Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial).

BACKGROUND: Locally advanced pancreatic ductal adenocarcinoma (PDAC), accounting for about 30% of PDAC patients, is difficult to cure by radical resection or systemic chemotherapy alone. A multidisciplinary strategy is required and our TT-LAP trial aims to evaluate whether triple-modal treatment with proton beam therapy (PBT), hyperthermia, and gemcitabine plus nab-paclitaxel is a safe and synergistically effective treatment for patients with locally advanced PDAC. METHODS: This trial is an interventional, open-label, non-randomized, single-center, single-arm phase I/II clinical trial organized and sponsored by the University of Tsukuba. Eligible patients who are diagnosed with locally advanced pancreatic cancer, including both borderline resectable (BR) and unresectable locally advanced (UR-LA) patients, and selected according to the inclusion and exclusion criteria will receive triple-modal treatment consisting of chemotherapy, hyperthermia, and proton beam radiation. Treatment induction will include 2 cycles of chemotherapy (gemcitabine plus nab-paclitaxel), proton beam therapy, and 6 total sessions of hyperthermia therapy. The initial 5 patients will move to phase II after adverse events are verified by a monitoring committee and safety is ensured. The primary endpoint is 2-year survival rate while secondary endpoints include adverse event rate, treatment completion rate, response rate, progression-free survival, overall survival, resection rate, pathologic response rate, and R0 (no pathologic cancer remnants) rate. The target sample size is set at 30 cases. DISCUSSION: The TT-LAP trial is the first to evaluate the safety and effectiveness (phases1/2) of triple-modal treatment comprised of proton beam therapy, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer. ETHICS AND DISSEMINATION: This protocol was approved by the Tsukuba University Clinical Research Review Board (reference number TCRB22-007). Results will be analyzed after study recruitment and follow-up are completed. Results will be presented at international meetings of interest in pancreatic cancer plus gastrointestinal, hepatobiliary, and pancreatic surgeries and published in peer-reviewed journals. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031220160. Registered 24 th June 2022, https://jrct.niph.go.jp/en-latest-detail/jRCTs031220160 .

Proton beam therapy for hepatocellular carcinoma with bile duct invasion.

AIM: Hepatocellular carcinoma (HCC) with bile duct invasion (BDI) (BDIHCC) has a poor prognosis. Moreover, due to the paucity of reports, there is no consensus regarding optimal management of this clinical condition yet. The aim of this study was to clarify the efficacy and safety of proton beam therapy (PBT) for BDIHCC. METHODS: Between 2009 and 2018, 15 patients with BDIHCC underwent PBT at our institution. The overall survival (OS), local control (LC), and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria of Adverse Events version 4.0. RESULTS: The median follow-up time was 23.4 months (range, 7.9-54.3). The median age was 71 years (range, 58-90 years). Many patients were Child A (n = 8, 53.3%) and most had solitary tumors (n = 11, 73.3%). Additionally, most patients had central type BDI (n = 11, 73%). The median tumor size was 4.0 cm (range, 1.5-8.0 cm). The 1-, 2-, and 3-year OS rates were 80.0%, 58.7% and 40.2%, respectively, and the corresponding LC and PFS rates were 93.3%, 93.3%, and 74.7% and 72.7%, 9.7%, and 0.0%, respectively. Acute grade 1/2 dermatitis (n = 7, 46.7%), and grades 2 (n = 1, 6.7%) and 3 (n = 1, 6.7%) cholangitis were observed. Late toxicities such as grade 3 gastric hemorrhage and pleural effusion were observed. No toxicities of grade 4 or higher were observed. CONCLUSIONS: PBT was feasible with tolerable toxicities for the treatment of BDIHCC.

Anti-Inflammatory Effects of ß-Cryptoxanthin on 5-Fluorouracil-Induced Cytokine Expression in Human Oral Mucosal Keratinocytes.

