Unsupervised AI reveals insect species-specific genome signatures.

Insects are a highly diverse phylogeny and possess a wide variety of traits, including the presence or absence of wings and metamorphosis. These diverse traits are of great interest for studying genome evolution, and numerous comparative genomic studies have examined a wide phylogenetic range of insects. Here, we analyzed 22 insects belonging to a wide phylogenetic range (Endopterygota, Paraneoptera, Polyneoptera, Palaeoptera, and other insects) by using a batch-learning self-organizing map (BLSOM) for oligonucleotide compositions in their genomic fragments (100-kb or 1-Mb sequences), which is an unsupervised machine learning algorithm that can extract species-specific characteristics of the oligonucleotide compositions (genome signatures). The genome signature is of particular interest in terms of the mechanisms and biological significance that have caused the species-specific difference, and can be used as a powerful search needle to explore the various roles of genome sequences other than protein coding, and can be used to unveil mysteries hidden in the genome sequence. Since BLSOM is an unsupervised clustering method, the clustering of sequences was performed based on the oligonucleotide composition alone, without providing information about the species from which each fragment sequence was derived. Therefore, not only the interspecies separation, but also the intraspecies separation can be achieved. Here, we have revealed the specific genomic regions with oligonucleotide compositions distinct from the usual sequences of each insect genome, e.g., Mb-level structures found for a grasshopper Schistocerca americana. One aim of this study was to compare the genome characteristics of insects with those of vertebrates, especially humans, which are phylogenetically distant from insects. Recently, humans seem to be the "model organism" for which a large amount of information has been accumulated using a variety of cutting-edge and high-throughput technologies. Therefore, it is reasonable to use the abundant information from humans to study insect lineages. The specific regions of Mb length with distinct oligonucleotide compositions have also been previously observed in the human genome. These regions were enriched by transcription factor binding motifs (TFBSs) and hypothesized to be involved in the three-dimensional arrangement of chromosomal DNA in interphase nuclei. The present study characterized the species-specific oligonucleotide compositions (i.e., genome signatures) in insect genomes and identified specific genomic regions with distinct oligonucleotide compositions.

A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity.

Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) (p = 0.0328) and tended to improve overall survival compared to the no-treatment control (p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 (p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway.

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.

BACKGROUND: We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction of systemic antitumor immunity by HS201-PDT alone or by the combination strategy with immune checkpoint blockade has yet to be determined. METHODS: Using unilateral and bilateral implantation models of syngeneic breast tumors (E0771, MM3MG-HER2, and JC-HER3) in mice, we assessed whether HS201-PDT could induce local and systemic antitumor immunity. In an attempt to achieve a stronger abscopal effect for distant tumors, the combination strategy with anti-PD-L1 antibody was tested. Tumor-infiltrating leukocytes were analyzed by single cell RNA-sequencing and receptor-ligand interactome analysis to characterize in more detailed the mechanisms of action of the treatment and key signaling pathways involved. RESULTS: HS201-PDT demonstrated greater tumor control and survival in immune competent mice than in immunocompromised mice, suggesting the role of induced antitumor immunity; however, survival was modest and an abscopal effect on distant implanted tumor was weak. A combination of HS201-PDT with anti-PD-L1 antibody demonstrated the greatest antigen-specific immune response, tumor growth suppression, prolonged mouse survival time and abscopal effect. The most significant increase of intratumoral, activated CD8+T cells and decrease of exhausted CD8+T cells occurred following combination treatment compared with HS201-PDT monotherapy. Receptor-ligand interactome analysis showed marked enhancement of several pathways, such as CXCL, GALECTIN, GITRL, PECAM1 and NOTCH, associated with CD8+T cell activation in the combination group. Notably, the expression of the CXCR3 gene signature was the highest in the combination group, possibly explaining the enhanced tumor infiltration by T cells. CONCLUSIONS: The increased antitumor activity and upregulated CXCR3 gene signature induced by the combination of anti-PD-L1 antibody with HS201-PDT warrants the clinical testing of HS201-PDT combined with PD-1/PD-L1 blockade in patients with breast cancer, and the use of the CXCR3 gene signature as a biomarker.

