Estrogen/progesterone Receptor and HER2 Discordance Between Primary Tumor and Brain Metastases in Breast Cancer and Its Effect on Treatment and Survival

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment

Factors Affecting the Baseline and Post-Treatment Scores on the Hopkins Verbal Learning Test-Revised Japanese Version before and after Whole-Brain Radiation Therapy

Our objectives were to (1) investigate the feasibility of the use of the Japanese version of the Hopkins Verbal Learning Test-Revised (HVLT-R); (2) identify the clinical factors influencing the HVLT-R scores of patients undergoing whole-brain radiation therapy (WBRT); and (3) compare the neurocognitive function (NCF) after WBRT in different dose fractionation schedules. We administered the HVLT-R (Japanese version) before (baseline) and at four and eight months after WBRT in 45 patients who received either therapeutic (35Gy-in-14, n = 16; 30Gy-in-10, n = 18) or prophylactic (25Gy-in-10, n = 11) WBRT. Sixteen patients dropped out before the eight-month examination, due mostly to death from cancer. The Karnofsky Performance Status (KPS) 80–100 group had significantly higher baseline total recall (TR) scores (p = 0.0053), delayed recall (DR) scores (p = 0.012), and delayed recognition (DRecog) scores (p = 0.0078). The patients aged ≤65 years also had significantly higher TR scores (p = 0.030) and DRecog scores (p = 0.031). The patients who underwent two examinations (worse-prognosis group) had significantly decreased DR scores four months after WBRT compared to the baseline (p = 0.0073), and they were significantly more likely to have declined individual TR scores (p = 0.0017) and DR scores (p = 0.035) at four months. The eight-month HVLT-R scores did not significantly decline regardless of the WBRT dose fractionation. The baseline NCF was determined by age and KPS, and the early decline in NCF is characteristic of the worse-prognosis group

Green cocoon-derived sericin reduces cellular damage caused by radiation in human keratinocytes

Abstract Radiation therapy used in the treatment of cancer causes skin damage, and no method of care has been established thus far. Recently, it has become clear that sericin derived from silkworm cocoons has moisturizing and antioxidant functions. In addition, green cocoon-derived sericin, which is rich in flavonoids, may have enhanced functions. However, whether this green cocoon-derived sericin can reduce radiotherapy-induced skin damage is unclear. In the present study, we aimed at establishing care methods to reduce skin cell damage caused by X-irradiation using green cocoon-derived sericin. We investigated its effect on human keratinocytes using lactate dehydrogenase activity to indicate damage reduction. Our results showed that green cocoon-derived sericin reduced cell damage caused by X-irradiation. However, this effect was not observed when cells were treated before X-irradiation or with a sericin derived from white cocoons. In addition, green cocoon-derived sericin decreased the levels of reactive oxygen species and lipid peroxidation. Our results suggest that green cocoon sericin mitigates the damaging effect of X-irradiation on cells, hence presenting potential usefulness in reducing skin damage from radiation therapy and opening new avenues in the care of cancer patients

Nanodisc-to-Nanofiber Transition of Noncovalent Peptide–Phospholipid Assemblies

We report a novel molecular architecture of peptide–phospholipid coassemblies. The amphiphilic peptide Ac-18A-NH₂ (18A), which was designed to mimic apolipoprotein α-helices, has been shown to form nanodisc structures with phospholipid bilayers. We show that an 18A peptide cysteine substitution at residue 11, 18A­[A11C], forms fibrous assemblies with 1-palmitoyl-2-oleoyl-phosphatidylcholine at a lipid-to-peptide (L/P) molar ratio of 1, a fiber diameter of 10–20 nm, and a length of more than 1 μm. Furthermore, 18A­[A11C] can form nanodiscs with these lipid bilayers at L/P ratios of 4–6. The peptide adopts α-helical structures in both the nanodisc and nanofiber assemblies, although the α-helical bundle structures were evident only in the nanofibers, and the phospholipids of the nanofibers were not lamellar. Fluorescence spectroscopic analysis revealed that the peptide and lipid molecules in the nanofibers exhibited different solvent accessibility and hydrophobicity from those of the nanodiscs. Furthermore, the cysteine substitution at residue 11 did not result in disulfide bond formation, although it was responsible for the nanofiber formation, suggesting that this free sulfhydryl group has an important functional role. Alternatively, the disulfide dimer of 18A­[A11C] preferentially formed nanodiscs, even at an L/P ratio of 1. Interconversions of these discoidal and fibrous assemblies were induced by the stepwise addition of free 18A­[A11C] or liposomes into the solution. Furthermore, these structural transitions could also be induced by the introduction of oxidative and reductive stresses to the assemblies. Our results demonstrate that heteromolecular lipid–peptide complexes represent a novel approach to the construction of controllable and functional nanoscale assemblies

