOSE: Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancers and it is rapidly fatal without any effective therapeutic regimens. There are some clinical trials showing that paclitaxel-based chemotherapy for ATC can achieve a relatively high response rate and low incidence of adverse reaction. The aim of this study was to evaluate potential therapeutic activity of novel taxoids in ATC cells. METHODS: We evaluated antitumor activity of five novel 3'-difluorovinyltaxoids (DFV-taxoids) in anaplastic thyroid cancer cells by a series of in vitro and in vivo experiments. Besides, we also explored the potential mechanism underlying the difference among the taxoids and paclitaxel by molecular docking and tubulin polymerization assays. RESULTS: Our data showed that these novel DFV-taxoids were more effective than paclitaxel in ATC cell lines and xenografts, as reflected by the inhibition of cell proliferation, colony formation and tumorigenic potential in nude mice, and the induction of G2/M phase arrest and cell apoptosis. Using tubulin polymerization assays and molecular docking analysis, we found that these DFV-taxoids promoted more rapid polymerization of ß-tubulin than paclitaxel. CONCLUSIONS: Our data demonstrate that these novel taxoids exhibit stronger antitumor activity in ATC cells than paclitaxel, thereby providing a promising therapeutic strategy for the patients with ATC.

Targeted therapy of Apt-siRNA combining with docetaxel for PSMA-positive prostate cancer and monitoring imaging of 99Tc m-Apt-siRNA / 中华核医学与分子影像杂志

Objective:Apt-A10-3.2 (aptamer of prostate specific membrane antigen (PSMA)) can be used as a specific ligand for early diagnosis and targeted treatment of prostate cancer. Mouse double minute 2 homolog (MDM2) is closely related to the malignancy of prostate cancer, and MDM2 small interfering RNA (siRNA) can silence MDM2 gene through RNA interference. To design a novel chimera of PSMA Apt-MDM2 siRNA and combine it with docetaxel (DTX) to explore a new diagnosis and treatment model combining targeted therapy of PSMA-positive prostate cancer with 99Tc m-chimera imaging monitoring. Methods:Apt-siRNA were obtained by covalent connection of PSMA Apt-A10-3.2 and MDM2 siRNA, which was combined with DTX to treat PSMA-positive prostate cancer cell lines (22RV1 and LNCaP). Cell lines were treated with Apt-siRNA alone or in combination with DTX. The levels of MDM2 and apoptosis-related proteins (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), poly ADP-ribose polymerase (PARP), caspase-3) were detected by Western blot, which were used to evaluate the therapeutic effect. Fifteen BALB/c mice bearing 22RV1 xenografts were treated with PBS, DTX+ Apt-siRNA (200 pmol) and DTX+ Apt-siRNA (400 pmol), respectively. Tumor volume and MDM2 level were observed, and 99Tc m-Apt-siRNA SPECT imaging was performed to obtain the tumor/muscle (T/M) ratio. One-way analysis of variance, Tukey′s test and linear regression analysis were used for data analysis. Results:The levels of MDM2 protein were significantly decreased by Apt-siRNA (0.25±0.02, F=183.40, P<0.001; 0.56±0.03, F=37.15, P<0.001) in 22RV1 and LNCaP cells. After the treatment of Apt-siRNA+ DTX, the levels of Bcl-2 were significantly decreased, and the levels of Bax, PARP and caspase-3 were significantly increased. MDM2 protein level (400 pmol: 0.59±0.12; F=49.99, P=0.023) and tumor volume (400 pmol: (0.22±0.07) cm 3;F=71.30, P=0.039) were significantly inhibited by Apt-siRNA+ DTX in mice bearing 22RV1 xenografts. As for 99Tc m-Apt-siRNA SPECT imaging in vivo, T/M ratio of treatment group was significantly decreased (400 pmol: 2.07±0.22; F=34.99, P=0.022), and there was a linear regression relationship between T/M ratio and the expression level of MDM2 ( R2=0.875, P<0.001). Conclusion:Apt-siRNA combined with DTX can effectively inhibit the progression of prostate cancer, and realize visual targeted diagnosis and treatment of PSMA-positive prostate cancer by coupling radionuclide technetium.