Laparoscopic Colectomy: A Risk Factor for Postoperative Peritoneal Metastasis.

BACKGROUND: The oncologic outcomes are generally considered equivalent for both laparoscopic and open surgery. However, our previous single-center study found a greater risk of postoperative peritoneal metastasis (PM) after laparoscopic colectomy (LC) than after open colectomy (OC) in patients with pathological T4a (pT4a) colon cancer. This multicenter study aimed to clarify if the risk of PM was increased after LC. METHODS: This study used the multicenter database of the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer, which included patients with colorectal cancer treated between 1997 and 2012 in 24 referral hospitals across Japan. The analysis included 17,323 patients with pathological stage I-III colon cancer, including 2380 patients with pT4a disease. The risk of PM was compared between the LC and OC groups. RESULTS: The cumulative incidence of PM was significantly higher after LC in patients with pT4a colon cancer (13.0% vs. 7.7%; P = .001). Multivariable analyses showed LC was a significant risk factor for PM (hazard ratio [HR]: 1.36, 95% confidence interval [CI]: 1.04-1.78, P = .023), which was confirmed by propensity score analyses (HR: 1.36, 95% CI: 1.04-1.78, P = .024). CONCLUSION: This study demonstrated a significant increase in the risk of PM after LC than after OC.

Identification of diverticular bleeding needs early colonoscopy rather than preparation.

Background and study aims When patients present with acute colonic diverticulum bleeding (CDB), a colonoscopy is performed to identify stigmata of recent hemorrhage (SRH), but valuable time can be lost in bowel preparation. This study retrospectively examined groups of patients who either had a standard pre-colonoscopy regimen or no preparation. Patients and methods This study compared data from 433 patients who either followed a lengthy regimen of bowel preparation (prepared group, 266 patients) or had no preparation (unprepared group, 60 patients). We compared the association between time (hours) between admission before starting a colonoscopy (TMS) and identification of SRH using a chi-square test. Results In 48 of 60 cases (80.0 %) in the unprepared group, a total colonoscopy was performed and the time to identify SRH was decreased. The respective rates of SRH identification in the unprepared and prepared groups were 55.2 % (16/29) vs. 46.7 % (7/15) if the TMS was < 3 hours; 47.1 % (8/7) vs. 36.8 % (35/95) in 3 to 12 hours; 0 % (0/3) vs. 22.0% (13/59) in 12 to 18 hours; and 21.8 % (3/11) vs. 20.6% (42/204) in > 18 hours. There were no significant differences between the two groups. However, the SRH identification rates before and after 12 hours were 42.3 % (66/156) and 20.9 % (58/277) ( P  < 0.001). Conclusions Our data suggest that the bowel preparation method before colonoscopy is an independent variable predicting success in identifying SRH among patients with CDB. Decreasing the time before colonoscopy to no more than 12 hours after admission played an important role in identifying SRH.

Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity.

