Multidisciplinary management of locally recurrent rectal cancer with carbon ion radiotherapy followed by prophylactic removal of the irradiated bowel: a case report.

BACKGROUND: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT. CASE PRESENTATION: A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion. CONCLUSIONS: The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

Profiles of central nervous system surgical site infections in endoscopic transnasal surgery exposing the intradural space.

OBJECTIVE: Despite its efficacy and minimal invasiveness, the clean-contaminated nature of endoscopic transnasal surgery (ETS) may be susceptible to central nervous system surgical site infections (CNS-SSIs), especially when involving intradural exposure. However, the profiles of ETS-associated CNS-SSIs are not fully elucidated. METHODS: The institutional ETS cases performed between May 2017 and March 2023 were retrospectively analysed. The incidences of CNS-SSIs were calculated, and their risk factors examined. RESULTS: The incidence of CNS-SSIs was 2.3% (7/305) in the entire cohort and 5.0% (7/140) in ETSs with intradural exposure. All the CNS-SSIs were meningitis and developed following ETS with intradural exposure. The incidences were 0%, 5.6% and 5.8% in ETSs with Esposito grade 1, 2 and 3 intraoperative cerebrospinal fluid leakage, respectively. Among the pre- and intra-operative factors, body mass index (unit odds ratio (OR), 0.62; 95% confidence interval (CI), 0.44-0.89; P<0.01), serum albumin (unit OR, 0.03; 95% CI, 0.0007-0.92; P=0.02), and American Society of Anesthesiologists physical status score (unit OR, 20.7; 95% CI, 1.65-259; P<0.01) were significantly associated with CNS-SSIs. Moreover, postoperative cerebrospinal fluid leakage was also significantly associated with CNS-SSIs (OR, 18.4; 95% CI, 3.55-95.0; P<0.01). CONCLUSIONS: The incidence of ETS-associated CNS-SSIs is acceptably low. Intradural exposure was a prerequisite for CNS-SSIs. Malnutrition and poor comorbidity status should be recognized as important risks for CNS-SSIs in ETS.

Erratum: Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande [Phys. Rev. Lett. 130, 031802 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.031802.

Effect of Blonanserin on the Proliferation and Migration of Glioblastoma Cells.

Glioblastoma is a highly malignant and invasive brain tumor, and there is an urgent need to establish a treatment option that prevents its growth and metastasis. Blonanserin is an antipsychotic drug widely used in the treatment of schizophrenia. It has recently been reported to inhibit the growth of breast cancer cells. In this study, we investigated the effect of blonanserin on the proliferation and migration of glioblastoma cells. The anti-proliferative activity of blonanserin was evaluated in terms of cell viability, competition, and cell death pathways in glioblastoma. Cell viability studies showed that blonanserin had growth inhibitory ability regardless of the malignancy of glioblastoma cells, but at concentrations close to its IC50, it only had a slight cell death-inducing effect. Blonanserin showed growth inhibitory activity without D2 antagonism following an independent competition analysis using blonanserin and D2 antagonists. When the anti-migration activity of U251 cells was measured, blonanserin was found to attenuate cell migration. Furthermore, treatment with blonanserin at concentrations close to its IC50 value inhibited extensive filament actin formation. In conclusion, blonanserin inhibited the proliferation and migration of glioblastoma cells independent of D2 antagonism. The present study shows that blonanserin may serve as a seed compound for the discovery of new glioblastoma therapeutics to prevent the growth and metastasis of glioblastoma.

Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande.

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton×years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross section between 10^{-33}cm^{2} and 10^{-27}cm^{2} for dark matter mass from 1 MeV/c^{2} to 300 MeV/c^{2}.

SWI by 7T MR Imaging for the Microscopic Imaging Diagnosis of Astrocytic and Oligodendroglial Tumors.

