Rectal cancer lateral lymph nodes: multicentre study of the impact of obturator and internal iliac nodes on oncological outcomes.

BACKGROUND: In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes. METHODS: Patients with low cT3-4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response. RESULTS: More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease. CONCLUSION: Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.

No significant association between stable iodine intake and thyroid dysfunction in children after the Fukushima Nuclear Disaster: an observational study.

PURPOSE: Stable iodine prophylaxis helps prevent childhood thyroid cancer in nuclear emergencies; however, there is limited information on its effect on thyroid function. This study aimed to examine thyroid function and autoimmunity among children and adolescents that took stable iodine after the Fukushima Nuclear Disaster. METHODS: For this observational study, data were obtained from children and adolescents that underwent thyroid cancer screening at Hirata Central Hospital from April 2012 to March 2018. Participant characteristics, including possible hypothyroidism and hyperthyroidism, were compared between the prophylaxis and no-prophylaxis groups. Multivariable logistic regression models were used to assess for possible hypothyroidism, autoantibodies positive, and hyperthyroidism. RESULTS: A total of 1,225 participants with stable iodine prophylaxis and 3,946 without prophylaxis were enrolled. Of those participants, blood samples were available for 144 and 1,201 participants in the prophylaxis and no-prophylaxis groups, respectively. There were 17 (11.8%) and 146 cases (12.2%) of possible hypothyroidism or autoantibodies positive cases in the prophylaxis and no-prophylaxis groups, respectively, and there were no cases and 3 cases (0.2%) of possible hyperthyroidism in those two groups, respectively. Multivariable analysis for possible hypothyroidism revealed no association between stable iodine intake and possible hypothyroidism or autoantibodies positive [odds ratio 0.716 (95% confidence interval 0.399-1.284)] (p = 0.262). We did not perform multivariable analysis for hyperthyroidism due to the limited number of cases. CONCLUSION: Significant adverse effects of stable iodine intake on thyroid function were not observed among children and adolescents 7 years after the Fukushima Nuclear Disaster.

Automated diagnosis of intestinal parasites: A new hybrid approach and its benefits.

Intestinal parasites are responsible for several diseases in human beings. In order to eliminate the error-prone visual analysis of optical microscopy slides, we have investigated automated, fast, and low-cost systems for the diagnosis of human intestinal parasites. In this work, we present a hybrid approach that combines the opinion of two decision-making systems with complementary properties: (DS1) a simpler system based on very fast handcrafted image feature extraction and support vector machine classification and (DS2) a more complex system based on a deep neural network, Vgg-16, for image feature extraction and classification. DS1 is much faster than DS2, but it is less accurate than DS2. Fortunately, the errors of DS1 are not the same of DS2. During training, we use a validation set to learn the probabilities of misclassification by DS1 on each class based on its confidence values. When DS1 quickly classifies all images from a microscopy slide, the method selects a number of images with higher chances of misclassification for characterization and reclassification by DS2. Our hybrid system can improve the overall effectiveness without compromising efficiency, being suitable for the clinical routine - a strategy that might be suitable for other real applications. As demonstrated on large datasets, the proposed system can achieve, on average, 94.9%, 87.8%, and 92.5% of Cohen's Kappa on helminth eggs, helminth larvae, and protozoa cysts, respectively.

Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer.

BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.

A case with good response to belimumab for lupus nephritis complicated by IgG4-related disease.