BACKGROUND: Despite multimodal adjuvant management with radiotherapy, chemotherapy and hormonal therapies, most surgically resected primary breast cancers relapse or metastasize. A potential solution to late and distant recurrence is to augment systemic antitumor immunity, in part by appropriately presenting tumor antigens, but also by modulating the immunosuppressive tumor microenvironment (TME). We previously validated this concept in models of murine carcinoma treated with a novel predominately microcavitating version of high-intensity focused ultrasound (HIFU), mechanical high-intensity focused ultrasound (M-HIFU). Here we elucidated the mechanisms of enhanced antitumor immunity by M-HIFU over conventional thermal high-intensity focused ultrasound (T-HIFU) and investigated the potential of the combinatorial strategy with an immune checkpoint inhibitor, anti-PD-L1 antibody. METHODS: The antitumor efficacy of treatments was investigated in syngeneic murine breast cancer models using triple-negative (E0771) or human ErbB-2 (HER2) expressing (MM3MG-HER2) tumors in C57BL/6 or BALB/c mice, respectively. Induction of systemic antitumor immunity by the treatments was tested using bilateral tumor implantation models. Flow cytometry, immunohistochemistry, and single-cell RNA sequencing were performed to elucidate detailed effects of HIFU treatments or combination treatment on TME, including the activation status of CD8 T cells and polarization of tumor-associated macrophages (TAMs). RESULTS: More potent systemic antitumor immunity and tumor growth suppression were induced by M-HIFU compared with T-HIFU. Molecular characterization of the TME after M-HIFU by single-cell RNA sequencing demonstrated repolarization of TAM to the immunostimulatory M1 subtype compared with TME post-T-HIFU. Concurrent anti-PD-L1 antibody administration or depletion of CD4+ T cells containing a population of regulatory T cells markedly increased T cell-mediated antitumor immunity and tumor growth suppression at distant, untreated tumor sites in M-HIFU treated mice compared with M-HIFU monotherapy. CD8 T and natural killer cells played major roles as effector cells in the combination treatment. CONCLUSIONS: Physical disruption of the TME by M-HIFU repolarizes TAM, enhances T-cell infiltration, and, when combined with anti-PD-L1 antibody, mediates superior systemic antitumor immune responses and distant tumor growth suppression. These findings suggest M-HIFU combined with anti-PD-L1 may be useful in reducing late recurrence or metastasis when applied to primary tumors.

Excellent Deformable Oxide Glass Electrolytes and Oxide-Type All-Solid-State Li2S-Si Batteries Employing These Electrolytes.

Oxide-type all-solid-state lithium-ion batteries have attracted great attention as a candidate for a next-generation battery with high safety performance. However, batteries based on oxide systems exhibit much lower energy densities and rate performances than liquid-type lithium-ion batteries, owing to the difficulty in preparing the ion- and electron-transfer path between particles. In this study, Li2SO4-Li2CO3-LiX (X = Cl, Br, and I) glass systems are investigated as highly deformable and high-ionic-conductive oxide electrolytes. These electrolytes show excellent deformable properties and better ionic conductivity. The LiI oxide glass system is a suitable electrolyte for the negative electrode because it shows a higher ionic conductivity and is stable up to 2.8 V. The LiCl or LiBr oxide glass systems are suitable electrolytes for the positive electrode and separation layer because they show high ionic conductivity and kinetic stability up to 3.2 V. The Li2S positive and Si negative composite electrodes employing LiBr and LiI oxide glass electrolytes, respectively, show high battery performances because of increased reaction points between active materials and the solid electrolyte and carbon via a mechanical milling process and are capable of forming good interparticle contact. Therefore, it suggests that the excellent deformable electrolytes are suitable for solid electrolytes in composite electrodes because their ionic conductivity does not change by the mechanical milling process. Furthermore, an oxide-type all-solid-state Li2S-Si full-battery cell employing these positive and negative composite electrodes and a LiBr oxide glass electrolyte separation layer is demonstrated. The full-battery cell indicates a relatively high discharge capacity of 740 mA h g-1(Li2S) and an area capacity of 2.8 mA h cm-2 at 0.064 mA cm-2 and 45 °C despite using only safe oxide electrolytes.

The Characteristics of 206 Long-Term Survivors with Peritoneal Metastases from Colorectal Cancer Treated with Curative Intent Surgery: A Multi-Center Cohort from PSOGI.

BACKGROUND: We conducted this study to review the patient characteristics associated with long-term survival in patients with peritoneal metastases from colorectal cancer who underwent cytoreductive surgery (CRS). METHODS: We retrospectively investigated patients with peritoneal metastases from CRC treated with curative intent surgery with or without hyperthermic intraperitoneal chemotherapy at 13 institutions worldwide between January 1985 and April 2015 and survived longer than five years after the first CRS for peritoneal metastases. Clinical and oncological features and therapeutic parameters were described and analyzed. RESULTS: Two hundred six long-term survivors were available for study. The median peritoneal cancer index (PCI) of this cohort was 4 (interquartile range (IQR), 2-7), and the median score of the small bowel regions of the PCI (SB-PCI) was 0 (IQR, 0-2). Complete cytoreduction (CC-0) was achieved in 180 (87.4%) patients. Recurrence was observed in 122 (59.2%) patients at a median of 1.8 (IQR, 1.2-2.6) years. CONCLUSIONS: While most long-term survivors showed low PCI/SB-PCI and CCR-0, some had characteristics considered associated with poor prognosis. Curative intent treatments may be considered in well-informed and fit patients showing negative factors affecting survival outcome.

