Effect of iron deficiency without anaemia on days alive and out of hospital in patients undergoing valvular heart surgery.

Comprehensive evidence regarding the treatment of non-anaemic iron deficiency in patients undergoing valvular heart surgery is lacking. This study aimed to investigate the association between non-anaemic iron deficiency and postoperative outcomes in these patients. We retrospectively analysed 321 patients of which 180 (56%) had iron deficiency (defined as serum ferritin < 100 ng.ml-1 or < 300 ng.ml-1 with transferrin saturation < 20%). While the iron-deficient group had lower pre-operative haemoglobin levels than the non-iron deficient group (median (IQR [range]) 134 (127-141 [120-172]) g.l-1 , 143 (133-150 [120-179]) g.l-1 , p = 0.001), there was no between-group difference in allogeneic red blood cell transfusion. Median (IQR [range]) days alive and out of hospital at postoperative day 90 was 1 day shorter in the iron-deficient group (80 (77-82 [9-85]) days vs. 81 (79-83 [0-85]) days, p = 0.026). In multivariable analysis, only cardiopulmonary bypass duration (p = 0.032) and intra-operative allogeneic red blood cell transfusion (p = 0.011) were significantly associated with reduced days alive and out of hospital at postoperative day 90. Iron deficiency did not exert any adverse influence on secondary outcomes except length of hospital stay. Our findings indicate that non-anaemic iron deficiency alone is not associated with adverse effects in patients undergoing valvular heart surgery when it does not translate into an increased risk of allogeneic transfusion.

Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Convolutional Neural Network to Stratify the Malignancy Risk of Thyroid Nodules: Diagnostic Performance Compared with the American College of Radiology Thyroid Imaging Reporting and Data System Implemented by Experienced Radiologists.

BACKGROUND AND PURPOSE: Comparison of the diagnostic performance for thyroid cancer on ultrasound between a convolutional neural network and visual assessment by radiologists has been inconsistent. Thus, we aimed to evaluate the diagnostic performance of the convolutional neural network compared with the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) for the diagnosis of thyroid cancer using ultrasound images. MATERIALS AND METHODS: From March 2019 to September 2019, seven hundred sixty thyroid nodules (≥10 mm) in 757 patients were diagnosed as benign or malignant through fine-needle aspiration, core needle biopsy, or an operation. Experienced radiologists assessed the sonographic descriptors of the nodules, and 1 of 5 American College of Radiology TI-RADS categories was assigned. The convolutional neural network provided malignancy risk percentages for nodules based on sonographic images. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated with cutoff values using the Youden index and compared between the convolutional neural network and the American College of Radiology TI-RADS. Areas under the receiver operating characteristic curve were also compared. RESULTS: Of 760 nodules, 176 (23.2%) were malignant. At an optimal threshold derived from the Youden index, sensitivity and negative predictive values were higher with the convolutional neural network than with the American College of Radiology TI-RADS (81.8% versus 73.9%, P = .009; 94.0% versus 92.2%, P = .046). Specificity, accuracy, and positive predictive values were lower with the convolutional neural network than with the American College of Radiology TI-RADS (86.1% versus 93.7%, P < .001; 85.1% versus 89.1%, P = .003; and 64.0% versus 77.8%, P < .001). The area under the curve of the convolutional neural network was higher than that of the American College of Radiology TI-RADS (0.917 versus 0.891, P = .017). CONCLUSIONS: The convolutional neural network provided diagnostic performance comparable with that of the American College of Radiology TI-RADS categories assigned by experienced radiologists.

A new aortoiliac calcification scoring system to predict grade C anastomotic leak following rectal cancer surgery.

BACKGROUND: Aortoiliac calcification may be a surrogate marker of decreased visceral perfusion causing anastomotic leak (AL). The aim of this study was to evaluate the predictive role of aortoiliac calcification for AL after rectal cancer surgery. METHODS: We enrolled patients with primary rectal cancer who had restorative resection at our institution between January 2013 and December 2015. An aortoiliac calcification score was calculated as the sum of calcification scores at the infrarenal aorta (0: no, 1: ≤ 3 cm, 2: > 3 cm) and the common iliac arteries (0: no, 1: unilateral, 2: bilateral). AL was classified into three grades: grade A, requiring no intervention; grade B, requiring therapeutic intervention without re-laparotomy; and grade C, requiring re-laparotomy. Clinicopathological characteristics were analyzed to identify risk factors for AL. RESULTS: There were 583 patients. Three-hundred forty-five (59.2%) had an aortoiliac calcification score ≥ 3, and 37 (6.3%) patients experienced AL, in 30 cases (5.1%) grade C AL. Patients with an aortoiliac calcification score ≥ 3 had a higher incidence of grade C AL (6.7% vs. 2.9%, p = 0.045). Multivariate logistic regression analysis revealed that an aortoiliac calcification score ≥ 3 was an independent risk factor for grade C AL (odds ratio = 2.669, 95% confidence interval 1.066-6.686, p = 0.036). CONCLUSIONS: Aortoiliac calcification may be considered a risk factor for grade C AL after rectal cancer surgery.

