Synthesis of Isoamyl Fatty Acid Ester, a Flavor Compound, by Immobilized Rhodococcus Cutinase.

Isoamyl fatty acid esters (IAFEs) are widely used as fruity flavor compounds in the food industry. In this study, various IAFEs were synthesized from isoamyl alcohol and various fatty acids using a cutinase enzyme (Rcut) derived from Rhodococcus bacteria. Rcut was immobilized on methacrylate divinylbenzene beads and used to synthesize isoamyl acetate, butyrate, hexanoate, octanoate, and decanoate. Among them, Rcut synthesized isoamyl butyrate (IAB) most efficiently. Docking model studies showed that butyric acid was the most suitable substrate in terms of binding energy and distance from the active site serine (Ser114) γ-oxygen. Up to 250 mM of IAB was synthesized by adjusting reaction conditions such as substrate concentration, reaction temperature, and reaction time. When the enzyme reaction was performed by reusing the immobilized enzyme, the enzyme activity was maintained at least six times. These results demonstrate that the immobilized Rcut enzyme can be used in the food industry to synthesize a variety of fruity flavor compounds, including IAB.

Hypofractionated Partial Breast Irradiation With Intensity-Modulated Radiotherapy in Early Breast Cancer or Carcinoma In Situ: An Investigational Short-Term Analysis.

PURPOSE: This study aimed to analyze the treatment outcomes and adverse effects of moderately hypofractionated partial breast irradiation (PBI) in patients with early breast cancer. METHODS: In total, 473 patients with early breast cancer or carcinoma in situ were diagnosed with Tis or T1N0 disease and underwent PBI following breast-conserving surgery. All histologic tumor types, close surgical margins within 1 mm of the tumor, and multifocal tumors were included in this study. A radiation dose of 50 Gy in 20 fractions was delivered over 4 weeks using intensity-modulated radiotherapy technique. Dosimetric data, recurrence patterns, survival outcomes, and adverse events were retrospectively analyzed. RESULTS: During a median follow-up of 28.9 months, seven patients (1.5%) experienced ipsilateral breast tumor recurrence (IBTR). Two patients had regional recurrence, four patients developed contralateral breast cancer, and no distant metastases were observed. The locoregional recurrence rate in the ipsilateral breast was 1.8%. Two deaths occurred during the follow-up period, but were not attributed to breast cancer. The 2-year disease-free survival and 2-year overall survival rates were was 94.0% and 99.8%, respectively. Acute adverse events occurred in 131 patients (27.1%), and were distributed among all grades, with only two patients (0.4%) experiencing grade 3 events. Late adverse events were noted in 16 patients (3.4%), and were distributed among all grades, including grade 3 events in four patients (0.8%). No grade 4 or 5 events were observed. CONCLUSION: Hypofractionated PBI demonstrated favorable IBTR rates in patients with early breast cancer, with low incidence of acute and late toxicities in the short-term analysis.

A randomized controlled trial using surgical gloves to prevent chemotherapy-induced peripheral neuropathy by paclitaxel in breast cancer patients (AIUR trial).

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of taxane treatment and can significantly affect patient quality of life. Currently, there are no effective treatments to alleviate symptoms of CIPN; thus, starting with prevention steps in high-risk patients is considered advantageous. However, for these prevention steps to be applicable to all patients, their side effects or accompanying discomforts should be minimal, and the intervention cost-effective. Compression therapy can be considered a prevention intervention, and using surgical gloves is feasible and cost-effective (approximately $0.6 per pair). Although previous studies on compression therapy using surgical gloves have reported decreased incidence of PN, these studies were non-randomized, limited to nab-paclitaxel treatment, and involved the use of small gloves, which may have caused discomfort. Therefore, this study aimed to assess the preventive effects of compression therapy using normal-sized surgical gloves on CIPN in patients treated with paclitaxel. METHODS: This clinical trial is designed to evaluate the preventive effects of compression therapy using surgical gloves on CIPN in women with stage II-III breast cancer who received paclitaxel chemotherapy for at least 12 weeks. This multicenter, randomized-controlled, open-label study will be conducted in six academic hospitals. Patients with medication or a medical history related to neuropathy or hand disease will be excluded. The primary outcome will be the preventive effect of compression therapy using surgical gloves, measured based on changes in the neurotoxicity component of the Functional Assessment of Cancer Therapy-Taxane questionnaire. Furthermore, we will assess the National Cancer Institute's Common Terminology Criteria for Adverse Events grade of CIPN after 6 months. Notably, the estimated sample size, based on a p-value < 0.025 and statistical power of 0.9, will consist of 104 patients (52 per group), accounting for a 10% sample loss. DISCUSSION: This intervention can be easily implemented in clinical practice and may serve as a preventive strategy for CIPNs with strong patient adherence. If successful, this intervention could improve the quality of life and treatment adherence in patients receiving chemotherapy that can induce PN, extending beyond paclitaxel treatment alone. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05771974; Registered on March 16, 2023.