Taxane-induced scleroderma: report of two cases / Esclerodermia inducida por taxanos: informe de dos casos

ABSTRACT Taxanes are a class of chemotherapeutic agents with common associated dermatologic adverse events, such as skin hyperpigmentation, hand-foot skin syndrome, paronychia and onycholysis. Taxane-induced scleroderma is rare. Few cases with skin findings resembling systemic sclerosis, have been reported after the administration of these agents. We report two cases with stage IV breast cancer, aged 66 and 71 years, who developed sclerodermic skin lesions in their extremities after starting treatment with placlitaxel and nabplaclitaxel respectively.

Los taxanos son agentes quimioterapéuticos cuyo uso se asocia a problemas dermatológicos tales como hiperpigmentación, síndrome manos-pies, paroniquia y onicolisis. La esclerodermia inducida por taxanos es rara, con pocos casos informados en la literatura. Informamos los casos de dos pacientes con cáncer de mama en estado IV, de 66 y 71 años, que desarrollaron lesiones esclerodérmicas en las extremidades después de ser tratadas con placlitaxel y nabplaclitaxel, respectivamente.

Omic analysis of the endangered Taxaceae species Pseudotaxus chienii revealed the differences in taxol biosynthesis pathway between Pseudotaxus and Taxus yunnanensis trees.

BACKGROUND: Taxol is an efficient anticancer drug accumulated in Taxus species. Pseudotaxus chienii is an important member of Taxaceae, however, the level of six taxoids in P. chienii is largely unknown. RESULTS: High accumulation of 10-DAB, taxol, and 7-E-PTX suggested that P. chienii is a good taxol-yielding species for large-scale cultivation. By the omics approaches, a total of 3,387 metabolites and 61,146 unigenes were detected and annotated. Compared with a representative Taxus tree (Taxus yunnanensis), most of the differentially accumulated metabolites and differential expressed genes were assigned into 10 primary and secondary metabolism pathways. Comparative analyses revealed the variations in the precursors and intermediate products of taxol biosynthesis between P. chienii and T. yunnanensis. Taxusin-like metabolites highly accumulated in P. chienii, suggesting a wider value of P. chienii in pharmaceutical industry. CONCLUSIONS: In our study, the occurrence of taxoids in P. chienii was determined. The differential expression of key genes involved in the taxol biosynthesis pathway is the major cause of the differential accumulation of taxoids. Moreover, identification of a number of differentially expressed transcription factors provided more candidate regulators of taxol biosynthesis. Our study may help to reveal the differences between Pseudotaxus and Taxus trees, and promote resource utilization of the endangered and rarely studied P. chienii.

Persistent taxane-induced neuropathy in elderly patients treated for localized breast cancer.

Breast cancer is the most common cancer among women. Localized breast cancer treatments involve taxanes which are often responsible for acute peripheral neuropathy. The persistence of taxane-induced peripheral neuropathy (TIPN) is scarcely described among elderly women. A monocenter historical cohort study including all women over 65 years of age treated between 2001 and 2016 with a taxane-based chemotherapy for localized breast cancer was carried out at the Paul Strauss Regional Comprehensive Cancer Center. All cases included were followed up for at least 2 years, deaths from causes unrelated to TIPN were excluded. We report on the frequency and risk factors and establish a prognostic score of persistent Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and 3 TIPN. Among the 302 included patients, 21% and 9% developed persistent TIPN of grade 2 and 3, respectively. Two patients died from complications of grade 3 TIPN. Risk factors of persistent grade 2 and higher neuropathy included age (P < .0001), body mass index (P < .0001), and diabetes (P = .0093). Persistent TIPN was more frequent with paclitaxel than docetaxel (OR = 5.43; P < .0001). Patients presenting all four major risk factors had a 97.2% probability of developing long-term symptoms against 1.2% for patients showing no risk factor. We therefore identified 3 prognostic groups. TIPN is a frequent and sometimes severe persistent side effect of breast cancer treatment among elderly women with a major impact on health-related quality of life. Chemotherapy regimens without taxane could therefore be a valid option in elderly patients with neurotoxicity risk factors.

Simultaneous determination of taxoids and flavonoids in twigs and leaves of three Taxus species by UHPLC-MS/MS.

