Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases.

PURPOSE: To investigate the impact of radiotherapy (RT) and immune checkpoint inhibitor (ICI) sequence on the survival outcome in NSCLC patients with brain metastasis, and decide the best time to initiate RT. METHODS: Patients were managed with delayed RT (ICI delivered over 2 weeks prior to RT), concurrent RT (ICI delivered within 2 weeks prior to or after RT), or upfront RT (RT delivered over 2 weeks prior to ICI). Overall survival (OS), intracranial local progression-free survival (iLPFS), and intracranial distant progression-free survival (iDPFS) were assessed. A meta-analysis was performed to analyze the association between survival outcome and RT/ICI sequence. RESULTS: A total of 73 NSCLC patients were identified with a median follow-up of 13.9 months. Patients who receive delayed RT demonstrated shorter iLPFS (P = 0.0029), iDPFS (P = 0.016), and OS (P < 0.001). A meta-analysis was conducted and a total of 4 studies, 254 patients were included. The HR was 0.44 for iDPFS (P = 0.03), 0.41 for OS (P < 0.01) when compared concurrent with delayed RT, 0.21 for iDPFS (P < 0.01), 0.32 for OS (P < 0.01) when compared upfront with delayed RT, consistent with our conclusion that delayed RT brought with worst iDPFS and OS. More importantly, the best overall response rate (BOR) decreased in cases with longer RT and ICI intervals. Patients who receive intervals of RT and ICI within 7 days achieve the best median BOR of - 53%. CONCLUSIONS: Delayed RT brought poor survival outcomes including iLPFS, iDPFS, and OS in NSCLC patients. The shorter interval of RT and ICI is associated with better BOR.

Molecular hydrogen: A potential radioprotective agent.

In recent years, many studies have shown that hydrogen has therapeutic and preventive effects on various diseases. Its selective antioxidant properties were well noticed. Most of the ionizing radiation-induced damage is caused by hydroxyl radicals (OH) from radiolysis of H2O. Since hydrogen can mitigate such damage through multiple mechanisms, it presents noteworthy potential as a novel radio-protective agent. This review analyses possible mechanisms for hydrogen's radioprotective properties and effective delivery methods. We also look into details of vitro and vivo studies for hydrogen's radioprotective effects, and clinical practices. We conclude that hydrogen has good potential in radio-protection, with evidence that warrants greater research efforts in this field.

Practical Safety Considerations for Integration of Magnetic Resonance Imaging in Radiation Therapy.

Interest in integrating magnetic resonance imaging (MRI) in radiation therapy (RT) practice has increased dramatically in recent years owing to its unique advantages such as excellent soft tissue contrast and capability of measuring biological properties. Continuous real-time imaging for intrafractional motion tracking without ionizing radiation serves as a particularly attractive feature for applications in RT. Despite its many advantages, the integration of MRI in RT workflows is not straightforward, with many unmet needs. MR safety remains one of the key challenges and concerns in the clinical implementation of MR simulators and MR-guided radiation therapy systems in radiation oncology. Most RT staff are not accustomed to working in an environment with a strong magnetic field. There are specific requirements in RT that are different from diagnostic applications. A large variety of implants and devices used in routine RT practice do not have clear MR safety labels. RT-specific imaging pulse sequences focusing on fast acquisition, high spatial integrity, and continuous, real-time acquisition require additional MR safety testing and evaluation. This article provides an overview of MR safety tailored toward RT staff, followed by discussions on specific requirements and challenges associated with MR safety in the RT environment. Strategies and techniques for developing an MR safety program specific to RT are presented and discussed.

Stereotactic body radiotherapy based treatment for hepatocellular carcinoma with extensive portal vein tumor thrombosis.

BACKGROUND: There is currently no worldwide consensus for the management of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). We evaluated the efficacy of stereotactic body radiotherapy (SBRT) as the initial treatment for HCC with extensive PVTT based on a relatively large number of patients. METHODS: In our multidisciplinary approach for patients with hepatobiliary tumors, SBRT is recommended for unresectable HCC with PVTT or those with contraindication for transarterial chemoembolization (TACE). The aim is to shrink the tumor thrombus and preserve adequate portal venous flow, thus facilitating subsequent treatments such as TACE and tumor resection. In the present study, 70 continuous cases of HCC patients with extensive PVTT initially treated with SBRT were studied. The median follow-up period was 9.5 months (range, 1.0-21.0 months). The dynamic changes of tumor thrombosis with time after SBRT were also analyzed. RESULTS: The median survival time for the whole group was 10.0 months (95% CI, 7.7-12.3 months), with a 6- and 12-month overall survival (OS) rate of 67.3%, and 40.0% respectively. Patients who received combined SBRT and TACE showed significantly longer OS than those without indication for TACE after SBRT (12.0 ± 1.6 vs. 3.0 ± 1.0 months). Patients with good response to radiation usually had better survival. SBRT was well tolerated in our patient series. CONCLUSIONS: In conclusion, SBRT used as the initial treatment for HCC patients with extensive PVTT originally unsuitable for resection or TACE can achieve adequate thrombus shrinkage and portal vein flow restoration in the majority of cases. It could thus offer the patients an opportunity to undergo further treatment such as resection or TACE procedure. Such therapeutic strategy may result in survival advantage, especially for those who do receive combined modality with SBRT.

