Natural Product Bis-Intercalator Depsipeptides as a New Class of Payloads for Antibody-Drug Conjugates.

A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase.

Biosynthetic engineering and fermentation media development leads to gram-scale production of spliceostatin natural products in Burkholderia sp.

A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. Spliceostatins are polyketide-nonribosomal peptide natural products that bind to the spliceosome, an emerging target in cancer therapy. The wild-type bacterium Burkholderia sp. FERM BP-3421 produces a suite of spliceostatin congeners with varying biological activities and physiological stabilities. Hemiketal compounds such as FR901464 were the first to be described. Due to its improved properties, we were particularly interested in a carboxylic acid precursor analog that was first reported from Burkholderia sp. MSMB 43 and termed thailanstatin A. Inactivation of the iron/α-ketoglutarate-dependent dioxygenase gene fr9P had been shown to block hemiketal biosynthesis. However, a 4-deoxy congener of thailanstatin A was the main product seen in the dioxygenase mutant. We show here that expression of the cytochrome P450 gene fr9R is a metabolic bottle neck, as use of an l-arabinose inducible system led to nearly complete conversion of the 4-deoxy analog to the target molecule. By integrating fermentation media development approaches with biosynthetic engineering, we were able to improve production titers of the target compound >40-fold, going from the starting ~60 mg/L to 2.5 g/L, and to achieve what is predominantly a single component production profile. These improvements were instrumental in enabling preclinical development of spliceostatin analogs as chemotherapy.

Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities.

A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64µM for AChE and 0.42µM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10µM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.

[Research on Collateral-unblocking Medicines for Cardiovascular Diseases under the Guidance of Vessels Collateral Theory].

OBJECTIVE: "Vessels Collateral Theory", as the inherit and development of "blood vessels" in Huangdi Neijing, is a systematic system by integrating severe vascular diseases. In this article, by taking cardiovascular diseases (CVD) as a cut-in point, roles of "minute collateral-microvascular" lesions in the occurrence and development of CVD were further explored. The interventional effect of collateral-unblocking medicines under the guidance of Vessels Collateral Theory was also in-depth explored, hoping to leading Chinese medical prevention and treatment of CVD.

[Effects of tongxinluo on angiogenesis and the volume of blood perfusion in ischemic stroke rats].

OBJECTIVE: To observe the effects of Tongxinluo (TXL) on angiogenesis and the volume of blood perfusion in ischemic stroke rats. METHODS: The model of middle cerebral artery occlusion (MCAO) was established using craniotomy ligation of the middle cerebral artery on one side. After screening, the male SD rats were randomly divided into the sham-operation group, the model group, the large dose TXL group, the middle dose TXL group, the low dose TXL group, and the Nimodipine group. The expression of microvascular density (MVD, CD31) of the MCAO rats was detected using immunohistochemical assay after 14 days of medication. The microvascular morphology and the volume of blood perfusion in the brain tissue were observed under laser scanning confocal microscope (LSCM). RESULTS: The positive CD31 expression was intense with significant coloring in the large dose TXL group, the middle dose TXL group, and the Nimodipine group, better than that of the model group. The blood perfusion volume in the ischemic brain cortex could be promoted in the large dose TXL group, the middle dose TXL group, and the Nimodipine group (P<0.01, P<0.05). The optimal effects were shown in the large dose TXL group (P<0.01). CONCLUSION: TXL significantly increased the MVD of the ischemic brain tissue, promoted the post-ischemic angiogenesis, and increased the volume of blood perfusion of ischemic brain tissue, playing certain blood flow compensatory roles.

[Effects of fatigue and restraint stress on the expression of carnitine palmitoyltransferase-I and 5-hydroxytryptamine receptors in aorta of rats].