Prognostic factors after isolated ipsilateral local and regional recurrence in HER2-negative luminal breast cancer: a multi-center retrospective study.

BACKGROUND: Although the incidence of isolated ipsilateral local and regional recurrence (IILRR) in human epidermal growth factor 2 (HER2)-negative luminal breast cancer is low, it is important because of its potential risk of distant metastasis and breast cancer related mortality. The aim of this study was to investigate prognostic factor and survival of IILRR using a large multi-center cohort. METHODS: Data on patients with HER2-negative luminal breast cancer between 2005 and 2015 were retrieved. The endpoint was IILRR rate, post-recurrence progression-free survival (P-PFS), and post-recurrence overall survival (P-OS). Prognostic factors for progression and overall survival (OS) after IILRR were assessed by multivariate analysis. RESULTS: Eighty (2.37%) patients experienced IILRR. Of them, 27 (33.7%) experienced a disease progression, including 23 (85.2%) who had distant metastasis. The median DFS was 48.5 months (range, 4-138 months). In 72.5% of cases, the first IILRR occurred after 3 years. Estimated 5-year P-PFS rates were 86.2%, 69.7%, 69.0%, 42.7%, and 82.2% for patients with age < 40 at diagnosis (p = 0.015), T1 stage (p = 0.012), stage I (p < 0.001), lymphovascular invasion (p = 0.003), and patients with post-recurrence endocrine therapy (p < 0.001), respectively. The 5-year Kaplan-Meier P-OS rate for patients was 81.4%. Post-recurrence endocrine therapy was independent factor for progression (HR: 0.176, p < 0.001) and OS (HR: 0.080, p < 0.001). CONCLUSIONS: Although there is no standardized treatment for IILRR yet, endocrine therapy after local resection plays a more important role in improving prognosis than chemotherapy or radiotherapy in HER2-negative luminal breast cancer.

Quality Assessment and Trend for Breast Cancer Treatment Practice across South Korea Based on Nationwide Analysis of Korean Health Insurance Data during 2013-2017.

PURPOSE: Quality assessment of breast cancer treatment in South Korea showed the upward standardization of the grade since 2013, but treatment disparities still have existed. This study analyzed the five year trend between 2013 and 2017 in the assessment of breast cancer treatment practice using the Korean health insurance data. Materials and Methods: All the medical records including surgery, chemotherapy, and radiotherapy for 7,354 patients a year on average were evaluated. Twenty indices were consisted of one structural, 17 process-related, and 2 result-related factors. We calculated the coefficient of variation (CV) annually to determine the variation in adherence rate of evaluation indices according to the type of institution (advanced vs. general hospital vs. clinic). RESULTS: Based on the initial assessment in 2013, 10 out of 20 indicators showed significant variation among the types of institutions with a CV of less than 0.1%. Six of them had a CV decline of less than 0.1%. The CV was still 0.1% or higher in the four indicators, including the composition of professional staff, the implementation of target therapy, the average length of hospital stay, and the hospitalization cost. Regarding the first-grade of assessment, there was a statistically significant relationship between the institution type (p=0.029) and region (metropolitan vs. province, p<0.001). CONCLUSION: There were disparities in the structural and systemic treatment factors depending on the institutional type. The quality improvement of the regional institutions and multidisciplinary experts for breast cancer is necessary.

COVID-19 Prevention Guidance and the Incidence of Febrile Neutropenia in Patients with Breast Cancer Receiving TAC Chemotherapy with Prophylactic Pegfilgrastim.

Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that causes severe adverse effects and death. Respiratory infections are one of the main causes of fever in patients with FN. We studied whether infection prevention and control (IPC) guidance for coronavirus 2019 disease reduced the incidence of FN. We reviewed female patients with breast cancer treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide with prophylactic pegfilgrastim between 2019 and 2021. IPC guidance was implemented in April 2020. There was no difference in the incidence of chemotherapy-induced neutropenia between patients with and without IPC. In patients with IPC, the incidence of FN (9.5%) was lower than that of patients without IPC (27.9%). The hospitalization duration (0.7 ± 1.5 days) and total hospital cost (279.6 ± 42.6 USD) of the IPC group were significantly lower than that of the non-IPC group (2.0 ± 3.8 days and 364.7 ± 271.6 USD, respectively). IPC guidance should be implemented to prevent FN in high-risk patients with breast cancer.

Effects of Ruxolitinib and Calcitriol Combination Treatment on Various Molecular Subtypes of Breast Cancer.

The anticancer effects of ruxolitinib and calcitriol against breast cancer were reported previously. However, the effect of ruxolitinib and calcitriol combination treatment on various molecular subtypes of breast cancer remains unexplored. In this study, we used MCF-7, SKBR3, and MDA-MB-468 cells to investigate the effect of ruxolitinib and calcitriol combination treatment on cell proliferation, apoptosis, cell cycle, and cell signaling markers, in vitro and in vivo. Our results revealed the synergistic anticancer effect of ruxolitinib and calcitriol combination treatment in SKBR3 and MDA-MB-468 cells, but not in MCF-7 cells in vitro, via cell proliferation inhibition, apoptosis induction, cell cycle arrest, and the alteration of cell signaling protein expression, including cell cycle-related (cyclin D1, CDK1, CDK4, p21, and p27), apoptosis-related (c-caspase and c-PARP), and cell proliferation-related (c-Myc, p-p53, and p-JAK2) proteins. Furthermore, in the MDA-MB-468 xenograft mouse model, we demonstrated the synergistic antitumor effect of ruxolitinib and calcitriol combination treatment, including the alteration of c-PARP, cyclin D1, and c-Myc expression, without significant drug toxicity. The combination exhibited a synergistic effect in HER2-enriched and triple-negative breast cancer subtypes. In conclusion, our results suggest different effects of the combination treatment of ruxolitinib and calcitriol depending on the molecular subtype of breast cancer.

Potentiation of the Anticancer Effects by Combining Docetaxel with Ku-0063794 against Triple-Negative Breast Cancer Cells.

PURPOSE: mTORC1 and mTORC2 inhibition by Ku-0063794 could confer profound anticancer effects against cancer cells because it eliminates feedback activation of Akt. Herein, we aimed to determine anticancer effects of docetaxel and Ku-0063794, individually or in combination, against breast cancer cells, especially triple-negative breast cancer (TNBC) cells. MATERIALS AND METHODS: MCF-7 breast cancer and MDA-MB-231 TNBC cell lines for in vitro studies and mouse xenograft model for in vivo studies were used to investigate the effect of docetaxel, Ku-0063794, or their combination. RESULTS: In the in vitro experiments, combination therapy synergistically reduced cell viability and induced higher apoptotic cell death in breast cancer cells than the individual monotherapies (p < 0.05). Western blot analysis and flow cytometric analysis showed that the combination therapy induced higher apoptotic cell death than the individual monotherapies (p < 0.05). In the in vivo experiment, docetaxel and Ku-0063794 combination therapy reduced the growth of MDA-MB-231 cells xenografted in the nude mice better than in the individual monotherapies (p < 0.05). Immunohistochemistry showed that the combination therapy induced the highest expression of cleaved caspase-3 and the lowest expression of Bcl-xL in the MDA-MB-231 cells xenografted in the nude mice (p < 0.05). Western blot analysis and immunofluorescence, incorporating both in vitro and in vivo experiments, consistently validated that unlike individual monotherapies, docetaxel and Ku-0063794 combination therapy significantly inhibited epithelial-mesenchymal transition (EMT) and autophagy (p < 0.05). CONCLUSION: These data suggest that docetaxel and Ku-0063794 combination therapy has higher anticancer activities over individual monotherapies against MDA-MB-231 TNBC cells through a greater inhibition of autophagy and EMT.