Oral mucositis is a typical adverse effect of chemotherapy, causing oral pain that significantly reduces the patient's quality of life. ß-cryptoxanthin (ß-cry) is a carotenoid abundant in citrus fruits with antioxidant and anti-inflammatory effects. However, the ß-cry effect on oral mucositis remains unclear. We investigated the effects of 5-fluorouracil (5-FU) and ß-cry on human normal oral mucosal keratinocytes (hOMK). hOMK was seeded on a culture plate and cultured with 5-FU and ß-cry. The cell number, mRNA expression of inflammatory cytokines and matrix metalloproteinases (MMPs), and production of inflammatory cytokines in hOMK were evaluated. Additionally, the cell count and inflammatory cytokine production were analyzed when hOMK was co-stimulated with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) in addition to 5-FU. The numbers of hOMK significantly reduced with 5-FU stimulation, whereas it increased with ß-cry treatment. mRNA expression of interleukin (IL)-6, IL-8, metalloproteinase (MMP)-2, and MMP-9 and protein production of IL-6 and IL-8 in hOMK were augmented on 5-FU stimulation. Simultaneously, ß-cry treatment significantly suppressed IL-8 and MMP-9 mRNA expression, and IL-8 production was induced on 5-FU stimulation. Co-stimulation with P. gingivalis LPS and 5-FU enhanced IL-6 and IL-8 production in hOMK. ß-cry could enhance cell proliferation and suppress 5-FU-induced expression of inflammatory cytokines and MMP in hOMK. Thus, ß-cry can alleviate the symptoms of chemotherapy-induced oral mucositis, and its combination with oral care is effective in managing oral mucositis.

Effects of mechanical stress on human oral mucosa-derived cells.

OBJECTIVES: Placement of a denture results in the application of mechanical stress (MS), such as occlusal force, onto the oral mucosa beneath the denture. To better understand the molecular mechanism underlying MS-induced inflammation in the oral mucosa, we examined the impact of MS on human oral epithelial cells (HO-1-N-1) and human fibroblasts (HGFs) in this study. MATERIALS AND METHODS: MS was applied on HO-1-N-1 and HGFs using a hydrostatic pressure apparatus. The expression and production of inflammatory cytokines and growth factors were examined by real-time RT-PCR and ELISA. MS-induced intracellular signal transduction via MAP kinase (MAPK) was also examined. RESULTS: 1 MPa MS resulted in a significant increase in inflammatory cytokines, and 3 MPa MS resulted in a significant increase in FGF-2. MS also increased p-38 phosphorylation and the addition of a p-38 inhibitor significantly suppressed the production of inflammatory cytokines. DISCUSSION: Our study suggested that MS applied through a denture increases the production of inflammatory cytokines from oral mucosal epithelial cells and fibroblasts via the p38 MAPK cascade. These responses to MS likely lead to inflammation of the mucosal tissue beneath dentures. On other hand, up-regulation of growth factors is likely a manifestation of the biological defense mechanism against excessive MS.

Robotic rehabilitation of the paralyzed upper limb for a stroke patient using the single-joint hybrid assistive limb: a case study assessed by accelerometer on the wrist.

[Purpose] Recent studies have reported the effectiveness of robotic rehabilitation of paralyzed upper limbs in stroke patients. For example, the Single-Joint Hybrid Assistive Limb has been shown to improve upper limb impairments. However, limited data are available on the effectiveness of robotic rehabilitation of the upper limb with regards to daily living. In this case study, an accelerometer was adopted to examine whether rehabilitation using the Single-Joint Hybrid Assistive Limb improved upper limb activity during daily living in a stroke patient. [Participant and Methods] The participant was a 69-year-old male diagnosed with stroke and left hemiparesis. The Single-Joint Hybrid Assistive Limb was applied to the participant's elbow on the paralyzed side. The participant wore an accelerometer on each wrist to measure the activities of the upper limbs. Clinical tests of the paralyzed upper limb were also performed. [Results] The activity of the paralytic limb was significantly higher after Single-Joint Hybrid Assistive Limb intervention than before the intervention. On the other hand, none of the results of the clinical tests changed beyond a clinically important difference. [Conclusion] The Single-Joint Hybrid Assistive Limb could be useful for promoting active use of a paralyzed upper limb in daily living. In addition, an accelerometer could be especially useful for evaluating the effects of robotic rehabilitation.

[Particle Therapy in Cancer Treatment-Current and Future Perspective].

