The Difference in the Cytoskeletal Machinery of Growth Cones of Growing Axons and Leading Processes.

Neuronal migration and axon elongation in the developing brain are essential events for neural network formation. Leading processes of migrating neurons and elongating axons have growth cones at their tips. Cytoskeletal machinery for advance of growth cones of the two processes has been thought the same. In this study, we compared axonal-elongating growth cones and leading-process growth cones in the same conditions that manipulated filopodia, lamellipodia, and drebrin, the latter mediates actin filament-microtubule interaction. Cerebral cortex (CX) neurons and medial ganglionic eminence (MGE) neurons from embryonic mice were cultured on less-adhesive cover glasses. Inhibition of filopodia formation by triple knockdown of mammalian-enabled, Ena-VASP-like, and vasodilator-stimulated phosphoprotein or double knockdown of Daam1 and fascin affected axon formation of CX neurons but did not affect the morphology of leading process of MGE neurons. On the other hand, treatment with CK666, to inhibit lamellipodia formation, did not affect axons but destroyed the leading-process growth cones. When drebrin was knocked down, the morphology of CX neurons remained unchanged, but the leading processes of MGE neurons became shorter. In vivo assay of radial migration of CX neurons revealed that drebrin knockdown inhibited migration, while it did not affect axon elongation. These results showed that the filopodia-microtubule system is the main driving machinery in elongating growth cones, while the lamellipodia-drebrin-microtubule system is the main system in leading-process growth cones of migrating neurons.

The Golgi apparatus is the main microtubule-organizing center in differentiating skeletal muscle cells.

Studies in differentiating skeletal muscle cells in vitro have revealed that the microtubule-organizing center shifts from the centrosome to the perinuclear sites. As the Golgi apparatus surrounds the nucleus in a myotube, it is unclear whether microtubules are nucleated at the nuclear envelope or at the surrounding Golgi apparatus. In this study, we investigated the positional relationship between the microtubule nucleating sites and the Golgi apparatus in C2C12 myotubes and in primary cultured mouse skeletal myotubes. We focused on gaps in the perinuclear Golgi apparatus where the nuclear envelope was not covered with the Golgi apparatus. In microtubule regrowth assay, microtubule regrowth after cold-nocodazole depolymerization of preexisting microtubules was not found at the gap of the perinuclear Golgi apparatus. Most of the microtubule regrowth was detected at the CDK5RAP2 (CDK5 regulatory subunit-associated protein 2)-rich spots on the perinuclear Golgi apparatus. Disruption of the perinuclear Golgi apparatus with brefeldin A treatment eliminated the perinuclear microtubule regrowth. The Golgi apparatus of undifferentiated myoblasts and those at the cytoplasm of myotubes were also the microtubule nucleating sites. From these observations, we concluded that most of the perinuclear microtubule nucleation occurs on the Golgi apparatus surrounding the nucleus.

Dosimetric verification of IMPT using a commercial heterogeneous phantom.

The purpose of this study was to propose a verification method and results of intensity-modulated proton therapy (IMPT), using a commercially available heterogeneous phantom. We used a simple simulated head and neck and prostate phantom. An ionization chamber and radiochromic film were used for measurements of absolute dose and relative dose distribution. The measured doses were compared with calculated doses using a treatment planning system. We defined the uncertainty of the measurement point of the ionization chamber due to the effective point of the chamber and mechanical setup error as 2 mm and estimated the dose variation base on a 2 mm error. We prepared a HU-relative stopping power conversion table and fluence correction factor that were specific to the heterogeneous phantom. The fluence correction factor was determined as a function of depth and was obtained from the ratio of the doses in water and in the phantom at the same effective depths. In the simulated prostate plan, composite doses of measurements and calculations agreed within ±1.3% and the maximum local dose differences of each field were 10.0%. Composite doses in the simulated head and neck plan agreed within 4.0% and the maximum local dose difference for each field was 12.0%. The dose difference for each field came within 2% when taking the measurement uncertainty into consideration. In the composite plan, the maximum dose uncertainty was estimated as 4.0% in the simulated prostate plan and 5.8% in the simulated head and neck plan. Film measurements showed good agreement, with more than 92.5% of points passing a gamma value (3%/3 mm). From these results, the heterogeneous phantom should be useful for verification of IMPT by using a phantom-specific HU-relative stopping power conversion, fluence correction factor, and dose error estimation due to the effective point of the chamber.