Evaluating the benefit of adjuvant chemotherapy in patients with ypT0-1 rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: Adjuvant chemotherapy (ACTx) is recommended in rectal cancer patients after preoperative chemoradiotherapy (PCRT), but its efficacy in patients in the early post-surgical stage who have a favorable prognosis is controversial. AIM: To evaluate the long-term survival benefit of ACTx in patients with ypT0-1 rectal cancer after PCRT and surgical resection. METHODS: We identified rectal cancer patients who underwent PCRT followed by surgical resection at the Asan Medical Center from 2005 to 2014. Patients with ypT0-1 disease and those who received ACTx were included. The 5-year overall survival (OS) and 5-year recurrence-free survival (RFS) were analyzed according to the status of the ACTx. RESULTS: Of 520 included patients, 413 received ACTx (ACTx group) and 107 did not (no ACTx group). No significant difference was observed in 5-year RFS (ACTx group, 87.9% vs no ACTx group, 91.4%, P = 0.457) and 5-year OS (ACTx group, 90.5% vs no ACTx group, 86.2%, P = 0.304) between the groups. cT stage was associated with RFS and OS in multivariate analysis [hazard ratio (HR): 2.57, 95% confidence interval (CI): 1.07-6.16, P = 0.04 and HR: 2.27, 95%CI: 1.09-4.74, P = 0.03, respectively]. Furthermore, ypN stage was associated with RFS and OS (HR: 4.74, 95%CI: 2.39-9.42, P < 0.00 and HR: 4.33, 95%CI: 2.20-8.53, P < 0.00, respectively), but only in the radical resection group. CONCLUSION: Oncological outcomes of patients with ypT0-1 rectal cancer who received ACTx after PCRT showed no improvement, regardless of the radicality of resection. Further trials are needed to evaluate the efficacy of ACTx in these group of patients.

Nomogram for the Prediction of Biochemical Incomplete Response in Papillary Thyroid Cancer Patients.

PURPOSE: To develop a nomogram for predicting biochemical incomplete response (BIR) in the dynamic risk stratification (DRS) of papillary thyroid carcinoma (PTC) patients without structural recurrence, and to investigate its validity. PATIENTS AND METHODS: Overall, 1705 (1005 and 700 in the training and validation cohorts, respectively) PTC patients treated with total thyroidectomy without structural recurrence were included. multivariate logistic regression analyses were performed to determine the significant predictors of BIR in the training cohort. A nomogram was subsequently constructed for BIR risk prediction. Assessments for the predictive accuracy, discrimination, and calibration of the nomogram were performed. Subsequently, internal and external validations were conducted. RESULTS: In the multivariate analysis, age, sex, lymph node metastasis site, extrathyroidal extension, and lymphovascular invasion showed significant predictive value; using these predictive factors and tumor size, a nomogram for BIR risk prediction was constructed. In the training cohort, the nomogram showed good predictive performance and discrimination in the receiver operating characteristic (ROC) curve analysis, with an area under the curve (AUC) of 0.765. In internal validation, the bootstrap-corrected AUC was 0.76. The calibration plot showed good agreement between the predicted and actual observation. The Hosmer-Lemeshow (HL) test did not suggest a lack of fit (p=0.1613). In the external validation, the AUC was 0.828 in the ROC curve analysis; the calibration plot showed good quality, and the HL test did not suggest a lack of fit (p=0.2161). CONCLUSION: The constructed nomogram may effectively predict the risk of BIR in DRS in PTC patients without structural recurrence. LEVEL OF EVIDENCE: Level 4.

Intermuscular fat density as a novel prognostic factor in breast cancer patients treated with adjuvant chemotherapy.

BACKGROUND: Body composition, including sarcopenia and fat parameters, has received much attention as a prognostic factor in breast cancer. METHODS: A total of 479 breast cancer patients who underwent surgery and received adjuvant chemotherapy were enrolled in this study. Body composition, including the index and density of skeletal muscle, visceral fat, subcutaneous fat, and intermuscular fat calculated by CT scan, was used as a prognostic factor. The endpoints were breast cancer-specific survival (BCSS) and overall survival (OS). RESULTS: The number of patients with stages I, II, and III was 146 (30.5%), 237 (49.5%), and 96 (20%), respectively. Sarcopenia and muscle density were not significant prognostic factors for BCSS and OS. A high visceral fat index (VFI) was an independent prognostic factor for BCSS (HR, 2.55; 95% CI 1.10-5.95, p = 0.03) and OS (HR 2.55, 95% CI 1.26-5.16, p = 0.01). In addition, high intermuscular fat density (IMFD) was also a significant prognostic factor for BCSS (HR, 2.95; 95% CI 1.34-6.46, p = 0.007) and OS (HR 2.28, 95% CI 1.22-4.26, p = 0.01) in multivariate analysis. CONCLUSION: VFI and IMFD were significant prognostic factors for BCSS and OS in breast cancer patients treated with adjuvant chemotherapy.

Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy.

PURPOSE: Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. METHODS: We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. RESULTS: The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). CONCLUSION: The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis.

[Evaluation of Post-Neoadjuvant Chemotherapy Pathologic Complete Response and Residual Tumor Size of Breast Cancer: Analysis on Accuracy of MRI and Affecting Factors]. / ì‹ ë³´ê°•í™”í•™ìš”ë²• 후 ìœ ë°©ì•”ì˜ ë³‘ë¦¬í•™ì  ì™„ì „ 관해 예측 및 잔류 암 평가: ìœ ë°©ìžê¸°ê³µëª ì˜ìƒì˜ ì •í™•ë„ 및 영향인자 분석.

Purpose: To evaluate the accuracy of MRI in predicting the pathological complete response (pCR) and the residual tumor size of breast cancer after neoadjucant chemotherapy (NAC), and to determine the factors affecting the accuarcy. Materials and Methods: Eighty-eight breast cancer patients who underwent surgery after NAC at our center between 2010 and 2017 were included in this study. pCR was defined as the absence of invasive cancer on pathological evaluation. The maximum diameter of the residual tumor on post-NAC MRI was compared with the tumor size of the surgical specimen measured pathologically. Statistical analysis was performed to elucidate the factors affecting pCR and the residual tumor size-discrepancy between the MRI and the pathological measurements. Results: The pCR rate was 10%. The diagnostic accuracy of MRI and the area under the curve for predicting pCR were 90.91% and 0.8017, respectively. The residual tumor sizes obtained using MRI and pathological measurements showed a strong correlation (r = 0.9, p < 0.001), especially in patients with a single mass lesion (p = 0.047). The size discrepancy between MRI and the pathological measurements was significantly greater in patients with the luminal type (p = 0.023) and multifocal tumors/non-mass enhancement on pre-NAC MRI (p = 0.047). Conclusion: MRI is an accurate tool for evaluating pCR and residual tumor size in breast cancer patients who receive NAC. Tumor subtype and initial MRI features affect the accuracy of MRI.

Impact of the COVID-19 Pandemic on the Diagnosis and Surgery of Breast Cancer: A Multi-Institutional Study.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the rates of screening, case identification, and referral for cancer diagnosis. We investigated the diagnosis and surgery status of breast cancer before and after the COVID-19 pandemic at a multi-institutional level. METHODS: We collected breast cancer data from the clinical data warehouse which contained the medical records of patients from six academic institutions in South Korea. Patients were divided into two groups: February to April (period A) and May to July (period B). The data from the two groups were then compared against the same periods in 2019 and 2020. The primary objective was to investigate the differences in breast cancer stages before and after the COVID-19 pandemic. RESULTS: Among 3,038 patients, there was a 9.9% reduction in the number of diagnoses in 2020. This decrease was more significant during period A than period B. The breast cancer stage was not statistically different in period A (p = 0.115), but it was in period B (p = 0.001). In the subset analysis according to age, there was a statistical difference between 2019 and 2020 in period B for patients under the age of 65 years (p = 0.002), but no difference was observed in the other groups. CONCLUSION: The number of breast cancer cases declined during the pandemic, and the staging distribution has changed after the pandemic peak.

Causal Attributions and Quality of Life of Korean Breast Cancer Survivors.

