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.

Prognostic impact of residual lateral lymph node metastasis after neoadjuvant (chemo)radiotherapy in patients with advanced low rectal cancer.

Background: There is a lack of large studies focusing on the prognostic significance of lateral lymph node (LLN) metastasis following LLN dissection (LLND) in rectal cancer. The aim of this study was to evaluate the prognostic impact of LLN metastases on survival of patients with advanced low rectal cancer. Methods: Consecutive patients with locally advanced, but not metastatic, extraperitoneal rectal cancer treated with neoadjuvant (chemo)radiotherapy plus total mesorectal excision between 2004 and 2015 were included in the study. LLND was performed when pretreatment imaging documented enlarged LLNs (7 mm or greater in size). Localization of nodal metastases and long-term outcomes were analysed. Kaplan-Meier analysis was used to compare the survival of patients with ypN0 disease with that of patients with mesorectal ypN+/LLN- status and patients with positive LLNs. The Cox proportional hazards model was used to evaluate predictors of disease-free survival (DFS) and local recurrence. Results: A total of 613 patients were included in the study; LLND was performed in 212 patients (34·6 per cent) and 57 (9·3 per cent) had LLN metastasis. Patients with LLN metastasis had improved DFS and local recurrence cumulative incidence rates compared with patients with mesorectal ypN2+/LLN- disease (DFS: P = 0·014; local recurrence: P = 0·006). Although the DFS rate of patients with LLN metastasis was worse than that of patients with ypN0 disease (P < 0·001), the cumulative incidence of local recurrence was similar (P = 0·491). In multivariable analysis, residual LLN metastasis was not an independent predictor of worse DFS or local recurrence. Conclusion: LLN metastasis is not an independent predictor of local recurrence or survival. Survival of patients presenting with LLN metastasis after (chemo)radiotherapy was intermediate between that of patients with ypN0 status and those with mesorectal ypN2 positivity.

Antecedentes: No existen en la literatura grandes estudios dirigidos a investigar la importancia pronóstica de las metástasis en los ganglios linfáticos laterales (lateral lymph nodes, LLN) después de la disección de los mismos (LLN dissection, LLND) en pacientes con cáncer de recto. El objetivo de este estudio fue evaluar el impacto pronóstico de las metástasis en los LLN sobre la supervivencia de los pacientes con cáncer de recto. Métodos: Se analizaron 613 pacientes consecutivos con cáncer de recto localmente avanzado extraperitoneal y no metastásico tratados con (quimio)radioterapia neoadyuvante seguida de resección total del mesorrecto (total mesorectal excision, TME) entre 2004 y 2015. Se realizó una LLND cuando el estudio mediante pruebas de imagen previo el tratamiento mostró LLN aumentados de tamaño ≥ 7 mm. Se analizó la localización de las metástasis ganglionares y los resultados a largo plazo. El análisis de supervivencia se realizó mediante el método de Kaplan­Meier para comparar las supervivencias de los pacientes ypN0 frente a los pacientes ypN con positividad mesorrectal/LLN negativos y frente a los pacientes LLN positivos. Se utilizó el modelo de riesgo proporcional de Cox para evaluar los factores predictivos de supervivencia libre de enfermedad y de recidiva local. Resultados: Se realizó una LLND en 212 (34,6%) pacientes, y 57 (9,3%) pacientes presentaban metástasis en los LLN. Los pacientes con metástasis en los LLN presentaron mejores curvas de incidencia acumulada de recidiva local y de supervivencia libre de enfermedad en comparación con los pacientes con ganglios mesorrectales ypN2 positivos/LLN negativos (respectivamente, P = 0,0135 y P = 0,0060). Aunque la curva de la supervivencia libre de enfermedad de los pacientes con metástasis en los LLN fue peor que la de los pacientes ypN0 (P < 0,0001), la incidencia acumulada de recidiva local fue similar (P = 0,4905). En el análisis multivariable, la metástasis residual en los LLN no fue un factor predictivo independiente de peor supervivencia libre de enfermedad ni de recidiva local. Conclusión: Las metástasis en los LLN no es un factor predictivo independiente de recidiva local o supervivencia. Los pacientes que presentaron metástasis en los LLN después de (quimio)radioterapia mostraron características de supervivencia intermedias entre ypN0 y pacientes con ganglios mesorrectales ypN2 positivos.

Coulomb pre-stress and fault bends are ignored yet vital factors for earthquake triggering and hazard.