Immunoglobulin (Ig)G4-related disease (IgG4-RD) is an unusual complication of systemic lupus erythematosus (SLE). We report a case in which belimumab proved efficacious for not only SLE, but also IgG4-RD. A 58-year-old Japanese woman had suffered from photodermatosis and erythema on the limbs for 20 years. She presented in slight fever and fatigue since 2016. Laboratory data showed hypergammaglobulinemia, proteinuria and positive results for anti-nuclear antibody and anti-double-stranded DNA antibody. Furthermore, elevated levels of serum IgG4 were detected. Contrast-enhanced computed tomography disclosed multiple areas of poor enhancement in the kidneys. The patient was diagnosed with lupus nephritis and IgG4-RD from renal biopsy. Treatment was started with prednisolone at 40 mg/day and mycophenolate mofetil. Proteinuria and serological findings improved initially, but tapering the dose of glucocorticoid proved difficult. After treatment was started with belimumab, clinical symptoms and proteinuria resolved completely. The dose of glucocorticoid was successfully tapered and serum concentration of IgG4 fell further. This appears to represent the first report of a case in which both SLE and IgG4-RD were effectively treated using belimumab.

Preoperative CT-based predictive factors for resectability and medium-term overall survival in patients with peritoneal carcinomatosis from colorectal cancer.

AIM: To determine preoperative radiological findings that may correlate with resectability and medium-term overall survival (OS) in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC). MATERIALS AND METHODS: The study included 81 consecutive patients with PC scheduled for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). PCI scores from preoperative computed tomography (CT) were compared with Peritoneal Cancer Index (PCI) scores at laparotomy. Odds ratio (OR), a Cox proportional hazards regression model, and Kaplan-Meier survival analyses were performed to evaluate resectability ("open and close procedure" [O&C]) and OS. RESULTS: A radiological PCI score ≥20 (OR; 20.61 p=0.001), involvement of the perihepatic region (OR; 3.63, p=0.047) and extensive small bowel involvement (OR; 9.90, p=0.019) were risk factors for O&C. Involvement of the left abdominal region correlated adversely to OS (HR; 6.86, p<0.001). CONCLUSIONS: The location of PC, in addition to the extent of PC as determined by preoperative CT, predicts resectability and medium-term survival.

Measurements of metastatic renal cell tumours as determined by diffusion weighted imaging or computed tomography are in close agreement, a pilot study.

BACKGROUND: Diffusion weighted magnetic resonance imaging (DWI) provides both functional and anatomical information regarding tumours but can also be used for tumour detection. Today, tumour treatment response in clinical trials is mainly assessed on Computed Tomography (CT) using established criteria. Despite availability of dedicated software, CT still requires significant manual work for selection and measurement in treatment response evaluation of solid tumours. PURPOSE: To compare the maximum diameter of tumour lesions on CT with the corresponding measurements on diffusion weighted images. MATERIALS AND METHODS: In this prospective cohort, metastatic lesions were identified on CT and on DWI in five patients with metastatic renal cell carcinoma before and after three months of treatment with pazopanib. Two radiologists independently measured the same lesions on axial CT images and separately also on axial DWI images. The measurements were compared between CT and DWI with respect to the number of target lesions measured, size of the lesions, size reduction due to treatment and the inter-observer variability. Wilcoxon signed rank test, linear regression and Bland-Altman plots were used for statistical analyses. RESULTS: In this pilot study, there was no significant inter-observer variability in terms of numbers of lesion selected between CT and DWI. A significant reduction of lesion size was observed both for CT and DWI when post-treatment scans were compared to pre-treatment scans. There was no significant difference in measurement of lesion size on both pre- and post treatment scans between CT and DWI (p = 0.099 and p = 0.388 respectively). CONCLUSION: Measurement of the size of metastatic lesions on the basis of axial DWI images are in close agreement with measurement based on conventional axial CT images, the most often employed approach in clinical trials today. The results in this pilot study can be used to estimate sufficient sample size in a larger trial with adequate power, were the results can be confirmed in a wider range of cancers other than renal cell carcinoma.

Effects of caffeine on sperm characteristics after thawing and inflammatory response in the uterus after artificial insemination with frozen-thawed boar semen.