OBJECTIVE: To investigate the effect of fatigue and restraint stress on the expressions of CPT (carnitine palmitoyltransferase)-I, PPAR (peroxisome proliferator-activated receptor) δ, 5-HT (hydroxytryptamine) 1D and 5-HT2A receptors in aorta of rats. METHODS: A total of 45 healthy male Wistar rats were randomly divided into control group, excessive fatigue group and restraint stress group (n = 15 each). The general condition, morphological changes of aortic endothelium cell and the blood levels of ET-1 (endothelin) and NO (nitric oxide) were observed. The real-time reverse transcription PCR (polymerase chain reaction) and Western blot were used to detect the gene and protein expressions of CPT-I, PPAR δ, 5-HT1D and 5-HT2A receptors in aorta. RESULTS: Compared with control group, the structural damages of endothelial cell were induced by excessive fatigue and restraint stress. The plasma levels of ET-1 increased [(124 ± 18) ng/L vs (161 ± 18) ng/L, (154 ± 17) ng/L] (P < 0.01, P < 0.05) while the serum levels of NO decreased [(63 ± 16) µmol/L vs (39 ± 8) µmol/L, (41 ± 7) µmol/L] (P < 0.05); the mRNA expressions of CPT-Iand PPARδ decreased in excessive fatigue rats, [(1.23 ± 0.21) vs (0.42 ± 0.05)], [(1.09 ± 0.10) vs (0.25 ± 0.07)] (P < 0.01); the protein expressions of CPT-Iand PPARδ decreased in excessive fatigue rats, [(1.32 ± 0.07) vs (0.83 ± 0.04)], [(1.41 ± 0.05) vs. (0.75 ± 0.06)]; the mRNA and protein expressions of 5-HT1D receptor decreased in excessive fatigue rats and restraint stress rats, [(1.10 ± 0.15) vs (0.46 ± 0.13), (0.45 ± 0.02)], [(1.19 ± 0.05) vs (0.71 ± 0.06), (0.70 ± 0.05)] (P < 0.01); the mRNA and protein expressions of 5-HT2A receptor increased in excessive fatigue rats and restraint stress rats, [(0.99 ± 0.08) vs (6.73 ± 0.46), (7.01 ± 1.56)], [(0.64 ± 0.03) vs (0.79 ± 0.05), (0.82 ± 0.03)] (P < 0.01). CONCLUSION: Excessive fatigue and restraint stress can injure the structure and function of endothelial cell. The changes in energy of abnormal carnitine metabolism and 5-HT receptors may play important roles.

Liquid perfluorochemical inhibits inducible nitric oxide synthase expression and nitric oxide formation in lipopolysaccharide-treated RAW 264.7 macrophages.

Partial liquid ventilation with various types of perfluorocarbon (PFC) has been shown to be beneficial in treating acute lung injury, a clinical outcome that may involve the anti-inflammatory activity of PFC. FC-77 is a type of PFC with relatively higher vapor pressure and evaporative loss than other PFCs during partial liquid ventilation. Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been proposed to play a crucial role in the pathogenesis of inflammatory diseases. However, whether the iNOS/NO pathway is affected by FC-77 is unknown. Thus, the aim of this study was to investigate whether FC-77 inhibits iNOS expression and NO production in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. We found that treatment with FC-77 significantly attenuated LPS-induced iNOS expression/activity and production of NO and reactive oxygen species (ROS). FC-77 also attenuated LPS-induced pro-inflammatory cytokine formation, but enhanced interleukin-10 production. Furthermore, the LPS-induced degradation of cytosolic IkappaB-alpha and activation of nuclear transcription factor-kappaB (NF-kappaB) were also inhibited by FC-77. In conclusion, the present study is the first to demonstrate that FC-77 decreases LPS-induced NO production in macrophages, which may be associated with the suppression of pro-inflammatory cytokines, and ROS production, as well as NF-kappaB activation. These results also provide a novel explanation for its anti-inflammatory activity.

The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144.