BACKGROUND AND PURPOSE: Despite advances in molecular imaging, preoperative diagnosis of astrocytomas and oligodendrogliomas can be challenging. In the present study, we assessed whether 7T SWI can be used to distinguish astrocytomas and oligodendrogliomas and whether malignant grading of gliomas is possible. MATERIALS AND METHODS: 7T SWI was performed on 21 patients with gliomas before surgery with optimization for sharp visualization of the corticomedullary junction. Scoring for cortical thickening and displacement of medullary vessels, characteristic of oligodendroglial tumors, and cortical tapering, characteristic of astrocytic tumors, was performed. Additionally, characteristics of malignancy, including thickening of the medullary veins, the presence of microbleeds, and/or necrosis were scored. RESULTS: Scoring for oligodendroglial (highest possible score, +3) and astrocytic (lowest score possible, -3) characteristics yielded a significant difference between astrocytomas and oligodendrogliomas (mean, -1.93 versus +1.71, P < .01). Scoring for malignancy was significantly different among the World Health Organization grade II (n = 10), grade III (n = 4), and grade IV (n = 7) tumors (mean, 0.20 versus 1.38 versus 2.79). Cortical thickening was observed significantly more frequently in oligodendrogliomas (P < .02), with a sensitivity of 71.4% and specificity of 85.7%; observation of tapering of the cortex was higher in astrocytomas (P < .01) with a sensitivity of 85.7% and specificity of 100%. CONCLUSIONS: Visualization of the corticomedullary junction by 7T SWI was useful in distinguishing astrocytomas and oligodendrogliomas. Observation of tapering of the cortex was most sensitive and specific for diagnosing astrocytomas. Reliably predicting malignant grade was also possible by 7T SWI.

Inhibition of growth and virulence of Vibrio cholerae by carvacrol, an essential oil component of Origanum spp.

AIMS: In the age where bacterial resistance to conventional antibiotics is increasing at an alarming rate, the use of the traditional plant, herb extracts or other bioactive constituents is gradually becoming popular as an anti-virulence agent to treat pathogenic diseases. Carvacrol, a major essential oil fraction of Oregano, possesses a wide range of bioactivities. Therefore, we aimed to study the effect of sub-inhibitory concentrations of carvacrol on major virulence traits of Vibrio cholerae. METHODS AND RESULTS: We have used in vitro as well as ex vivo models to access the anti-pathogenic role of carvacrol. We found that the sub-inhibitory concentration of carvacrol significantly repressed bacterial mucin penetrating ability. Carvacrol also reduced the adherence and fluid accumulation in the rabbit ileal loop model. Reduction in virulence is associated with the downregulated expression of tcpA, ctxB, hlyA and toxT. Furthermore, carvacrol inhibits flagellar synthesis by downregulating the expression of flrC and most of the class III genes. CONCLUSIONS: Carvacrol exhibited anti-virulence activity against V. cholerae, which involved many events including the inhibition of mucin penetration, adhesion, reduced expression of virulence-associated genes culminating in reduced fluid accumulation. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings indicate that carvacrol possesses inhibitory activity against V. cholerae pathogenesis and might be considered as a potential bio-active therapeutic alternative to combat cholera.

Pilot Study of Hyperpolarized 13C Metabolic Imaging in Pediatric Patients with Diffuse Intrinsic Pontine Glioma and Other CNS Cancers.

BACKGROUND AND PURPOSE: Pediatric CNS tumors commonly present challenges for radiographic interpretation on conventional MR imaging. This study sought to investigate the safety and tolerability of hyperpolarized carbon-13 (HP-13C) metabolic imaging in pediatric patients with brain tumors. MATERIALS AND METHODS: Pediatric patients 3 to 18 years of age who were previously diagnosed with a brain tumor and could undergo MR imaging without sedation were eligible to enroll in this safety study of HP [1-13C]pyruvate. Participants received a one-time injection of HP [1-13C]pyruvate and were imaged using dynamic HP-13C MR imaging. We assessed 2 dose levels: 0.34 mL/kg and the highest tolerated adult dose of 0.43 mL/kg. Participants were monitored throughout imaging and for 60 minutes postinjection, including pre- and postinjection electrocardiograms and vital sign measurements. RESULTS: Between February 2017 and July 2019, ten participants (9 males; median age, 14 years; range, 10-17 years) were enrolled, of whom 6 completed injection of HP [1-13C]pyruvate and dynamic HP-13C MR imaging. Four participants failed to undergo HP-13C MR imaging due to technical failures related to generating HP [1-13C]pyruvate or MR imaging operability. HP [1-13C]pyruvate was well-tolerated in all participants who completed the study, with no dose-limiting toxicities or adverse events observed at either 0.34 (n = 3) or 0.43 (n = 3) mL/kg. HP [1-13C]pyruvate demonstrated characteristic conversion to [1-13C]lactate and [13C]bicarbonate in the brain. Due to poor accrual, the study was closed after only 3 participants were enrolled at the highest dose level. CONCLUSIONS: Dynamic HP-13C MR imaging was safely performed in 6 pediatric patients with CNS tumors and demonstrated HP [1-13C]pyruvate brain metabolism.

