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The aim of this study was to verify the prognostic impact of the tumor exposure at the liver transection margin (LTM) in left-sided perihilar cholangiocarcinoma and the impact of middle hepatic vein (MHV) resection on this exposure.In perihilar cholangiocarcinoma, tumors are unexpectedly exposed at the LTM during left hemihepatectomy (LH).Patients who underwent LH for perihilar cholangiocarcinoma during 2002 to 2018 were retrospectively evaluated. LH was classified into conventional and extended types, which preserved and resected the MHVs, respectively. Positive LTM was defined as the involvement of invasive carcinoma at the liver transection plane and/or the adjacent Glissonean pedicle exposed. The clinicopathologic features and survival outcomes were compared between procedures.Among 236 patients, conventional and extended LHs were performed in 198 and 38 patients, respectively. The LTM was positive in 31 (13%) patients, with an incidence of 14% versus 8% (P = 0.432) and 24% versus 0% in advanced tumors (P = 0.011). Tumor size ≥18 mm (P = 0.041), portal vein invasion (P = 0.009), and conventional LH (P = 0.028) independently predicted positive LTM. In patients with negative LTM, the survival was comparable between the two groups: 60.4% versus 59.2% at 3 years (P = 0.206), which surpassed 17.7% for those with positive LTM in the conventional group (P0.001). Multivariable analysis demonstrated that LTM status was an independent prognostic factor (P = 0.009) along with ductal margin status (P = 0.030).The LTM status is an important prognostic factor in perihilar cholangiocarcinoma. Extended LH reduced the risk of tumor exposure at the LTM with a subsequent improvement in the survival, particularly in advanced tumors.

Infection directly influences adult hematopoietic stem cell (HSC) function and differentiation, but much less is known about the fetal hematopoietic response to infection during pregnancy. Here, we investigated the fetal hematopoietic response to maternal infection withToxoplasma gondii(T. gondii), an intracellular parasite that elicits Type II IFNγ-mediated maternal immunity. The effects of maternal IFNγ on developing HSCs and the signals that mediate these interactions have not been investigated. Our investigation reveals that the fetal HSCs respond toT. gondiiinfection with virulence-dependent changes in proliferation, self-renewal potential, and lineage output. We demonstrate that maternal IFNγ crosses the fetal-maternal interface and is perceived by fetal HSCs. By comparing the effects of maternal IFNγ injection with maternalT. gondiiinfection, our observations reveal that IFNγ mimics aspects of the fetal HSC response to infection. Moreover, our data disentangle the role of infection-induced inflammatory cytokines in driving the expansion of downstream hematopoietic progenitors. Our findings illuminate that the fetal HSC response to prenatal infection is distinct from the adult HSC response to IFNγ-induced inflammation.

Background The relationship between carotid artery ultrasound findings and clinical outcomes in percutaneous coronary intervention (PCI) patients has not been fully elucidated. Purpose To investigate the relationship between carotid artery ultrasound findings and cardiovascular risks in PCI patients. Methods This was a single-center retrospective study investigating 691 patients who underwent PCI and carotid ultrasound testing. Maximum carotid intima-media thickness (CIMT) was defined as the greatest CIMT at the maximally thick point among the common carotid artery, carotid bulb, and internal carotid artery. A carotid plaque was defined as vessel wall thickening with a CIMT ≥1.5 mm. The characteristics of carotid plaque (heterogeneity, calcification, or irregular/ulcerated surface) were evaluated visually. Patients were divided into those with and without heterogeneous carotid plaque (maximum CIMT ≥1.5 mm and heterogeneous texture). The endpoint was the incidence of a major adverse cardiovascular event (MACE) defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. Results Among 691 patients, 312 were categorized as having a heterogeneous plaque. Patients with heterogeneous plaques were at a higher risk of MACE than those without (p=0.002). A heterogeneous plaque was independently associated with MACE after adjusting for covariates (hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.06–3.04; p=0.03). Calcified or irregular/ulcerated plaques were correlated with a higher incidence of MACE but both were not independently associated with MACE (HR, 1.37; 95% CI, 0.70–2.67, p=0.36 and HR, 1.13; 95% CI, 0.66–1.93; p=0.66, respectively). Conclusions The presence of a heterogeneous carotid plaque in patients who underwent PCI predicted future cardiovascular events. These patients may require more aggressive medical therapy and careful follow-up. Funding Acknowledgement Type of funding sources: None.

Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing (1) the development and function of fetal-derived immune cells that regulate tissue development and homeostasis, and (2) the establishment and function of developing hematopoietic stem cells (HSCs) that continually generate immune cells across the lifespan. To disentangle the complexities of these interlinked systems, we propose the cochlea as an ideal model tissue to investigate how perinatal infection affects immune, tissue, and stem cell development. The cochlea contains complex tissue architecture and a rich immune milieu that is established during early life. A wide range of congenital infections cause cochlea dysfunction and sensorineural hearing loss (SNHL), likely attributable to early life inflammation. Furthermore, we show that both immune cells and bone marrow hematopoietic progenitors can be simultaneously analyzed within neonatal cochlear samples. Future work investigating the pathogenesis of SNHL in the context of congenital infection will therefore provide critical information on how perinatal inflammation drives disease susceptibility in offspring.

Background Hepatectomy with vascular resection (VR) for perihilar cholangiocarcinoma (PHCC) is a challenging procedure. However, only a few reports on this procedure have been published and its clinical significance has not been fully evaluated. Methods Patients undergoing surgical resection for PHCC from 2002–2017 were studied. The surgical outcomes of VR and non-VR groups were compared. Results Some 238 patients were included. VR was performed in 85 patients. The resected vessels were hepatic artery alone (31 patients), portal vein alone (37 patients) or both (17 patients). The morbidity rates were almost the same in the VR (49.4 per cent) and non-VR (43.8 per cent) groups (P = 0.404). The mortality rates of VR (3.5 per cent) and non-VR (3.3 per cent) were also comparable (P > 0.999). The median survival time (MST) was 45 months in the non-VR group and 36 months in VR group (P = 0.124). Among patients in whom tumour involvement was suspected on preoperative imaging and whose carbohydrate antigen 19-9 (CA19-9) value was 37 U/ml or less, MST in the VR group was significantly longer than that in the non-VR group (50 versus 34 months, P = 0.017). In contrast, when the CA19-9 value was greater than 37 U/ml, MST of the VR and non-VR groups was comparable (28 versus 29 months, P = 0.520). Conclusion Hepatectomy with VR for PHCC can be performed in a highly specialized hepatobiliary centre with equivalent short- and long-term outcomes to hepatectomy without VR., Major hepatectomy with vascular (hepatic artery and/or portal vein) resection and reconstruction was performed in 85 consecutive patients with advanced perihilar cholangiocarcinoma. This surgery is technically demanding but can be performed with equivalent short- and long-term outcomes in a highly specialized hepatobiliary centre.

To investigate how clinical, demographic and treatment-related factors in non-small cell lung cancer (NSCLC) patients impact the risk of mortality in the 30 days following receipt of systemic anti-cancer therapies (SACT), and undertake a comprehensive review of the treatment decisions and experiences of a real-world population.We reviewed NSCLC patients receiving SACT from 2005 to 2014, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data. The 30-day post-SACT mortality rate was calculated, and regimen changes in the last 14 days of life were identified. Univariate analysis and multivariate logistic regression were used to identify demographic, tumor and treatment-related factors that correlated with mortality risk.1044 patients receiving ≥ 1 cycle of SACT in 2005-2014 were identified. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt; 32 (13.7%) of which had new SACT regimens ≤ 14 days prior to death. Risk of 30-day mortality and regimen changes at the end of life increased in association with being male [OR: 1.48 (1.12-1.95), p = 0.005], advanced disease at diagnosis [OR: 1.85 (1.19-2.88), p = 0.006], palliative-intent treatment [OR: 6.75 (3.88-11.77), p 0.001], and use of EGFR-targeting agents [OR: 4.5 (3.27-6.18) p 0.001]. Risk of early mortality decreased for never-smokers [OR: 0.62 (0.41-0.95), p = 0.028], and those receiving SACT in more recent years (2010-2014) [OR: 0.65 (0.49-0.86), p = 0.002].Our findings identified several factors that affected the risk of early mortality in NSCLC patients following SACT. These results from a representative population provide insights regarding the benefits and risks of SACT and can serve to inform clinical and palliative best practices.