PURPOSE: The purpose of this study was threefold: to explore the causal attributions of breast cancer, examine underlying factors of the attributes, and determine their relationship to quality of life among Korean breast cancer survivors. METHODS: The study used a descriptive correlational design, which included quantitative survey questionnaires and an open-ended question to complement the study. Three hundred and three breast cancer survivors were recruited from two university hospitals in South Korea, between January and April 2018. The causal attributions were explored using the Illness Perception Questionnaire Revised and an open-ended question. The survivors' quality of life was assessed using the Functional Assessment of Cancer Therapy for Breast Cancer. The quantitative analysis was performed using the SPSS 25.0 software package; the ATLAS.ti 8 software was used for thematic analysis. RESULTS: Quantitative and qualitative data of 321 and 238 breast cancer survivors, respectively, were analyzed. "Stress and worry" and "diet or eating habits" were believed to be the two most likely causes of breast cancer. Eleven new causal attributes emerged from the analysis. Being diagnosed with breast cancer at an older age (p < .05), having received chemotherapy (p < .05), and holding nonbehavioral causal attributes (p < .001), were significantly related to lower quality of life. CONCLUSION: There were differences between the survivors' beliefs on their causes of disease, and causal factors available from the literature. As the survivors' causal attributes were significantly related to their quality of life, healthcare providers should individually assess and incorporate these attributes into their care.

Clinical Implications of Serum 25-Hydroxyvitamin D Status after 5-Year Adjuvant Endocrine Therapy for Late Recurrence of Hormone Receptor-positive Breast Cancer.

PURPOSE: The prognostic implications of serum vitamin D status after a 5-year adjuvant endocrine therapy on the risk of late recurrence among hormone receptor (HR)-positive breast cancer patients remain unclear. Hence, we investigated this among Korean HR-positive breast cancer patients. METHODS: A total of 455 patients with HR-positive stage I-III invasive breast cancer who underwent curative surgery at St. Vincent's Hospital between February 2004 and April 2012 were included in this retrospective study. Patients were categorized based on their serum 25-hydroxyvitamin D (25(OH)D) levels after the 5-year adjuvant endocrine therapy. Initial recurrence sites were categorized. The primary clinical outcome was late recurrence-free survival (LRFS). RESULTS: Among the 455 patients, 242 and 213 were included in the 25(OH)D-deficient group and 25(OH)D-sufficient group, respectively. Forty-eight patients experienced late recurrence. Across all recurrence sites, the 25(OH)D-deficient group showed significantly worse LRFS rates than the 25(OH)D-sufficient group (hazard ratio [HR], 2.284; 95% confidence interval [CI], 1.155-4.515; p = 0.018). After patient subgrouping based on recurrence site, the 25(OH)D-deficient group also showed significantly worse LRFS rates in terms of regional lymph node (LN) (HR, 17.453; 95% CI, 2.46-128.83; p = 0.005), bone (HR, 2.394; 95% CI, 1.024-5.599; p = 0.044), and visceral (HR, 2.735; 95% CI, 1.182-6.328; p = 0.019) recurrence. However, there was no significant difference between the 2 groups in terms of local recurrence (p = 0.611). CONCLUSIONS: We found that 25(OH)D deficiency after the 5-year adjuvant endocrine therapy was associated with worse LRFS among HR-positive breast cancer patients, particularly with respect to regional LN, bone, and visceral recurrence.

Clinical Impact of Primary Prophylactic Pegfilgrastim in Breast Cancer Patients Receiving Adjuvant Docetaxel-Doxorubicin-Cyclophosphamide Chemotherapy.

PURPOSE: The regimen including concurrent docetaxel, doxorubicin, and cyclophosphamide (TAC) has been categorized as an important risk factor for febrile neutropenia (FN). This comparative study examined the clinical impact of long-acting granulocyte colony-stimulating factor (G-CSF) (pegfilgrastim) during adjuvant TAC chemotherapy in Korean patients with advanced breast cancer. METHODS: We analyzed data from 239 patients who received 6 cycles of adjuvant TAC chemotherapy. We categorized patients into 2 groups according to the use of primary prophylactic pegfilgrastim and compared the incidence and risk of FN, hospital care costs, and survival in the 2 groups. RESULTS: The incidence of FN decreased from 54.2% to 21.2% in all patients, after the use of pegfilgrastim. The analysis of a total of 1,432 chemotherapy cycles showed that the incidence of FN decreased from 36.1% to 9.1% after the use of pegfilgrastim. Moreover, the decrease in the incidence of FN with the use of pegfilgrastim resulted in a significant decrease in the mean duration of neutropenia (4.15 to 1.29 days), the risk of hospitalization (99.5% to 29.7%) and the mean total hospital care cost (USD 3,038 to USD 2,347). High relative dose intensity (RDI) in patients treated with pegfilgrastim than in those not treated with pegfilgrastim (99.18% vs. 93.85%) was associated with a better overall survival (p = 0.033). CONCLUSIONS: The use of pegfilgrastim during adjuvant TAC chemotherapy was significantly associated with a decrease in the incidence and risk of FN, hospital care costs, and risk of death compared to the use of adjuvant TAC without primary prophylaxis.

