•Carbon ion radiotherapy is useful for inoperable head and neck cancers.•Re-irradiation with carbon ion radiotherapy after recurrence was explored.•Long-term efficacy and toxicity profiles were ...examined in recurrent disease.•Re-irradiation using carbon ions is moderately efficacious, with moderate toxicity.•Carbon ion radiotherapy is a viable treatment option for recurrent head and neck tumors.
Locoregional recurrence after carbon-ion radiotherapy (CIRT) for primary head and neck malignancies, such as malignant mucosal melanoma, adenoid cystic carcinoma, and sarcoma, occurs occasionally. However, the treatment options are limited. We report on the toxicity and efficacy of re-irradiation using carbon ions for recurrent head and neck malignancies after CIRT.
Data of 48 patients with recurrent head and neck malignancies treated with re-irradiation with CIRT at our institution (2007–2016) were retrospectively analyzed. Twenty-one patients (43.8%) had malignant mucosal melanoma, 17 (35.4%) had adenoid cystic carcinoma, six (12.5%) had bone and soft tissue sarcomas, and four patients (8.3%) had other disease types. Tumor recurrences at re-irradiation were located in the paranasal cavity (n = 18, 37.5%), nasal cavity (n = 9, 18.8%), nasopharynx (n = 4, 8.3%), orbit (n = 3, 6.3%), cavernous sinus (n = 3, 6.3%), and at other sites (n = 11, 22.9%). The median dose of initial CIRT and that at re-irradiation were 57.6 Gy and 54.0 Gy (relative biological effectiveness RBE), respectively. None of the patients received concurrent chemotherapy.
The median follow-up period after re-irradiation was 27.1 months. Five patients (10.4%) developed Grade 3 acute toxicities and 18 (37.5%) developed Grade ≥3 late toxicities, including Grade 5 central nervous system necrosis in one patient. The 2-year local control, locoregional control, progression-free survival, and overall survival rates were 40.5, 33.5%, 29.4%, and 59.6%, respectively.
Re-irradiation using carbon ions may be a reasonable treatment option with tolerable toxicity for patients with recurrent head and neck malignancies after CIRT.
Purpose
The clinical significance of carbon-ion radiotherapy (CIRT) for octogenarians with locally advanced non-small-cell lung cancer (LA-NSCLC) remains unclear. We aimed to evaluate the clinical ...outcomes of CIRT alone for octogenarians with LA-NSCLC.
Materials and methods
We evaluated 32 patients who underwent CIRT alone between 1997 and 2015. The median age was 82.0 years (range, 80–88 years). In terms of clinical stage (UICC 7th edition), 7 (21.9%), 10 (31.3%), 11 (34.4%), and 4 (12.5%) patients had stage IIA, IIB, IIIA, and ΙΙΙB disease, respectively. The median CIRT dose was 72.0 Gy (relative biological effectiveness), and the median follow-up period was 33.1 months.
Results
All patients successfully completed CIRT. Regarding grade ≥ 2 toxicities, 1 (3.1%), 3 (9.4%), and 4 (0.7%) patients developed grade 3 radiation pneumonitis, grade 2 radiation pneumonitis, and grade 2 dermatitis, respectively. No grade ≥ 4 toxicities were observed. The 2 year LC, PFS, and OS rates were 83.5%, 46.7%, and 68.0%, respectively.
Conclusion
CIRT alone is safe and effective for octogenarians with LA-NSCLC.