Background Little is known about the effect of additional resection for a frozen-section-positive distal bile duct margin (DM) in perihilar cholangiocarcinoma. Methods Patients who underwent surgical resection for perihilar cholangiocarcinoma between 2001 and 2015 were analysed retrospectively, focusing on the DM. Results Of 558 consecutive patients who underwent frozen-section examination for a DM, 74 (13·3 per cent) had a frozen-section-positive DM with invasive cancer or carcinoma in situ. Eventually, 53 patients underwent additional resection (bile duct resection in 44 and pancreatoduodenectomy in 9), whereas the remaining 21 patients did not. Ultimately, R0 resection was achieved in 30 of the 53 patients (57 per cent). No patient who underwent additional resection died from surgical complications. The 44 patients with additional bile duct resection had a 5-year overall survival rate of 31 per cent. Overall survival of the nine patients who had pancreatoduodenectomy was better, with a 10-year rate of 67 per cent. Survival of the 21 patients without additional resection was dismal: all died within 5 years. Multivariable analyses identified nodal status and additional resection as independent prognostic factors (lymph node metastasis: hazard ratio (HR) 2·26, 95 per cent c.i. 1·26 to 4·07; bile duct resection versus no additional resection: HR 0·32, 0·17 to 0·60; pancreatoduodenectomy versus no additional resection: HR 0·08, 0·02 to 0·29). Conclusion Additional resection for frozen-section-positive DM in perihilar cholangiocarcinoma frequently yields R0 margins. It offers a better chance of long-term survival, and thus should be performed in carefully selected patients.

To compare the clinical characteristics and outcomes between relapsed and de novo metastatic non-small cell lung cancer (NSCLC).We reviewed all NSCLC diagnoses between January 1999 and December 2013 in the institutional Glans-Look Lung Cancer Database, which contains demographic, clinical, pathologic, treatment, and outcome information. Patients with distant metastasis at diagnosis (American Joint Committee on Cancer [AJCC] eighth edition, stage IV), the "de novo" cohort, were compared with the "relapsed" cohort, consisting of patients diagnosed with early stage disease (stage I/II) undergoing curative intent treatment and subsequently experiencing metastatic relapse. Survival analysis, along with univariate and multivariable analysis was performed.A total of 185 relapsed and 3039 de novo patients were identified. Significantly different patterns of smoking history, histology, systemic therapy use, and disease extent were observed between the relapsed and de novo cohorts. Median overall survival from time of metastasis was significantly longer in relapsed than in de novo disease (8.9 vs. 3.7 mo, P0.001). Relapsed patients demonstrated significant improvements in outcomes over time. In multivariate analysis, de novo metastatic disease continued to bode a worse prognosis (adjusted hazard ratio [HR], 1.4) as did male sex (HR, 1.2), never-smoking history (HR, 1.2), and presence of extrapulmonary metastases (HR, 1.3). Systemic therapy receipt conferred better outcome (HR, 0.4), although the impact of relapsed versus de novo disease on outcomes persisted regardless of systemic therapy receipt.Relapsed and de novo patients represent significantly different subpopulations within metastatic NSCLC with the latter exhibiting poorer survival. This information facilitates discussions about prognosis with patients and supports screening initiatives aimed at reducing de novo disease.

Convective precipitation systems in the summer often cause sudden heavy precipitation and largely affect various human activities, but the rapid evolution limits our predicting capability. Phased-array weather radars (PAWRs) with a high spatiotemporal resolution are useful for observing such precipitation system. A recently developed numerical weather prediction (NWP) system assimilates PAWR observations with a 500-m mesh NWP model. It initiates 30-min extended forecasts every 30 s, much more frequently than the operational NWP and nowcasting systems. This study investigates the benefits of the 30-s-updating NWP system in a single but representative convective precipitation event in which a convective cloud developed within 10 min, and its evolution was not well predicted by operational precipitation nowcasting. The rapidly updating NWP system successfully predicts the evolution of the convective cloud. Assimilating the PAWR observations every 30 s continuously modifies the moisture and dynamical fields and improves the forecast accuracy consistently.