Increasing Effects of Selective 5-Hydroxytryptamine Type 2C Receptor Stimulation on Evoked Momentary Urethral Closure in Female Rats and Humans.

Under healthy conditions, more than one urethra-closing reflex, including both bladder afferent-independent and -dependent actions, function during momentary elevation of intravesical (bladder) pressure to prevent urinary incontinence. In the current study, the effects of a novel selective 5-hydroxytryptamine type 2C (5-HT2C) receptor agonist, TAK-233, on evoked momentary urethra-closing functions were investigated in female rats and humans to elucidate 5-HT2C receptor functions. In anesthetized female rats, TAK-233 dose-dependently and significantly increased urethral resistance during sneezing in rats with distended vaginas and bilaterally transected pelvic nerves. The drug also dose-dependently and significantly increased urethral resistance during momentary intravesical pressure elevation by electrical stimulation of abdominal muscles in rats with a transected spinal cord at the T8-T9 level and intact pelvic nerves. The increased effects observed during electrical stimulation were abolished by either an intravenously administered selective 5-HT2C receptor antagonist, SB 242084, or bilateral transection of the pelvic nerves or somatic nerves innervating the external urethral sphincter and pelvic floor muscles. In the spinal cord-transected and pelvic nerve-intact rats, TAK-233 enlarged the urethra-closing responses induced by both passive and abrupt intravesical pressure elevation, measured by a microtip transducer located in the middle urethra. Additionally, the effects of TAK-233 on the stimulus threshold of urethral contractile responses induced by transcranial magnetic stimulation were investigated in healthy female volunteers. The drug dose-dependently and significantly lowered this stimulus threshold, indicating an increased sensitivity of the response. These results demonstrate that 5-HT2C receptor stimulation enhances the evoked momentary urethra-closing functions in both female rats and humans. SIGNIFICANCE STATEMENT: 5-hydroxytryptamine (serotonin) type 2C (5-HT2C) receptor stimulation by TAK-233 enhanced urethral resistance in rats during an evoked momentary event in which the bladder afferent-independent or -dependent reflex functions via striated muscle-mediated mechanisms. The increases in sensitivity of transcranial magnetic stimulation-evoked urethral contractile responses in healthy female subjects indicates that this mechanism also functions in humans. The evoked momentary conditions activating these reflexes provide a suitable model to demonstrate the effects of 5-HT2C receptor stimulation.

Intratumoral Plasmid IL12 Expands CD8+ T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy.

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T-cell infiltration, and predict responsiveness is critically needed. PATIENTS AND METHODS: Using mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single-arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma datasets. RESULTS: Single-cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T-cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pretreatment and posttreatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T-cell infiltration following treatment. One patient, previously unresponsive to anti-PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti-PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response. CONCLUSIONS: These data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the antitumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of nonresponsive tumors, potentially even beyond TNBC.

Epithelial-mesenchymal transition and metastatic ability of CD133+ colorectal cancer stem-like cells under hypoxia.