Although local tumor controls in various cancers by radiation therapy(RT)are dose dependent, dose-volume effects on late toxicities of surrounding normal tissues have been also observed. Particle beam therapy(PBT)using protons and carbonions have physical advantages in RT for the treatment of various cancers because they can create a desirable dose distribution to the target volume using fewer portals compared with photon-based RT. Thus, dose-escalation using charged particles is a reasonable approach in RT, theoretically. Based on accumulation of the evidences that PBT shows the efficacy in treatment for several cancers, the number of particle therapy facilities have been rapidly increasing worldwide. The Japanese Society for Radiation Oncology organized a joint effort among research groups to establish standardized treatment policies of particle therapy according to disease through systematic reviews. Furthermore, multicenter prospective studies have been conducted for hepatocellular carcinoma and prostate cancer. At the present, PBT for pediatric tumors, prostate cancer, unresectable bone and soft tissue sarcomas, head and neck non-squamous cell carcinomas is covered by the Japanese national health insurance system. Boron neutron capture therapy(BNCT)is also a promising modality as biochemically targeted RT, but it has been performed in only limited facilities. Recent advances in technology, accelerator-based neutron sources will increase in BNCT facilities and lead to wider application of BNCT for various cancers.

CTLA4-Ig suppresses development of experimental autoimmune uveitis in the induction and effector phases: Comparison with blockade of interleukin-6.

Recently, a number of biologics have been used in the treatment of autoimmune diseases. However, in the treatment of severe autoimmune uveitis, only TNF-alpha inhibitors are preferably used and the effect of other biologics such as interleukin-6 (IL-6) signaling blockade or cytotoxic T-lymphocyte antigen-4-immunoglobulin fusion protein (CTLA4-Ig) has not been well studied. Previously, we reported that IL-6 blockade effectively suppresses the development of experimental autoimmune uveitis (EAU), a mouse model for uveitis, by inhibiting Th17 cell development. In this study, we investigated the effect of CTLA4-Ig on EAU development and compared it with the effect of anti-IL-6 receptor monoclonal antibody (MR16-1). C57BL/6J mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and treated once with CTLA4-Ig or MR16-1. Both CTLA4-Ig and MR16-1 administered in the induction phase (the same day as immunization) significantly reduced the clinical and histopathological scores of EAU. Fluorescence-activated cell sorting studies using draining lymph node (LN) cells from EAU mice 10 days after immunization showed that CTLA4-Ig can suppress early T-helper cell activation. CTLA4-Ig administered in the effector phase of the disease (one week after immunization), when IRBP-reactive T cells have been primed, also significantly reduced the clinical and histopathological scores of EAU. In contrast, MR16-1 administered in the effector phase did not ameliorate EAU. To investigate the differences between these biologics in the effector phase, in vitro restimulation analysis of LN cells obtained from EAU mice one week after immunization was performed and revealed that CTLA4-Ig, but not MR16-1, added to culture media could inhibit the proliferation of IRBP-specific CD4(+) T cells which possessed capacities of producing IFN-gamma and/or IL-17. Collectively, CTLA4-Ig ameliorated EAU through preventing initial T-cell activation in the induction phase and suppressing proliferation of IRBP-specific T cells in the effector phase. Blockade of IL-6 signaling did not have such inhibitory effects after T-cell priming. CTLA4-Ig may have therapeutic effects on human chronic uveitis.

Analysis of choroidal folds in acute Vogt-Koyanagi-Harada disease using high-penetration optical coherence tomography.

PURPOSE: To characterize patients with Vogt-Koyanagi-Harada (VKH) disease with choroidal folds (CFs) and determine how the foveal choroidal thickness changes after initial treatment using high-penetration optical coherence tomography (HP-OCT). METHODS: In this retrospective observational study, we analyzed 42 eyes of 21 patients with new-onset VKH disease to determine the demographic and clinical differences between patients with and without CFs. RESULTS: Twenty-four eyes (57.1 %) of 13 patients with VKH disease had CFs. The mean age (p = 0.0009) of patients with CFs was significantly higher than that of those without CFs (49.1 vs 39.4 years respectively). The frequency of disc swelling (p = 0.0001) was significantly higher in eyes with CFs than in those without CFs (95.8 % vs 38.9 %). The choroidal thickness at the first visit (p = 0.0011) was significantly greater in eyes with CFs than in those without CFs (794 ± 144 µm vs 649 ± 113 µm). The choroid 6 months after the initial treatment (p = 0.0118) was significantly thinner in eyes with CFs than in those without CFs (270 ± 92 µm vs 340 ± 80 µm). The frequency of sunset glow fundus at 6 months (p = 0.0334) in eyes with CFs was significantly higher than in those without CFs (62.5 % vs 27.8 %). CONCLUSION: The development of CFs in patients with VKH disease was significantly correlated with age, disc swelling, and choroidal thickness. The eyes with CFs frequently developed a sunset glow fundus. The findings suggested that patients with CFs might have severe and longstanding inflammation of the choroidal tissues.