Effect of setup error in the single-isocenter technique on stereotactic radiosurgery for multiple brain metastases

In conventional stereotactic radiosurgery (SRS), treatment of multiple brain metastases using multiple isocenters is time-consuming resulting in long dose delivery times for patients. A single-isocenter technique has been developed which enables the simultaneous irradiation of multiple targets at one isocenter. This technique requires accurate positioning of the patient to ensure optimal dose coverage. We evaluated the effect of six degrees of freedom (6DoF) setup errors in patient setups on SRS dose distributions for multiple brain metastases using a single-isocenter technique. We used simulated spherical gross tumor volumes (GTVs) with diameters ranging from 1.0 to 3.0 cm. The distance from the isocenter to the target's center was varied from 0 to 15 cm. We created dose distributions so that each target was entirely covered by 100% of the prescribed dose. The target's position vectors were rotated from 0 degrees-2.0 degrees and translated from 0-1.0 mm with respect to the three axes in space. The reduction in dose coverage for the targets for each setup error was calculated and compared with zero setup error. The calculated margins for the GTV necessary to satisfy the tolerance values for loss of GTV coverage of 3% to 10% were defined as coverage-based margins. In addition, the maximum isocenter to target distance for different 6DoF setup errors was calculated to satisfy the tolerance values. The dose coverage reduction and coverage-based margins increased as the target diameter decreased, and the distance and 6DoF setup error increased. An increase in setup error when a single-isocenter technique is used may increase the risk of missing the tumor; this risk increases with increasing distance from the isocenter and decreasing tumor size

Definitive chemoradiotherapy with low-dose continuous 5-fluorouracil reduces hematological toxicity without compromising survival in esophageal squamous cell carcinoma patients

Background and purpose: To compare chemoradiotherapy (CRT) with low-dose continuous 5-fluorouracil (5FU) to CRT with 5FU+cisplatin (CDDP) for esophageal squamous cell carcinoma (ESCC) in a retrospective cohort study. Methods and materials: We reviewed the cases of Stage I–IV ESCC patients who underwent definitive CRT in 2000–2014. Concomitant chemotherapy was one of the three regimens: (1) high-dose intermittent 5FU and CDDP (standard-dose FP: SDFP), (2) low-dose continuous 5FU and CDDP (LDFP), or (3) low-dose continuous 5FU (LD5FU). The general selection criteria for chemotherapy were: SDFP for patients aged <70 yrs; LDFP for those aged 70–74 yrs; LD5FU for those aged ≥75 yrs or with performance status (PS) ≥3. Propensity scores were derived with chemotherapy (LD5FU vs. 5FU+CDDP) as the dependent variable. Results: In a multivariate analysis, chemotherapy (LD5FU vs. SDFP, p = .24; LDFP vs. SDFP, p = .52) did not affect the overall survival (OS). LD5FU caused significantly less grade 3–4 leukopenia (9%) compared to SDFP (47%) and LDFP (44%) (p < .001). In a propensity-matched analysis, LD5FU affected neither OS (HR 1.06; 95%CI 0.55–2.05; p = .87) nor progression-free survival (HR 0.95, 95%CI 0.50–1.81; p = .87). Conclusion: CRT with low-dose continuous 5FU may be a less toxic option for elderly ESCC patients