Four new indolosesquiterpenes, lecanindoles A-D (1-4), were isolated from fermentations of the terrestrial fungus Verticillium lecanii 6144. The structures of compounds 1-4 were elucidated from analysis of spectroscopic data. Compound 2 was reduced to give 4 and its isomer 5. Compound 4 was found to be a potent and selective progesterone receptor agonist with an EC50 of 1.1 +/- 0.4 nM in a cell-based luciferase reporter assay.

The lead optimization of the polyamine conjugate of flavonoid with a naphthalene motif: Synthesis and biological evaluation.

Polyamine conjugated flavonoid with a naphthalene moiety (ZYY14) displayed excellent therapeutic activity against hepatocellular carcinoma. In this study, three different series of novel flavonoid-polyamine conjugates were designed and screened against tumor cell lines. The structure-activity relationship study demonstrated the importance of the naphthalene moiety (as the B-ring), the basic side chains in the A-ring, and the methoxy group linked to the C-ring. The optimized compound 9b displayed better antitumor potency in vitro and in vivo than the lead compound ZYY14. Fluorescent assays revealed that 9b could enter cancer cells via polyamine transporter (PAT) and locate in mitochondria and endoplasmic reticulum. Compound 9b and ZYY14 demonstrated similar apoptotic mechanism in the cytotoxicity studies and stimulated the expression of apoptosis-related proteins, such as p-p38, p-JNK, p53 and Bax. In addition, 9b can initiate autophagy which inhibited the occurrence of apoptosis. Thus, 9b can be used as a valuable lead for the future development of antitumor agents.

Inhibition of miR-128-3p by Tongxinluo Protects Human Cardiomyocytes from Ischemia/reperfusion Injury via Upregulation of p70s6k1/p-p70s6k1.

Background and Aims: Tongxinluo (TXL) is a multifunctional traditional Chinese medicine that has been widely used to treat cardiovascular and cerebrovascular diseases. However, no studies have explored whether TXL can protect human cardiomyocytes (HCMs) from ischemia/reperfusion (I/R) injury. Reperfusion Injury Salvage Kinase (RISK) pathway activation was previously demonstrated to protect the hearts against I/R injury and it is generally activated via Akt or (and) Erk 1/2, and their common downstream protein, ribosomal protein S6 kinase (p70s6k). In addition, prior studies proved that TXL treatment of cells promoted secretion of VEGF, which could be stimulated by the increased phosphorylation of one p70s6k subtype, p70s6k1. Consequently, we hypothesized TXL could protect HCMs from I/R injury by activating p70s6k1 and investigated the underlying mechanism. Methods and Results: HCMs were exposed to hypoxia (18 h) and reoxygenation (2 h) (H/R), with or without TXL pretreatment. H/R reduced mitochondrial membrane potential, increased bax/bcl-2 ratios and cytochrome C levels and induced HCM apoptosis. TXL preconditioning reversed these H/R-induced changes in a dose-dependent manner and was most effective at 400 µg/mL. The anti-apoptotic effect of TXL was abrogated by rapamycin, an inhibitor of p70s6k. However, inhibitors of Erk1/2 (U0126) or Akt (LY294002) failed to inhibit the protective effect of TXL. TXL increased p70s6k1 expression and, thus, enhanced its phosphorylation. Furthermore, transfection of cardiomyocytes with siRNA to p70s6k1 abolished the protective effects of TXL. Among the micro-RNAs (miR-145-5p, miR-128-3p and miR-497-5p) previously reported to target p70s6k1, TXL downregulated miR-128-3p in HCMs during H/R, but had no effects on miR-145-5p and miR-497-5p. An in vivo study confirmed the role of the p70s6k1 pathway in the infarct-sparing effect of TXL, demonstrating that TXL decreased miR-128-3p levels in the rat myocardium during I/R. Transfection of HCMs with a hsa-miR-128-3p mimic eliminated the protective effects of TXL. Conclusions: The miR-128-3p/p70s6k1 signaling pathway is involved in protection by TXL against HCM apoptosis during H/R. Overexpression of p70s6k1 is, therefore, a potential new strategy for alleviating myocardial reperfusion injury.