Comparative outcomes of robot-assisted minimally invasive versus open esophagectomy in patients with esophageal squamous cell carcinoma: a propensity score-weighted analysis.

Robots are increasingly used in minimally invasive surgery. We evaluated the clinical benefits of robot-assisted minimally invasive esophagectomy (RAMIE) in comparison with the conventional open esophageal surgery. From 2012 to 2016, 371 patients with esophageal squamous cell carcinoma underwent an Ivor Lewis or McKeown procedure at our institution. Of these, 130 patients underwent laparoscopic gastric conduit formation followed by RAMIE, whereas 241 patients underwent conventional esophageal surgery, including laparotomy and open esophagectomy (OE). We compared the short- and long-term clinical outcomes of these patients using the propensity score-based inverse probability of treatment weighting technique (IPTW). Among the early outcomes, the OE group showed a higher incidence of pneumonia (P = 0.035) and a higher requirement for vasopressors (P = 0.001). Regarding the long-term outcomes, all-cause mortality was significantly higher (P = 0.001) and disease-free survival was lower (P = 0.006) in the OE group. Wound-related problems also occurred more frequently in the OE group (P = 0.020) during the long-term follow-up. There was no statistical intergroup difference in the recurrence rates (P = 0.191). The Cox proportional-hazard analysis demonstrated that wound problems (HR 0.16, 95% CI 0.02-0.57; P = 0.017), pneumonia (HR 0.23, 95% CI 0.06-0.68; P = 0.019), and use of vasopressors (HR 0.14, 95% CI 0.08-0.25; P = 0.001) were independent predictors of mortality. RAMIE could be a better surgical option for selected patients with esophageal squamous cell carcinoma.

Amoxicillin Modulates ApoA-I Transcription and Secretion, Predominantly via PPARα Transactivation Inhibition.

In a recent human study, we observed that amoxicillin treatment decreased HDL-C concentration. We hypothesize that antibiotics lower the transcription and secretion of ApoA-I, the responsible protein for HDL production. HepG2 and Caco-2 cells were exposed to increasing dose of amoxicillin, penicillin, and streptomycin. Secreted ApoA-I protein and mRNA transcripts were analyzed using ELISA and qPCR, respectively. To unravel underlying mechanisms, KEAP1, CPT1, and CHOP mRNA expressions were determined as well as PPARα transactivation. In HepG2 and Caco-2, amoxicillin decreased ApoA-I transcription and secretion. Effects on ApoA-I expression were clearly there for amoxicillin while no effects were observed for penicillin or streptomycin. KEAP1, CPT1, and CHOP mRNA expressions were reduced by amoxicillin treatments. Moreover, a significant correlation between ApoA-I and CPT1 mRNA expressions was found. Furthermore, amoxicillin lowered PPARα transactivation. All together, these data suggest that inhibited PPARα transactivation is involved in the effects of amoxicillin on ApoA-I. In conclusion, the direct effect of amoxicillin in treated HepG2 and Caco-2 cells was a lower ApoA-I secretion and transcription. Based on evaluating alterations in KEAP1, CPT1, and CHOP mRNA expressions plus PPARα transactivation, we suggest that a reduced PPARα activation is a potential mechanism behind the observed amoxicillin effects on ApoA-I expression.

The effects of short-chain fatty acids on the transcription and secretion of apolipoprotein A-I in human hepatocytes in vitro.