KATNAL1 is a more active and stable isoform of katanin, and is expressed dominantly in neurons.

Microtubule severing is essential for reorganization of microtubules during neuronal migration and process elongation. Katanin is a microtubule-severing enzyme, of which the major catalytic subunits are katanin A1 (KATNA1) and katanin A-like 1 (KATNAL1). The domain organization of the two subunits are almost the same; however, little is known about their functional difference. Here, we compared the expression pattern, microtubule-severing activity, intracellular degradation and knockdown phenotype in cultured cells of the two subunits. While KATNA1 was expressed ubiquitously among tissues of young adult mice, KATNAL1 was highly expressed in the brain and the testis. Neurons expressed almost only KATNAL1. When introduced into Neuro2a cells, KATNAL1 showed higher microtubule-severing activity. Cycloheximide chase analysis revealed that KATNAL1 is more stable in cells. To elucidate which part of the molecules are responsible for these characteristics, we generated chimeric molecules by swapping the amino-terminal and carboxyl-terminal halves between the two subunits. Experiments using these chimeras revealed that the amino-terminal half region is the determinant for their characteristics. Furthermore, KATNAL1 knockdown in Neuro2a cells resulted in enhancement of process elongation, while KATNA1 knockdown showed no effect. These data suggest that more active and more stable katanin subunit, KATNAL1, plays more important role in process elongation.

Changes in the axo-glial junctions of the optic nerves of cuprizone-treated mice.

Demyelination induced by cuprizone in mice has served a useful model system for the study of demyelinating diseases, such as multiple sclerosis. Severity of demyelination by cuprizone, however, varies across different regions of the central nervous system; the corpus callosum is sensitive, while the optic nerves are resistant. Here, we investigated the effects of cuprizone on optic nerves, focusing on the axo-glial junctions. Immunostaining for sodium channels, contactin-associated protein, neurofascins, and potassium channels revealed that there were no massive changes in the density and morphology of the axo-glial junctions in cuprizone-treated optic nerves. However, when we counted the number of incomplete junctional complexes, we observed increased numbers of isolated paranodes. These isolated paranodes were immunopositive for both axonal and glial membrane proteins, indicating that they were the contact sites between axons and glia. These were not associated with sodium channels or potassium channels, suggesting the absence of physiological functions. When teased axons from cuprizone-treated optic nerves were immunostained, the isolated paranodes were found at the internode region of the myelin. From these observations, we conclude that cuprizone induces new contacts between axons and myelins at the internode region.

Evaluation of dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy for the shallow depth tumor.

In this study, we evaluate dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy (IMPT) for head and neck tumors at the shallow depth. We used four types of patient-specific aperture system (PSAS) to irradiate shallow regions less than 4 g/cm2 with a sharp lateral penumbra. Ten head and neck IMPT plans with or without aperture were optimized separately with the same 95% prescription dose and same dose constraint for organs at risk (OARs). The plans were compared using dose volume histograms (DVHs), dose distributions, and some dose indexes such as volume receiving 50% of the prescribed dose (V50 ), mean or maximum dose (Dmean and Dmax ) to the OARs. All examples verified in this study had decreased V50 and OAR doses. Average, maximum, and minimum relative reductions of V50 were 15.4%, 38.9%, and 1.0%, respectively. Dmax and Dmean of OARs were decreased by 0.3% to 25.7% and by 1.0% to 46.3%, respectively. The plans with the aperture over more than half of the field showed decreased V50 or OAR dose by more than 10%. The dosimetric advantage of patient-specific apertures with IMPT was clarified in many cases. The PSAS has some dosimetric advantages for clinical use, and in some cases, it enables to fulfill dose constraints.

