A phase I/II study on stereotactic body radiotherapy with real-time tumor tracking using CyberKnife based on the Monte Carlo algorithm for lung tumors.

BACKGROUND: In this phase I/II study, we assessed the safety and initial efficacy of stereotactic body radiotherapy (SBRT) for lung tumors with real-time tumor tracking using CyberKnife based on the Monte Carlo algorithm. METHODS: Study subjects had histologically confirmed primary non-small-cell lung cancer staged as T1a-T2aN0M0 and pulmonary oligometastasis. The primary endpoint was the incidence of Grade ≥3 radiation pneumonitis (RP) within 180 days of the start of SBRT. The secondary endpoint was local control and overall survival rates. Five patients were initially enrolled at level 1 [50 Gy/4 fractions (Fr)]; during the observation period, level 0 (45 Gy/4 Fr) was opened. The dose was escalated to the next level when grade ≥3 RP was observed in 0 out of 5 or 1 out of 10 patients. Virtual quality assurance planning was performed for 60 Gy/4 Fr; however, dose constraints for the organs at risk did not appear to be within acceptable ranges. Therefore, level 2 (55 Gy/4 Fr) was regarded as the upper limit. After the recommended dose (RD) was established, 15 additional patients were enrolled at the RD. The prescribed dose was normalized at the 95% volume border of the planning target volume based on the Monte Carlo algorithm. RESULTS: Between September 2011 and September 2015, 40 patients (primary 30; metastasis 10) were enrolled. Five patients were enrolled at level 0, 15 at level 1, and 20 at level 2. Only one grade 3 RP was observed at level 1. Two-year local control and overall survival rates were 98 and 81%, respectively. CONCLUSION: The RD was 55 Gy/4 Fr. SBRT with real-time tumor tracking using CyberKnife based on the Monte Carlo algorithm was tolerated well and appeared to be effective for solitary lung tumors.

Long-term results of hypofractionated stereotactic radiotherapy with CyberKnife for growth hormone-secreting pituitary adenoma: evaluation by the Cortina consensus.

The aim of the present study was to evaluate the safety and feasibility of hypofractionated stereotactic radiotherapy (SRT) with CyberKnife for growth hormone-secreting pituitary adenoma (GH-PA). Fifty-two patients with GH-PA were treated with hypofractionated SRT between September 2001 and October 2012. Eight patients had clinically silent GH-PA and 44 were symptomatic. Only 1 patient was inoperable. The other patients had recurrent or postoperative residual tumors on MRI. All patients had received pharmacotherapy prior to SRT with a somatostatin analog, dopamine agonist, and/or GH receptor antagonist. The marginal doses were 17.4-26.8 Gy for the 3-fraction schedule and 20.0-32.0 Gy for the 5-fraction schedule. Endocrinological remission was assessed by the Cortina consensus criteria 2010 (random GH <1 ng/ml or nadir GH after an oral glucose tolerance test <0.4 ng/ml and normalization of age- and sex-adjusted insulin-like growth factor-1). The median follow-up period was 60 months (range 27-137). The 5-year overall survival, local control, and disease-free survival rates were 100, 100, and 96 %, respectively. Nine patients (5 clinically silent and 4 symptomatic patients) satisfied the Cortina criteria without receiving further pharmacotherapy, whereas the remaining 43 patients did not. No post-SRT grade 2 or higher visual disorder occurred. Symptomatic post-SRT hypopituitarism was observed in 1 patient. CyberKnife hypofractionated SRT is safe and effective when judged by imaging findings for GH-PA. However, it may be difficult to satisfy the Cortina consensus criteria in most symptomatic patients with SRT alone. Further investigations of optimal treatments are warranted.

Hypofractionated Stereotactic Radiotherapy for Auditory Canal or Middle Ear Cancer.

BACKGROUND: Stereotactic radiotherapy (SRT) may represent a new treatment option for individuals with auditory canal or middle ear cancer. METHODS: Study participants with pathologically proven ear cancer were treated with SRT (35 Gy for 3 fractions or 40 Gy for 5 fractions) as first-line therapy. When local tumor recurrence developed following SRT, subtotal temporal bone resection and postoperative chemoradiotherapy were performed as salvage treatment. Boluses were used for the initial 14 study patients. RESULTS: Twenty-nine study participants were enrolled and staged with T1 (n = 3), T2 (n = 7), T3 (n = 14), or T4 disease (n = 5). Three-year overall survival rates were 69% for T1/2 disease, 79% for T3 disease, and 0% for T4 disease. Three-year local control rates were 70% for T1/2 disease, 50% for T3 disease, and 20% for T4 disease. Grade 2 or higher dermatitis or soft-tissue necrosis occurred more frequently in study patients treated with boluses (8/14 vs 2/15; P = .02). Salvage treatment was safely performed for 12 recurrent cases. CONCLUSIONS: These results suggest that SRT outcomes are promising for patients with ear cancer (? T3 disease). The rate of toxicity was acceptable in the study patients treated without boluses. Outcomes of salvage surgery and postoperative radiotherapy following SRT were also encouraging.