The efficacy and safety of carbon‐ion radiotherapy (CIRT) for locally advanced non‐small‐cell lung cancer (LA‐NSCLC) remain unclear. We reported the clinical outcomes of CIRT for LA‐NSCLC. Data for ...141 eligible patients who received CIRT between 1995 and 2015 were retrospectively analyzed. Local control (LC), locoregional control (LRC), progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan‐Meier method. The median age was 75.0 years. Overall, 21 (14.9%), 57 (40.4%), 43 (30.5%) and 20 (14.2%) patients had T1, T2, T3 and T4 disease, respectively. Moreover, 51 (36.2%), 45 (31.9%), 40 (28.4%) and 5 (3.5%) patients had N0, N1, N2 and N3 disease, respectively. Furthermore, 34 (24.1%), 42 (29.8%), 45 (31.9%) and 20 (14.2%) patients had stages IIA, IIB, IIIA and ΙΙΙB disease, respectively. Overall, 62 (44.0%), 60 (42.6%), 8 (5.7%) and 11 (7.8%) patients had adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and others, respectively. The median dose was 72.0 Gy (relative biological effectiveness). No patient received concurrent chemotherapy. Median follow‐up periods were 29.3 (1.6‐207.7) and 40.0 (10.7‐207.7) months for all patients and survivors, respectively. Two‐year LC, PFS and OS rates were 80.3%, 40.2% and 58.7%, respectively. Overall, 1 (0.7%), 5 (3.5%) and 1 (0.7%) patient developed Grades 4 (mediastinal hemorrhage), 3 (radiation pneumonitis) and 3 (bronchial fistula) toxicities, respectively. Multivariate analysis showed adenocarcinoma and N2/3 classification as significant poor prognosticators of PFS. CIRT is an effective treatment with acceptable toxicity for LA‐NSCLC, especially for elderly patients or patients with severe comorbidities who cannot be treated with surgery or chemoradiotherapy.
Carbon‐ion radiotherapy is an effective treatment option with acceptable toxicity for LA‐NSCLC. It is especially useful for elderly patients and those with severe comorbidities.
Lithium cations were observed to accelerate the hydrolysis of esters with hydroxides (KOH, NaOH, LiOH) in a water/tetrahydrofuran (THF) two-phase system. Yields in the hydrolysis of substituted ...benzoates and aliphatic esters using the various hydroxides were compared, and the effects of the addition of lithium salt were examined. Moreover, it was presumed that a certain amount of LiOH was dissolved in THF by the coordination of THF with lithium cation and hydrolyzed esters even in the THF layer, as in the reaction by a phase-transfer catalyst.
The molecular profiles of tumors may inform the selection of appropriate targeted therapies. Circulating tumor cells (CTCs) reflect the real-time status of tumor genotypes. CTCs exhibit high genetic ...heterogeneity within a patient; accordingly, the analysis of individual CTCs, including their heterogeneity, may enable more precise treatments. We analyzed KRAS mutations in single CTCs from patients with metastatic colorectal cancer (mCRC) using a new single-cell picking system.
Blood samples were obtained from 61 patients with mCRC. CTCs were enriched and fluorescently labeled using the CellSearch® System. They were recovered using the single-cell picking system based on the fluorescence intensity of marker dyes. Single CTCs and tumor tissue samples were examined for mutations in codons 12 and 13 of the KRAS gene.
CTCs were detected in 27 of 61 patients with mCRC. We isolated at least two CTCs from 15 of 27 patients. KRAS genotype was evaluated in a total of 284 CTCs from 11 patients, and 15 cells with mutations were identified in four patients. In 10 of 11 patients, the KRAS status was the same in the primary tumor and CTCs. In one patient, the KRAS status was discordant between the primary tumor and CTCs. In two patients, different KRAS mutations were found among individual CTCs.
We successfully isolated single CTCs and detected KRAS mutations in individual cells from clinical samples using a novel application of single-cell isolation system. Using the system, we detected CTC heterozygosity and heterogeneity in KRAS status among CTCs within a patient and between CTCs and tumor tissues.
Carbon ion radiotherapy has been utilized even for X-ray resistant tumors. However, control of distant metastasis remains a major challenge in carbon ion irradiation. We investigated whether carbon ...ion irradiation combined with dual immune checkpoint blockade therapy (anti-PD-L1 and anti-CTLA-4 antibodies P1C4) provides anti-tumor efficacy for both local and distant sites. A mouse osteosarcoma cell line (LM8) was inoculated into both hind legs of C3H mice assigned to four groups: no treatment (NoTX), P1C4, 5.3 Gy of carbon ion irradiation to one leg (Cion), and combination (Comb) groups. In the Comb group, tumor growth delay was observed not only in the irradiated tumors but also in the unirradiated tumors. Notably, a complete response of unirradiated tumors was observed in 64% of mice in the Comb group, while only 20% of mice in the P1C4 group showed a complete response. Significant activation of immune cells was observed in the Comb group, with an increase in CD8+/GzmB+ tumor-infiltrating lymphocytes (TILs) in the irradiated tumor, and of CD8+/GzmB+ and CD4+ TILs in the unirradiated tumor, respectively. Depletion of CD8 abolished the tumor growth delay in unirradiated tumors in mice treated by Cion and P1C4. Overall survival was significantly prolonged in the Comb group. HMGB-1 release from irradiated tumors was significantly increased after Cion both
and
. These data suggest that carbon ion therapy enhances P1C4 efficacy against osteosarcoma in both the primary tumor and distant metastases mediated by immune activation.