Cell Shape Change by Drebrin.

Drebrin is localized in actin-rich regions of neuronal and non-neuronal cells. In mature neurons, its localization is strictly restricted to the postsynaptic sites. In order to understand the function of drebrin in cells, many studies have been performed to examine the effect of overexpression or knocking down of drebrin in various cell types, including neurons, myoblasts, kidney cells, and intestinal epithelial cells. In most cases alteration of cell shape and impairment or facilitation of actin-based activities of these cells were observed. Interestingly, overexpression of drebrin in matured neurons results in the alteration in dendritic spine morphology. Further studies have shown alteration in the localization of postsynaptic receptors and even changes in synaptic transmission caused by drebrin overexpression or depletion in neurons. These drebrin's effects are thought to come from drebrin's actin-cross-linking activity or competitive binding to actin against tropomyosin, fascin, and α-actinin. Furthermore, drebrin binds to various molecules, such as homer, EB3, and cell-cell junctional proteins, indicating that drebrin is a multifunctional cytoskeletal regulator.

Spot scanning proton therapy for unresectable bulky retroperitoneal dedifferentiated liposarcoma: a case report.

The development of effective treatment strategies for unresectable retroperitoneal sarcoma is desirable. Herein, we suggest that definitive proton therapy (PT) could be a promising treatment option, regardless of the large size of the tumor. A 52-year-old man presented with a discomfort of the lower abdomen. Computed tomography revealed a retroperitoneal tumor, measuring over 20 cm in the largest dimensions, which was surrounded by the gastrointestinal (GI) tract. Biopsy revealed dedifferentiated liposarcoma. Neoadjuvant chemotherapy was ineffective, and the tumor was ultimately deemed unresectable. The patient opted to receive PT instead of continuation of chemotherapy. Spot scanning PT (SSPT) at a total dose of 60.8 Gy (relative biological effectiveness) in 16 fractions was employed. SSPT administered a dose to the tumor while successfully sparing the surrounding GI tract. He did not receive any maintenance systemic therapy after PT. The tumor gradually shrunk over more than 7 years, with no evidence of recurrence outside the irradiation field. The initial measurable tumor volume of 2925 cc decreased to 214 cc at the final follow-up, seven and a half years after PT. The patient is alive without any severe complications.

Long-term survival outcomes and quality of life of image-guided proton therapy for operable stage I non-small cell lung cancer: A phase 2 study.

BACKGROUND AND PURPOSE: This study evaluated long-term efficacy, safety, and changes in quality of life (QOL) of patients after image-guided proton therapy (IGPT) for operable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This single-institutional prospective phase 2 study enrolled patients with operable histologically confirmed stage IA or IB NSCLC (7th edition of UICC). The prescribed dose was 66 Gy relative biological effectiveness equivalents (GyRBE) in 10 fractions for peripheral lesions, or 72.6 GyRBE in 22 fractions for central lesions. The primary endpoint was the 3-year overall survival (OS). The secondary endpoints included disease control, toxicity, and changes in QOL score. RESULTS: We enrolled 43 patients (median age: 68 years; range, 47-79 years) between July 2013 to January 2021, of whom 41 (95 %) had peripheral lesions and 27 (63 %) were stage IA. OS, local control, and progression-free survival rates were 95 % (95 % CI: 83-99), 95 % (82-99), and 86 % (72-94), respectively, at 3 years, and 83 % (66-92), 95 % (82-99), and 77 % (60-88), respectively, at 7 years. Four patients (9 %) developed grade 2, and one patient (2 %) developed grade 3 radiation pneumonitis. No other grade 3 or higher adverse events were observed. In the QOL analysis, global QOL remained favorable; however, approximately 40 % of patients reported dyspnea at 3 and 24 months. CONCLUSION: Our findings suggest that IGPT provides effective disease control and survival in operable stage I NSCLC, particularly for peripheral lesions. Moreover, toxicity associated with IGPT was minimal, and patients reported favorable QOL.