Proof-of-principle experiment for laser-driven cold neutron source.

The scientific and technical advances continue to support novel discoveries by allowing scientists to acquire new insights into the structure and properties of matter using new tools and sources. Notably, neutrons are among the most valuable sources in providing such a capability. At the Institute of Laser Engineering, Osaka, the first steps are taken towards the development of a table-top laser-driven neutron source, capable of producing a wide range of energies with high brightness and temporal resolution. By employing a pure hydrogen moderator, maintained at cryogenic temperature, a cold neutron ([Formula: see text]) flux of [Formula: see text]/pulse was measured at the proximity of the moderator exit surface. The beam duration of hundreds of ns to tens of [Formula: see text] is evaluated for neutron energies ranging from 100s keV down to meV via Monte-Carlo techniques. Presently, with the upcoming J-EPoCH high repetition rate laser at Osaka University, a cold neutron flux in orders of [Formula: see text] is expected to be delivered at the moderator in a compact beamline.

Relativistic magnetic reconnection in laser laboratory for testing an emission mechanism of hard-state black hole system.

Magnetic reconnection in a relativistic electron magnetization regime was observed in a laboratory plasma produced by a high-intensity, large energy, picoseconds laser pulse. Magnetic reconnection conditions realized with a laser-driven several kilotesla magnetic field is comparable to that in the accretion disk corona of black hole systems, i.e., Cygnus X-1. We observed particle energy distributions of reconnection outflow jets, which possess a power-law component in a high-energy range. The hardness of the observed spectra could explain the hard-state x-ray emission from accreting black hole systems.

Prognostic and predictive values of tumour budding in stage IV colorectal cancer.

BACKGROUND: Tumour budding is an important prognostic feature in early-stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated. METHODS: Patients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence-free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline. RESULTS: Of 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5-year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P < 0·001). Survival analyses according to metastatic and resection status also showed that BD3 was associated with shorter OS than BD1 + BD2. In multivariable analysis, BD3 (hazard ratio (HR) 1·51, 95 per cent c.i. 1·11 to 2·10; P = 0·009), T4 status (HR 1·39) and R2/unresected status (HR 3·50) were associated with decreased OS. In the R0/R1 subgroup, the 2-year RFS rate was similar for BD3 and BD1 + BD2 according to metastatic status. There was no significant difference between BD3 and BD1 + BD2 for change in tumour size in the R2/unresected subgroup (P = 0·094). Of 141 patients with initially unresectable metastases who had chemotherapy, 35 achieved conversion from unresectable to resectable status. The conversion rate was significantly higher for BD1 + BD2 than for BD3 (36 versus 18 per cent; P = 0·016). CONCLUSION: Stage IV colorectal cancer with high-grade tumour budding according to ITBCC criteria correlates with poor prognosis.

ANTECEDENTES: La esofaguectomía por cáncer se asocia con un descenso de la calidad de vida relacionada con la salud (health-related quality of life, HRQoL) a largo plazo. El objetivo de este estudio fue evaluar el efecto de las comorbilidades sobre la HRQOL entre pacientes supervivientes de cánceres de esófago o de la unión gastroesofágicas después de 10 años o más. MÉTODOS: Este estudio incluye una cohorte de base poblacional recogida de forma prospectiva que incluía todos los pacientes operados de cáncer de esófago o de la unión gastroesofágica en Suecia en 2001-2005 con seguimiento hasta el 31 de diciembre de 2016. Todos los datos relacionados con las características de los pacientes y del tumor, detalles del tratamiento y HRQoL se recogieron en una base de datos prospectiva. Se utilizaron modelos de regresión multivariable ANCOVA, ajustados por edad, sexo, histología del tumor, estadio, y técnica quirúrgica, para calcular las puntuaciones medias ajustadas con los i.c. del 95% para todas las variables de la HRQoL. RESULTADOS: Un total de 92 (88%) supervivientes respondieron a los cuestionarios. En función del impacto de las comorbilidades en la salud en general, se clasificaron a los pacientes en los grupos de bajo versus alto impacto. Los resultados muestran que los pacientes en el grupo de alto impacto presentaban un descenso clínicamente significativo de la HRQoL y un aumento en el nivel de síntomas, pero las diferencias entre estos dos grupos no fueron estadísticamente significativas. CONCLUSIÓN: A los 10 años de la esofaguectomía por cáncer, las comorbilidades con un alto impacto sobre la salud general siguen contribuyendo en el deterioro de la HRQoL.