Dynamic MRI follow-up of radiation encephalopathy in the temporal lobe following nasopharyngeal carcinoma radiotherapy.

The natural course of radiation encephalopathy following nasopharyngeal carcinoma (NPC) radiotherapy remains poorly understood. The present study aimed to investigate the magnetic resonance imaging (MRI) characteristics and evolution of radiation encephalopathy. A series of 162 follow-up MRI examinations from 68 NPC patients with radiation encephalopathy in the temporal lobes were analyzed retrospectively. Each component of radiation encephalopathy was defined as follows: i) contrast enhanced lesions were enhanced lesions on contrast enhanced T1-weighted images (T1WI); ii) white matter lesions were lesions of homogeneous hyperintensity on T2-weighted images (T2WI) and hypointensity on T1WI; iii) cysts were round or oval well-defined lesions of hyperintensity on T2WI; iv) hemosiderin deposition were nodular or annular hypointense lesions with lower hypointense than normal white matter on both T1WI and T2WI; v) gray matter lesions were defined as disruption or erosion of hyperintensity in the cortex on T2WI. Contrast enhanced lesions, white matter lesions, gray matter lesions, cysts and hemosiderin deposition were detected in 105 (100.0%), 98 (93.3%), 94 (89.5%), 2 (1.7%) and 2 (1.7%) cases of the 105 initial diagnosed temporal lobe lesions. Contrast enhanced lesions were the most commonly observed, followed by white matter lesions, gray matter lesions, temporal lobe atrophy, cysts and hemosiderin deposition. In addition, 12 new lesions were identified during the follow-up, 4 of which presented as solid enhanced nodular lesions. Importantly, in 11 of the 117 (9.4%) affected temporal lobes, solid enhanced nodular lesions were observed to be the only initial abnormalities to occur. For those enhanced nodular lesions measuring <0.8 cm, no necrosis could be detected. On the contrary, all the contrast enhanced lesions measuring >2.0 cm exhibited a necrotic core. To the best of our knowledge, the present study revealed for the first time solid enhanced nodular lesions as the earliest MRI abnormalities of radiation encephalopathy following NPC radiotherapy.

Long-Term Relief of Cerebral Radiation Necrosis Treated with Low-Dose Bevacizumab - a Report of 2 Cases.

BACKGROUND: Radiation necrosis is 1 of the most significant complications of brain tumor irradiation. The standard treatment for patients with radiation necrosis consists of corticosteroids to reduce the amount of cerebral edema and, if required, cyst drainage. CASE REPORTS: 2 patients with symptomatic radiation necrosis initially unresponsive to steroid treatment were treated with repeated low-dose bevacizumab at 5 mg/kg body weight. Rapid and lasting symptom relief, as well as neuroradiological improvement was seen in both cases. A dramatic rapid magnetic resonance imaging response with decrease in contrast enhancement was found shortly after administering the first dose of bevacizumab. The improvement of perifocal edema was relatively slower than of the reduction of enhancement. Only a slight reduction in size of the involved area could be expected after the first dose of bevacizumab. Further shrinkage was seen after the second and third doses. The individuals reported have been doing well for more than 45 and 22 months, respectively, after the initiation of bevacizumab treatment. CONCLUSION: Our data add to the literature supporting of the use of bevacizumab as an effective therapeutic agent for radiation necrosis, particularly in cases unresponsive to steroid treatment.

IGFBP, a novel target of lung cancer?

The insulin-like growth factor-1 receptor (IGF-1R) is a central component of lung cancer signal transduction pathways. A phase III study failed for carboplatin, paclitaxel, with or without figitumumab in first-line treating metastatic non-small cell lung cancer (NSCLC). There is an urgent need for a better understanding of signaling in IGF system. Insulin-like growth factor-binding proteins (IGFBPs) function as modulators for IGF signaling through sequestration of IGFs in serum and the extracellular fluid. IGFBPs can also act as transporters or modulators for IGF action and insulin action. IGFBPs have attracted increased attention for their lung cancer-related role in recent years. Recent studies have demonstrated the critical role of IGFBPs in risk assessment, early detection, prognosis evaluation, and drug resistance appraisal for lung cancer. These observations suggest a potential new approach to understand the pathogenesis of lung cancer, have important clinical implications, while additional investigations are necessary.