Thermal and Chemical Phase Engineering of Two-Dimensional Ruthenate.

Monolayer ruthenate nanosheets obtained by exfoliating layered ruthenium oxide exhibit excellent electrical conductivity, redox activity, and catalytic activity, which render them suitable for advanced electronic and energy devices. However, to fully exploit the benefits, we require further structural insights into a complex polymorphic nature and diversity in relevant electronic states of two-dimensional (2D) ruthenate systems. In this study, the 2D structures, stability, and electronic states of 2D ruthenate are investigated on the basis of thermal and chemical phase engineering approaches. We reveal that contrary to a previous report, exfoliation of an oblique 1T phase precursor leads to nanosheets having an identical phase without exfoliation-induced phase transition to a 1H phase. The oblique 1T phase in the nanosheets is found to be metastable and, thus, transforms successively to a rectangular 1T phase upon heating. A phase-controllable synthesis via Co doping affords nanosheets with metastable rectangular and thermally stable hexagonal 1T phases at a Co content of 5-10 and 20 at%, respectively. The 1T phases show metallic electronic states, where the d-d optical transitions between the Ru 4d (t2g) orbital depend on the symmetry of the Ru framework. The Co doping in ruthenate nanosheets unexpectedly suppresses the redox and catalytic activities under acidic conditions. In contrast, the Co2+/3+ redox pair is activated and produces conductive nanosheets with high electrochemical capacitance in an alkaline condition.

Rear-side localization of the centrosome in migrating neuroblastoma Neuro-2a cells and its roles in process elongation.

Axon elongation is usually performed by the migration of growth cones that leave axons. Axon microtubules are generated by enhanced polymerization of tubulin in the growth cones. Some kinds of neurons like cerebellar granule cells, however, generate axons as a result of migration of the cell body leaving axons at the rear. The mechanism to generate microtubules during such growth cone-independent elongation of axons is not well understood. To establish an experimental model to study this mechanism, we cultured neuroblastoma (Neuro-2a) cells on substrates that facilitate cell migration. When cultured on laminin-treated substrate, cells migrated actively and left processes at the rear. We investigated the role of the centrosome in this process formation. The centrosomes were always located at the base of the processes, i.e., at the rear side of the migrating cell body. Close observation of cytoskeletons revealed microtubules limited around the centrosomes, but concentrated at the periphery of the cells or within the processes. Microtubule regrowth experiments showed the ability of the centrosomes to nucleate microtubules. We thus examined the role of microtubule release from the centrosomes, by knocking down the expression of spastin, a microtubule-severing enzyme. Introducing siRNA for spastin into Neuro-2a cells reduced both the migration speed and the length of the processes. Taken together, Neuro-2a cells on laminin proved useful as a model to study the alternative type of axon elongation in which cell migration leaves axons at the rear. This model provided evidence for the involvement of microtubule release from centrosomes in the mechanisms for this type of process elongation.

An alternative splice isoform of mouse CDK5RAP2 induced cytoplasmic microtubule nucleation.

The centrosome lacks microtubule (MT)-nucleation activity in differentiated neurons. We have previously demonstrated that MTs were nucleated at the cytoplasm of mouse neurons. They are supposed to serve seeds for MTs required for dendrite growth. However, the factors that activate the cytoplasmic γ-tubulin ring complex (γTuRC) are unknown. Here we report an alternative splicing isoform of cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CKD5RAP2) as a candidate for the cytoplasmic γTuRC activator. This isoform lacked exon 17 and was expressed predominantly in the brain and testis. The expression was transient during the development of cortical neurons, which period coincided with the period we reported cytoplasmic MT nucleation. This isoform resulted in a frameshift and generated truncated protein without a centrosomal localization signal. When this isoform was expressed in cells, it localized diffusely in the cytoplasm. It was co-immunoprecipitated with γ-tubulin and MOZART2, suggesting that it can activate cytosolic γTuRCs. After cold-nocodazole depolymerization of MTs and subsequent washout, we observed numerous short MTs in the cytoplasm of cells transfected with the cDNA of this isoform. The isoform-overexpressing cells exhibited an increased amount of MTs and a decreased ratio of acetylated tubulin, suggesting that MT generation and turnover were enhanced by the isoform. Our data suggest the possibility that alternative splicing of CDK5RAP2 induces cytoplasmic nucleation of MTs in developing neurons.