Relative Survival Benefit by Hormonal Receptor Status of Adding Trastuzumab to Neoadjuvant Chemotherapy in Breast Cancer Patients.

PURPOSE: Neoadjuvant chemotherapy (NAC) involving trastuzumab markedly increases pathologic complete response (pCR) rates in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Despite increasing pCR rates, long-term survival gains are controversial owing to distinctive biologic behavior mediated by the presence of hormonal receptors (HRs) that may interact with HER2 receptors. We, therefore, investigated the differences in relative survival gain provided by neoadjuvant trastuzumab-based chemotherapy on HR positive (HR+) status of patients. METHODS: We retrospectively analyzed women with stage II or III HER2+ breast cancer who underwent NAC followed by a breast cancer surgery between 2008 and 2013. The survival benefits of adding trastuzumab to NAC were analyzed by classifying patients into HR+ and HR negative (HR-) groups. RESULTS: Of 666 patients included in the study, 374 (52.1%) were HR+ and 319 (47.9%) were HR-. In the HR+ group, trastuzumab treatment led to higher pCR rates and significantly better breast cancer specific survival (BCSS) and overall survival (OS) than no trastuzumab treatment. However, among patients with HR- breast cancer, trastuzumab treatment showed no statistically significant difference between BCSS and OS following multivariate analysis. CONCLUSION: We found that the addition of trastuzumab to NAC improved relative survival benefit in HER2+/HR+ patients than in HER2+/HR- patients, even though the pCR rate increases were lower. Although pCR has been regarded as a surrogate marker for estimating long-term survival benefits after NAC, it alone may not translate into real long-term oncologic outcomes in particular cancer subtypes after trastuzumab-based NAC. Further longer-term evaluation of the objective survival benefit after NAC driven by a dual HER2 block according to HR status is warranted.

Correction: ßPix-d promotes tubulin acetylation and neurite outgrowth through a PAK/Stathmin1 signaling pathway.

[This corrects the article DOI: 10.1371/journal.pone.0230814.].

ßPix-d promotes tubulin acetylation and neurite outgrowth through a PAK/Stathmin1 signaling pathway.

Microtubules are a major cytoskeletal component of neurites, and the regulation of microtubule stability is essential for neurite morphogenesis. ßPix (ARHGEF7) is a guanine nucleotide exchange factor for the small GTPases Rac1 and Cdc42, which modulate the organization of actin filaments and microtubules. ßPix is expressed as alternatively spliced variants, including the ubiquitous isoform ßPix-a and the neuronal isoforms ßPix-b and ßPix-d, but the function of the neuronal isoforms remains unclear. Here, we reveal the novel role of ßPix neuronal isoforms in regulating tubulin acetylation and neurite outgrowth. At DIV4, hippocampal neurons cultured from ßPix neuronal isoform knockout (ßPix-NIKO) mice exhibit defects in neurite morphology and tubulin acetylation, a type of tubulin modification which often labels stable microtubules. Treating ßPix-NIKO neurons with paclitaxel, which stabilizes the microtubules, or reintroducing either neuronal ßPix isoform to the KO neurons overcomes the impairment in neurite morphology and tubulin acetylation, suggesting that neuronal ßPix isoforms may promote microtubule stabilization during neurite development. ßPix-NIKO neurons also exhibit lower phosphorylation levels for Stathmin1, a microtubule-destabilizing protein, at Ser16. Expressing either ßPix neuronal isoform in the ßPix-NIKO neurons restores Stathmin1 phosphorylation levels, with ßPix-d having a greater effect than ßPix-b. Furthermore, we find that the recovery of neurite length and Stathmin1 phosphorylation via ßPix-d expression requires PAK kinase activity. Taken together, our study demonstrates that ßPix-d regulates the phosphorylation of Stathmin1 in a PAK-dependent manner and that neuronal ßPix isoforms promote tubulin acetylation and neurite morphogenesis during neuronal development.