Stereotactic body radiation therapy for metastatic lung metastases.

Although systemic therapy is standard management for patients with metastatic disease, several recent reports have indicated that an addition of local therapies including stereotactic body radiation therapy (SBRT) for patients with oligometastatic disease (OMD) could improve survival. The lung is the most common site of distant metastasis from many solid tumors, and the strategy of SBRT, such as dose-fraction schedules, timing, etc., would be different depending on the type of primary tumor, location, and patterns of OMD. This review describes the role of SBRT with curative-intent for patients with pulmonary OMD for each of these variables. First, differences according to the type of primary tumor, for which many studies suggest that SBRT-mediated local control (LC) for patients with pulmonary OMD from colorectal cancer (CRC) is less successful than for those from non-CRC tumors. In addition, higher dose-fraction schedules seemed to correlate with higher LC; hence, different SBRT treatment strategies may be needed for patients with pulmonary OMD from CRC relative to other tumors. Second, differences according to location, where the safety of SBRT for peripheral pulmonary tumors has been relatively well established, but safety for central pulmonary tumors including pulmonary OMD is still considered controversial. To determine the optimal dose-fraction schedules, further data from prospective studies are still needed. Third, differences according to the patterns of OMD, the number of metastases and the timing of SBRT whereby 1-5 lesions in most patients and patients with synchronous or metachronous OMD are considered good candidates for SBRT. We conclude that there are still several problems in defining suitable indications for local therapy including SBRT, and that further prospective studies are required to resolve these issues.

The Current Role of Stereotactic Body Radiation Therapy (SBRT) in Hepatocellular Carcinoma (HCC).

The role of stereotactic body radiotherapy (SBRT), which can deliver high radiation doses to focal tumors, has greatly increased in not only early-stage hepatocellular carcinoma (HCC), but also in portal vein or inferior vena cava thrombi, thus expanding this therapy to pre-transplantation and the treatment of oligometastases from HCC in combination with immune checkpoint inhibitors (ICI). In early-stage HCC, many promising prospective results of SBRT have been reported, although SBRT is not usually indicated as a first treatment potion in localized HCC according to several guidelines. In the treatment of portal vein or inferior vena cava tumor thrombi, several reports using various dose-fraction schedules have shown relatively good response rates with low toxicities and improved survival due to the rapid advancements in systemic therapy. Although SBRT is regarded as a substitute therapy when conventional bridging therapies to transplantation, such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), are not applicable or fail in controlling tumors, SBRT may offer advantages in patients with borderline liver function who may not tolerate TACE or RFA, according to several reports. For oligometastases, the combination of SBRT with ICI could potentially induce an abscopal effect in patients with HCC, which is expected to provide the rationale for SBRT in the treatment of oligometastatic disease in the near future.

Investigation of interfractional variation in lung tumor position under expiratory-phase breath hold using cone-beam computed tomography in stereotactic body radiation therapy.

PURPOSE: We investigated the interfractional variation in the tumor position during lung stereotactic body radiotherapy (SBRT) under expiratory-phase breath hold (BH) using cone-beam computed tomography (CBCT). METHODS: A total of 79 patients with lung cancer were treated with lung SBRT, wherein the Abches system under expiratory-phase BH was used to study interfractional variation. The tumors were located in the upper lobe in 31 cases, in the middle lobe in 11 cases, and in the lower lobe in 37 cases. Planning CTs were scanned under expiratory-phase BH with the Abches system. The 3-degrees-of-freedom (DOF) tumor-based setup using CBCT images under expiratory-phase BH was performed after a 6-DOF bony vertebrae-based setup using an ExacTrac X-ray system. Interfractional variation in the lung tumor position was defined as the difference in the position of the lung tumor relative to the bone anatomy in the left-right (LR), antero-posterior (AP), and craniocaudal (CC) directions represented as absolute values. RESULTS: The interfractional variation in the lung tumor position was very similar in all the lung regions, and its mean ± standard deviation values in all patients were 1.0 ± 1.1, 1.6 ± 1.9, and 1.6 ± 1.9 mm in the LR, AP, and CC directions, respectively. Further, 99.1%, 92.4%, and 92.7% of all the fractions for the interfractional tumor positional variation in the LR, AP, and CC directions were less than 5 mm, respectively. CONCLUSION: The interfractional variation in the tumor position was small for lung cancer patients treated with the Abches system under expiratory-phase BH.

Effectiveness of salvage radiotherapy for superficial esophageal Cancer after non-curative endoscopic resection.