The KamLAND-Zen 800 experiment is searching for the neutrinoless double-beta decay of $^{136}$Xe by using $^{136}$Xe-loaded liquid scintillator. The liquid scintillator is enclosed inside a balloon made of thin, transparent, low-radioactivity film that we call Inner Balloon (IB). The IB, apart from guaranteeing the liquid containment, also allows to minimize the background from cosmogenic muon-spallation products and $^{8}$B solar neutrinos. Indeed these events could contribute to the total counts in the region of interest around the Q-value of the double-beta decay of $^{136}$Xe. In this paper, we present an overview of the IB and describe the various steps of its commissioning minimizing the radioactive contaminations, from the material selection, to the fabrication of the balloon and its installation inside the KamLAND detector. Finally, we show the impact of the IB on the KamLAND background as measured by the KamLAND detector itself., 23 pages, 16 figures, to be submitted to JINST

Background Hepatectomy with extrahepatic bile duct resection is associated with a high risk of posthepatectomy liver failure (PHLF). However, the utility of the remnant liver volume (RLV) in cholangiocarcinoma has not been studied intensively. Methods Patients who underwent major hepatectomy with extrahepatic bile duct resection between 2002 and 2018 were reviewed. The RLV was divided by body surface area (BSA) to normalize individual physical differences. Risk factors for clinically relevant PHLF were evaluated with special reference to the RLV/BSA. Results A total of 289 patients were included. The optimal cut-off value for RLV/BSA was determined to be 300 ml/m2. Thirty-two patients (11.1 per cent) developed PHLF. PHLF was more frequent in patients with an RLV/BSA below 300 ml/m2 than in those with a value of 300 ml/m2 or greater: 19 of 87 (22 per cent) versus 13 of 202 (6.4 per cent) (P, The present study showed the importance of considering the remnant liver volume (RLV) / body surface area (BSA) in addition to indocyanine green test for hepatectomy with extrahepatic bile duct resection. An RLV/BSA of 300 mL/m2 is a simple and useful cut-off value to predict posthepatectomy liver failure in patients who undergo major hepatectomy for cholangiocarcinoma. Remnant liver volume normalized using body surface area is a potential tool for predicting postoperative liver failure.

AIM We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8–5.4, p p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3–7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

Despite advances in our understanding of the molecular mechanisms underlying the aggressiveness of triple-negative breast cancer (TNBC), the contribution of tumor-associated macrophages (TAMs) to TNBC pathogenesis has not been therapeutically exploited. TAMs are the most abundant cell types in the tumor microenvironment (TME) and the key contributor to tumor progression and invasion. We have found that c-Jun NH2-terminal kinase (JNK), a member of the MAPK family and a major regulator of inflammation, contributes to TNBC tumorigenesis by promoting the cancer stem-like cell phenotype. However, whether the JNK pathway regulates TAMs and their cross-talk with tumor cells in TNBC remains unknown. Here, we tested the hypothesis that JNK signaling contributes to TNBC aggressiveness by promoting the tumor cell–TAM cross-talk that facilitates TNBC cell invasiveness. We found that, among 80 patients with primary inflammatory breast cancer (IBC), TNBC tumors (n=18) had 2-fold more TAMs than non-TNBC tumors (n=62, P=0.05) and that high TAM counts were correlated with shorter disease-free survival of patients with IBC (P=0.05). Both JNK1 and c-Jun were highly activated in TAMs, and JNK-IN-8, a pan-inhibitor of JNK, suppressed c-Jun activation. JNK-IN-8 also increased expression of M1 macrophage markers (CD80 and HLA-DR) but reduced expression of TAM markers (CD163 and CD206), suggesting that JNK suppresses M1 macrophage differentiation but promotes TAM differentiation. Co-culture with TAMs significantly enhanced migration and invasion of HCC70 and MDA-MB-468 human and 4T1 murine TNBC cells. Similarly, an enhancement in TNBC cells migration and invasion was observed following culture with TAM-conditioned medium, suggesting that TAMs enhance TNBC cellular activities through paracrine signaling. In addition, inhibition of JNK signaling in TNBC cells or in TAMs by JNK-IN-8 significantly suppressed TAM-promoted enhancement of TNBC cell migration and invasion. These studies strongly suggest that JNK regulates M1/TAM differentiation and TNBC cell–TAM cross-talk. Furthermore, cytokine/chemokine profiling analysis showed that, of the identified molecules, MCP-1 (secreted by TAMs) and VEGF (secreted by TNBC cells) had the highest expression levels and that their expression was dramatically reduced following JNK-IN-8 treatment. Stimulation with recombinant VEGF increased proliferation of MDA-MB-468 cells, and stimulation with recombinant MCP-1 enhanced migration of the cells. These findings suggest that VEGF and MCP-1 are involved in JNK-mediated TNBC cell–TAM cross-talk. Together, our results suggest that JNK signaling regulates tumor cell–TAM cross-talk through MCP-1– and/or VEGF-mediated paracrine signaling and that JNK is an important therapeutic target in TNBC. Further animal studies using JNK-knockout TNBC cells co-injected with TAMs are needed to confirm our in vitro findings. Citation Format: Xie X, Otsuka S, Chu K, Lu AY, Tripathy D, Dalby KN, Hittelman WN, Van Laere S, Bartholomeusz C, Ueno NT. JNK signaling regulates tumor cell–tumor-associated macrophage cross-talk in triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-05-03.

