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Platelet-derived growth factor (PDGF) is mainly believed to be an important mitogen for connective tissue, especially for fibroblasts that serve in wound healing. However, PDGF also has important roles during embryonal development, and its overexpression has been linked to different types of fibrotic disorders and malignancies. Platelet-derived growth factor is synthesized by many different cell types, and its expression is broad. Its synthesis is in response to external stimuli, such as exposure to low oxygen tension, thrombin, or stimulation by other cytokines and growth factors. In addition, PDGF may function in autocrine stimulation of tumor cells, regulation of interstitial fluid pressure, and angiogenesis. Recently, several drugs were developed that are potent inhibitors of the tyrosine kinase activity of PDGF receptors. Thus, it is important to understand the physiology of PDGF and its receptors and the role of PDGF in different diseases. This review summarizes the physiologic activity of PDGF, the expression of PDGF during embryonal development, and the roles of PDGF expression in nonmalignant disease and in different tumors. [ABSTRACT FROM AUTHOR]

Purpose: Positron emission tomography/computed tomography (PET/CT) is increasingly being utilized for staging of inflammatory breast cancer (IBC). The purpose of this study was to define how pretreatment PET/CT studies affected postmastectomy radiation treatment (PMRT) planning decisions for IBC.Methods and Materials: We performed a retrospective analysis of 62 patients diagnosed with IBC between 2004 and 2009, who were treated with PMRT in our institution and who had a staging PET/CT within 3 months of diagnosis. Patients received a baseline physical examination, staging mammography, ultrasonographic examination of breast and draining lymphatics, and chest radiography; most patients also had a bone scan (55 patients), liver imaging (52 patients), breast MRI (46 patients), and chest CT (25 patients). We compared how PET/CT findings affected PMRT, assuming that standard PMRT would target the chest wall, level III axilla, supraclavicular fossa, and internal mammary chain (IMC). Any modification of target volumes, field borders, or dose prescriptions was considered a change.Results: PET/CT detected new areas of disease in 27 of the 62 patients (44%). The areas of additional disease included the breast (1 patient), ipsilateral axilla (1 patient), ipsilateral supraclavicular (4 patients), ipsilateral infraclavicular (1 patient), ipsilateral IMC (5 patients), ipsilateral subpectoral (3 patients), mediastinal (8 patients), other distant/contralateral lymph nodes (15 patients), or bone (6 patients). One patient was found to have a non-breast second primary tumor. The findings of the PET/CT led to changes in PMRT in 11 of 62 patients (17.7%). These changes included additional fields in 5 patients, adjustment of fields in 2 patients, and higher doses to the supraclavicular fossa (2 patients) and IMC (5 patients).Conclusions: For patients with newly diagnosed IBC, pretreatment PET/CT provides important information concerning involvement of locoregional lymph nodes, mediastinal lymph nodes, and unsuspected sites of distant metastasis. This information is important in the design of radiotherapy treatment fields and, therefore, we recommend that PET/CT be a component of initial staging for IBC. [ABSTRACT FROM AUTHOR]

Purpose: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study., Methods: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion., Results: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred., Conclusion: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