Transcription factor EB influences invasion and migration in oral squamous cell carcinomas.

OBJECTIVE: Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and plays an important role in various cancers. However, the function of TFEB in oral squamous cell carcinomas has not been examined. The aim of this study was to elucidate the role of TFEB in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of TFEB were examined in six different human oral squamous carcinoma cells: HSC2, HSC3, HSC4, SAS, OSC20, and SCC25. Knockdown of TFEB using small interfering RNA in HSC2 and HSC4 cells was performed. Cell morphology was observed by immunofluorescence microscopy. Cell proliferation, invasion, and adhesion were analyzed. RESULTS: Expression levels of TFEB were high in HSC2, moderate in HSC4 and SCC25, and low in HSC3 and OSC20 cells. Knockdown of TFEB did not affect proliferation of HSC2 and HSC4 cells, but did induced enlargement of lysosomes and endosomes in HSC4 cells. TFEB silencing reduced invasion and migration of these HSC cell squamous carcinoma cells; however, increased cell adhesion was also observed. CONCLUSION: TFEB knockdown reduces invasion and migration of cancer cells, likely through lysosomal regulation. Taken together, TFEB influences cell invasion and migration of oral squamous cell carcinomas.

Flocked nylon swabs versus RODAC plates for detection of multidrug-resistant organisms on environmental surfaces in intensive care units.

To compare two culture methods [nylon fiber flocked swabs with broth enrichment versus RODAC ('replicate organism detection and counting') plates] for recovery of multidrug-resistant organisms, 780 environmental surfaces in 63 rooms of patients on contact precautions in four intensive care units at one hospital were examined. Among sites that had at least one positive culture, swab culture with broth enrichment detected the target organisms more frequently than RODAC plates (37.5% vs 26.0%, P = 0.06). There was moderate agreement between the two methods (κ = 0.44) with agreement better for small or flat surfaces compared to large or irregular surfaces.

A novel in vivo model for predicting myelotoxicity of chemotherapeutic agents using IL-3/GM-CSF transgenic humanized mice.

Evaluating myelotoxicity is essential for ensuring the safety of novel drugs before they are approved for clinical applications. Although in vivo prediction of the maximum tolerated doses (MTDs) of anticancer drugs is usually performed in rodents, the results are not always applicable to clinical treatment because drugs may have different effects in human and rodent cells. Previously, we generated a human IL-3 and GM-CSF transgenic humanized mouse (hu-IL-3/GM Tg), in which human granulocytes effectively differentiated after hematopoietic stem cell transplantation. In this study, we established a novel in vivo preclinical evaluation model for predicting human myelotoxicity of anticancer drugs using these hu-IL-3/GM Tg mice. The myelotoxicity was investigated by kinetic flow cytometry of human or murine granulocytes and by colony-forming unit granulocyte/macrophage (CFU-GM) assays. In both in vivo and in vitro analyses, topotecan was more myelotoxic to human than murine granulocytes. In contrast, oxaliplatin was more myelotoxic to murine granulocytes. The level of myelotoxicity of paclitaxel treatment was comparable between human and mouse cells. These results demonstrate that our humanized mouse model can simultaneously evaluate myelotoxicity against human and mouse cells in vivo, and provides an effective preclinical tool for predicting appropriate doses of anticancer agents for clinical treatment.

Perioperative outcomes of single-port mediastinoscope-assisted transhiatal esophagectomy for thoracic esophageal cancer.

