Exercise improves the outcome of anticancer treatment with ultrasound-hyperthermia-enhanced nanochemotherapy and autophagy inhibitor.

It has been shown that exercise has a direct impact on tumor growth along with functional improvement. Previous studies have shown that exercise decreases the risk of cancer recurrence across various types of cancer. It was indicated that exercise stimulates the immune system to fight cancer. Previous study demonstrated that pulsed-wave ultrasound hyperthermia (pUH) combined with PEGylated liposomal doxorubicin (PLD) and chloroquine (CQ) inhibits 4T1 tumors growth and delays their recurrence. In this study, we investigated if the combinatorial treatment with high-intensity interval training (HIIT) combined with pUH-enhanced PLD delivery and CQ improved the outcome. The mouse experiment composed of three groups, HIIT+PLD+pUH+CQ group, PLD+pUH+CQ group, and the control group. HIIT+PLD+pUH+CQ group received 6 weeks of HIIT (15 min per day, 5 days per week) before 4T1 tumor implantation. Seven days later, they received therapy with PLD (10 mg/kg) + pUH (3 MHz, 50% duty cycle, 0.65 W/cm2, 15min) + CQ (50 mg/kg daily). Results showed that HIIT+PLD+pUH+CQ significantly reduced the tumor volumes and brought about longer survival of tumor-bearing mice than PLD+pUH+CQ did. Blood cell components were analyzed and showed that neutrophil and reticulocytes decreased while lymphocytes increased after exercise.

Influence of Acoustic Parameters and Sonication Schemes on Transcranial Blood-Brain Barrier Disruption Induced by Pulsed Weakly Focused Ultrasound.

Pulsed ultrasound combined with microbubbles use can disrupt the blood-brain barrier (BBB) temporarily; this technique opens a temporal window to deliver large therapeutic molecules into brain tissue. There are published studies to discuss the efficacy and safety of the different ultrasound parameters, microbubble dosages and sizes, and sonication schemes on BBB disruption, but optimal the paradigm is still under investigation. Our study is aimed to investigate how different sonication parameters, time, and microbubble dose can affect BBB disruption, the dynamics of BBB disruption, and the efficacy of different sonication schemes on BBB disruption. Method: We used pulsed weakly focused ultrasound to open the BBB of C57/B6 mice. Evans blue dye (EBD) was used to determine the degree of BBB disruption. With a given acoustic pressure of 0.56 MPa and pulse repetitive frequency of 1 Hz, burst lengths of 10 ms to 50 ms, microbubbles of 100 µL/kg to 300 µL/kg, and sonication times of 60 s to 150 s were used to open the BBB for parameter study. Brain EBD accumulation was measured at 1, 4, and 24 h after sonication for the time-response relationship study; EBD of 100 mg/kg to 200 mg/kg was administered for the dose-response relationship study; EBD injection 0 to 6 h after sonication was performed for the BBB disruption dynamic study; brain EBD accumulation induced by one sonication and two sonications was investigated to study the effectiveness on BBB disruption; and a histology study was performed for brain tissue damage evaluation. Results: Pulsed weakly focused ultrasound opens the BBB extensively. Longer burst lengths and a larger microbubble dose result in a higher degree of BBB disruption; a sonication time longer than 60 s did not increase BBB disruption; brain EBD accumulation peaks 1 h after sonication and remains 81% of the peak level 24 h after sonication; the EBD dose administered correlates with brain EBD accumulation; BBB disruption decreases as time goes on after sonication and lasts for 6 h at least; and brain EBD accumulation induced by two sonication increases 74.8% of that induced by one sonication. There was limited adverse effects associated with sonication, including petechial hemorrhages and mild neuronal degeneration. Conclusions: BBB can be opened extensively and reversibly by pulsed weakly focused ultrasound with limited brain tissue damage. Since EBD combines with albumin in plasma to form a conjugate of 83 kDa, these results may simulate ultrasound-induced brain delivery of therapeutic molecules of this size scale. The result of our study may contribute to finding the optimal paradigm of focused ultrasound-induced BBB disruption.

Cerebrospinal fluid predictors of shunt-dependent hydrocephalus after hemorrhagic stroke: a systematic review and meta-analysis.