Parametric contrast-enhanced ultrasound as an early predictor of radiation-based therapeutic response for lymph node metastases of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common type of cancer in South East Asia with peculiar epidemiology, pathology, clinical behavior and response to treatment characteristics. To the best of our knowledge, this is the first study to investigate the use of a contrast-enhanced ultrasound (CEUS) as a predictor for the therapeutic response in lymph node metastases of NPC patients treated with radiation-based therapy. Sixty-seven NPC patients with lymph node metastases underwent the lymph nodes CEUS examination twice; pre- and in-treatment (at the 5th fraction radiotherapy), respectively. The CEUS parameters were acquired through Qontrast_4.0 software and mainly included peak intensity (PI) and time to peak (TTP). The response assessment at the lymph nodes revealed a complete response (CR) in 48 patients and partial response (PR) in 19 patients. There was a significant difference in pre-treatment PI (PIpre) between the patients who showed CR or PR, but the predicted sensitivity and specificity of PIpre was low. The mean in-treatment PI (PIin) value of the lymph nodes that achieved a CR was 34.24±3.78%, which was significantly higher than the PIin value for PR, 25.62±2.30% (P<0.001). Furthermore, the PIratio, a PI-quotient, was calculated by dividing the PIin by the corresponding PIpre. The higher PIratio was also observed in CR lymph nodes (0.81±0.01 vs. 0.66±0.01; P=0.001), and the mean change in PI (PIΔ; PIΔ = PIpre-PIin) was smaller in the patients with CR nodes compared to the patients with PR nodes (7.79±3.28 vs. 13.77±1.90%; P=0.000). No difference was observed in TTPpre or TTPin between the CR or PR lymph nodes patients. A receiver operating characteristic curve was constructed to assess the accuracy of the parameters for the prediction of the therapeutic responses. The sensitivity and specificity of PIin in predicting the therapeutic response was 94.3 and 88.2%, and the corresponding figures of the PIratio were 92.5 and 83.8%, respectively. The CEUS parameters during the early course of radiation-based therapy, PIin and PIratio, are associated with the therapeutic response of NPC lymph node metastases, with a high predicted sensitivity and specificity, thus yielding the conceivable predictors with the potential to individualize treatment.

Lack of association between MDR1 C3435T polymorphism and chemotherapy response in advanced breast cancer patients: evidence from current studies.

The transmembrane transport of anticancer drugs is mainly regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 gene (MDR1). Since there were controversies regarding the association between MDR1 C3435T polymorphism and response to chemotherapy among patients with advanced breast cancer, a meta-analysis of the link was conducted. A total of 7 studies consist of 464 advanced breast cancer patients relating MDR1 C3435T polymorphism to the response of chemotherapy were included in this meta-analysis. The main analysis revealed a lack of association between the MDR1 C3435T and response to chemotherapy, with odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) of 1.37 (95% CI: 0.78-2.40), 1.17 (95% CI: 0.69-2.01), 1.18 (95% CI: 0.76-1.84) and 1.61 (95% CI: 0.70-3.68) for homozygous comparison, heterozygous comparison, dominant model and recessive model, respectively. The subgroup analysis by ethnicity did not change the pattern of results, with ORs of 0.99 (95% CI: 0.11-9.07), 0.68 (95% CI: 0.29-1.60), 0.81 (95% CI: 0.36-1.85) and 1.51 (95% CI: 0.77-2.96), in homozygous comparison, heterozygous comparison, dominant model and recessive model, respectively in Caucasian, and 1.50 (95% CI: 0.75-3.03), 1.72 (95% CI: 0.85-3.47), 1.59 (95% CI: 0.90-2.80) and 2.29 (95% CI: 0.51-10.35), respectively in Asian. The available evidence indicates that MDR1 C3435T polymorphism cannot be considered as a reliable predictor of response to chemotherapy in patients with advanced breast cancer.

Comparison of the epidermal growth factor receptor protein expression between primary non-small cell lung cancer and paired lymph node metastases: implications for targeted nuclide radiotherapy.