We developed an en bloc lymphadenectomy method in the upper mediastinum with a single-port mediastinoscopic cervical approach. This study was designed to evaluate the safety and efficacy of single-port mediastinoscope-assisted transhiatal esophagectomy for thoracic esophageal cancer. The perioperative outcomes of 60 patients with thoracic esophageal cancer who underwent this operation between March 2014 and June 2016 were retrospectively analyzed. The upper mediastinal dissection including lymphadenectomy along the left recurrent laryngeal nerve, using a left cervical approach, was performed with a single-port mediastinoscopic technique, which was used to improve the visibility and handling in the deep mediastinum around the aortic arch. The lymphadenectomy along the right recurrent laryngeal nerve was performed under direct vision using a right cervical approach. Bilateral cervical approaches were followed by hand-assisted laparoscopic transhiatal esophagectomy with en bloc lymphadenectomy in the middle and lower mediastinum. Tumors were mainly located in the middle thoracic esophagus (n = 33), and most tumors were squamous cell carcinoma (n = 58). Pretreatment diagnoses were stage I, 19; II, 13; III, 24; IV, 4. Preoperative chemotherapy was performed for 40 patients. The median operation time and blood loss were 363 minutes and 235 mL, respectively. There were two patients who underwent conversion to thoracotomy. Perioperative complications were evaluated and graded according to the Clavien-Dindo (CD) and the Esophagectomy Complications Consensus Group (ECCG) classifications. Postoperatively, pneumonia was observed in four patients (CD, Grade II, 2; Grade IIIb, 2), although vocal cord palsy was more frequent (ECCG, Type I, 12; Type III, 8). The median number of thoracic lymph nodes resected was 21, and the R0 resection rate was 95%. Single-port mediastinoscope-assisted transhiatal esophagectomy is feasible, in terms of perioperative outcomes, for a radical surgery for thoracic esophageal cancer, although its safety needs to be further demonstrated.

Cathepsin K modulates invasion, migration and adhesion of oral squamous cell carcinomas in vitro.

OBJECTIVE: Cathepsin K was initially discovered as an osteoclast-specific cysteine proteinase, but the enzyme is also expressed in various cancers including oral squamous cell carcinomas. This study aimed to clarify the function of cathepsin K in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of cathepsin K were examined in six types of cell carcinomas. Carcinomas overexpressing cathepsin K were constructed. Effects of cathepsin K overexpression and treatment with odanacatib, a specific cathepsin K inhibitor, on cell invasion, migration and adhesion were analysed. RESULTS: Different levels of cathepsin K were expressed in carcinomas. Cathepsin K was predominantly localised in lysosomes. Cathepsin K overexpression impaired the proliferation of carcinomas. Invasion analysis showed that cathepsin K overexpression enhanced invasion and migration of carcinomas, whereas inhibition of cathepsin K by odanacatib caused the opposite effects in carcinomas. Cathepsin K overexpression also increased cell adhesion and slightly increased surface expression of the adhesion receptor CD29/integrin ß1 . CONCLUSIONS: The enhanced invasion of carcinomas resulting from cathepsin K overexpression is probably due to the increased cell migration and adhesion. Thus, cathepsin K is implicated not only in protein degradation but also in invasion, migration and adhesion of oral squamous cell carcinomas.

Evaluation of prognostic value and stage migration effect using positive lymph node ratio in gastric cancer.

AIMS: To detect the best cut-off value of the positive lymph node ratio (PLNR) for stratifying the prognosis and analyzing its value with regard to stage migration effect using PLNR in gastric cancer. METHODS: We retrospectively analyzed 1069 consecutive gastric cancer patients, who underwent curative gastrectomy with radical lymphadenectomy from 1997 through 2009. RESULTS: 1) The mean number of dissected lymph nodes was 42.6 in pStage I, 32.4 in pStage II and 37.1 in pStage III. The PLNR of 0.2 was proved to be the best cut-off value to stratify the prognosis of patients into two groups (P < 0.0001; PLNR <0.2 vs. PLNR ≥0.2), and patients were correctly classified into four groups: PLNR 0, PLNR 0-<0.2, PLNR 0.2-<0.4 and PLNR ≥0.4 by the Kaplan-Meier method. 2) Compared patients with the PLNR <0.2, those with the PLNR ≥0.2 had a significantly higher incidence of pT3 or greater, pN2 or greater, lymphatic invasion, vascular invasion and undifferentiated cancer. Multivariate analysis showed that the PLNR ≥0.2 was an independent prognostic factor [P < 0.0001, HR 2.77 (95% CI: 1.87-4.09)]. 2) The PLNR cut-off value of 0.2 could discriminate a stage migration effect in pN2-N3 and pStage II-III, which patients with PLNR ≥0.2 might be potentially diagnosed as a lower stage after gastrectomy. CONCLUSION: The PLNR contributes to evaluating prognosis and stage migration effect even in a single institute and enable to identify those who need meticulous treatments and follow-up in patients with gastric cancer.