Parotid gland-sparing 3-dimensional conformal radiotherapy results in less severe dry mouth in nasopharyngeal cancer patients: a dosimetric and clinical comparison with conventional radiotherapy.

BACKGROUND AND PURPOSE: This study examined the efficacy of parotid gland sparing of three-dimensional conformal radiotherapy (3DCRT) compared with conventional radiotherapy for NPC patients. Both the dose given to the parotids and clinical assessment of dry mouth were conducted. MATERIALS AND METHODS: Dry mouth was assessed for 108 patients treated with conventional technique and 72 treated with 3DCRT. Dose analysis was performed in 48 patients of the 3DCRT group. A dose of 70 Gy was given to the midplane in conventional radiotherapy and to 90% isodose volume in 3DCRT. Prognostic factors affecting the severity of dry mouth were analyzed using Generalized Estimating Equation (GEE). RESULTS: In the 3DCRT group about 50% of the patients' parotid glands received less than 25 Gy. Parallel analysis of dry mouth shows a significant decrease in the incidence of severe xerostomia after 3DCRT. The proportion of patients without dry mouth was also significantly higher in the 3DCRT group than the conventional group at 1-3 years after completion of radiotherapy. Although 3DCRT delivered a higher dose to the tumor, it spared the parotid gland significantly better than the conventional treatment. Late toxicities were mostly similar between the 2 groups while local control in T4 patients and survival were improved for 3DCRT. CONCLUSION: Dosimetrically and clinically 3DCRT is better than conventional technique regarding parotid gland protection.

Evaluation of nitric oxide and homocysteine levels in primary dysmenorrheal women in Taiwan.

In this study, we investigated the possible pathophysiological mechanisms in primary dysmenorrhea. The study was undertaken to determine the effect of homocysteine on the nitric oxide (NO) pathway in primary dysmenorrheal women. A total of 94 students from a local nursing college participated. Group 1 consisted of 51 normal subjects with no dysmenorrhea. Group 2 had 43 subjects with dysmenorrheal symptoms. Our results show that serum NO levels in group 2 are higher than those in group 1. However, the serum homocysteine level was lower in group 2. These observations indicate that the NO pathway is involved in the pathophysiological mechanism responsible for the damaging effects of homocysteine on dysmenorrheal women.

Lichenicolins A and B, new bisnaphthopyrones from an unidentified lichenicolous fungus, strain LL-RB0668.

Lichenicolous fungus LL-RB0668 was isolated from a processed lichen thallus on a modified Lilly-Barnett solid medium. Two new bisnaphthopyrone compounds, lichenicolins A (1) and B (2), were isolated from the culture broth of this organism fermented on a rice-based solid medium. These results demonstrate that lichen-associated fungi potentially are a good resource for new bioactive natural products for current screening programs.

Long-term treatment results of invasive cervical cancer patients undergoing inadvertent hysterectomy followed by salvage radiotherapy.