Taxus species are highly concerned due to the presence of anticancer taxoids (especially paclitaxel) and health beneficial flavonoids. For the first time, an UHPLC-MS/MS method was developed for the simultaneous determination of seven taxoids and seven flavonoids in twigs and leaves of three Taxus species. The satisfactory separation of fourteen target compounds was achieved within 5 min of running time on an Agilent ZORBAX Eclipse Plus C18 column (50 mm × 2.1 mm I.D., 1.8 µm) using an acetonitrile-water gradient elution program. Mass transitions of all analytes in selected reaction monitoring acquisition mode were systematically optimized for obtaining the highest signal intensities. Regression equations of all analytes exhibited excellent linearities with coefficients higher than 0.9990, and the lowest limits of quantification of all analytes ranged from 0.01 to 1.66 ng/mL. The intra- and inter-day precisions (relative standard deviations) of all analytes were less than 4.17% for retention time and less than 7.42% for peak area, and the spiking standard recoveries of all analytes ranged from 96.85%-104.77%. By the aid of the proposed method, the distribution of fourteen target compounds in twigs and leaves of Taxus chinensis, Taxus cuspidata, and Taxus media was clearly figured out. Overall, the present work provided a rapid and valid UHPLC-MS/MS approach, which could not only be useful for quality control and applicability assessment of twigs and leaves of the three Taxus species in pharmaceutical and nutraceutical industries, but also offer a good reference for the systematic analysis of taxoids and flavonoids in other Taxus species.

Does the Sequence of Anthracycline and Taxane Matter? The NeoSAMBA Trial.

BACKGROUND: Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, there is no biological rationale that justifies this current standard of care. We compared a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting. PATIENTS AND METHODS: In a randomized, open-label, single-center phase II trial, women with inoperable, locally advanced, HER2-negative breast cancer were stratified by hormone receptor status and randomized to three cycles of docetaxel (T) followed by three cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus three cycles of FAC followed by three cycles of docetaxel. Surgery, radiotherapy, and adjuvant hormonal therapy were administered as per local guidelines. The primary endpoint was pathological complete response (pCR), and secondary endpoints included toxicity, event-free survival (EFS), and overall survival (OS). RESULTS: Treatment sequence did not improve pCR, which was 7% with T-FAC and 3% with FAC-T. However, after a median follow-up of 79 months, the 5-year EFS rate was 75.7% (95% confidence interval [CI], 65.4%-87.7%) with T-FAC and 48.2% (95% CI, 37.0%-62.7%) with FAC-T (hazard ratio [HR], 0.46; 95% CI, 0.26-0.81; log-rank p = .0054), and the 5-year OS rate was 89.7% (95% CI, 82.2%-97.8%) with T-FAC and 64.7% (95% CI, 53.6%-78.1%) with FAC-T (HR, 0.41; 95% CI, 0.22-0.78; p = .0052). There were no unexpected toxicities. CONCLUSION: We showed for the first time an improvement in EFS and OS with taxane-first compared with anthracycline-first sequencing chemotherapy in HER2-negative, locally advanced breast cancer. Confirmation of these results may have implications for clinical practice. This trial was registered with Clinicatrials.gov identifier NCT01270373. IMPLICATIONS FOR PRACTICE: The NeoSAMBA trial showed a benefit for taxane-first sequencing chemotherapy consistent with the systematic review of the literature as well as the larger Neo-tAnGo study. Many recent and current ongoing clinical trials have already followed this treatment strategy. As a taxane-before-anthracycline sequence carries neither an incremental cost nor an increased toxicity, and given the available literature on this issue, reinforced that taxane-first regimen can be easily incorporated into daily clinical practice while awaiting confirmation of these findings from larger trials.

Patient factors associated with discrepancies between patient-reported and clinician-documented peripheral neuropathy in women with breast cancer receiving paclitaxel: A pilot study.