Evaluation of the long-term efficacy and safety of infliximab treatment for uveitis in Behçet's disease: a multicenter study.

PURPOSE: To evaluate the long-term efficacy and safety of infliximab for the treatment of uveitis in Behçet's disease (BD). DESIGN: Retrospective multicenter study using a questionnaire. PARTICIPANTS: A total of 164 consecutive patients with BD treated with infliximab for more than 1 year were studied. The mean age at initiation of infliximab treatment was 42.6±11.7 years, and the mean treatment duration was 32.9±14.4 months. METHODS: Data before and at the last visit during infliximab treatment were analyzed in 4 groups divided by duration of treatment: group A (n = 43, 12-<24 months), group B (n = 62, 24-<36 months), group C (n = 42, 36-<48 months), and group D (n = 17, ≥48 months). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), relapse of ocular inflammation, numbers of ocular inflammatory attacks per year, and adverse effects of infliximab therapy. RESULTS: The frequency of ocular attacks decreased in all groups (from 5.3±3.0 to 1.0±0.3 in group A, 4.8±4.6 to 1.4±0.3 in group B, 4.1±2.9 to 0.9±0.3 in group C, and 9.5±5.8 to 1.6±0.5 in group D; all P < 0.05). The BCVA was improved in approximately 55% of the eyes after treatment. Mean BCVA converted to logarithm of the minimum angle of resolution was improved after treatment with infliximab in groups A to C (from 0.79±1.04 to 0.59±0.94 in group A, 0.59±1.07 to 0.41±1.04 in group B, and 1.15±1.77 to 0.92±1.73 in group C; all P < 0.05) but not in group D. Uveitis relapsed in 59.1% of all patients after infliximab treatment, and no difference in duration until relapse was observed between individual groups. Approximately 80% of relapses occurred within 1 year after the initiation of infliximab treatment in all groups, 90% of which were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. Adverse effects were observed in 65 cases or 35% of all subjects. Infliximab treatment was continued in 85% of the patients, but 15% of the patients discontinued infliximab treatment because of adverse effects or insufficient efficacy. CONCLUSIONS: Infliximab reduced the frequency of ocular attacks and improved visual acuity in patients with BD-related uveitis and was generally well tolerated with few serious adverse events.

CXCL12 secreted from glioma stem cells regulates their proliferation.

Emerging evidence suggests that the chemokine CXCL12 and its receptor CXCR4, which are expressed by glioma stem cells (GSCs), play an important role in tumorigenesis. To provide evidence for establishing a new therapy targeting the CXCL12/CXCR4 pathway, we investigated whether CXCL12 secreted from GSCs contributed to their proliferation and promoted angiogenesis in murine GSCs. Angiogenetic functions and proliferation of GSCs with or without CXCL12 inhibitors were evaluated in an in vitro model using tube formation assays, RT-PCR, and proliferation, as well as in an in vivo syngenic model. In endothelial culture, the morphology and gene expression of GSCs changed from stem cell-like characteristics to endothelial cell-like features. CXCL12 expression increased in endothelial cell-like GSCs. CXCL12 blockage with siRNA or shRNA markedly inhibited cell proliferation in vitro. CXCL12 knockdown with shRNA also inhibited tumor growth in vivo. On the other hand, CXCL12/CXCR4 blockage affected neither tube formation in vitro nor angiogenesis in vivo. The CXCL12 secreted from GSCs (autocrine/paracrine CXCL12) regulates their proliferation, but probably not angiogenesis.

Association between ocular findings and preventive therapy with onset of central nervous system involvement in patients with primary vitreoretinal lymphoma.