PURPOSE: To evaluate the long-term results of salvage radiotherapy for patients of invasive cervical cancer after inadequate surgery. METHODS AND MATERIALS: Between October 1975 and January 1994, 90 patients were treated with radiotherapy for invasive cervical carcinoma after simple hysterectomy. The inadequate surgery was performed for a variety of reasons. All patients had postoperative external beam irradiation or intravaginal brachytherapy, or both. The end points of this study were local control, survival, and treatment-related toxicity. RESULTS: The patients' age varied between 33 and 76 with a median of 53 years. The most common histopathology was squamous cell carcinoma, which accounted for 91% of the patients. The most frequent reason for inadvertent hysterectomy was understaged disease with preoperative diagnosis as carcinoma in situ for 51 patients (57%). Malignancy was not suspected before surgery in 28 patients (31%). After surgery, 72 patients (80%) were restaged as Ib, 12 patients (13.3%) as IIa, and 6 patients (6.7%) as IIb. Median follow-up time was 83 months. Seventy-three patients had follow-up times of 5 years or more. The overall 5-year and 10-year survival rates of 90 patients were 85.5% and 74.1%, respectively. Disease-specific 5-year and 10-year survival rates were 85.5% and 80.5%, respectively. All 16 patients with either locoregional or distant failure eventually died of disease. Fourteen patients (15.5%) had late morbidities. Radiation proctitis developed in 6 patients, intestinal obstruction in 4 patients, and hemorrhagic cystitis in 3. There was only 1 patient (1%) with terminal ileum stenosis and severe intestinal obstruction requiring surgical intervention. CONCLUSIONS: Most cases of inadequately treated invasive cervical cancer were the result of suboptimal preoperative workups. Patients who had early tumors and no gross residual tumor after inadequate hysterectomy can have excellent prognoses when given postoperative radiotherapy. The severe long-term complication related to salvage radiotherapy is rare.

Dose escalation using twice-daily radiotherapy for nasopharyngeal carcinoma: does heavier dosing result in a happier ending?

PURPOSE: To present our experience using a twice-daily radiotherapy (RT) technique, including hyperfractionated and accelerated-hyperfractionated RT, on nasopharyngeal carcinoma (NPC) patients. The dose to the primary tumor was increased in the hope that local control could be increased without the cost of increased late complications. We analyzed acute and late complications and local control and compared the results with the results of NPC patients treated during the same period using conventional once-daily RT. METHODS AND MATERIALS: Between October 1991 and July 1998, 222 histologically confirmed, Stage M0, previously unirradiated NPC patients completed RT at our hospital. Most patients had American Joint Committee on Cancer (AJCC) 1992 Stage III and IV disease. Among them, 88 received altered fractionated, twice-daily RT; 76 patients received hyperfractionated RT and 12 accelerated-hyperfractionated RT. The remaining 134 patients received a conventional once-daily regimen. Hyperfractionated RT was delivered using 120 cGy b.i.d. separated by 6-h intervals throughout the course. For the accelerated-hyperfractionated patients, 160 cGy b.i.d. was given, also at 6-h intervals. The median dose in the twice-daily group was 7810 cGy (range 6840-8200). In the once-daily regimen, RT was delivered using 180-200 cGy q.d. The median tumor dose to the primary tumor was 7000 cGy (range 6560-8100) given during about 8 weeks. The median follow-up time was 70.5 and 72 months for the twice-daily and once-daily groups, respectively. RESULTS: The incidence of acute toxicities was higher in the twice-daily group with more severe mucositis and moist desquamation than in the once-daily group. Both groups had a similar incidence of late complications, except for 3 cases of temporal lobe necrosis in the twice-daily group, all in patients treated with 160 cGy. No difference was noted in recurrence-free local control between the two groups when the individual T stage was compared using AJCC 1992 or 1997 criteria (p = 0.51 and 0.59, respectively). The 5-year local control rate for T1-3 (AJCC 1997) was 93.2% for the twice-daily group and 86.4% for the once-daily group (p = 0.45). In Stage T4 (AJCC 1997) patients, the local control rate dropped drastically to 43.5% and 36.9% for the twice-daily and once-daily groups, respectively. The overall neck control rate at 5 years was 87.3% and 80.3% for the twice-daily and once-daily patients, respectively (p = 0.16). The overall locoregional control rate was 82.7% for the twice-daily group and 66.6% for the once-daily group. The difference was again not statistically significant, but showed a tendency in favor of the twice-daily regimen (p = 0.055). Locoregional failure occurred mainly in Stage T4 patients with central nervous invasion for whom local control was particularly poor, with a failure rate of about 60%. CONCLUSION: The present data suggest that NPC patients can be safely treated using a 120-cGy twice-daily program with a 6-h interval up to 8000 cGy. The accelerated-hyperfractionated technique is not recommended. A large discrepancy in local control between patients with T1-3 and T4 disease was noted. For T1-3 disease, an excellent local control rate >90% was achieved using the twice-daily regimen. In contrast, failure in the T4 patients was as high as 55% in the twice-daily group and reached 65% in the once-daily group. More rigorous treatment is needed using either additional dose escalation or other strategies for T4 NPC patients. With a dose escalation of 1000 cGy using 120-cGy twice-daily RT, a trend toward better locoregional control and disease-specific survival was noted in the twice-daily group. Whether this difference was truly the result of an increased dose needs additional confirmation in studies with larger patient numbers.