We previously reported that AI with frozen-thawed boar semen supplemented with caffeine increased the number of uterine sperm by inhibiting migration of polymorphonuclear leukocytes (PMNs) into the uterine lumen, and also improved fertility of gilts and sows. The objective of the present study was to determine the effects of the addition of caffeine to a thawing solution on postthaw sperm quality and uterine inflammatory response after AI with frozen-thawed boar semen. Incubation of frozen-thawed sperm in Modena solution supplemented with 10 mM caffeine for 90 minutes improved (P < 0.05) percentages of progressive motility, straightness, and linearity of sperm movement compared with no caffeine, without causing damage to plasma or acrosomal membranes. Gilts inseminated once with 2 × 10(9) frozen-thawed sperm suspended in Modena solution with or without caffeine, and gilts that did not receive AI, were slaughtered 4 hours later. Uteri were recovered for analysis of number of uterine PMNs and mRNA expression (quantitative reverse transcription polymerase chain reaction) of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1, and cyclooxygenase 2 in the endometrium. Caffeine decreased (P < 0.05) both the number of total uterine PMNs and expression of IL-8 mRNA in the endometrium after AI. The amount of IL-8 and cyclooxygenase 2 mRNA after AI in the absence of caffeine were higher than samples from gilts that did not receive AI (P < 0.05), whereas there were no significant differences between treatments in expression levels of tumor necrosis factor-α, IL-1ß, IL-6, or monocyte chemoattractant protein-1 mRNA. Pregnancy rate in sows inseminated with sperm supplemented with caffeine (16 of 23; 70%) tended (P < 0.1) to exceed that without caffeine (12 of 26; 46%), but litter size was not affected. In conclusion, the addition of caffeine to the thawing solution inhibited migration of uterine PMNs, probably by downregulating IL-8 mRNA expression in the endometrium.

A derivative of Lactococcus lactis strain H61 with less interleukin-12 induction has a different cell wall.

Lactococcus lactis H61 can increase the cellular immune responses of aged (14-mo-old) senescence-accelerated mice. The aim of this study was to investigate the factors contributing to IL-12 induction by strain H61 by analyzing strains derived from it. Strain H61 derivative no. 13 was obtained by growing the parent strain at 37°C. This derivative induced significantly lower production of IL-12 from J774.1 macrophage cells than did the parent strain H61. The 2 strains differed in the resistance of their whole cells or cell walls to lysozyme, a cell wall-degrading enzyme. Sodium hydroxide treatment to de-O-acetylate muramic acid in the cell walls of the 2 strains reduced the lysozyme resistance, compared with untreated cell walls: at 3h after adding lysozyme, the lysozyme resistance of untreated and NaOH treated cell wall from strain H61 was 55.4% and 11.7%, respectively. The values of untreated and NaOH-treated cell walls from strain no.13 were 73.7 and 42.8%, respectively. The reduction was higher in strain H61, indicating that the cell walls of strain H61 were highly O-acetylated. Trichloroacetic acid treatment to remove wall-associated polymers such as teichoic acids made the lysozyme resistance of the cell walls of both strains similar. The sugar content of cell walls prepared from strain H61 was significantly higher than that of strain no. 13 cell wall. A derivative with less activity for inducing IL-12 by macrophage cells had less O-acetylation and had lower sugar content in the cell wall than did strain H61. Modifying the cell wall of strain H61 may be a useful way to regulate its ability to induce IL-12. Strain H61 has been used as a starter bacterium in the dairy industry. This study could lead to enhancing the value of dairy products made by strain H61 by characterizing the key factor(s) responsible for its stimulation of immunity.

The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy.

BACKGROUND: To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. PATIENTS AND METHODS: The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS). RESULTS: The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%. CONCLUSIONS: The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Lactococcus strains treated with heat and hen-egg-white lysozyme induce abundant interleukin-12 production by J774.1 macrophages and murine spleen cells.