PURPOSE: To investigate if the site of ocular lesions and prophylactic treatment in patients with primary vitreoretinal lymphoma (PVRL) are associated with the time to onset of central nervous system (CNS) involvement. METHODS: We retrospectively studied 26 patients (seven men, 19 women; mean age, 67.0 ± 11.1 years) with a diagnosis of PVRL at our hospital between January 2001 and October 2011 and a minimum 2-year follow-up after treatment. We classified the PVRL lesions as: (1) the vitreous opacity type, vitreous opacity of 2+ or higher without retinal lesions, (2) the retina type, vitreous opacity of 1+ or less with retinal lesions only, or (3) the concomitant type, with both. We also evaluated whether prophylactic treatment of systemic chemotherapy such as high-dose methotrexate (HD-MTX) and intrathecal MTX (IT-MTX), or topical ocular treatments such as intravitreal injections of MTX and rituximab, inhibited the onset of CNS involvement in patients with PVRL without cerebral involvement. RESULTS: During a mean follow-up of 44.0 ± 18.7 months, CNS involvement began in 14 patients (53.8 %), i.e., three (60 %) of five patients with retina-type lesions, five (41.7 %) of 12 patients with vitreous opacity-type lesions, and six (66.7 %) of nine patients with concomitant-type lesions. There was no significant (P = 0.496) association between the site of the ocular lesions and the onset of brain lesions. In addition, CNS involvement occurred in eight of 11 patients receiving CNS prophylactic chemotherapy and six of 15 patients receiving no prophylaxis; the difference between the two did not reach significance (P = 0.131). The time to onset of cerebral involvement in the CNS prophylactic chemotherapy group (42.8 ± 13.8 months) was significantly (P = 0.0005) longer than in the group that did not receive prophylaxis (10.2 ± 2.0 months). Preventive systemic chemotherapy, especially HD-MTX, significantly prolonged the time to the onset of brain lesions compared to IT-MTX and local ocular therapy. CONCLUSIONS: While prophylactic systemic chemotherapy did not inhibit the onset of CNS involvement in most of patients with PVRL, it significantly prolonged the time to cerebral involvement.

Choroidal thickness in eyes with tilted disk syndrome.

PURPOSE: To investigate the choroidal thickness in eyes with tilted disk syndrome within/without posterior staphyloma. METHODS: Twenty-one eyes examined in 16 patients with tilted disk syndrome were included. The thicknesses of the choriocapillaris, the medium-to-large choroidal vessels, and total choroids found 1 mm and 3 mm superior and inferior to the fovea and in the area with the thinnest choroid were measured using enhanced-depth imaging optical coherence tomography or high-penetration optical coherence tomography. The results were compared with the findings on indocyanine green angiography. RESULTS: The mean thicknesses of total choroid found 3 mm and 1 mm inferior (114.3 µm ± 77.8 µm, 145.0 µm ± 85.9 µm) to the fovea were significantly thinner than those found superior (174.5 µm ± 89.7 µm, 145.0 µm ± 85.9 µm) to it. The minimal choroidal thickness of 80.5 µm ± 67.1 µm was obtained at a mean 1.04 mm below the fovea at the upper edge of the posterior staphyloma. The thickness of the layer of choriocapillaris was not significantly different according to the regions but the layer of medium-to-large choroidal vessels found 3 mm and 1 mm inferior to the fovea was significantly thinner than that found superior to the fovea. The ratio of choriocapillaris to medium-to-large vessels found 1 mm superior also was significantly smaller than those found inferior. The diameter of medium-to-large choroidal vessels on ICGA was not significantly different in the areas although less number of vessels were seen around the area inferior to the fovea. CONCLUSION: In the eyes of patients with tilted disk syndrome, the choroid is thinnest at approximately 1 mm inferior to the fovea at the upper edge of the posterior staphyloma rather than at the bottom of the posterior staphyloma. Thinning of the layer of medium-to-large choroidal vessels seems to be associated with the thinning of choroid thickness.

Choroidal observations in posterior scleritis using high-penetration optical coherence tomography.