Hydrocephalus is a common complication of hemorrhagic stroke and has been reported to contribute to poor neurological outcomes. Herein, we aimed to investigate the validity of cerebrospinal fluid (CSF) data in predicting shunt-dependent hydrocephalus (SDHC) in patients with hemorrhagic stroke. PubMed, CENTRAL, and Embase databases were searched for relevant studies published through July 31, 2021. The 16 studies with 1505 patient included those in which CSF data predicted risk for SDHC and reports on CSF parameters in patients in whom SDHC or hydrocephalus that was not shunt-dependent developed following hemorrhagic stroke. We appraised the study quality using Newcastle-Ottawa Scale and conducted a meta-analysis of the pooled estimates of the CSF predictors. The meta-analysis revealed three significant CSF predictors for shunt dependency, i.e., higher protein levels (mean difference [MD] = 32.09 mg/dL, 95% confidence interval [CI] = 25.48-38.70, I2 = 0%), higher levels of transforming growth factor ß1 (TGF-ß1; MD = 0.52 ng/mL, 95% CI = 0.42-0.62, I2 = 0%), and higher ferritin levels (MD = 108.87 µg/dL, 95% CI = 56.68-161.16, I2 = 36%). The red blood cell count, lactate level, and glucose level in CSF were not significant in predicting SDHC in patients with hemorrhagic stroke. Therefore, higher protein, TGF-ß1, and ferritin levels in CSF are significant predictors for SDHC in patients with hemorrhagic stroke. Measuring these CSF parameters would help in the early recognition of SDHC risk in clinical care.

Intracranial solitary fibrous tumor/hemangiopericytoma - A case series.

BACKGROUND: Intracranial solitary fibrous tumor/hemangiopericytoma (HPC) is a rare and aggressive tumor. We conducted this retrospective study to investigate the outcome of patients after treatment, the efficacy of postoperative adjuvant radiotherapy, and the factors not conducive to total resection. METHODS: We conducted a retrospective review of the medical records of patients harboring fresh intracranial solitary fibrous tumor/HPC treated from January 2009 to December 2019 in our hospital. We reviewed their clinical presentations, radiologic appearances, tumor size and location, extent of resection, estimate intraoperative blood loss, treatment modalities and results, and duration of follow-up. RESULTS: There were seven consecutive patients (three males and four females). The ages of the patients at the time of diagnosis ranged from 35 to 77 years (mean: 52.86 years). Five patients (71.43%) got tumor bigger than 5 cm in dimension and only 1 patient (14.29%) underwent gross total tumor resection in the first operation without complication. Five patients (71.43%) underwent postoperative adjuvant radiotherapy. Follow-up period ranged from 4.24 to 123.55 months and the median follow-up period was 91.36 months. Three patients had favorable outcome with Glasgow Outcome Scale (GOS) equal to 4; four patients had unfavorable outcome with GOS equal to 2 or 3. No mortality was happened. CONCLUSION: Gross total tumor resection in the initial surgery is very important to achieve a better outcome. Massive intraoperative bleeding and venous sinus or major vessels adjoining are factors not conducive to total resection. Radiotherapy can be administered as adjuvant therapy for cases showing an aggressive phenotype or not treated with gross total resection.

Combination Therapy of Pulsed-Wave Ultrasound Hyperthermia and Immunostimulant OK-432 Enhances Systemic Antitumor Immunity for Cancer Treatment.

PURPOSE: In this study, we hypothesized that systemic antitumor immunity might be enhanced by combining pulsed-wave ultrasound hyperthermia (pUSHT) with OK-432 and that the induced antitumor immunity could confer protection against tumorigenesis. These hypotheses were tested in bilateral and rechallenged tumor models. METHODS AND MATERIALS: Bilateral and rechallenged tumor models were applied in the studies. In the bilateral tumor model, BALB/c mice were inoculated in both flanks with CT26-luc tumor cells. The tumors in the right flank were treated with 4 courses of pUSHT with or without OK-432. In the rechallenged tumor model, tumor cells were implanted into the right flank. Once formed, the tumors were treated with pUSHT with OK-432, followed by surgical resection. New tumor cells were then implanted into the contralateral flank. The antitumor response was evaluated via infiltrated immune cells and the severity of necrosis/apoptosis in tumors. RESULTS: In the bilateral tumor model, the tumor growth rate and growth activity of both treated (100% reduction) and untreated tumors (90.5% reduction) were significantly inhibited with the combination treatment compared with the sham control group, and the systemic antitumor effect was prolonged. The survival rate was significantly enhanced (sham control, 8 days; OK plus pUSHT, >20 days). IFNγ+ CD4 (treated tumor, 8.6-fold; untreated tumor, 4-fold), IFNγ+ CD8 (treated tumor, 6.7-fold; untreated tumor, 2.6-fold), and T cell and NK cell (treated tumor, 4-fold; untreated tumor, 2.5-fold) infiltration was increased in the combination group compared with the control group. In the rechallenged tumor model, new tumors failed to form with the combination treatment. CONCLUSION: This experimental study combining pUSHT and OK-432 explored a new therapeutic strategy for controlling colon cancer metastasis. The results show that the combination treatment may produce an effective antitumor immune response.