// Aleksi Suo 1 , Allison Childers 2 , Adrijana D’Silva 1 , Lars F. Petersen 2 , Shannon Otsuka 1 , Michelle Dean 2, 3 , Haocheng Li 1, 4 , Emeka K. Enwere 2, 3 , Brant Pohorelic 3 , Alexander Klimowicz 3 , Ivana A. Souza 5 , Jawed Hamid 5 , Gerald W. Zamponi 5 and DGwyn Bebb 1, 2 1 Department of Oncology, Tom Baker Cancer Centre, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada 2 Translational Laboratories, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada 3 Functional Tissue Imaging Unit, Translational Laboratory, Tom Baker Cancer Centre, Calgary, AB, Canada 4 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada 5 Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Correspondence to: Aleksi Suo, email: aleksi.suo@albertahealthservices.ca Keywords: T-type VGCC; Cav3.1; NSCLC Received: April 04, 2017 Accepted: December 05, 2017 Published: January 12, 2018 ABSTRACT Introduction : Voltage-gated calcium channels (VGCC) have been found to be differentially expressed in several different tumor types, but their role in tumor growth, malignant invasion, metastases and impact on clinical outcomes has not been clarified. Materials and Methods : From a cohort database of 193 patients with early-stage NSCLC, 163 formalin-fixed paraffin-embedded specimens were available for analysis to construct tissue microarrays. Cav3.1 protein expression was detected using fluorescence immunohistochemistry, and quantified using automated image acquisition and analysis. Results : Among the cohort of 193 NSCLC patients, adenocarcinoma (53.9%) and squamous cell carcinoma (SCC) (30.1%) were the most common histologies. There was no difference between SCC and non-SCC subtypes in overall survival (OS) or relapse-free survival (RFS); 74.2 vs 90.1 months ( p = 0.543) and 48.8 vs 52.6 months ( p = 0.766), respectively. T-type VGCC 3.1 (Cav3.1) overexpression was assessed by tissue microarray immunohistochemistry analysis from 163 available patient samples. Eighteen (11.0%) NSCLC primaries were found to have Cav3.1 overexpression levels, and were significantly associated with SCC histology ( p < 0.001), larger tumor size ( p < 0.001) and later stage disease at diagnosis ( p = 0.019). Median OS was 48.6 vs 106.7 months for Cav3.1 overexpressing and non-overexpressing patients, respectively ( p = 0.032). Regression analysis revealed a significantly negative effect for Cav3.1 overexpression on RFS (Hazard ratio [HR] = 2.02, p = 0.048). Conclusions : Cav3.1 overexpression is a potential biomarker for poorer patient outcomes. These results bring supportive evidence for calcium channels inducing an aggressive phenotype in NSCLC and potentially may serve as a therapeutic target in overexpressing tumors.

Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p < 0.01). This effect was pronounced in stage II/III patients, even after adjusting for other clinical co-variates (p < 0.001). Additionally, we provide evidence that ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients.

We present a precision analysis of the ^{136}Xe two-neutrino ββ electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ββ rate allows us to measure the ratio of the leading and subleading 2νββ nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ββ decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ββ NMEs.

Differentiation between perihilar cholangiocarcinoma (PHCC) and benign strictures is frequently difficult. The aim of this study was to investigate the incidence and long-term outcome of patients with tumours resected because of suspicion of PHCC, which ultimately turned out to be benign (malignancy masquerade).Patients who underwent surgical resection with a diagnosis of PHCC between 2001 and 2016 were reviewed retrospectively.Among 707 consecutive patients, 685 had PHCC and the remaining 22 (3·1 per cent) had benign biliary stricture. All patients with benign disease underwent major hepatectomy, with no deaths. Preoperative histological assessment using bile duct biopsy or aspiration cytology had a high specificity (90 per cent), low sensitivity (62 per cent) and unsatisfactory accuracy (63 per cent). Despite the increasing use of histological assessment, the incidence of benign strictures resected did not decrease over time, being 0·9 per cent in 2001-2004, 4·0 per cent in 2005-2008, 3·8 per cent in 2009-2012 and 2·9 per cent in 2013-2016. The final pathology of benign strictures included IgG4-related sclerosing cholangitis (9 patients), hepatolithiasis (4), granulomatous cholangitis (3), non-specific chronic cholangitis (3), benign strictures after cholecystectomy (2), and a benign stricture possibly caused by parasitic infection (1). The 10-year overall survival rate for the 22 patients with benign stricture was 87 per cent, without recurrence of biliary stricture.The incidence of benign strictures resected as PHCC as a proportion of all resections was relatively low, at 3·1 per cent. Currently, unnecessary surgery for suspected PHCC is unavoidable.La diferenciación entre colangiocarcinoma perihilar (perihilar colangiocarcinoma, PHCC) y estenosis benignas es con frecuencia difícil. El objetivo de este estudio fue investigar la incidencia y el resultado a largo plazo de los tumores resecados con sospecha diagnóstica de PHCC, que finalmente resultaron ser benignos (malignidad enmascarada). MÉTODOS: Se revisaron retrospectivamente los pacientes con diagnóstico de PHCC que se sometieron a resección quirúrgica entre 2001 y 2016.Entre 707 pacientes consecutivos, 685 pacientes presentaban PHCC y los 22 restantes (3,1%) tenían una estenosis biliar benigna. Todos los pacientes con patología benigna se sometieron a una hepatectomía mayor, sin mortalidad. La evaluación histológica preoperatoria mediante biopsia de conducto biliar o citología por aspiración tuvo una alta especificidad (90%), una baja sensibilidad (62%) y una exactitud diagnóstica insatisfactoria (63%). A pesar del uso creciente de la evaluación histológica, la incidencia de estenosis benignas resecadas no disminuyó con el tiempo, con un 0,9% en 2001-2004, un 4,0% en 2005-2008, un 3,8% en 2009-2012 y un 2,9% en 2013-2016. La patología final de las estenosis benignas incluyó colangitis esclerosante relacionada con IgG4 (n = 9), hepatolitiasis (n = 4), colangitis granulomatosa (n = 3), colangitis crónica no específica (n = 3), estenosis benignas tras una colecistectomía (n = 2) y una estenosis benigna posiblemente causada por una infección parasitaria (n = 1). Los resultados a largo plazo de los 22 pacientes con estenosis benigna fueron mejores (tasa de supervivencia a 10 años; 87,4%) sin recidiva de la estenosis biliar. CONCLUSIÓN: La incidencia de pacientes con estenosis benignas resecadas como PHCC en comparación con todas las resecciones fue relativamente baja, del 3,1%. Actualmente, la cirugía "innecesaria" por sospecha de PHCC es inevitable.

Introduction Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. Methods Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003–2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). Results 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. Conclusions CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.