PURPOSE: Discrepancies between clinicians' assessment of chemotherapy-induced peripheral neuropathy (CIPN) and patient-reported outcomes (PRO) have been described, though the underlying reasons are unknown. Our objective was to identify potential patient-specific factors associated with under-describing of CIPN to clinicians in women with non-metastatic breast cancer treated with paclitaxel. METHODS: Patients enrolled in an observational study (n = 60) completed weekly CIPN PRO using the EORTC CIPN20. Clinician-documented CIPN using the NCI CTCAE were abstracted from the electronic medical record and paired with CIPN20 data at weeks 7 and 10. Patients were classified as under-describers if their CIPN20 was above the 80th percentile of the CIPN20 distribution for that CTCAE grade from an independent clinical trial (N08CA). Demographics, Assessment of Survivor Concerns (ASC), Trust in Oncologist Scale (TiOS), and health literacy assessment were collected post-treatment via survey. Repeated measures cumulative logistic regression models were used to identify factors associated with under-describing CIPN. RESULTS: Forty-two women completed the survey (response rate 70%). Three and 9 patients were categorized as under-describers at weeks 7 and 10, respectively. Women who were not working (OR = 9.00, 95%CI 1.06-76.15), had lower income (OR = 7.04, 95%CI 1.5-32.99), and displayed higher trust in their oncologist's competence (OR = 1.29, 95%CI 1.03-1.62 for a 0.1-unit increase in score) were more likely to under-describe CIPN symptoms. CONCLUSIONS: This preliminary study identified non-working status, low income and trust in oncologist's competence as potential factors influencing under-description of CIPN to the clinical team. Further work is needed to clarify these relationships and test additional factors.

Reporting of paclitaxel-induced peripheral neuropathy symptoms to clinicians among women with breast cancer: a qualitative study.

PURPOSE: Cases of chemotherapy-induced peripheral neuropathy (CIPN) under-reporting have been sporadically described in the literature, but no studies have focused on actively examining this behavior. Our primary aim was to identify women who purposefully under-reported CIPN, along with reasons for doing so. A secondary aim was to explore factors enabling or hindering communication of CIPN to clinicians. METHODS: Semi-structured interviews were conducted with women with breast cancer who had received paclitaxel in a prospective observational study. The interview guide was developed based on factors hypothesized to influence side effect disclosure to clinicians. Interviews were recorded, transcribed verbatim, and thematically content analyzed. RESULTS: Thirty-four women were interviewed. Three main themes emerged from the analysis: (1) enablers of CIPN reporting (e.g., positive relationship with the oncology team, sufficient appointment time, existence of alternative communication channels to office visits, expectation of CIPN as a side effect); (2) deterrents to CIPN reporting (e.g., perception of need to complete the full course of therapy, fear of treatment discontinuation, lack of knowledge of long-term consequences of CIPN); and (3) balancing survival versus functional impairment due to CIPN. Women prioritized efficacy over CIPN until physical functioning was meaningfully affected. No patients reported purposeful CIPN under-reporting, but three women admitted having considered doing so. CONCLUSIONS: Despite the lack of evidence of CIPN withholding, women considered both the effectiveness and the toxicity of paclitaxel treatment, as well as beliefs about treatment and long-term consequences of CIPN and relationship with the oncology team, when deciding whether to report CIPN symptoms.

Synthesis and Cytotoxicity of 7,9-O-Linked Macrocyclic C-Seco Taxoids.

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.

Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method.

PURPOSE: This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR). MATERIALS AND METHODS: Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation. RESULTS: For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR. CONCLUSION: We successfully constructed a multi-study-derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.

Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR). MATERIALS AND METHODS: Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation. RESULTS: For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR. CONCLUSION: We successfully constructed a multi-study–derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.

Adjuvant chemotherapeutic treatment of 1650 patients with early breast cancer in routine care in Germany: data from the prospective TMK cohort study.

BACKGROUND: Several regimens for which efficacy was established in randomized controlled trials are recommended in current treatment guidelines for early breast cancer. However, knowledge on use and effectiveness of commonly administered chemotherapeutic agents in real-life care and across all breast cancer subtypes is limited. METHODS: The prospective, multicentre German TMK cohort study (Tumour Registry Breast Cancer) recruited patients in 148 oncology outpatient-centres. Data from 1650 patients who completed adjuvant chemotherapy were analysed regarding treatment regimens and taxane use from 2007 to 2014. The association of patient characteristics with application of taxane-free regimens was examined with a multivariate regression model. RESULTS: The preferred adjuvant treatment shifted from fluorouracil, anthracycline and cyclophosphamide containing regimens to anthracycline/taxane combinations. Taxane use increased for all subtypes, and the greatest rise was among node-negative patients. Older age, node-negativity, lower grading, HR-positive/HER2-negative subtype and earlier start year of therapy were significantly associated with taxane-free therapy. CONCLUSIONS: Treatment with anthracycline/taxane-based chemotherapy in Germany has been rising for every subtype. The increased taxane use reflects updated guideline recommendations over the past decade. Cohort studies like the TMK provide insight into real-life treatment of patients outside of clinical trials.