BACKGROUND: The knowledge of Epidermal growth factor receptor (EGFR) expression in metastases of NSCLC was limited. In receptor-mediated targeted nuclide radiotherapy, tumor cells are killed with delivered radiation and therapeutic efficiency is mainly dependent on the receptor expression. Thus, the level and stability of receptor expression in both primary tumors and corresponding metastases is crucial in the assessment of a receptor as target. The goal of this study was to evaluate whether EGFR is suitable as target for clinical therapy. METHODS: Expression of EGFR was investigated immunohistochemically in paired samples of lymph node metastases and corresponding NSCLC primary lesions (n = 51). EGFR expression was scored as 0, 1+, 2+ or 3+. RESULTS: Positive (1+, 2+ or 3+) EGFR immunostaining was evident in 36 of 47 (76.6%) analysed NSCLC primary tumors, and in 78.7% of the corresponding lymph node metastases. When EGFR expression is classified as positive or negative, discordance between the primary tumors and the corresponding metastases was observed in 5 cases (10.6%). EGFR overexpression (2+ or 3+) was found in 53.2% (25/47) of the NSCLC primary tumors and 59.6% of the corresponding metastases. Nine out of the 47 paired samples (19.2%) were discordant: Only three patients who had EGFR overexpression in the primary tumors showed EGFR downregulation (0 or 1+) in lymph node metastases, while six patients changed the other way around. CONCLUSIONS: The EGFR expression in the primary tumor and the corresponding metastasis is discordant in about 10% of the patients. When overexpression is considered, the discordance is observed in about 20% of the cases. However, concerning EGFR overexpression in the primary tumors, similar expression in the metastases could be predicted with a reasonably high probability, which is encouraging for testing of EGFR targeted nuclide radiotherapy.

Epidermal growth factor receptor and human epidermal growth receptor 2 expression in parotid mucoepidermoid carcinoma: possible implications for targeted therapy.

The expression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) was analyzed in immunohistochemical preparations from 46 primary parotid mucoepidermoid carcinomas (MEC). For the cases with lymph node metastases, the receptor expressions were investigated in parallel samples, primary tumour and metastasis, from each patient (n=11). The goal was to evaluate whether any of these receptors are suitable as a target for radionuclide-based imaging and therapy. The HercepTest scoring was used for the analysis of both HER2 and EGFR expression (0, 1+, 2+ or 3+). EGFR overexpression (2+/3+) was found in 67.4% (31/46) of the primary tumours. Out of the 11 cases with evaluated paired samples, EGFR overexpression was observed in 81.8% (9/11) of the primary tumours and 72.7% (8/11) of the corresponding lymph node metastases. There was only one patient who had EGFR overexpression in the primary tumours which changed to negative in the lymph node metastases but no changes occurred reciprocally. The HER2 overexpression was only found in 4.3% (2/46) of the primary mucoepidermoid carcinoma and none of the lymph node metastases (0/11). EGFR and HER2 stainings were mainly found in the cell membranes. It was concluded that the majority of parotid mucoepidermoid carcinomas express EGFR strongly in their cell membranes and that lymph node metastases generally express EGFR to approximately the same extent as in the primary tumours. The stability in the EGFR expression is encouraging in the effort to develop radionuclide-based EGFR imaging agents. It is also possible that EGFR targeting agents (e.g. Iressa, Tarceva, Erbitux or radiolabelled antibodies) can be applied for the therapy of mucoepidermoid carcinoma.

EGFR, HER2, and HER3 expression in laryngeal primary tumors and corresponding metastases.

BACKGROUND: There are several substances available to target members of the epidermal growth factor receptor (EGFR) family, both for imaging in nuclear medicine and for various forms of therapy. The level and stability of expression in both primary tumors and corresponding metastases is crucial in the assessment of a receptor as a target in systemic tumor therapy. To date, the expression of EGFR family members has only been determined in primary laryngeal carcinomas, and we have not found published data regarding the receptor status in corresponding metastatic lesions. METHODS: Expression of EGFR, HER2, and HER3 was investigated immunohistochemically in both lymph node metastases and corresponding primary laryngeal squamous carcinomas (n = 40). RESULTS: EGFR overexpression (2+ or 3+) was found in 87.5% (35/40) of the laryngeal primary tumors and 82.5% (33/40) of the corresponding lymph node metastases. There was a good agreement between the primary tumors and the paired metastases regarding EGFR expression. HER2 overexpression was found in only four cases (10.5%) of the studied primary tumors and in all cases the HER2 expression was retained in the paired metastases. Another two metastases gained HER2 status when compared to the corresponding primary tumors. Strong HER3 staining was found in 26.7% of both the primary tumors and the corresponding metastases. CONCLUSIONS: The high frequency and stability in EGFR expression is encouraging for efforts to use EGFR targeting agents (e.g. Iressa, Tarceva, Erbitux or radiolabeled antibodies) for therapy of laryngeal carcinoma. For a few laryngeal carcinoma patients with HER2 overexpression, anti-HER2 agents could possibly be used.