Successive locations of individual large earthquakes (Mw > 5.5) over years to centuries can be difficult to explain with simple Coulomb stress transfer (CST) because it is common for seismicity to circumvent nearest-neighbour along-strike faults where coseismic CST is greatest. We demonstrate that Coulomb pre-stress (the cumulative CST from multiple earthquakes and interseismic loading on non-planar faults) may explain this, evidenced by study of a 667-year historical record of earthquakes in central Italy. Heterogeneity in Coulomb pre-stresses across the fault system is >±50 bars, whereas coseismic CST is <±2 bars, so the latter will rarely overwhelm the former, explaining why historical earthquakes rarely rupture nearest neighbor faults. However, earthquakes do tend to occur where the cumulative coseismic and interseismic CST is positive, although there are notable examples where earthquake propagate across negatively stressed portions of faults. Hence Coulomb pre-stress calculated for non-planar faults is an ignored yet vital factor for earthquake triggering.

Genetic diversity of highly pathogenic H5N8 avian influenza viruses at a single overwintering site of migratory birds in Japan, 2014/15.

We isolated eight highly pathogenic H5N8 avian influenza viruses (H5N8 HPAIVs) in the 2014/15 winter season at an overwintering site of migratory birds in Japan. Genetic analyses revealed that these isolates were divided into three groups, indicating the co-circulation of three genetic groups of H5N8 HPAIV among these migratory birds. These results also imply the possibility of global redistribution of the H5N8 HPAIVs via the migration of these birds next winter.

Folliculocentric squamous cell carcinoma with tricholemmal differentiation: a reappraisal of tricholemmal carcinoma.

BACKGROUND: The diagnostic criteria for tricholemmal carcinoma remain controversial, and even the existence of tricholemmal carcinoma has been the subject of debate. Follicular (infundibular) squamous cell carcinoma (SCC) is a distinctive subset of SCC, which develops solely with folliculocentricity, and displays the features of conventional SCC without tricholemmal differentiation. AIM: To examine the existence of pure folliculocentric SCCs showing tricholemmal differentiation, that is, tricholemmal carcinoma. METHODS: In total, 812 SCCs were examined, and those meeting the following diagnostic criteria were selected: (i) pure folliculocentricity without any associated Bowen's disease or actinic keratosis; (ii) composition primarily of lightly eosinophilic cells or clear cells containing glycogen; (iii) columnar lightly eosinophilic or clear cells aligned in a palisade along a discernible basement membrane; (iv) tricholemmal keratinization; (v) glycogen contained within the pale/clear cells; and (vi) cytological atypia and or infiltrative growth. We also evaluated whether the immunohistochemical profile [cytokeratin (CK)1, CK10, CK17, CD34 and D2-40] seen in normal hair follicles was retained in the selected lesions. RESULTS: Only two lesions met the criteria. The immunohistochemical profile of the normal outer root sheath cells was generally retained in these lesions, except for CD34. CONCLUSIONS: Tricholemmal carcinoma is a rare occurrence, but it does exist, and at least one type of tricholemmal carcinoma is considered to be related to follicular (infundibular) SCC.

Histiocytoid and signet-ring cell carcinoma of the axilla: a type of cutaneous apocrine carcinoma equivalent to histiocytoid lobular carcinoma of the breast?

There is a histopathological similarity between cutaneous apocrine carcinoma (CAC) and breast carcinoma. Cutaneous histiocytoid or signet-ring cell (SRC) carcinoma is a rare neoplasm, which usually occurs on the eyelid, and less commonly on the axilla. The precise histogenesis of this carcinoma remains controversial. We report the case of a man with a cutaneous histiocytoid SRC carcinoma of the axilla having histopathological and immunohistochemical features that were quite similar to histiocytoid lobular carcinoma (histiocytoid LC) of the breast, which is a subtype of classic invasive lobular carcinoma of the breast with apocrine differentiation. We consider this case to be a type of CAC equivalent to histiocytoid LC of the breast, based on the features and the occurrence on the axilla. The patient was treated with adjuvant chemotherapy according to the general guidelines for the treatment of breast carcinoma.

An organotypic culture system of Merkel cells using isolated epidermal sheets.