Although CD133 is a representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia remains unclear. Therefore, the present study aimed to investigate the associations between CD133, the epithelial-mesenchymal transition and distant metastasis in colorectal cancer. CD133+ and CD133- cells were isolated from a single colorectal cancer cell line LoVo, and their adhesive and migratory properties were compared under hypoxic conditions. Immunostaining analysis was performed to determine CD133 expression in clinical samples of primary tumors, as well as liver and peritoneal metastases. Under hypoxia, the expression levels of hypoxia-inducible factor (HIF)-1α and the epithelial-mesenchymal transition markers N-cadherin and vimentin were significantly higher in the CD133+ compared with those in the CD133- cells. Furthermore, the migratory ability of the CD133+ cells was higher compared with that of the CD133- cells under hypoxia. By contrast, the expression levels of ß1 integrin were significantly lower in the CD133+ cells under hypoxia compared with those in the CD133- cells. Immunohistochemical analysis of clinical samples revealed that the levels of CD133 expression in metastatic tissues from the liver were significantly higher compared with those in the corresponding primary tumors, whereas CD133 expression levels in peritoneal metastatic tissues were significantly lower compared with those in the corresponding primary tumors. In conclusion, compared with the CD133- cells, the CD133+ colorectal cancer cells exhibited enhanced levels of HIF-1α expression and tumor cell migration during hypoxia. This was associated with an increased ability of epithelial-mesenchymal transition, possibly leading to the acquisition of an increased hematogenous metastatic potential and eventually resulting in liver metastasis. High ß1 integrin expression levels in the CD133- cells under hypoxia may serve a key role in cell adhesion to the peritoneum, resulting in peritoneal metastasis.

Efficacy of intraperitoneally administered paclitaxel for colorectal cancer with peritoneal metastases.

PURPOSE: Prognosis after peritoneal metastases in colorectal cancer is worse than that after lung or liver metastases. Previously, we demonstrated the safety of intraperitoneal (ip) administration of paclitaxel (PTX) combined with mFOLFOX6/CapeOX plus bevacizumab for colorectal cancer with peritoneal metastasis in a phase-I trial. Here, we evaluated the efficacy of this chemotherapy. METHODS: We enrolled six patients with histologically confirmed peritoneal metastases secondary to colorectal cancer. PTX was administered through a peritoneal access port, in combination with oxaliplatin-based systematic chemotherapy. Response rate, progression-free survival, 1-year survival rate, frequency of improvement in peritoneal cancer index (PCI), and cytology in peritoneal lavage were evaluated. This study was registered in the University Hospital Medical Information Network Clinical Trial Registry on July 1, 2016 (UNIN000022924). RESULTS: Three patients received the mFOLFOX6-bevacizumab regimen, whereas the other three received the CapeOX-bevacizumab regimen. The response rate was 25%. PCI score improved in 50% of the cases. Peritoneal lavage cytology that was positive in five patients before initiating the chemotherapy turned negative during chemotherapy in all patients. One-year survival rate was 100%, progression-free survival was 8.8 months (range, 6.8-12 months), and median survival time was 29.3 months. CONCLUSION: The ip administration of PTX with systemic chemotherapy can potentially control peritoneal metastases in colorectal cancer.

Laparoscopic surgery for T4 colon cancer: a risk factor for peritoneal recurrences?

BACKGROUND: Although some preclinical studies have inferred that laparoscopic surgery for advanced cancer may increase the risk of peritoneal metastasis, this potential hazard has not been fully evaluated in the clinical setting. This study aimed to clarify whether laparoscopic surgery is associated with an increased risk of postoperative peritoneal recurrence after resection of T4 colon cancer. METHODS: This study included 272 patients who underwent curative resection for pathological T4a colon cancer without distant metastases at the University of Tokyo Hospital between 1997 and 2017. Multivariable Fine-Gray analysis was performed to evaluate whether the use of laparoscopy was an independent risk factor for postoperative peritoneal recurrence. Thereafter, oncological outcomes (overall and relapse-free survival, and organ-specific recurrence) were compared between laparoscopic colectomy and open colectomy using propensity score matching. RESULTS: Multivariable analysis found that laparoscopic surgery was a significant risk factor for postoperative peritoneal recurrence (hazard ratio: 1.89; 95% confidence interval: 1.01-3.65; P = .046). Comparison after propensity score matching revealed that the incidence of peritoneal recurrence was significantly higher after laparoscopic colectomy than after open colectomy (5-year cumulative incidence: 28.1% vs 12.1%; P = .003). CONCLUSION: This study suggested that laparoscopic surgery may be related to an increased risk of peritoneal recurrence in patients with pathological T4a colon cancer. Clinicians should be fully aware of this potential risk and seek an optimal treatment plan for the prevention and early detection of peritoneal metastasis.

Development and Validation of a Prediction Model for Organ-Specific Recurrences After Curative Resection of Colon Cancer.