Development of system using beam's eye view images to measure respiratory motion tracking errors in image-guided robotic radiosurgery system.

The accuracy of the CyberKnife Synchrony Respiratory Tracking System (SRTS) is considered to be patient-dependent because the SRTS relies on an individual correlation between the internal tumor position (ITP) and the external marker position (EMP), as well as a prediction method to compensate for the delay incurred to adjust the position of the linear accelerator (linac). We aimed to develop a system for obtaining pretreatment statistical measurements of the SRTS tracking error by using beam's eye view (BEV) images, to enable the prediction of the patient-specific accuracy. The respiratory motion data for the ITP and the EMP were derived from cine MR images obtained from 23 patients. The dynamic motion phantom was used to reproduce both the ITP and EMP motions. The CyberKnife was subsequently operated with the SRTS, with a CCD camera mounted on the head of the linac. BEV images from the CCD camera were recorded during the tracking of a ball target by the linac. The tracking error was measured at 15 Hz using in-house software. To assess the precision of the position detection using an MR image, the positions of test tubes (determined from MR images) were compared with their actual positions. To assess the precision of the position detection of the ball, ball positions measured from BEV images were compared with values measured using a Vernier caliper. The SRTS accuracy was evaluated by determining the tracking error that could be identified with a probability of more than 95% (Ep95). The detection precision of the tumor position (determined from cine MR images) was < 0.2 mm. The detection precision of the tracking error when using the BEV images was < 0.2mm. These two detection precisions were derived from our measurement system and were not obtained from the SRTS. The median of Ep95 was found to be 1.5 (range, 1.0-3.5) mm. The difference between the minimum and maximum Ep95 was 2.5mm, indicating that this provides a better means of evaluating patient-specific SRTS accuracy. A suitable margin, based on the predicted patient-specific SRTS accuracy, can be added to the clinical target volume.

Factors affecting the accuracy of respiratory tracking of the image-guided robotic radiosurgery system.

PURPOSE: To analyze the factors affecting the tracking accuracy of the CyberKnife Synchrony Respiratory Tracking System (SRTS). MATERIALS AND METHODS: A dynamic motion phantom (motion phantom) reproduced the respiratory motions of each patient treated with the SRTS using a ball as the target. CyberKnife tracked the ball using the SRTS, and this process was recorded by a video camera mounted on the linear accelerator head. The tracking error was evaluated from the images captured by the video camera. Multiple regression analysis was used to identify factors affecting tracking accuracy from 91 cases. RESULTS: The median tracking error was 1.9 mm (range 0.9-5.3 mm). Four factors affected the tracking accuracy: the average absolute amplitude of the tumor motion in the cranio-caudal (CC) direction (p = 0.007), average position gap due to the phase shift between the internal tumor and external marker positions in the CC direction (p < 0.001), and average velocity of the tumor in the CC (p < 0.001) and anterior-posterior directions (p = 0.033). CONCLUSION: We identified factors that affected tracking accuracy. This information may assist the identification of suitable margins that should be added to each patient's clinical target volume.

Effects of ulvoid (Ulva spp.) accumulation on the structure and function of eelgrass (Zostera marina L.) bed.

The objective of this study is to clarify the effect of ulvoid (Ulva spp.) accumulation on the structure and function of an eelgrass bed by the coast of Iwakuni, Seto Inland Sea, Japan. We monitored eelgrass shoot density and volume of ulvoid accumulation in the study site and evaluated effects of the accumulated ulvoid canopy on the percent survival, seedling density, growth rates, photosynthetic photon flux density (PPFD) and carbon contents of eelgrass. Eelgrass shoot density decreased by the accumulation of ulvoid. Also, seedling density decreased by the increase in the ulvoid volumes. Shoot density, seedling density and leaf elongation were negatively correlated with ulvoid volume. Carbon contents in eelgrass decreased by the accumulation of ulvoid (canopy height: 25cm). These results suggest that accumulation of ulvoid bloom has significant negative impacts on the structure and function of eelgrass bed, i.e. decreases in vegetative shoot density, seedling density, shoot height and growth rate.