Patient-Reported Quality of Life Outcomes after Moderately Hypofractionated and Normofractionated Proton Therapy for Localized Prostate Cancer.

We retrospectively evaluated the three-year patient-reported quality of life (QOL) after moderately hypofractionated proton therapy (MHPT) for localized prostate cancer in comparison with that after normofractionated PT (NFPT) using the Expanded Prostate Cancer Index Composite-50. Patients who received MHPT (60-63 Gy (relative biological effectiveness equivalents; RBE)/20-21 fractions) (n = 343) or NFPT (74-78 Gy (RBE)/37-39 fractions) (n = 296) between 2013 and 2016 were analyzed. The minimum clinically important difference (MCID) threshold was defined as one-half of a standard deviation of the baseline value. The median follow-up was 56 months and 83% completed questionnaires at 36 months. Clinically meaningful score deterioration was observed in the urinary domain at 1 month in both groups and in the sexual domain at 6-36 months in the NFPT group, but not observed in the bowel domain. At 36 months, the mean score change for urinary summary was -0.3 (MHPT) and -1.6 points (NFPT), and that for bowel summary was +0.1 and -2.0 points; the proportion of patients with MCID was 21% and 24% for urinary summary and 18% and 29% for bowel summary. Overall, MHPT had small negative impacts on QOL over three years, and the QOL after MHPT and NFPT was similar.

Outcomes of proton therapy for non-small cell lung cancer in patients with interstitial pneumonia.

BACKGROUND: Interstitial pneumonia (IP) is a disease with a poor prognosis. In addition, IP patients are more likely to develop lung cancer. Since IP patients frequently develop toxicities during cancer treatment, minimally invasive cancer treatment is warranted for such patients to maintain their quality of life. This study retrospectively investigated the efficacy and safety of proton therapy (PT) for non-small cell lung cancer (NSCLC) in patients with IP. METHODS: Twenty-nine NSCLC patients with IP were treated with PT between September 2013 and December 2019. The patients had stage IA to IIIB primary NSCLC. Ten of the 29 patients exhibited the usual interstitial pneumonia pattern. The prescribed dose was 66-74 Grays (relative biological effectiveness) in 10-37 fractions. RESULTS: The median follow-up period was 21.1 months [interquartile range (IQR), 15.6-37.3] for all patients and 37.2 months (IQR, 24.0-49.9) for living patients. The median patient age was 77 years (IQR, 71-81). The median planning target volume was 112.0 ml (IQR, 56.1-246.3). The 2-year local control, progression-free survival, and overall survival rates were 85% (95% confidence interval: 57-95), 30% (15-47), and 45% (26-62), respectively. According to the Common Terminology Criteria for Adverse Events (version 4.0), grade 3 acute radiation pneumonitis (RP) was observed in 1 patient. Two patients developed grade 3 late RP, but no other patients experienced serious toxicities. The patients' quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 and SF-36) scores had not changed after 3 months. CONCLUSIONS: PT may be a relatively safe treatment for NSCLC patients with IP, without deteriorating quality of life scores within 3 months.

Spot Scanning Proton Therapy for Sinonasal Malignant Tumors.