Intrathoracic recurrence after carbon‐ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer‐related deaths. However, treatment options are limited. Herein, we report ...on the toxicity and efficacy of re‐irradiation with carbon‐ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon‐ion radiotherapy who were treated with re‐irradiation with carbon‐ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy‐three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon‐ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re‐irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow‐up period after re‐irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2‐year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re‐irradiation with carbon‐ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re‐irradiation with carbon‐ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors.
Kaplan‐Meier curves of (a) local control and (b) overall survival following re‐irradiation
Background
Most of the primary sphenoid sinus tumors present with locally advanced stages with involvement of adjacent critical structures and are not amenable to radical resection. We sought to ...evaluate the safety and efficacy of carbon‐ion radiotherapy (C‐ion RT) for sphenoid sinus malignancies.
Methods
This is a retrospective analysis of 22 patients of primary sphenoid carcinomas treated with definitive C‐ion RT.
Results
Adenoid cystic carcinoma was the most common histology (15 patients, 68.2%). The median follow‐up of this cohort was 48.5 months. The actuarial local control and overall survival at 5 years were 51.0% and 62.7%, respectively. Grade 4 visual impairment and grade 4 brain necrosis were seen in six and one patient, respectively.
Conclusion
C‐ion RT can provide a reasonably good clinical outcome in locally advanced sphenoid sinus malignancies with a marginally higher late toxicity profile because of extremely close proximity of the target volume to critical structures.
In obese and diabetic patients, plasma free fatty acid (FFA) levels are often elevated and may play a causal role in insulin resistance and reactive oxygen species (ROS) production. We have ...previously shown that ursodeoxycholic acid (UDCA) has antioxidative activity through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling-mediated glutathione production. In this study, we investigated the effects of UDCA on insulin response by analyzing intracellular ROS and the activation of the PI3K/Akt signaling pathway in HepG2 cells treated with palmitate. The level of ROS was quantified using 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA), and the activation of the PI3K/Akt signaling pathway was determined by Western blotting assay using appropriate antibodies. The intracellular ROS levels were increased by palmitate but were reduced by treatment with UDCA and insulin. Furthermore, insulin significantly stimulated the phosphorylation of Akt. When the cells were pre-treated with palmitate, insulin-induced Akt-phosphorylation was markedly inhibited. However, when the cells were treated with palmitate and UDCA, the effects of insulin were partially restored. UDCA may have protective effects against palmitate-induced decreases in responsiveness to insulin.
Epstein-Barr virus (EBV) mainly persists in B cells, which differentiate into antibody-producing cells, and thus, EBV has been implicated in autoimmune diseases. We aimed to describe the EBV ...reactivation and its relevance to autoimmune disease, focusing on Graves' disease, which is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies. Circulating autoreactive B cells that have evaded from the selection have difficulties differentiating to produce antibodies. However, once EBV infects such B cells and reactivates, the B cells may become plasma cells and produce autoantibody. We herein proposed an EBV reactivation-induced Ig production system, which is a distinct pathway from the antibody production system through germinal centers and bone marrow and has the following characteristics: 1. IgM dominance, 2. ubiquitous Ig production, and 3. the rescue of autoreactive B cells, which skews Ig production toward autoantigens. IgM autoantibodies induced by EBV reactivation may activate the classical complement pathway and injure healthy tissue, which supply autoantigens for the production of affinity-matured IgG autoantibodies. Antibodies induced by EBV reactivation may play important roles in the development and exacerbation of autoimmune diseases.
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