Spontaneous resolution of diabetes insipidus after pituitary stalk sectioning during surgery for large craniopharyngioma. Endocrinological evaluation and clinical implications for surgical strategy.

The mechanism of spontaneous resolution of diabetes insipidus (DI) was investigated after surgery for large craniopharyngioma. Twenty-two adult patients (mean age 48.9 years old), who underwent surgery via the anterior interhemispheric trans-lamina terminalis approach, were divided into three groups: Group I, the entire pituitary stalk was preserved (n = 2); Group II, the stalk was dissected distally from the tumor but ultimately sacrificed (n = 9); Group III, the stalk was not identified and was sacrificed (n = 11). All patients were discharged without neurological deficits 1 month after surgery. Four patients underwent gamma-knife treatment for residual tumor or recurrence. Postoperative endocrinological functions were normal in Group I, and no replacement therapy was required. Hormonal replacement for pan-hypopituitarism and DI was necessary in Groups II and III (mean follow-up period 5.9 years). DI resolved at 2.7 +/- 1.3 years after surgery in four patients in Group II, and a hypertonic saline infusion test revealed production of small amounts of intrinsic antidiuretic hormone (ADH). Urine osmolarity was high in the morning, and a significant increase in urinary osmolarity was noted after Pitressin injection. These results indicate induction of hypersensitivity of the distal renal tubules to small amounts of intrinsic ADH, resulting in decreased urinary output. Recovery from DI can be expected, despite permanent impairment of anterior pituitary function, if the pituitary stalk is dissected as distally as possible.

Miscellaneous Topics in Computer-Aided Drug Design: Synthetic Accessibility and GPU Computing, and Other Topics.

BACKGROUND: Computer-aided drug design is still a state-of-the-art process in medicinal chemistry, and the main topics in this field have been extensively studied and well reviewed. These topics include compound databases, ligand-binding pocket prediction, protein-compound docking, virtual screening, target/off-target prediction, physical property prediction, molecular simulation and pharmacokinetics/pharmacodynamics (PK/PD) prediction. Message and Conclusion: However, there are also a number of secondary or miscellaneous topics that have been less well covered. For example, methods for synthesizing and predicting the synthetic accessibility (SA) of designed compounds are important in practical drug development, and hardware/software resources for performing the computations in computer-aided drug design are crucial. Cloud computing and general purpose graphics processing unit (GPGPU) computing have been used in virtual screening and molecular dynamics simulations. Not surprisingly, there is a growing demand for computer systems which combine these resources. In the present review, we summarize and discuss these various topics of drug design.

Re-irradiation of recurrent anaplastic ependymoma using radiosurgery or fractionated stereotactic radiotherapy.

PURPOSE: Recurrent ependymomas were retreated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). The efficacy, toxicities, and differences between SRS and FSRT were analyzed. METHODS: Eight patients with recurrent ependymomas fulfilling the criteria described below were evaluated. Inclusion criteria were: (1) the patient had previously undergone surgery and conventional radiotherapy as first-line treatment; (2) targets were located in or adjacent to the eloquent area or were deep-seated; and (3) the previously irradiated volume overlapped the target lesion. RESULTS: FSRT was delivered to 18 lesions, SRS to 20 lesions. A median follow-up period was 23 months. The local control rate was 76 % at 3 years. No significant differences in local control were observed due to tumor size or fractionation schedule. Lesions receiving >25 Gy/5 fr or 21 Gy/3 fr did not recur within 1 year, whereas no dose-response relationship was observed in those treated with SRS. No grade ≥2 toxicity was observed. CONCLUSION: Our treatment protocol provided an acceptable LC rate and minimal toxicities. Because local recurrence of tumors may result in patient death, a minimum dose of 21 Gy/3 fr or 25 Gy/5 fr or higher may be most suitable for treatment of these cases.

Evaluation of Dose Uncertainty to the Target Associated With Real-Time Tracking Intensity-Modulated Radiation Therapy Using the CyberKnife Synchrony System.