PURPOSE: Treatment of sinonasal malignant tumors is challenging, and evidence to establish a standard treatment is limited. Our objective was to evaluate the efficacy and safety of spot scanning proton therapy (SSPT) for sinonasal malignant tumors. PATIENTS AND METHODS: We retrospectively analyzed patients with sinonasal malignant tumors (T1-4bN0-2M0) who underwent SSPT between May 2014 and September 2019. The prescription dose was typically either 60 GyRBE in 15 fractions or 60.8 GyRBE in 16 fractions for mucosal melanoma and 70.2 GyRBE in 26 fractions for other histologic subtypes. Endpoints included local control (LC), progression-free survival, overall survival (OS), and incidence of toxicity. Prognostic factors were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of 62 enrolled patients, the common histologic subtypes were mucosal melanoma (35%), squamous cell carcinoma (27%), adenoid cystic carcinoma (16%), and olfactory neuroblastoma (10%). Locally advanced stages were common (T3 in 42% and T4 in 53%). Treatment-naïve tumors and postsurgical recurrent tumors accounted for 73% and 27%, respectively. No patient had previous radiotherapy. The median follow-up was 17 months (range, 6-66) for all patients and 21.5 months (range, 6-66) for survivors. The 2-year LC, progression-free survival, and OS rates of all patients were 92%, 50%, and 76%, respectively. Univariate analysis revealed histology as a prognostic factor for OS, being higher in adenoid cystic carcinoma and olfactory neuroblastoma than in other tumors. Sixteen grade ≥3 late toxicities were observed in 12 patients (19%), including 11 events resulting in visual impairment; the most common was cataract. There was 1 grade 4 toxicity, and there were no grade 5 toxicities. CONCLUSION: SSPT was well tolerated and yielded good LC for sinonasal malignant tumors. Although we consider SSPT to be a leading treatment modality, further studies are required to establish its status as a standard treatment.

Image-Guided Proton Therapy for Elderly Patients with Hepatocellular Carcinoma: High Local Control and Quality of Life Preservation.

This study retrospectively investigated the efficacy and safety of image-guided proton therapy (IGPT) for elderly (≥80 years old) hepatocellular carcinoma (HCC) patients. Proton therapy was performed using respiratory-gated and image-guided techniques. Seventy-one elderly HCC patients were treated using IGPT. The Child-Pugh score was A5 in 49 patients, A6 in 15, and B7-9 in 7. Forty-seven patients with a peripherally located tumor were administered 66 gray relative biological effectiveness (GyRBE) in 10 fractions, whereas 24 with a centrally located tumor received 72.6 GyRBE in 22 fractions. The median follow-up period of surviving patients was 33 months (range: 9-68). Two-year overall survival (OS) and local control (LC) rates estimated by the Kaplan-Meier method were 76% (95% confidence interval: 66-87%) and 88% (80-97%), respectively. According to the Common Terminology Criteria for Adverse Events version 4.0, no grade 2 or higher radiation-induced liver disease was observed, and only 1 patient developed grade 3 dermatitis. The quality of life score (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0, QLQ-HCC18, and SF-36) did not change after 1 year, except for the three-mental component summary (SF-36, improvement). IGPT is a safe and effective treatment for HCC in elderly patients.

Changes in sexual function and serum testosterone levels in patients with prostate cancer after image-guided proton therapy.

Since sexual function and testosterone levels after image-guided proton therapy (IGPT) have not yet been examined in detail, we prospectively evaluated changes before and after IGPT. Among patients treated with IGPT with or without combined androgen blockade (CAB) therapy between February 2013 and September 2014, patients who agreed to participate in the study and were followed up for >3 years after IGPT were evaluated. Serum testosterone levels were regularly measured together with prostate-specific antigen (PSA) levels before and after IGPT. The Erection Hardness Score (EHS) and the sexual domain summary, function subscale and bother subscale of the sexual domain in the Expanded Prostate Cancer Index Composite (EPIC) were assessed. There were 38 low-risk, 46 intermediate-risk and 43 high- or very-high-risk patients (NCCN classification). Although serum testosterone levels in low-risk patients did not decrease after IGPT, reductions were observed in the average EHS and the sexual domain summary score of the EPIC. In intermediate-, high- and very-high-risk patients, testosterone and PSA levels both increased following the termination of CAB after IGPT, and the average EHS increased. The sexual domain summary score gradually increased, but not above minimally important differences. In intermediate-risk patients, the function subscale increased from 4.4 to 14.8 (P < 0.05) 12 months after IGPT and reached a plateau after 60 months. The results of the present study would suggest the potential of IGPT, and further prospective studies to directly compare IGPT with other modalities are warranted.