BACKGROUND: Early detection of postoperative recurrence is beneficial for patients with cancer; however, optimal surveillance remains an issue. To optimize the follow-up plan, the estimation of an individual patient's risk of recurrence is indispensable. OBJECTIVE: This study aimed to establish a statistical model for predicting the risk of organ-specific recurrence after curative resection of colon cancer. DESIGN: This was a retrospective cohort study at a tertiary referral hospital. SETTINGS: This study included 1720 patients with colon cancer treated at the University of Tokyo Hospital between 1997 and 2015. Data were retrospectively retrieved from patient medical charts. The risk score was developed using a competing risk model in a derivation cohort (973 patients treated in 1997-2009) and then validated in a validation cohort (747 patients treated in 2010-2015). PATIENTS: Patients who underwent curative resection for stage I to III colon cancer were included. MAIN OUTCOME MEASURES: The prediction of the incidence of postoperative liver and lung metastasis of colon cancer was measured. RESULTS: The factors selected for the prediction model for liver metastasis included differentiation, T category, venous invasion, N category, and preoperative CEA level. The model for lung metastasis included sex, lymphatic invasion, venous invasion, N category, preoperative CEA level, and malignant bowel obstruction. During external validation, the area under the curve at 60 months was 0.78 (95% CI, 0.71-0.84) for liver metastasis and 0.72 (95% CI, 0.64-0.81) for lung metastasis. LIMITATIONS: The generalizability of the model to different healthcare settings remains to be elucidated. CONCLUSIONS: We developed a prediction model to estimate the risk of recurrence in the liver and lung after curative resection of colon cancer, which demonstrated good discrimination ability in the external validation cohort. Our model can aid clinicians and patients in customizing postoperative surveillance according to an individual patient's risk of organ-specific recurrence. See Video Abstract at http://links.lww.com/DCR/A977. DESARROLLO Y VALIDACIÓN DE UN MODELO DE PREDICCIÓN PARA RECURRENCIAS ESPECÍFICAS DESPUÉS DE RESECCIÓN CURATIVA DE UN CÁNCER DE COLON: La detección temprana de una recidiva postoperatoria es beneficiosa para los pacientes afectados de cáncer. Sin embargo, la mejor vigilancia sigue siendo un problema. Para optimizar el plan de seguimiento, la estimación del riesgo individual de recurrencia de un paciente es indispensable. OBJETIVO: Establecer un modelo estadístico para predecir el riesgo de recurrencia en un organo específico luego de la resección curativa de un cáncer de colon. DISEÑO:: Estudio retrospectivo de cohortes en un hospital de referencia terciaria. AJUSTES: Este estudio incluyó 1720 pacientes con cáncer de colon tratados en el Hospital de la Universidad de Tokio entre 1997 y 2015. Los datos se recuperaron retrospectivamente de las historias clinicas de los pacientes. La puntuación de riesgo fué desarrollada utilizando un modelo de riesgo competitivo en cohortes de derivación (973 pacientes tratados en 1997-2009) y luego se lo validó en cohortes de validación (747 pacientes tratados en 2010-2015). PACIENTES: Todos aquellos casos que se sometieron a una resección curativa de cáncer de colon en estadio I-III RESULTADOS PRINCIPLES:: La predicción de la incidencia de metástasis hepáticas y pulmonares postoperatorias del cáncer de colon. RESULTADOS: Los factores seleccionados para el modelo de predicción de metástasis hepáticas incluyeron diferenciación tumoral, categoría T, invasión venosa, categoría N y nivel de antígeno carcinoembrionario preoperatorio. El modelo de predicción de metástasis pulmonar incluyó el sexo del paciente, la invasión linfática, la invasión venosa, la categoría N, el nivel de antígeno carcinoembrionario preoperatorio y la obstrucción intestinal maligna. Durante la validación externa, el área inferior de la curva a 60 meses fue de 0,78 (intervalo de confianza del 95%: 0,71 a 0,84) para las metástasis hepáticas y de 0,72 (intervalo de confianza del 95%: 0,64 a 0,81) para las metástasis pulmonares. LIMITACIONES: La generalización del presente modelo a diferentes entornos de atención en salud aún no ha podido ser dilucidado. CONCLUSIONES: Desarrollamos un modelo de predicción para estimar el riesgo de recurrencia en el hígado y el pulmón después de resección curativa de cáncer de colon, éste modelo demostró una buena capacidad de discriminación en las cohortes de validación externa. El modelo puede ayudar a médicos y pacientes a personalizar la vigilancia postoperatoria de acuerdo con el riesgo individual de recurrencia específica en un órgano específico. Vea el Resumen del Video en http://links.lww.com/DCR/A977.