To investigate the choroidal morphologic changes in two patients with posterior scleritis. We used high-penetration optical coherence tomography (HP-OCT) in vivo with a long-wavelength light source (1,060 nm) to view the choroidal changes. In patient 1 with unilateral scleritis, the subfoveal choroidal thickness of the right eye was 418 µm with a serous retinal detachment (SRD) at the initial visit. The treatment regimen was prednisolone 30 mg/day, and the posterior scleritis resolved. Follow-up HP-OCT showed the following choroidal thicknesses-266 µm on day 27 with no SRD, 245 µm on day 69, and 200 µm on day 216. In patient 2 with bilateral scleritis, the subfoveal choroidal thickness of the left eye was 279 µm at the initial visit. The inflammation was more severe in the left eye compared to the right eye on day 99. The choroidal thickness again increased markedly with recurrent disease in the left eye despite treatment. The posterior scleritis resolved with treatment. Follow-up HP-OCT showed the following choroidal thicknesses of the left eye--321 µm on day 99, 257 µm on day 176, and 228 µm on day 358. Significant choroidal changes underlie posterior scleritis. HP-OCT can show these deep choroidal pathologies in patients with posterior uveitis. The choroidal thickness recovers following treatment.

A Case of Circumscribed Choroidal Hemangioma Treated With Proton Beam Therapy and Followed Up for 15 Years.

Circumscribed choroidal hemangiomas are rare and benign tumors but often have a progressive course and are complicated by retinal detachment and glaucoma. The effectiveness of external radiation for large tumors that are difficult to treat with photodynamic therapy was recently reported; however, few studies have conducted long-term follow-ups. We encountered a case of localized choroidal hemangioma that was treated with proton beam therapy and followed up for 15 years. A 37-year-old man was diagnosed with a 10 × 4 mm circumscribed choroidal hemangioma involving the macular area with retinal detachment. Proton beam therapy was performed at 26.4 Gy relative biological effectiveness (RBE) in 8 fractions. The choroidal hemangioma gradually shrank over three years, and the retinal detachment also improved. A cataract developed on the affected side 11 years after irradiation, and eye coordination issues developed 15 years after irradiation. Glaucoma was not observed during the follow-up period; however, visual acuity did not recover, and the patient developed light perception. Although vision was not preserved, proton beam therapy effectively shrank the tumor and maintained quality of life.

Long-term follow-up of unresectable adenoid cystic carcinoma of the trachea and bronchus treated with high-dose proton beam therapy: A report of two cases.

Adenoid cystic carcinoma (ACC) of the trachea is a rare disease that is slow growing and has a risk of distant metastasis. The standard treatment for ACC of the trachea is surgery, but this tumor is often unresectable. In definitive radiotherapy using photons for unresectable ACC of the trachea, it is sometimes difficult to deliver a sufficient dose to the target without exceeding the tolerable dose to the surrounding normal tissues. Here, we report two cases of ACC of the trachea that received a high dose (74 Gy [relative biological effectiveness]) of proton beam therapy and achieved long-term survival.

Methyl-11C-L-methionine positron emission tomography for radiotherapy planning for recurrent malignant glioma.

OBJECTIVE: To investigate differences in uptake regions between methyl-11C-L-methionine positron emission tomography (11C-MET PET) and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI), and their impact on dose distribution, including changing of the threshold for tumor boundaries. METHODS: Twenty consecutive patients with grade 3 or 4 glioma who had recurrence after postoperative radiotherapy (RT) between April 2016 and October 2017 were examined. The study was performed using simulation with the assumption that all patients received RT. The clinical target volume (CTV) was contoured using the Gd-enhanced region (CTV(Gd)), the tumor/normal tissue (T/N) ratios of 11C-MET PET of 1.3 and 2.0 (CTV (T/N 1.3), CTV (T/N 2.0)), and the PET-edge method (CTV(P-E)) for stereotactic RT planning. Differences among CTVs were evaluated. The brain dose at each CTV and the dose at each CTV defined by 11C-MET PET using MRI as the reference were evaluated. RESULTS: The Jaccard index (JI) for concordance of CTV (Gd) with CTVs using 11C-MET PET was highest for CTV (T/N 2.0), with a value of 0.7. In a comparison of pixel values of MRI and PET, the correlation coefficient for cases with higher JI was significantly greater than that for lower JI cases (0.37 vs. 0.20, P = 0.007). D50% of the brain in RT planning using each CTV differed significantly (P = 0.03) and that using CTV (T/N 1.3) were higher than with use of CTV (Gd). V90% and V95% for each CTV differed in a simulation study for actual treatment using CTV (Gd) (P = 1.0 × 10-7 and 3.0 × 10-9, respectively) and those using CTV (T/N 1.3) and CTV (P-E) were lower than with CTV (Gd). CONCLUSIONS: The region of 11C-MET accumulation is not necessarily consistent with and larger than the Gd-enhanced region. A change of the tumor boundary using 11C-MET PET can cause significant changes in doses to the brain and the CTV.