BACKGROUND: Endoscopic resection is widely used as an effective treatment for superficial esophageal cancer. However, the risk of lymph node metastasis increases in cases of muscularis mucosae or deeper invasion, for which additional treatment such as radiotherapy or surgery is required. Accordingly, the current study investigated the efficacy and toxicity of salvage radiotherapy after non-curative endoscopic resection as an organ preservation strategy. METHODS: We retrospectively reviewed 37 esophageal cancer patients who received salvage radiotherapy after non-curative endoscopic resection. The pathological invasion depths were the muscularis mucosae, submucosal layer, and muscularis propria in 14, 22, and one patient, respectively. All patients received external beam radiotherapy. Among them, eight received intraluminal brachytherapy following external beam radiotherapy. Elective nodal irradiation was administered to all patients. Twenty-five patients received concurrent platinum and fluorouracil-based chemotherapy. RESULTS: The median follow-up time was 74 months (range: 3-212). The 5-year progression-free survival and overall survival rates were 64 and 78%, respectively. No local or regional lymph node recurrence was observed. The causes of death included esophageal cancer in one patient, metachronous esophageal cancer in one patient, other malignancies in eight patients, and other causes in six patients. Late cardiac toxicities ≥ grade 3 were observed in six patients, one of whom died of arrhythmia. CONCLUSIONS: Salvage radiotherapy after non-curative esophageal endoscopic resection is an effective treatment as an organ preservation strategy. Although muscularis mucosae and submucosal cancer have a high risk of lymph node metastasis, our results suggest that elective nodal irradiation contributes to reduced regional node metastases.

Inhibition of gentamicin binding to rat renal brush-border membrane by megalin ligands and basic peptides.

Our previous studies showed that coadministration of cytochrome c and a 20-residue basic peptide, N-WASP181-200 (NISHTKEKKKGKAKKKRLTK, pI=10.87) inhibits renal accumulation of gentamicin. In this study, we examined effects of ligands of megalin, an endocytic receptor involved in renal uptake of gentamicin, and basic peptides including N-WASP180-200 and its mutant peptides on gentamicin binding to isolated rat renal brush-border membrane (BBM). Gentamicin binding to BBM was inhibited by megalin ligands, basic peptide fragments of cytochrome c, and N-WASP181-200 in a concentration-dependent manner. Klotz plot analysis showed that N-WASP181-200 inhibited the binding of gentamicin in a competitive manner. By substituting glycines for lysines in N-WASP181-200 at positions 9 and 15, the inhibitory effect on gentamicin binding to BBM was reduced, which may be related to a decrease in the alpha-helix content in the peptide. Gentamicin binding to BBM treated with trypsin, in which megalin completely disappeared, was significantly but not completely decreased compared with the native BBM. In addition, treatment of BBM with trypsin led to a decrease in the inhibitory effect of N-WASP181-200 on gentamicin binding. These observations support that megalin ligands and basic peptides including N-WASP181-200 decrease renal accumulation of gentamicin by inhibiting its binding to BBM of proximal tubule cells, partly interacting with megalin. In addition, the alpha-helix conformation may play an important role in the inhibitory effect of N-WASP181-200 on the binding of gentamicin to BBM.

Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists.

Receptor-mediated endocytosis plays an important role in accumulation of aminoglycosides in renal proximal tubule. To prevent aminoglycoside-induced nephrotoxicity following concentrated accumulation of gentamicin in the kidney, effect of cationic proteins and their peptide fragments, which could inhibit gentamicin binding to its binding receptor(s), was investigated. Among several substrates for megalin, an endocytic receptor responsible for renal accumulation of aminoglycosides, cytochrome c potently inhibited gentamicin accumulation in renal cortex. Concentration-dependent inhibition by cytochrome c on gentamicin uptake was also observed in OK kidney epithelial cells expressing megalin. In addition, gentamicin-induced increase in urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG), a marker of renal tubular damage, was significantly reduced by cytochrome c. We next attempted to find a peptide fragment with lower molecular size showing inhibitory effect on gentamicin uptake. Cyto79-88 inhibited gentamicin uptake in OK cells, but had little effect on renal accumulation of gentamicin in mice in vivo. On one hand, a peptide fragment of neural Wiskott-Aldrich syndrome protein (N-WASP), which interacts with acidic phospholipids like aminoglycosides, inhibited gentamicin accumulation not only in OK cells but also in mouse kidney. These results show that substrates and/or their peptide fragments for aminoglycoside binding receptor such as megalin might be useful for preventing aminoglycoside-induced nephrotoxicity.