To treat local recurrence of brain metastases after gamma knife radiosurgery (GKS), we have used fractionated stereotactic radiotherapy (SRT). The purpose of this study was to evaluate the efficacy and toxicity of SRT in these patients.Fifty locally recurrent metastatic brain tumors in 47 patients were treated with SRT. The median prescribed dose of GKS was 20 Gy at the periphery. The median interval between the GKS (the last session in cases in which multiple GKS procedures were performed) and recurrence was 7.5 (range 1-33) months. Several dose-fractionation protocols were used for SRT, depending on the size and location of the tumor and previous GKS dose. The median prescribed dose of the SRT at the isocenter was 30 Gy with a median of ten fractions.Among the 50 lesions treated with SRT, 26 did not recur locally before the patient's death or the last follow-up examination, and 24 recurred locally. The median follow-up period for the surviving patients was 24 months after the first GKS procedure, and the overall survival rate was 80% at 1 year and 57% at 2 years. The median time to local re-recurrence after the SRT (16 months) was significantly longer than the median interval between the last GKS and recurrence (7.5 months; P 0.001). Only two patients developed ≥grade 2 radiation necrosis.Stereotactic radiotherapy appeared to be an effective treatment for recurrent metastatic brain tumors and yielded relatively good local control. The associated adverse events were generally acceptable.

To assess the impact of location versus number of extra-pulmonary metastatic sites (EPMS) on survival in stage IV non-small cell lung cancer (NSCLC). Retrospective analysis was conducted on patients diagnosed during 1999–2013 with stage IV, M1b (AJCC 7th edition) NSCLC using the large, institutional Glans-Look Database, which contains patient demographic, clinical, pathological, treatment, and outcome information. We assessed the impact of location and number of EPMS and identified correlates of overall survival using the Kaplan–Meier method and Cox regression. We identified a total of 2065 NSCLC patients with EPMS. Median age was 67 (IQR 58–75) years, 52% were men, and 78% were current or former smokers. 60% had one EPMS, and 40% had two or more EPMS. Among those with only one EPMS, most frequent organ involvement included bone (40%), brain (32%), and liver (13%). Median overall survival (mOS) was worst in those with liver metastasis and best in those with adrenal metastasis (2.0 vs. 5.2 months, p = 0.015). However, outcomes based on site of organ involvement were not significantly different in multivariable analysis. Compared to patients with one EPMS, individuals with two or more EPMS experienced worse outcomes (mOS ≤ 2.9 vs. 3.9 months, p

The aim of this study was to examine the applicability of the linear-quadratic (LQ) model to single and fractionated irradiation in EMT6 cells. First, the α/β ratio of the cells was determined from single-dose experiments, and a biologically effective dose (BED) for 20 Gy in 10 fractions (fr) was calculated. Fractional doses yielding the same BED were calculated for 1-, 2-, 3-, 4-, 5-, 7-, 15- and 20-fraction irradiation using LQ formalism, and then irradiation with these schedules was actually given. Cell survival was determined by a standard colony assay. Differences in cell survival between pairs of groups were compared by t-test. The α/β ratio of the cells was 3.18 Gy, and 20 Gy in 10 fr corresponded to a BED3.18 of 32.6 Gy. The effects of 7-, 15- and 20-fraction irradiation with a BED3.18 of 32.6 Gy were similar to those of the 10-fraction irradiation, while the effects of 1- to 5-fraction irradiation were lower. In this cell line, the LQ model was considered applicable to 7- to 20-fraction irradiation or doses per fraction of 2.57 Gy or smaller. The LQ model might be applicable in the dose range below the α/β ratio.

Since the dose delivery pattern in high-precision radiotherapy is different from that in conventional radiation, radiobiological assessment of the physical dose used in stereotactic irradiation and intensity-modulated radiotherapy has become necessary. In these treatments, the daily dose is usually given intermittently over a time longer than that used in conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. This phenomenon is almost universarily observed in vitro. In in vivo tumors, however, this decrease in effect can be counterbalanced by rapid reoxygenation, which has been demonstrated in a laboratory study. Studies on reoxygenation in human tumors are warranted to better evaluate the influence of prolonged radiation delivery. Another issue related to radiosurgery and hypofractionated stereotactic radiotherapy is the mathematical model for dose evaluation and conversion. Many clinicians use the linear-quadratic (LQ) model and biologically effective dose (BED) to estimate the effects of various radiation schedules, but it has been suggested that the LQ model is not applicable to high doses per fraction. Recent experimental studies verified the inadequacy of the LQ model in converting hypofractionated doses into single doses. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when it is used for tumor responses in vivo, since it does not take reoxygenation into account. For normal tissue responses, improved models have been proposed, but, for in vivo tumor responses, the currently available models are not satisfactory, and better ones should be proposed in future studies.