Proton Beam Therapy for Treating Patients with Hepatocellular Carcinoma with Major Portal Vein Tumor Invasion: A Single Center Retrospective Study.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, 100 males) with HCC with advanced PVTT (Vp3 or Vp4) who received PBT from April 2008 to March 2018. Of these patients, 63 received PBT as definitive treatment and 53 as palliative treatment. The representative dose was 72.6 Gy (RBE) in 22 fractions. Eight patients died in follow-up, including 72 due to tumor progression. The 5-year overall survival (OS) rate was 18.0% (95% CI 9.8-26.2%) and the 5-year local control (LC) rate was 86.1% (74.9-97.3%). In multivariate analyses, performance status and treatment strategy were significantly associated with OS. The median follow-up period for survivors with definitive treatment was 33.5 (2-129) months, and the 5-year OS rate was 25.1% (12.9-37.3%) in these cases. The median survival time after definitive irradiation was >20 months. The 5-year OS rate was 9.1% (0-19.7%) for palliative irradiation. These results compare favorably with those of other therapies and suggest that PBT is a useful option for cases of HCC with advanced PVTT that cannot undergo surgery, with an expected survival benefit and good local control. Determining the optimal indication for this treatment is a future challenge.

A systematic review and meta-analysis of radiotherapy and particle beam therapy for skull base chondrosarcoma: TRP-chondrosarcoma 2024.

Introduction: Chondrosarcoma is a rare malignant bone tumor. Particle beam therapy (PT) can concentrate doses to targets while reducing adverse events. A meta-analysis based on a literature review was performed to examine the efficacy of PT and photon radiotherapy for skull base chondrosarcoma. Methods: The meta-analysis was conducted using 21 articles published from 1990 to 2022. Results: After PT, the 3- and 5-year overall survival (OS) rates were 94.1% (95% confidence interval [CI]: 91.0-96.2%) and 93.9% (95% CI: 90.6-96.1%), respectively, and the 3- and 5-year local control rates were 95.4% (95% CI: 92.0-97.4%) and 90.1% (95% CI: 76.8-96.0%), respectively. Meta-regression analysis revealed a significant association of PT with a superior 5-year OS rate compared to three-dimensional conformal radiotherapy (p < 0.001). In the studies used in the meta-analysis, the major adverse event of grade 2 or higher was temporal lobe necrosis (incidence 1-18%, median 7%). Conclusion: PT for skull base chondrosarcoma had a good outcome and may be a valuable option among radiotherapy modalities. However, high-dose postoperative irradiation of skull base chondrosarcoma can cause adverse events such as temporal lobe necrosis.

Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier.

Background: Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. Methods: In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. Results: The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. Conclusions: This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.

Tumor Response on Diagnostic Imaging after Proton Beam Therapy for Hepatocellular Carcinoma.

BACKGROUND: Follow-up after treatment for hepatocellular carcinoma (HCC) can be mostly performed using dynamic CT or MRI, but there is no common evaluation method after radiation therapy. The purpose of this study is to examine factors involved in tumor reduction and local recurrence in patients with HCC treated with proton beam therapy (PBT) and to evaluate HCC shrinkage after PBT. METHODS: Cases with only one irradiated lesion or those with two lesions irradiated simultaneously were included in this study. Pre- and post-treatment lesions were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by measuring the largest diameter. RESULTS: The 6-, 12-, and 24-month CR + PR rates after PBT were 33.1%, 57.5%, and 76.9%, respectively, and the reduction rates were 25.1% in the first 6 months, 23.3% at 6-12 months, and 14.5% at 13-24 months. Cases that reached CR/PR at 6 and 12 months had improved OS compared to non-CR/non-PR cases. CONCLUSIONS: It is possible that a lesion that reached SD may subsequently transition to PR; it is reasonable to monitor progress with periodic imaging evaluations even after 1 year of treatment.