The IL-12-inducing ability of lactic acid bacteria could be a critical index of immunomodulatory activity, especially in promoting T-helper-1 responses and in suppressing T-helper-2-mediated allergic responses. We aimed to develop a simple method for enhancing the IL-12-inducing ability of bacteria. We examined the in vitro effects of strains of lysozyme-modified Lactococcus (ML-LYS), prepared by heat treatment of the Lactococcus strain in the presence of lysozyme, on the ability of mouse macrophage-like J774.1 cells and spleen cells to produce IL-12. An IL-12-inducing ability greater than that of heat-killed bacteria was shown by 41 of 46 ML-LYS strains in J774.1 cells and by all 46 ML-LYS strains in mouse spleen cells. In contrast, bacteria modified by α-lactalbumin, ß-lactoglobulin, or ovalbumin did not enhance IL-12 production in J774.1 cells. Microscopically, ML-LYS showed stronger resistance to lysozyme and macrophage digestion than did heat-killed bacteria or the other modified bacteria. Addition of chitotriose, a lysozyme inhibitor, enhanced IL-12 production by J774.1 cells stimulated with heat-killed bacteria. Therefore, enhancement of resistance to lysozyme may be a key factor in the strong IL-12-inducing ability of ML-LYS. These findings have important implications for the design of dairy products that have an immunomodulatory effect using the modified bacteria.

Prevention of excessive collagen accumulation by human intravenous immunoglobulin treatment in a murine model of bleomycin-induced scleroderma.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrotic changes in skin and other organs involving excessive collagen deposition. Here we investigated the effect of intravenous immunoglobulin (IVIG) on fibrosis in a murine model of bleomycin (BLM)-induced scleroderma. Scleroderma was induced in C3H/He J mice by subcutaneous BLM injections daily for 35 days. The collagen content in skin samples from the BLM-injected group (6·30 ± 0·11 mg/g tissue) was significantly higher than the PBS group (5·80 ± 0·10 mg/g tissue), and corresponded with dermal thickening at the injection site. In contrast, mice treated with IVIG for 5 consecutive days after initiating BLM injection showed lesser collagen content significantly (IVIG group, 5·61 ± 0·09 mg/g tissue; BLM vs. IVIG). In order to investigate the cellular and protein characteristics in the early stage of the model, the skin samples were obtained 7 days after the onset of experiment. Macrophage infiltration to the dermis, monocyte chemoattractant protein (MCP-1)-positive cells, and increased TGF-ß1 mRNA expression were also observed in the BLM group. IVIG inhibited these early fibrogenic changes; MCP-1 expression was significantly lesser for the IVIG group (1·52 ± 0·19 pg/mg tissue) than for the BLM group (2·49 ± 0·26 pg/mg tissue). In contrast, TGF-ß1 mRNA expression was significantly inhibited by IVIG. These results suggest that IVIG treatment may inhibit macrophage recruitment to fibrotic sites by down regulating MCP-1 and TGF-ß production, and thus could be a potential drug for managing fibrotic disorders such as SSc.

The minimum number of target lesions that need to be measured to be representative of the total number of target lesions (according to RECIST).

Response evaluation criteria in solid tumours (RECIST) were introduced as a means to classify tumour response with no definition of the minimum number of lesions. This study was conducted in order to evaluate discrepancies between full assessments based on either all target lesions or fewer lesions. RECIST evaluation was performed on separate occasions based on between one and seven of the target lesions, with simultaneous assessment of non-target lesions. 99 patients were included. 38 patients demonstrated progressive disease, in 61% of whom it was a result of the appearance of new lesions or unequivocal progress in non-target lesions. 32 patients showed stable disease, with 8 having results that differed when 1-3 target lesions were measured. 22 cases were considered as having partial regression, with only 1 case differing when performing 1-3 target lesion assessments. Seven cases demonstrated complete response. The number of discordant cases increased gradually from measuring three lesions to one target lesion. The average number of available target lesions among those with discrepancies was 7.1, which was significantly higher than those demonstrating concordance (4.1 lesions; p<0.05). In conclusion, measuring fewer than four target lesions might cause discrepancies when more than five target lesions are present.

Bcl-2 protects tubular epithelial cells from ischemia/reperfusion injury by dual mechanisms.