Effects of Burdock tea on recurrence of colonic diverticulitis and diverticular bleeding: An open-labelled randomized clinical trial.

Colonic diverticular bleeding (CDB) and acute colonic diverticulitis (ACD) show high recurrence rates. The establishment of optimal strategies that prevent the recurrence of CDB and ACD is a major concern among gastroenterologists. This study aimed to assess the efficacy of burdock tea for preventing CDB and ACD recurrences. Newly diagnosed patients with CDB (n = 91) or ACD (n = 70) were randomly assigned into two groups. The experimental group received 1.5 g of burdock tea three times a day, whereas the control group did not receive any treatment. The median (interquartile range) of observation for recurrence of CDB or ACD was 22.0 (14.1) months and 30.3 (18.6), respectively. The burdock tea treatment showed significant preventive effects on recurrence of ACD. A lower ACD recurrence rate (5/47 [10.6%] vs. 14/44 [31.8%]) and longer recurrence-free duration was observed in the burdock tea group (59.3 months [95% CI: 54.0-64.7] vs. 45.1 months [95% CI: 37.1-53.0] by the Kaplan-Meier analysis; p = 0.012 by log rank test) than in the control group, although there was no significant preventive effects on the CDB recurrence. This randomized clinical trial demonstrated that daily intake of burdock tea could be an effective strategy for prevention of ACD recurrence, but not for CDB recurrence.

LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer.

BACKGROUND: The aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer. METHODS: Expression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015. RESULTS: Peritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008). CONCLUSIONS: Negative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.

Prognostic significance of doubling time in patients undergoing radical surgery for metachronous peritoneal metastases of colorectal cancer.

PURPOSE: The doubling times of tumor volume and tumor markers are associated with the prognosis of liver or lung metastases from colorectal cancer (CRC). However, no studies have assessed peritoneal metastases. Therefore, we aimed to elucidate the association between doubling time and the prognosis of patients who underwent radical surgery for metachronous peritoneal metastases of CRC. METHODS: We calculated the tumor doubling times (TDT) of peritoneal metastases and serum carcinoembryonic antigen-doubling times (CEA-DT) in 33 consecutive patients who underwent radical surgery for metachronous peritoneal metastases between January 2006 and April 2017. The impact of short TDT and CEA-DT on overall survival (OS) and relapse-free survival (RFS) was retrospectively reviewed. RESULTS: In long TDT (> 137 days) group, the 5-year OS rate was 74.1% and median OS time was 6.6 years. In long CEA-DT (> 102 days) group, the 5-year OS rate was 50.0% and median OS time was 5.6 years. Conversely, in short TDT (≤ 137 days) and CEA-DT (≤ 102 days) group, the 5-year OS rates and median OS times were both 0.0% and 3.2 years, respectively. In the multivariate analysis, short TDT was an independent risk factor for poor RFS (P = 0.006) and OS (P = 0.010). Similarly, short CEA-DT was also a poor risk factor for RFS (P < 0.001) and OS (P = 0.012). CONCLUSIONS: Short TDT and CEA-DT are independent risk factors for poor OS and RFS after surgery for metachronous peritoneal metastases of CRC. TDT and CEA-DT should be considered when selecting candidates for surgical resection.

Safety of intraperitoneal paclitaxel combined with conventional chemotherapy for colorectal cancer with peritoneal carcinomatosis: a phase I trial.