BACKGROUND: Apolipoprotein-I (ApoA-I), the major component of high-density lipoprotein (HDL) particles, mediates cholesterol efflux by which it facilitates the removal of excess cholesterol from peripheral tissues. Therefore, elevating ApoA-I production leading to the production of new pre-ß-HDL particles is thought to be beneficial in the prevention of cardiovascular diseases. Recently, we observed that amoxicillin treatment led to decreased HDL concentrations in healthy human volunteers. We questioned whether this antibiotic effect was directly or indirectly, via changed short-chain fatty acids (SCFA) concentrations through an altered gut microflora. Therefore, we here evaluated the effects of amoxicillin and various SCFA on hepatic ApoA-I expression, secretion, and the putative underlying pathways. METHODS AND RESULTS: Human hepatocytes (HepG2) were exposed to increasing dose of amoxicillin or SCFA for 48 hours. ApoA-I messenger RNA (mRNA) transcription and secreted protein were analyzed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To study underlying mechanisms, changes in mRNA expression of KEAP1, CPT1, and PPARα, as well as a PPARα transactivation assay, were analyzed. Amoxicillin dose-dependently decreased ApoA-I mRNA transcription as well as ApoA-I protein secretion. SCFA treatment resulted in a dose-dependent stimulation of ApoA-I mRNA transcription, however, the ApoA-I protein secretion was decreased. Furthermore, SCFA treatment increased PPARα transactivation, PPARα and CPT1 mRNA transcription, whereas KEAP1 mRNA transcription was decreased. CONCLUSION: Direct treatment of HepG2 cells with amoxicillin has either direct effects on lowering ApoA-I transcription and secretion or indirect effects via modified SCFA concentrations because SCFA were found to stimulate hepatic ApoA-I expression. Furthermore, BET inhibition and PPARα activation were identified as possible mechanisms behind the observed effects on ApoA-I transcription.

Effectiveness of oral counselling for smoke cessation in Graves orbitopathy patients. / Efectividad del consejo médico para dejar de fumar en pacientes con orbitopatía de Graves.

OBJECTIVE: Smoking is an important risk factor for Graves orbitopathy (GO) and it is modifiable. The advice to stop smoking has been included in all the clinical practice guidelines of GO. However, the effectiveness of this practice remains unknown. The purpose of this study is to assess the change in the smoking habit in patients affected with GO after an oral counselling for smoking cessation. MATERIAL AND METHODS: A retrospective cohort of GO patients was studied. The patients received a significant oral counsel during the first consultation with the ophthalmologist. 33 GO patients were explored in the ophthalmology clinic during 2013 and 2014 and the study was done throughout a telephone questionnaire in 2015. The main outcome was the number of cigarettes smoked daily before and after consultation with the endocrinologist and the ophthalmologist. Other medical and socioeconomic factors were recorded. RESULTS: The mean number of cigarettes that were smoked was 13.6 (SD 9.66) and 6.3 (SD 7.73) before and after the consultation done at the ophthalmology office (T-test paired, P=0.0006). 42.42% achieved smoking cessation and 30.3% decreased their smoking habit. Patients who stopped smoking suffered usually from active and severe GO, had more stable jobs and received greater support from their relatives and friends. CONCLUSION: A firm and strong oral counsel held for smoke cessation was effective in GO patients. This disease deeply affects patients' quality of life, making them more prone to change their habits.

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma.

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression.

Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.

Occupational exposure and idiopathic pulmonary fibrosis: a multicentre case-control study in Korea.

SETTING: Multicentred hospital-based cases and control subjects in Korea. OBJECTIVE: To evaluate the association between idiopathic pulmonary fibrosis (IPF) and hazardous materials to which people are occupationally exposed. DESIGN: A multicentre, hospital-based, matched case-control study was performed. The ratio of IPF cases to controls was 1:1 (n = 78 in each group). IPF cases and controls were matched in terms of age group, sex and place of residence. Conditional logistic regression analysis was performed. RESULTS: In simple logistic regression analysis, exposure to metal dust and any exposure for >1 year in an occupational setting were significantly associated with IPF (metal dust OR 4.00, 95%CI 1.34-11.97; any exposure OR 3.67, 95%CI 1.02-13.14). After adjustment for environmental and military exposures and smoking history, the OR for metal dust exposure was 4.97 (95%CI 1.36-18.17) in multiple logistic regression analysis. CONCLUSIONS: Metal dust was associated with incident IPF in Seoul and Gyeonggi Provinces in Korea. This information will be used to support a tailored preventive strategy in specific industries or occupations.

Zebrafish as a model for von Hippel Lindau and hypoxia-inducible factor signaling.

Oxygen is a central molecule in the development of multicellular life, allowing efficient energy generation. Inadequate oxygen supply requires rapid adaptations to prevent cellular damage and the hypoxia-inducible factor (HIF) pathway plays a central role in this adaptation. Numerous diseases and disease processes are influenced by hypoxia and the HIF pathway. One component, von Hippel Lindau (VHL), is a well-known tumor suppressor, which acts at least in part via regulating HIF signaling. The zebrafish has become a central vertebrate model organism in which developmental and disease processes can be studied. In this review, we have tried to bring together knowledge on the HIF/hypoxic signaling pathway in zebrafish, including what is known on VHL functions.

Prognostic impact of the length of the longitudinal resection margin in colon cancer.