We investigated the dose uncertainty caused by errors in real-time tracking intensity-modulated radiation therapy (IMRT) using the CyberKnife Synchrony Respiratory Tracking System (SRTS). Twenty lung tumors that had been treated with non-IMRT real-time tracking using CyberKnife SRTS were used for this study. After validating the tracking error in each case, we did 40 IMRT planning using 8 different collimator sizes for the 20 patients. The collimator size was determined for each planning target volume (PTV); smaller ones were one-half, and larger ones three-quarters, of the PTV diameter. The planned dose was 45 Gy in 4 fractions prescribed at 95% volume border of the PTV. Thereafter, the tracking error in each case was substituted into calculation software developed in house and randomly added in the setting of each beam. The IMRT planning incorporating tracking errors was simulated 1000 times, and various dose data on the clinical target volume (CTV) were compared with the original data. The same simulation was carried out by changing the fraction number from 1 to 6 in each IMRT plan. Finally, a total of 240 000 plans were analyzed. With 4 fractions, the change in the CTV maximum and minimum doses was within 3.0% (median) for each collimator. The change in D99 and D95 was within 2.0%. With decreases in the fraction number, the CTV coverage rate and the minimum dose decreased and varied greatly. The accuracy of real-time tracking IMRT delivered in 4 fractions using CyberKnife SRTS was considered to be clinically acceptable.

Chronological changes of the contractile mechanism in prolonged vasospasm after subarachnoid hemorrhage: from protein kinase C to protein tyrosine kinase.

OBJECTIVE: Protein kinase C (PKC) plays a role in vasospasm after subarachnoid hemorrhage with a "two-hemorrhage" canine model until Day 7. However, clinical vasospasm continues during the course of 2 weeks. This study sought to clarify whether the contractile property of cerebral arteries might change in prolonged vasospasm. METHODS: In this model, angiography was not performed until Day 14. The maximal contracting response induced by high K(+) was measured by using basilar arteries on Days 1, 7, and 14 in an isometric tension study. After stretching arteries equivalent to angiographic diameter, papaverine-sensitive (myogenic) and papaverine-insensitive (nonmyogenic) tones of the developed tension were also measured. On nonmyogenic tone, the effect of genistein, a specific inhibitor of protein tyrosine kinase (PTK), was examined. The PKC and PTK activities in basilar arteries were measured from Day 1 to Day 14. RESULTS: Angiographic vasospasm on Day 14 was equivalent to that on Day 7. However, the maximum contractile response on Day 14 was significantly decreased compared with Day 7. Myogenic tone was significantly decreased, and the effect of genistein on nonmyogenic tone was significantly increased on Day 14 compared with Day 7. The activity of PKC on Day 14 declined to the Day 1 level, whereas that of PTK was enhanced from Day 7 and persisted until Day 14. CONCLUSION: These results indicate that stiffness of the arterial wall increased and that the contractile property of the artery shifted from active myogenic tone to nonmyogenic tone, from PKC to PTK, with prolonged vasospasm.

Bilateral cavernous sinus actinomycosis resulting in painful ophthalmoplegia. Case report.

The authors report the successful treatment of a 42-year-old man who suffered from recurrent painful ophthalmoplegia caused by bilateral cavernous sinus (CS) actinomycosis. A presumptive diagnosis of Tolosa-Hunt syndrome was made when he presented with left painful ophthalmoplegia. Recurrent ophthalmoplegia on the opposite side when steroid medications were tapered led to repeated imaging and a pterional craniotomy and biopsy sampling of the CS. These tests demonstrated acute inflammation and sulfur granules, which responded clinically and radiologically to parenterally administered penicillin therapy. Actinomycosis may present as a painful ophthalmoplegia with involvement of one or both CSs. Repeated imaging and possibly surgical exploration may be necessary to make a definitive diagnosis.

High-dose methylprednisolone prevents vasospasm after subarachnoid hemorrhage through inhibition of protein kinase C activation.

We have previously shown that the inflammatory process after subarachnoid hemorrhage causes vasospasm. The efficacy of methylprednisolone by suppression of the inflammatory process has been reported, although pharmacological mechanisms have not been clarified. The purpose of this study was to investigate the pharmacological mechanism of methylprednisolone on vasospasm. Using the 'two-hemorrhage' canine model, progression of angiographic vasospasm was assessed in nontreated and treated groups with methylprednisolone. Methylprednisolone 10 mg kg-1 was injected i.v. after the first injection of blood, and the same dose was injected every 12 h until day 7. Protein kinase C (PKC) activity of canine basilar arteries in both groups was measured during the course of vasospasm. In the isometric tension study, the effect of methylprednisolone on tensions induced by phorbol 12-myristate 13-acetate (PMA), or high-K+ solution, was also evaluated. Methylprednisolone significantly reduced severity of vasospasm. In the treated group, PKC activity was not enhanced compared with the nontreated group at any point. Methylprednisolone inhibited tonic tension induced by PMA, but not that induced by high-K+ solution. We conclude that methylprednisolone prevents severity of vasospasm through inhibition of PKC activation, but does not work as a Ca2+ channel blocker.