This paper presents a study on short-term ensemble flood forecasting specifically for small dam catchments in Japan. Numerical ensemble simulations of rainfall from the Japan Meteorological Agency Nonhydrostatic Model are used as the input data to a rainfall–runoff model for predicting river discharge into a dam. The ensemble weather simulations use a conventional 10 km and a high-resolution 2 km spatial resolution. A distributed rainfall–runoff model is constructed for the Kasahori dam catchment (approx. 70 km2) and applied with the ensemble rainfalls. The results show that the hourly maximum and cumulative catchment-average rainfalls of the 2 km-resolution JMA-NHM ensemble simulation are more appropriate than the 10 km-resolution rainfalls. All the simulated inflows based on the 2 and 10 km rainfalls become larger than the flood discharge of 140 m3 s−1; a threshold value for flood control. The inflows with the 10 km-resolution ensemble rainfall are all considerably smaller than the observations, while, at least one simulated discharge out of 11 ensemble members with the 2 km-resolution rainfalls reproduces the first peak of the inflow at the Kasahori dam with similar amplitude to observations, although there are spatiotemporal lags between simulation and observation. To take positional lags into account of the ensemble discharge simulation, the rainfall distribution in each ensemble member is shifted so that the catchment-averaged cumulative rainfall of the Kasahori dam maximizes. The runoff simulation with the position-shifted rainfalls show much better results than the original ensemble discharge simulations.

Purpose To evaluate the compliance of linear-quadratic (LQ) model calculations in the high-dose range as used in stereotactic irradiation in a murine tumor model. Methods and Materials Female 10-week-old Balb/c mice bearing 1-cm-diameter EMT6 tumors in the hind legs were used. Single doses of 10–25 Gy were compared with 2–5 fractions of 4–13 Gy given at 4-hour intervals. Cell survival after irradiation was determined by an in vivo – in vitro assay. Using an α/β ratio determined for in vitro EMT6 cells and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually measured equivalent single doses for the hypofractionated doses. These fractionation schedules were also compared simultaneously to investigate the concordance/divergence of dose–survival curves plotted against actual radiation doses and biologically effective doses (BED). Results Equivalent single doses for hypofractionated doses calculated from LQ formalism were lower than actually measured doses by 21%–31% in the 2- or 3-fraction experiments and by 27%–42% in the 4- or 5-fraction experiments. The differences were all significant. When a higher α/β ratio was assumed, the discrepancy became smaller. In direct comparison of the 2- to 5-fraction schedules, respective dose–response curves almost overlapped when cell survival was plotted against actual radiation doses. However, the curves tended to shift downward by increasing the fraction number when cell survival was plotted against BED calculated using an α/β ratio of 3.5 Gy for in vitro EMT6 cells. Conclusion Conversion of hypofractionated radiation doses to single doses using the LQ formalism underestimated the in vivo effect of hypofractionated radiation by approximately 20%–40%. The discrepancy appeared to be larger than that seen in the previous in vitro study and tended to increase with the fraction number. BED appeared to be an unreliable measure of tumor response.

While macroscopic observation reveals non-switching of domain in Na0.5Bi0.5TiO3 (NBT)-BaTiO3 (Ba;0.33%) rhombohedral (001) plate, microscopic observation, using the piezoresponse force microscopy (PFM), reveals two kinds of piezoresponse images, one with domain switching and the other without one. Such microscopic remarkable difference of domain switching depends on the coercive field caused by localized nucleation of domains with reversed polarization. Such coercive fields was discussed from the viewpoint of the relaxor states resulting from random fields based on lattice defects due to Bi ions and oxygen vacancies.