AIM: Although several guidelines recommend a longitudinal resection margin (LRM) of at least 5 cm, the impact of the LRM on survival is still unknown. The study assessed the prognostic significance of the LRM in patients with colon cancer. METHOD: We retrospectively reviewed 1343 primary colon cancer patients without distant metastasis who underwent curative resection between January 2004 and December 2012. Patients were classified into three groups: LRM < 3 cm (n = 186), LRM ≥ 3 and <5 cm (n = 376) and LRM ≥5 cm (n = 781). Clinicopathological characteristics and the oncological outcome in the three groups were compared. RESULTS: The median LRM length was 5.0 cm (range 0.5-26.0 cm). With increasing LRM, the number of retrieved lymph nodes (LNs) tended to increase (19.5 ± 12.0, 22.1 ± 12.8 and 30.0 ± 16.2; P < 0.001). After a median follow-up period of 45 (1-128) months, 3-year disease-free survival (DFS) (89.2%, 89.0% and 87.0%; P = 0.629) and 5-year overall survival (OS) (89.0%, 92.1% and 91.8%; P = 0.679) were not significantly different between the three groups. When confounders were adjusted, LRM was not significantly associated with either DFS or OS, but the number of retrieved LNs (< 12) was an independent risk factor for both DFS (hazard ratio 1.748, 95% confidence interval 1.048-2.917) and OS (hazard ratio 1.929, 95% confidence interval 1.046-3.559). CONCLUSION: LRM was not associated with oncological outcome, but care should be taken to obtain an adequate number of LNs for better survival.

Internal hernia following laparoscopic colorectal surgery: a rare but fatal complication.

PURPOSE: Internal hernia of the small bowel through a mesenteric defect following colorectal cancer surgery is a serious but rarely reported complication. The aim of this study was to evaluate the incidence, clinical features, and management of these hernias. METHODS: We retrospectively reviewed 4589 primary colorectal cancer patients who underwent surgical resection between January 2007 and December 2015. The incidence, clinical presentations, and short-term outcomes of patients with symptomatic internal hernia following colorectal surgery were investigated in detail. RESULTS: We found 9 (0.2 %) patients who presented with symptomatic internal hernia. In all cases, preceding surgical procedures were laparoscopic anterior resection (n = 9), including low anterior resection (n = 3) and intersphincteric resection (n = 3). The median time interval between initial surgery and the occurrence of internal hernia was 4 months (range 5 days-27 months). Main symptoms were abdominal distension and pain; 4 (44.4 %) patients presented with systemic inflammatory response syndrome. Most cases (7/9, 77.8 %) were suspected of internal hernia by preoperative abdominal computed tomography. Six (66.6 %) patients underwent emergency surgery, after which all developed postoperative complications without mortality. The median hospital stay was 27.5 days (range 25-54 days) among patients who underwent surgical intervention. CONCLUSIONS: Internal hernia following colorectal cancer surgery is a rare but potentially fatal complication, and as such, early recognition and management of these cases are important.

Computed tomography findings associated with bacteremia in adult patients with a urinary tract infection.

The use of computed tomography (CT) in the diagnosis of urinary tract infection (UTI) has rapidly increased recently at acute stage, but the CT findings associated with bacteremia in UTI patients are unknown. 189 UTI patients were enrolled who underwent a CT scan within 24 h after hospital admission. We classified CT findings into eight types: a focal or multifocal wedge-shaped area of hypoperfusion, enlarged kidneys, perinephric fat stranding, ureteritis or pyelitis, complicated renal cyst, renal papillary necrosis, hydronephrosis, and renal and perirenal abscess. A retrospective analysis was conducted to evaluate the CT findings associated with bacteremia. The mean age of these patients was 60 ± 17.2 years, and 93.1 % were women. Concurrent bacteremia was noted in 40.2 % of the patients. Abnormal CT findings were noted in 96.3 % of the patients and 62.4 % had two or more abnormal findings. The most frequent abnormal CT finding was a focal or multifocal wedge-shaped area of hypoperfusion (77.2 %), followed by perinephric fat stranding (29.1 %). Perinephric fat stranding, hydronephrosis, and the presence of two or more abnormal CT findings were significantly associated with bacteremia in patients with community-acquired UTI. In the multivariate logistic regression analysis, age [odds ratio (OR) 1.03; 95 % confidence interval (CI) 1.009-1.062], two or more abnormal CT findings (OR 3.163; 95 % CI 1.334-7.498), and hydronephrosis (OR 13.160; 95 % CI 1.048-165.282) were significantly associated with bacteremia. Physicians should be aware that appropriate early management is necessary to prevent fatality in patients with these CT findings.

Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.

Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met and FGFR pathways may have synergistic clinical benefits when targeting FGFR-dependent LC.