Pulsed-wave Ultrasound Hyperthermia Enhanced Nanodrug Delivery Combined with Chloroquine Exerts Effective Antitumor Response and Postpones Recurrence.

Autophagy is found to serve as a surviving mechanism for cancer cells. Inhibiting autophagy has been considered as an adjuvant anti-cancer strategy. In this study, we investigated the anti-tumor effect of combining pulsed-wave ultrasound hyperthermia (pUH) enhanced PEGylated liposomal doxorubicin (PLD) delivery with an autophagy inhibitor chloroquine (CQ). BALB/c mice bearing subcutaneous 4T1 tumor received intravenous injection of PLD (10 mg/kg) plus 15-minute on-tumor pUH on Day 5 after tumor implantation and were then fed with CQ (50 mg/kg daily) thereafter. Prolonged suppression of tumor growth was attained with PLD + pUH + CQ treatment, whereas in PLD + pUH group tumors quickly recurred after an initial inhibition. Treatment with CQ monotherapy had no benefit compared to the control group. Immunohistochemical staining and Western blotting showed that autophagy of cancer cells was blocked for the mice receiving CQ. It indicates that PLD + pUH + CQ is a promising strategy to treat cancer for a long-term inhibition.

Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type I disease.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB). METHODS: We divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain. RESULTS: Transcranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme. CONCLUSIONS: Transcranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy.

Pulsed-wave low-dose ultrasound hyperthermia selectively enhances nanodrug delivery and improves antitumor efficacy for brain metastasis of breast cancer.

The clinical application of chemotherapeutics for brain tumors remains a challenge due to limitation of blood-brain barrier/blood-tumor barrier (BBB/BTB). In this study, we investigated the effects of low-dose focused ultrasound hyperthermia (UH) on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer cells (4T1-luc2) expressing firefly luciferase were implanted into mouse striatum as a brain tumor model. The mice were intravenously injected with PLD with/without transcranial pulsed-wave/continuous-wave UH (pUH/cUH) treatment on day-6 after tumor implantation. pUH (frequency: 500kHz, PRF: 1000Hz, duty cycle: 50%) was conducted under equal acoustic power (2.2-Watt) and sonication duration (10-min) as cUH. The amounts of doxorubicin accumulated in the normal brain and tumor tissues were measured with fluorometry. The tumor growth responses for the control, pUH, PLD, PLD+cUH, and PLD+pUH groups were evaluated with IVIS. The PLD distribution and cell apoptosis were assessed with immunofluorescence staining. The results showed that pUH significantly enhanced the PLD delivery into brain tumors and the tumor growth was further inhibited by PLD+pUH without damaging the sonicated normal brain tissues. This indicates that low-dose transcranial pUH is a promising method to selectively enhance nanodrug delivery and improve the brain tumor treatment.

Prioritized Venous Coiling Facilitating Endovascular Treatment of Brain Arteriovenous Malformations with a Fistulous Component.

BACKGROUND: Brain arteriovenous malformation (AVM) with a fistulous component presents a treatment challenge. The presence of the fistulous component may be related to either a complication from endovascular treatment, perioperative hemorrhagic events during surgical resection, or incomplete obliteration after radiosurgery. CASE DESCRIPTION: From December 2010 to May 2014, 7 consecutive patients (3 men, 4 women, average age, 28.7 years; age range, 11 months to 67 years) with AVMs with a high-flow fistulous component were treated at our institute with venous coiling before transarterial liquid embolization. One AVM was grade I based on the Spetzler-Martin grading system, 1 was grade II, 3 were grade III, and 2 were grade IV. The nidus size ranged from 1.7 to 6.0 cm. Four patients had pure fistulous-type lesions, and 3 had lesions of the mixed fistulous-plexiform type. All AVMs shared a common feature of a high-flow fistulous component with a large venous pouch emerging from the nidus. After endovascular embolization of the AVMs, 3 patients had complete occlusion, 3 patients had near-complete occlusion, and 1 patient had significant reduction in volume. There was no immediate complication after embolization, but 1 patient experienced delayed hemorrhage 3 days after the procedure. CONCLUSIONS: Prioritized transarterial venous coiling is feasible for the embolization of AVMs with a high-flow fistulous component and the procedure had an acceptable complication rate.

Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer.

The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

Endovascular treatment and computed imaging follow-up of 14 anterior condylar dural arteriovenous fistulas.