Surgical strategy for spondylodiscitis due to Candida albicans in an immunocompromised host.

A 44-year-old woman receiving systemic chemotherapy for cerebellar medulloblastoma developed thoracolumbar spondylodiscitis due to Candida albicans associated with abscesses in the bilateral psoas muscles. As long-term medical therapy with fluconazole was not effective, radical removal of the affected lesions and anterior bone grafting were performed. Corpectomy of the infected vertebra with autologous bone grafting and removal of the psoas muscle were performed via the right transthoracic retroperitoneal approach. Additional posterior instrumentation was not used. Two years after the operation, the patient was doing well, and systemic chemotherapy for medulloblastoma has restarted. Corpectomy with radical resection of surrounding infectious tissues for C. albicans spondylodiscitis in an immunocompromised host should be performed when conservative medical treatment is not successful. Further instrumentation surgery might be necessary to prevent further deformity of the spine as the second surgery.

Encephalocele in the ethmoid sinus presenting as a massive intracerebral hemorrhage after a "polypectomy": a case report.

The discovery of a congenital transethmoidal encephalocele in an adult patient is very rare and is sometimes misdiagnosed as a polyp of the ethmoid sinus. It is important to note that a congenital transethmoidal encephalocele presenting as a massive intracerebral hemorrhage in an adult patient has never been reported. This study's patient underwent endoscopic polypectomy and suffered from massive intracerebral hemorrhage because the encephalocele contained a frontobasal artery. Transcranial surgery was successfully performed to repair the frontal base. We report on the patient's condition and discuss the clinical implications of the present case.

Attenuation of canine cerebral vasospasm after subarachnoid hemorrhage by protein kinase C inhibitors despite augmented phosphorylation of myosin light chain.

The purpose of the present study is to assess the roles of protein kinase C (PKC) isoforms, especially PKC delta and alpha, and 20-kD myosin light chain (MLC(20)) phosphorylation in the mechanism of cerebral vasospasm following subarachnoid hemorrhage (SAH). We had shown that those PKC isoforms are involved in the development of cerebral vasospasm. Using PKC isoform-specific inhibitors in a 'two- hemorrhage' canine model, we examined changes in the development of cerebral vasospasm, translocation of PKC isoforms and MLC(20) phosphorylation level in canine basilar arteries. A PKC inhibitor (5 microM rottlerin for PKC delta or chelerythrine for PKC alpha) was injected into the cisterna magna on day 4 before the second hemorrhage. The treatment was continued daily until day 7. Rottlerin inhibited the initial phase of vasospasm and PKC delta translocation, but did not significantly inhibit PKC alpha translocation. Chelerythrine inhibited cerebral vasospasm, and the translocation of both PKC delta and alpha throughout the entire course of the study. Although cerebral vasospasm after SAH was inhibited by each PKC inhibitor, the MLC(20) phosphorylation level remained elevated as in the untreated hemorrhage-control study. We conclude that cerebral vasospasm following SAH depends on PKC delta and alpha, while the enhancement of MLC(20) phosphorylation contributes little to this form of vasospasm.

Role of Wnt pathway in medulloblastoma oncogenesis.

To clarify the roles of Wnt pathway in medulloblastoma oncogenesis, immunohistochemical staining of beta-catenin and Wnt-1 and genomic analyses of CTNNB1 (beta-catenin) and AXIN1 (axin 1) were examined in 23 sporadic cases. Accumulation of beta-catenin in tumor cells was immunohistochemically proven in 5 cases; 2 cases showed positive immunoreactivity for Wnt-1 and another 2 showed mutation of either CTNNB1 or AXIN1. AXIN1 mutation was in exon 3, corresponding to GSK-3beta binding site and CTNNB1 mutation was in exon 3, corresponding to its phosphorylation site. Disruption of these proteins could result in upregulation of the Wnt signaling and accumulation of beta-catenin, followed by cell proliferation and medulloblastoma oncogenesis.