Ischemia/reperfusion (I/R) injury, which induces extensive loss of tubular epithelial cells, is associated with delayed graft function following kidney transplantation. Recent reports have suggested that cell death by I/R injury occurs by autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, as well as by apoptosis. Recently, we demonstrated that overexpression of the anti-apoptotic factor, Bcl-2, inhibited tubular apoptosis and subsequent tubulointerstitial damage after I/R injury. Autophagy is also observed in cells undergoing cell death in several diseases. Therefore, we hypothesized that increased Bcl-2 protein may protect tubular epithelial cells by suppressing autophagy and inhibiting apoptosis. In the present study, a transgenic mouse model (LC3-GFP TG) in which autophagosomes are labeled with LC3-GFP and Bcl-2/LC3-GFP double transgenic mice (Bcl-2/LC3-GFP TG) were used to examine the effect of Bcl-2 on I/R-induced autophagy. I/R injury, which is associated with marked disruption of normal tubular morphology, promoted the formation of LC3-GFP dots, representing extensively induced autophagosomes. On electron microscopy, the autophagosomes contained mitochondria in I/R-injured tubular epithelial cells. In contrast, Bcl-2 augmentation suppressed the formation of autophagosomes and there was less tubular damage. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R injury by suppressing autophagosomal degradation and inhibiting tubular apoptosis.

Morphological assessment of the interface between tumor and neighboring tissues, by magnetic resonance imaging, before and after radiotherapy in patients with locally advanced rectal cancer.

BACKGROUND: Magnetic resonance imaging (MRI) in rectal cancer is sometimes performed after radiotherapy (MRI 2) to evaluate tumor response and to choose alternative forms of surgery. The accuracy of MRI 2 in distinguishing tumor delineation might be difficult due to fibrosis. PURPOSE: To evaluate the morphological changes in the interface between the tumor and neighboring organs on MRI 2 performed after radiotherapy, and to assess the accuracies of MRI before and after radiotherapy compared to histopathology after surgery. MATERIAL AND METHODS: Sixteen patients with locally advanced primary rectal cancer, with MRI before and after radiotherapy, were retrospectively studied, concerning the interface between the tumor and neighboring structures. The accuracies of MRI before and after radiotherapy were compared based on histopathology as a reference. RESULTS: The accuracies of both MRI before and after radiotherapy were moderate, with no additional value of MRI after radiotherapy compared to MRI before radiotherapy. The most predictive form of interface for involvement of a neighboring organ after radiotherapy was nodular growth of the tumor into a neighboring structure. CONCLUSION: The morphological assessment of pelvic MRI after preoperative radiotherapy does not provide any significant new information about tumor extent in patients with locally advanced rectal cancer.

Different growth media alter the induction of interleukin 12 by a Lactococcus lactis strain.

Lactococcus lactis subsp. lactis G50 has immunomodulatory activity and is a candidate for use as a probiotic strain. We investigated the factors that affect the immunomodulatory activity of this strain. The macrophage-like cell line J774.1A was exposed to live or dead cells of strain G50 grown in different media, and the interleukin (IL) 12 produced by the cell line was then measured. Live cells grown in M17 supplemented with glucose (GM17 cells) induced IL-12 production by J774.1 cells significantly more than did cells grown in deMan Rogosa Sharpe (MRS) broth (MRS cells; P < 0.05). In the case of dead cells, the opposite results were obtained in these two samples. The sugar content of GM17 cells was significantly higher than that of MRS cells (P < 0.01). The fatty acid compositions of GM17 cells and MRS cells differed. Lysis of GM17 cells by lysozyme, which degrades the cell wall, was greater than in MRS cells. The cell wall fraction prepared from GM17 cells induced significantly more IL-12 production than did the fraction from MRS cells (P < 0.05). These results indicated that alterations in cellular components or in the structure of the cell surface by the growth media affected the immunomodulatory activity of strain G50. Attention should be paid to the selection of growth medium in testing for the immunomodulatory activity of lactic acid bacteria.