This study characterizes the ovarian volume, antral follicle count (AFC), and ovarian dynamics of cows at different ages. Nellore cows (Bos taurus indicus) were used in two experiments. In Experiment 1, 57 lactating cows ranging in age from 3 to 23 years had their estrous cycle synchronized based on progesterone/estradiol treatments. The ovaries were scanned by ultrasound to record ovarian volume and AFC prior to follicle aspiration (AFC1). A second AFC (AFC2) was performed 5 days later to count only the growing antral follicles. In Experiment 2, six long-lived (14- to 23-year-old) and three young (4- to 8-year-old) non-lactating cows were submitted to daily ovarian scanning ultrasound during an interovulatory interval. Blood samples were collected during the estrous cycle to assess serum progesterone concentration. Data were analyzed using Student's t-test, ANOVA, and regression analysis tests. In Experiment 1, there were more (P < 0.05) antral follicles in AFC1 (31.4 ± 3.5) than in AFC2 (22.6 ± 2.4). In AFC1, the volume of the right ovary (6.03 ± 0.5 cm 3 ) was greater (P < 0.01) than that of the left one (4.53 ± 0.4 cm 3 ), although the AFC did not differ between the two ovaries (15.3 ± 1.8 and 16.3 ± 1.8, respectively). In both AFC1 and AFC2, there was a decline in the number of antral follicles as the age of the cow increased (P < 0.01). Ovarian volume (average of both ovaries) was related (P < 0.01) with AFC (R² = 0.1499) and cow age (R² = 0.0911). In Experiment 2, young and old cows under the age of 20 had a pattern of follicular growth waves, while cows over 20 years old did not have waves of follicular growth. The progesterone profiles and corpus luteum size during the estrous cycle did not differ between the groups. In conclusion, although cows had increased ovarian volume and decreased follicular population as they age, the follicular growth pattern and corpus luteum functionality appear to be unaffected by age., Competing Interests: Declaration of Competing Interest The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated:, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Information on the follicular population and oocyte quality of cows in the final period of reproductive life is scarce. The present study aimed to compare the antral follicle count (AFC), oocyte production and embryonic developmental competence of young versus long-lived and senescent Bos indicus beef cows. Nellore cows (Bos indicus) were classified into three groups according to age: young (4-9 years, n = 10), long-lived (14-17 years, n = 10) and senescent (17-23 years, n = 10). At a random time in the estrus cycle, the cows received cloprostenol sodium salt (0.5 mg, IM), estradiol benzoate (1 mg, IM) and an intravaginal P4 device (1.4 g). Five days later, the P4 devise was removed and oocyte collection (OPU1) was performed. A second OPU (OPU2) was performed 5 days after the first in order to aspirate only growing follicles. During each OPU, AFC and the number and quality of cumulus-oocyte complexes (COCs) were evaluated. Then, the COCs were placed in standard maturation medium (IVM), fertilized and incubated for 9 days. The data were subjected to ANOVA and Multinomial Logistic Regression. The AFC was smaller in long-lived and senescent cows in both OPU1 and OPU2 when compared to younger cows. There was no difference in AFC between OPU1 (19.9 ± 1.8) and OPU2 (17.6 ± 1.9) in young cows, however, more follicles were punctured in long-lived and senescent cows in OPU1 (12.0 ± 2.6 and 19.3 ± 4.6) than in OPU2 (9.2 ± 1.9 and 10.3 ± 2.3), respectively (P < 0.01). The numbers of COCs recovered from young cows (OPU1 = 14.2 ± 1.8; OPU2 = 8.4 ± 0.9) were higher than those obtained from long-lived cows (OPU1 = 5.9 ± 2.3; OPU2 = 4.3 ± 1.0) and senescent cows (OPU1 = 7.2 ± 3.0; OPU2 = 4.1 ± 1.7), respectively (P < 0.05). The cleavage rate did not differ between groups. However, the rate of blastocyst formation was higher for young (64.8%) and long-lived (65.0%) compared to senescent (16.5%) cows (P < 0.01). In conclusion our results indicate that the AFC is lower in long-lived and senescent cows compared with young cows. However, unlike in senescent cows, the embryonic development of long-lived cows is similar to that of young cows. This suggests that Nellore cows aged >17 years begin to have reduced embryonic development capacity due to ovarian aging., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We aimed to compare the effect of three estradiol benzoate (EB) doses on follicular wave emergence (FWE) and dominant follicle growth of suckled Nelore cows submitted to TAI (D0). On a random day of estrous cycle (D-10), multiparous (MULT; n=36) and primiparous (PRIM; n=20) suckled Nelore cows received an intravaginal progesterone (P4) device and were assigned in three groups. Cows in the EB-1 (n=20), EB-1.5 (n=15) or EB-2 (n=21) groups received, respectively, an im treatment with 1, 1.5 or 2 mg EB. A subgroup (n=10-13 cows/group) were subject to daily ovarian evaluations from D-10 to D0. On D-2, P4 devices were removed, and all cows received the same treatment: 1 mg estradiol cypionate, 0.53 mg sodium cloprostenol, and 300 IU eCG. Statistical analyses were performed considering only the main effects of treatment group and parity order. The proportion of cows with a synchronized FWE and the moment of the FWE did not differ ( p >0.05) among the treatment groups (overall: 80% [28/35] and 4.1 ± 0.4 days); however, the FWE occurred earlier ( p =0.007) in MULT (3.8 ± 0.2 days) than PRIM (5.1 ± 0.4) cows. The proportion of animals detected in estrus was greater (86% [31/36] vs. 70% [14/20]; p =0.02) and the dominant follicle was larger on D-2 (9.7 ± 0.3 mm vs. 7.8 ± 0.7 mm; p =0.006) and D0 (11.9 ± 0.4 mm vs. 10 ± 0.5 mm; p =0.008) in MULT than PRIM cows. In conclusion, the three EB doses presented similar efficiency to synchronize the FWE in suckled Nelore cows. Moreover, a delayed FWE and smaller dominant follicle is observed in PRIM cows, contributing to the reduced reproductive performance in this parity category when using similar TAI protocols of MULT cows., Competing Interests: Conflicts of interest: The authors have no conflict of interest to declare., (Copyright © The Author(s).)

Background: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets., Objective: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations., Patients and Methods: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m 2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety., Results: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab., Conclusions: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations., Clinical Trial Registration: NCT02693535 (26 February, 2016).

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability., Patients and Methods: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea., Results: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold., Conclusions: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)