[Monitoring on spatial and temporal changes of snow cover in the Heilongjiang Basin based on remote sensing].

This paper extracted and verified the snow cover extent in Heilongjiang Basin from 2003 to 2012 based on MODIS Aqua and Terra data, and the seasonal and interannual variations of snow cover extent were analyzed. The result showed that the double-star composite data reduced the effects of clouds and the overall accuracy was more than 91%, which could meet the research requirements. There existed significant seasonal variation of snow cover extent. The snow cover area was almost zero in July and August while in January it expanded to the maximum, which accounted for more than 80% of the basin. According to the analysis on the interannual variability of snow cover, the maximum winter snow cover areas in 2003-2004 and 2009-2010 (>180 x 10(4) km2) were higher than that of 2011 (150 x 10(4) km2). Meanwhile, there were certain correlations between the interannual fluctuations of snow cover and the changes of average annual temperature and precipitation. The year with the low snow cover was corresponding to less annual rainfall and higher average temperature, and vice versa. The spring snow cover showed a decreasing trend from 2003 to 2012, which was closely linked with decreasing precipitation and increasing temperature.

18F-FDG PET and combined 18F-FDG-contrast CT parameters as predictors of tumor control for hepatocellular carcinoma after stereotactic ablative radiotherapy.

UNLABELLED: The application of stereotactic ablative radiotherapy (SABR) to hepatocellular carcinoma (HCC) is emerging. To identify pretreatment prognostic indicators is crucial for patient selection and optimal individual therapy. The aim of this study was to determine whether (18)F-FDG PET and a combined (18)F-FDG-contrast CT parameter could be useful tools to predict tumor control for patients with HCC treated by SABR. METHODS: We retrospectively identified 31 patients (41 tumors) who underwent (18)F-FDG PET before SABR between November 2007 and September 2011. (18)F-FDG PET parameters were collected as prognostic indicators, including visual PET scale (+/-), maximal standardized uptake value (SUV) of the tumor (T SUV max), ratio of T SUV max to maximal normal-liver SUV, ratio of T SUV max to mean normal-liver SUV, and score combining tumor volume and T SUV max (CT/(18)F-FDG PET score). They underwent SABR with a median dose of 42 Gy (ranging from 30 to 50 Gy) in 4-5 fractions. (18)F-FDG PET parameters and clinical factors were tested as predictors of tumor control and patient survival. RESULTS: The median follow-up time was 18 mo. Among the parameters examined, T SUV max and CT/(18)F-FDG PET score were significantly correlated with tumor control. T SUV max with a cutoff value of 3.2 was the most significant prognostic indicator. The 4-y control rate was 86.2% in tumors with a T SUV max of 3.2 or less but only 37.5% in those with a T SUV max of more than 3.2 (adjusted hazard ratio, 9.40; 95% confidence interval, 1.18-74.76; P = 0.034). CT/(18)F-FDG PET score (≤ 4 vs. >4) was also a significant predictor of tumor control after SABR. Tumors with a CT/(18)F-FDG PET score of more than 4 had a 5.23-fold risk of tumor failure. After adjustment for factors of sex, American Joint Committee on Cancer stage, Cancer of the Liver Italian Program score, and Child-Pugh classification, tumors with a score of more than 4 had a 4.96-fold risk of failure after SABR, compared with tumors with a score of 4 or less. For overall survival, none was statistically significant. CONCLUSION: The use of (18)F FDG PET to predict tumor control is feasible. T SUV max with a cutoff value of 3.2 is the best prognostic indicator. We suggest that (18)F-FDG PET may be a reference for prognostic prediction, patient selection, and radiation dose adjustment for HCC patients treated with SABR.

