Neck control after definitive radiochemotherapy without planned neck dissection in node-positive head and neck cancers

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to evaluate neck control outcomes after definitive radiochemotherapy without planned neck dissection in node-positive head and neck cancer.</p> <p>Methods</p> <p>We retrospectively reviewed medical records of fifty patients with node-positive head and neck cancer who received definitive radiochemotherapy. Twelve patients subsequently underwent neck dissection for suspicious recurrent or persistent disease. A median dose of 70 Gy (range 60-70.6) was delivered to involved nodes. Response evaluation was performed at a median of 5 weeks after completion of radiotherapy.</p> <p>Results</p> <p>Neck failure was observed in 11 patients and the 3-year regional control (RC) rate was 77.1%. Neck dissection was performed in 10 of the 11 patients; seven of these cases were successfully salvaged, and the ultimate rate of neck control was 92%. The remaining two patients who received neck dissection had negative pathologic results. On univariate analysis, initial nodal size > 2 cm, a less-than-complete response at the primary site, post-radiotherapy nodal size > 1.5 cm, and post-radiotherapy nodal necrosis were associated with RC. On multivariate analysis, less-than-complete primary site response and post-radiotherapy nodal necrosis were identified as independent prognostic factors for RC.</p> <p>Conclusions</p> <p>The neck failure rate after definitive radiochemotherapy without planned neck dissection was 22%. Two-thirds of these were successfully salvaged with neck dissection and the ultimate neck control rate was 92%. Our results suggest that planned neck dissection might not be necessary in patients with complete response of primary site, no evidence of residual lesion > 1.5 cm, or no necrotic lymph nodes at the 1-2 months follow-up evaluation after radiotherapy.</p

Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases

BACKGROUND: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR). METHODS: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined. RESULTS: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition). CONCLUSIONS: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas

Optical Imaging of Cancer-Related Proteases Using Near-Infrared Fluorescence Matrix Metalloproteinase-Sensitive and Cathepsin B-Sensitive Probes

Cathepsin B and matrix metalloproteinase (MMP) play key roles in tumor progression by controlled degradation of extracellular matrix. Consequently, these proteases have been attracted in cancer research, and many imaging probes utilizing these proteases have been developed. Our groups developed cathepsin B and MMP imaging nanoprobes based on polymer nanoparticle platform. Both cathepsin B and MMP imaging probes used near-infrared fluorescence (NIRF) dye and dark-quencher to for high sensitivity, and protease-sensitive peptide sequence in each probe authorized high specificity of the probes. We compared the bioactivities of cathepsin B and MMP sensitive probes in cancer-related environments to investigate the biological property of the probes. As a result, cathepsin B probe showed fluorescence recovery after the probe entered the cytoplasm. This property could be useful to evaluate the cytoplasmic targeted delivery by using probe-conjugated nanoparticles in vivo. On the other hand, MMP probe was superior in specificity in vivo and tissue study. This comparative study will provide precise information about peptide-based optical probes, and allow their proper application to cancer diagnosis

Feasibility of hippocampus-sparing VMAT for newly diagnosed glioblastoma treated by chemoradiation: pattern of failure analysis

To identify the pattern of failure and oncological safety of hippocampus (HC)-sparing IMRT (HSRT) in newly diagnosed glioblastoma (GBM) patients. Eighty-two GBM patients treated with temozolomide-based chemoradiation using HSRT between 2014 and 2018 were retrospectively reviewed. HSRT consisted of a sparing of Dmax of the contralateral HC < 17 Gy. Fifteen patients were unable to achieve the dose-constraints for adequate target coverage. The dose to ipsilateral HC was kept as low as possible. The pattern of failure was investigated, focusing on the area in the vicinity of the spared HC (organ and + 1 cm area). The median HSRT dose was 60 Gy in 30 fractions. The median follow-up for survivors was 11.7 months. The median progression-free and overall survival were 9.7 and 23.5 months, respectively. Six (7.3%) and eight (9.8%) patients eventually demonstrated progressive disease at the contralateral HC and HC + 1 cm, respectively. The 12-month contralateral HC and HC + 1 cm failure-free rate were 97.2 and 93.4%, respectively. However, no patient (0%) and two patients (2.4%) showed failure at contralateral HC and HC + 1 cm at initial progression, respectively. The dominant pattern of failure at the contralateral HC was by subependymal seeding (66.7%). The incidence of failure at the contralateral HC and HC + 1 cm is very low and mostly accompanied by disseminated disease progression after HSRT. Since HSRT does not compromise oncological outcomes, it could be considered especially for GBM patients who are expected to have favorable survival outcomes

KIOM-4 Protects against Oxidative Stress-Induced Mitochondrial Damage in Pancreatic β-cells via Its Antioxidant Effects

The protective effect of KIOM-4, a mixture of plant extracts, was examined against streptozotocin (STZ)-induced mitochondrial oxidative stress in rat pancreatic β-cells (RINm5F). KIOM-4 scavenged superoxide and hydroxyl radicals generated by xanthine/xanthine oxidase and Fenton reaction (FeSO4/H2O2), respectively, in a cell-free chemical system. In addition, a marked increase in mitochondrial reactive oxygen species (ROS) was observed in STZ-induced diabetic cells; this increase was attenuated by KIOM-4 treatment. Mitochondrial manganese superoxide dismutase (Mn SOD) activity and protein expression were down-regulated by STZ treatment and up-regulated by KIOM-4 treatment. In addition, NF-E2 related factor 2 (Nrf2), a transcription factor for Mn SOD, was up-regulated by KIOM-4. KIOM-4 prevented STZ-induced mitochondrial lipid peroxidation, protein carbonyl and DNA modification. Moreover, KIOM-4 treatment restored the loss of mitochondrial membrane potential (Δψ) that was induced by STZ treatment, and inhibited the translocation of cytochrome c from the mitochondria to the cytosol. In addition, KIOM-4 treatment elevated the level of ATP, succinate dehydrogenase activity and insulin level, which were reduced by STZ treatment. These results suggest that KIOM-4 exhibits a protective effect through its antioxidant effect and the attenuation of mitochondrial dysfunction in STZ-induced diabetic cells

Reduced Dose Intensity FOLFOX-4 as First Line Palliative Chemotherapy in Elderly Patients with Advanced Colorectal Cancer

To evaluate the toxicity and efficacy of a reduced dose intensity (mini-) FOLFOX-4 regimen as a first-line palliative chemotherapy in elderly patients (≥70 yr of age) with advanced colorectal cancer, data from prospective databases at Seoul National University Bundang Hospital and Seoul Municipal Boramae Hospital were analyzed. A total of 20 patients were enrolled between January 2001 and August 2004, and were treated with oxaliplatin 65 mg/m2 on day 1, and with 2-hr infusions of leucovorin 150 mg/m2 followed by a 5-FU bolus (300 mg/m2) and 22-hr continuous infusions (450 mg/m2) for 2 consecutive days every 2 weeks until progression, unacceptable toxicity or patient refusal. Sixteen patients were evaluable for response with an overall response rate of 43.8%. Median progression-free survival was 4.8 months (95% CI: 3.0-6.7) and overall survival was 13.5 months (95% CI: 11.1-16.0). The main side effects were anemia and neutropenia, which were observed in 20.8% and 17.7%, respectively, of the total cycles administered. There were no grade 4 toxicities and only one patient suffered from febrile neutropenia. No grade 3 toxicities occurred except for anemia (5.2%) and vomiting (1.0%). In conclusion, the mini-FOLFOX-4 regimen was found to be well tolerated with acceptable toxicity, and to provide a benefit for elderly patients with colorectal cancer