A Phase 2 Study of Image-Guided Proton Therapy for Operable or Ablation-Treatable Primary Hepatocellular Carcinoma.

PURPOSE: Because most previous data on proton therapy for hepatocellular carcinoma (HCC) were retrospectively collected from inoperable or previously treated cases, our aim was to evaluate the outcome of image-guided proton therapy (IGPT) for operable or radiofrequency ablation-treatable primary HCC. METHODS AND MATERIALS: This phase 2 study prospectively investigated the efficacy and safety of IGPT and quality of life (QoL) after IGPT for operable/ablatable HCC. The primary endpoint was overall survival, and the secondary endpoints were local control, incidence of grade ≥3 adverse events, and changes in QoL. Toxicities were evaluated with Common Terminology Criteria for Adverse Events, version 4.0. QoL scores were assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0, and Quality of Life Questionnaire-Hepatocellular Carcinoma/Primary Liver Cancer Module. IGPT was performed using respiratory-gated techniques. RESULTS: Forty-five patients (median age: 68 years; range, 36-80 years) were enrolled between June 2013 and February 2016; 38 were considered operable and 14 were indicated for radiofrequency ablation. The major underlying liver diseases were hepatitis B (n = 16), hepatitis C (n = 13), alcoholic hepatitis (n = 3), and nonalcoholic fatty liver disease (n = 13). The Child-Pugh score was A5 in 32 patients, A6 in 9 patients, and B7 in 4 patients. Thirty-seven patients with a peripherally located tumor were given 66 Gy relative biological effectiveness in 10 fractions, and 8 patients with a centrally located tumor received 72.6 Gy relative biological effectiveness in 22 fractions. The median follow-up period of surviving patients was 60 months (range, 42-75 months). Two- and 5-year overall survival rates were 84% (95% confidence interval [CI], 74%-95%) and 70% (95% CI, 56%-84%), respectively, and local control rates were 95% (95% CI, 89%-100%) and 92% (95% CI, 84%-100%), respectively. Grade 3 radiation-induced liver disease was observed in 1 patient. No significant changes were noted in QoL scores 1 year after treatment, except for body image. CONCLUSIONS: Although the primary endpoint did not meet statistical significance as planned in the study design, IGPT is a safe and effective treatment for solitary primary HCC and may become a treatment option.

Concurrent Chemo-Proton Therapy Using Adaptive Planning for Unresectable Stage 3 Non-Small Cell Lung Cancer: A Phase 2 Study.

PURPOSE: This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m2) on day 1 and S-1 (∼40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented. RESULTS: Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia. CONCLUSIONS: CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC.

Discovery of a Potent Anticancer Agent PVHD303 with in Vivo Activity.

As a part of our continuous structure-activity relationship (SAR) studies on 1-(quinazolin-4-yl)-1-(4-methoxyphenyl)ethan-1-ols, the synthesis of derivatives and their cytotoxicity against the human lung cancer cell line A549 were explored. This led to the discovery of 1-(2-(furan-3-yl)quinazolin-4-yl)-1-(4-methoxyphenyl)ethan-1-ol (PVHD303) with potent antiproliferative activity. PVHD303 disturbed microtubule formation at the centrosomes and inhibited the growth of tumors dose-dependently in the HCT116 human colon cancer xenograft model in vivo.