We report our experience in treating the anterior condylar dural arteriovenous fistula (DAVF) and confirm the location of the coils in the follow-up images after successful endovascular treatment. We retrospectively reviewed the 14 patients with anterior condylar DAVF treated successfully in our institute. Twelve of them had CT or MR follow-up images. All the patients had intravascular coiling of the fistula. Seven of our patients had retrograde drainage to different sinuses. Three had ocular symptoms as a clinical manifestation. We treated nine patients with coils alone (eight transvenous, one transarterial), four with adjuvant transarterial treatment with particles or liquid embolic for minimal residual after coiling packing. One patient had failed onyx treatment and successful treatment by following transvenous packing. All patients had total obliteration of the DAVF fistula on immediate post-procedure angiogram or on the follow-up images and no evidence of recurrence clinically. The mean follow-up period was 34.2 months (standard deviation=39.8). Twelve patients had computed images (CT alone in four, MR alone in five, both CT and MR in three). These findings were analyzed by four certified neuroradiologists. We found 100% of the coils at the anterior condylar veins inside the hypoglossal canal, 54.2% at the lateral lower clivus, and only 14.2% at the anterior condylar confluence which is ventrolateral to the anterior orifice of the hypoglossal canal. Intravascular coiling is the treatment of choice in patients with anterior condylar DAVF. All the coils were found at the anterior condylar veins inside the hypoglossal canal after successful treatment.

Clinical practice guidelines in severe traumatic brain injury in Taiwan.

BACKGROUND: Severe TBIs are major causes of disability and death in accidents. The Brain Trauma Foundation supported the first edition of the Guidelines for the Management of Severe Traumatic Brain Injury in 1995 and revised it in 2000. The recommendations in these guidelines are well accepted in the world. There are still some different views on trauma mechanisms, pathogenesis, and managements in different areas. Individualized guidelines for different countries would be necessary, and Taiwan is no exception. METHODS: In November 2005, we organized the severe TBI guidelines committee and selected 9 topics, including ER treatment, ICP monitoring, CPP, fluid therapy, use of sedatives, nutrition, intracranial hypertension, seizure prophylaxis, and second-tier therapy. We have since searched key questions in these topics on Medline. References are classified into 8 levels of evidence: 1++, 1+, 1-, 2++, 2+, 2-, 3, and 4 based on the criteria of the SIGN. RESULTS: Recommendations are formed and graded as A, B, C, and D. Grade A means that at least one piece of evidence is rated as 1++, whereas grade B means inclusion of studies rated as 2++. Grade C means inclusion of references rated as 2+, and grade D means levels of evidence rated as 3 or 4. Overall, 42 recommendations are formed. Three of these are rated as grade A, 13 as grade B, 21 as grade C, and 5 as grade D. CONCLUSIONS: We have completed the first evidence-based, clinical practice guidelines for severe TBIs. It is hoped that the guidelines will provide concepts and recommendations to promote the quality of care for severe TBIs in Taiwan.

Use of screw-rod system in occipitocervical fixation.

BACKGROUND: This study retrospectively reviewed 9 patients who underwent occipitocervical fixation with a newly developed screw-rod fixation system between April 2004 and November 2005. The objective was to evaluate the clinical result of occipitocervical fixation with the screw-rod fixation system, including symptom relief, fusion rate and complications. METHODS: All 9 patients received occipitocervical fixation surgery with screw-rod fixation system and autologous bone grafts for fusion. Fusion was assessed by plain cervical X-ray films, and the myelopathy by Nurick scale. RESULTS: Four males and 5 females were enrolled into this study. Mean age was 58.8 years, and mean follow-up period was 15 months. One female patient experienced surgical site infection with instrument pullout 20 months after surgery; she received a second operation for instrument revision. The overall fusion rate was 100%. The mean Nurick scores were 3 preoperatively and 2.1 postoperatively, with advancement of 0.9 points on average. Seven of 9 patients experienced pain or myelopathy improvement. There were no complications except for the 1 infection mentioned above. CONCLUSION: The fusion rate, complication rate and improvement in neurological function of occipitocervical fixation surgery using the screw-rod system were comparable to those of the widely used wire-rod system and screw-plate system.

Cervical spinal stenosis and myelopathy due to atlas hypoplasia.

This paper describes a patient who presented at our hospital with neurologic symptoms due to congenital cervical spinal stenosis at the atlas level. Congenital atlantal stenosis is usually due to hypoplasia of the posterior arch of the atlas. It is a rare cause of spinal stenosis, and only 12 symptomatic patients with isolated atlantal stenosis have been reported. Current treatment is surgical decompression, and all reported patients receiving surgical treatment improved to some degree.