PURPOSE: Peritoneal carcinomatosis of colorectal cancer origin is associated with poor prognosis. With regard to ovarian, gastric, and pancreatic cancer, the safety and efficacy of intraperitoneal administration of paclitaxel (ip PTX) has been demonstrated. This drug can be administered easily and repeatedly through a catheter into the peritoneal cavity. In this phase I study, we evaluated the safety of ip PTX combined with 5-fluorouracil, folinic acid, oxaliplatin, and bevacizumab (mFOLFOX6-bevacizumab) or capecitabine, oxaliplatin, and bevacizumab (CapeOX-bevacizumab) for colorectal cancer with peritoneal metastasis. METHODS: Colorectal cancer patients with histologically confirmed peritoneal carcinomatosis were enrolled. After the implantation of a peritoneal access port, 20 mg/m2 of ip PTX was administered weekly, in combination with mFOLFOX6-bevacizumab or CapeOX-bevacizumab. Primary endpoint was the safety of the combination chemotherapy. RESULTS: Among the six patients enrolled, three received the mFOLFOX6-bevacizumab plus ip PTX regimen and three received the CapeOX-bevacizumab plus ip PTX regimen. Dose-limiting toxicity was not observed. Overall, grade 3 adverse events, such as leukopenia and neutropenia, were observed in two of three patients (66.7%) for each chemotherapeutic regimen, but no grade 4 adverse events were observed. Moreover, adverse events associated with the peritoneal access port, such as infection or occlusion of the catheter, were not observed. CONCLUSIONS: The adverse events of mFOLFOX6-bevacizumab or CapeOX-bevacizumab in combination with ip PTX were considered similar to those described in previous studies of oxaliplatin-based treatment alone. 1 year after the start of chemotherapy, the efficacy of ip PTX will be evaluated as a secondary outcome.

High-Pressure Synthesis, Crystal Chemistry, and Ionic Conductivity of a Structural Polymorph of Li3BP2O8.

A new structural polymorph of Li3BP2O8 has been successfully synthesized via a solid-state reaction between Li3PO4 and BPO4 at 4 GPa and 600 °C. The high-pressure phase of Li3BP2O8 (HP-Li3BP2O8) was found to crystallize in monoclinic symmetry with the cell parameters of a = 8.57010(4) Å, b = 11.11812(5) Å, c = 5.55380(3) Å, and ß = 97.7269(3)° [space group P21/ a (No. 14)]. HP-Li3BP2O8 has a new crystal structure that has not been reported so far. The total ionic conductivities measured for the polycrystalline sample by alternating-currrent impedance were 3.4 × 10-7 and 2.1 × 10-6 S/cm at 399 and 456 K, respectively. The lithium ionic conductivity of HP-Li3BP2O8 was higher than that of the low-pressure phase Li3BP2O8 in the temperature range of 375-456 K. This is caused by the difference in the dimensions of the lithium arrangements between LP- and HP-Li3BP2O8.

Lithium-ion conducting oxide single crystal as solid electrolyte for advanced lithium battery application.

Today, all-solid-state secondary lithium-ion batteries have attracted attention in research and development all over the world as a next-generation energy storage device. A key material for the all-solid-state lithium batteries is inorganic solid electrolyte, including oxide and sulfide materials. Among the oxide electrolytes, garnet-type oxide exhibits the highest lithium-ion conductivity and a wide electrochemical potential window. However, they have major problems for practical realization. One of the major problems is an internal short-circuit in charging and discharging. In the polycrystalline garnet-type oxide electrolyte, dendrites of lithium metal easily grow through the void or impurity in grain boundaries of the sintered body, which causes serious internal short-circuits in the battery system. To solve these problems, we present an all-solid-state battery system using a single-crystal oxide electrolyte. We are the first to successfully grow centimeter-sized single crystals of garnet-type by the floating zone method. The single-crystal solid electrolyte exhibits an extremely high lithium-ion conductivity of 10-3 S cm-1 at 298 K. The garnet-type single-crystal electrolyte has an advantageous bulk nature to realize the bulk conductivity without grain boundaries such as in a sintered polycrystalline body, and will be a game-changing technology for achieving highly safe advanced battery systems.