Stereotactic body radiation therapy in recurrent hepatocellular carcinoma.

PURPOSE: To examine the safety and efficacy of Cyberknife stereotactic body radiation therapy (SBRT) and its effect on survival in patients of recurrent hepatocellular carcinoma (HCC). METHODS AND MATERIALS: This was a matched-pair study. From January 2008 to December 2009, 36 patients with 42 lesions of unresectable recurrent HCC were treated with SBRT. The median prescribed dose was 37 Gy (range, 25 to 48 Gy) in 4-5 fractions over 4-5 consecutive working days. Another 138 patients in the historical control group given other or no treatments were selected for matched analyses. RESULTS: The median follow-up time was 14 months for all patients and 20 months for those alive. The 1- and 2-year in-field failure-free rates were 87.6% and 75.1%, respectively. Out-field intrahepatic recurrence was the main cause of failure. The 2-year overall survival (OS) rate was 64.0%, and median time to progression was 8.0 months. In the multivariable analysis of all 174 patients, SBRT (yes vs. no), tumor size (≤4 cm vs. >4 cm), recurrent stage (stage IIIB/IV vs. I) and Child-Pugh classification (A vs. B/C) were independent prognostic factors for OS. Matched-pair analysis revealed that patients undergoing SBRT had better OS (2-year OS of 72.6% vs. 42.1%, respectively, p = 0.013). Acute toxicities were mild and tolerable. CONCLUSION: SBRT is a safe and efficacious modality and appears to be well-tolerated at the dose fractionation we have used, and its use correlates with improved survival in this cohort of patients with recurrent unresectable HCC. Out-field recurrence is the major cause of failure. Further studies of combinations of SBRT and systemic therapies may be reasonable.

Peritumoral edema after stereotactic radiosurgery for meningioma.

Peritumoral edema induced by radiosurgery after the treatment of intracranial meningioma has been reported and its mechanism remains unclear. A 65-year-old woman presented with a history of intermittent dizziness. A CT scan and MRI of the brain revealed an extra-axial space-occupying lesion in the left frontal region. She was treated by stereotactic radiosurgery (SRS). Seven months later, the patient began experiencing general weakness and drowsiness. She developed peritumoral edema around the left frontal tumor. Similarly, a 55-year-old woman complained of unstable gait and dizziness 1 month prior to admission. A CT scan and MRI of the brain revealed an extra-axial space-occupying lesion in the right posterior temporal region. Six months after SRS, this patient experienced deteriorated consciousness and general weakness. Peritumoral edema in the right temporal region was noted. We report these two patients, discuss possible causes and review the relevant literature.

Successful treatment of metastatic brain tumor by CyberKnife: a case report.

Stereotactic radiosurgery plays an important role in management of metastatic brain tumors, especially when the tumor has recurred after treatment with previous whole brain radiotherapy. Most metastatic brain tumors less than 1 cm(3) show a complete response after stereotactic radio-surgery. However, there are few reports of a dramatic change in the complete response of large metastatic brain tumors. Here, we report a case of adenocarcinoma of lung that had metastasized to the brain. Because the recurrence of the metastatic brain tumor measured approximately 3 cm in diameter, the tumor was previously treated with two prior craniotomies followed by whole brain radiation to the resection cavity. The tumor subsequently recurred and was treated with stereotactic radiosurgery (CyberKnife). A dramatic response was noted 3 months after radiosurgery with complete disappearance of the recurrent tumor.