BACKGROUND: Merkel cells (MCs) exist in the epidermal basal layer, in contact with keratinocytes. This direct contact seems critical for maintaining MCs in vitro. OBJECTIVES: To estimate the effects of nerve cells on the maintenance of MCs within epidermal sheets in a new organotypic culture system of MCs. METHODS: We developed a new organotypic culture system of MCs, using MC-containing epidermal sheets embedded in collagen gel. To estimate the effects of nerve cells on the maintenance of MCs within the epidermal sheets, we cocultured nerve cells and MC-containing epidermal sheets. In these culture assemblies, cellular behaviour was analysed by histochemistry, immunohistochemistry, electron microscopy and enzyme-linked immunosorbent assay. RESULTS: This culture, even in the absence of neurotrophin (NT)-3 and nerve growth factor (NGF) (which are crucial for MC biology), retained cytokeratin (CK)-20-positive and neuroendocrine granule-containing MCs within the sheets for over 2 weeks. Coculture of MCs with PC-12 nerve cells significantly increased the number of MCs within the epidermal sheets, and the keratinocytes had almost identical expression levels of CK1, CK10, CK14 and the progenitor marker p63 to those produced by keratinocytes in vivo. Uptake of the growth marker bromodeoxyuridine by MCs and levels of NT-3 and NGF in the culture supernatants were undetectable in this system, regardless of the presence or absence of PC-12. CONCLUSIONS: The data suggest, first, that direct contact between MCs and keratinocytes may be critical for retaining MCs in vitro; second, that nerve cell-affected maintenance of keratinocyte differentiation, but not NT-3 and NGF, may contribute to MC maintenance; and third, that MCs are not able to grow, at least in our system. Our method would be useful for studying MC biology.

The mechanism of mucus production in bronchial asthma.

Mucus production is a cardinal feature of bronchial asthma, contributing to morbidity and mortality in the disease. Goblet cells are major mucus-producing cells, and goblet cell hyperplasia (GCH) is one feature of airway remodeling, defined as structural changes occurring in the airway. A number of studies have demonstrated that Th2-type cells play critical roles in this process and that particularly interleukin-13 (IL-13), among Th2-type cytokines, is a central mediator for GCH. However, the mechanism underlying how Th2 cytokines induce mucus production or GCH is poorly understood. Mouse calcium-activated chloride channel-3 (mCLCA-3; gob-5)/human CLCA-1 acts as a downstream molecule of Th2 cytokines, IL-4/IL-9/IL-13 signals, playing an important role in mucus production. Moreover, we have recently found that pendrin, an anion transporter, is induced by IL-13 and causes mucus production in airway epithelial cells. It is hoped that if we can clarify how mucus is produced, this will lead to development of novel therapeutic reagents to suppress mucus production in bronchial asthma.

Effects of fluoride dentifrices on enamel lesion formation.

An in vitro pH cycling model was used to test the hypothesis that the effects of 3 different fluoride compounds on de/remineralization are a function of the free fluoride ion concentration. Groups of 10 human enamel specimens were treated with one of: (a) amine fluoride (AmF), 1250 ppm F; (b) sodium monofluorophosphate (NaMFP), 1000 ppm F; (c) sodium fluoride (NaF), 1100 ppm F; (d) NaF, 250 ppm F; (e) Placebo (< 1 ppm F) dentifrices; or with aqueous solutions (f) NaF 900 ppm F or (g) NaF 30 ppm F. Lesions were assessed by cross-sectional microhardness. Mean +/- SEM DeltaZ (vol.% x microm) values of 3 dentifrices were: (a) 344 +/- 155, (b) 4259 +/- 257, and (c) 591 +/- 83. The AmF (1250 ppm F) was not statistically significantly different from the NaF (1100 ppm F) dentifrice in this model. The NaMFP (1000 ppm F) dentifrice, without hydrolysis, had only the same efficacy as the NaF (30 ppm F) aqueous solution.

Quantification of oxidative metabolism in masseter muscle of denture wearers.

This study aimed to quantify oxidative metabolism in masseter muscle using near-infrared spectroscopy, in particular for denture wearers. Fourteen normal dentate subjects without malocclusion (ND group, 25-50 years) participated in the quantification of oxidative metabolism. Eleven partially edentulous patients without occlusal stops (PD group, 64-80 years) and ten edentulous patients (CD group, 57-84 years) also participated after prosthodontic treatment. Oxidative metabolism was recorded during gum chewing, maximum clenching and regulated clenching at 5 kgf. The oxygenated hemoglobin at 5 kgf clenching level was normalized to the oxygenated hemoglobin at the lowest blood flow and expressed as oxygen consumption rate (OCR). The relationship of the OCR to the maximum clenching force was analyzed using Pearson's correlation coefficient, and differences between the PD and CD groups were tested by unpaired Student's t-test. The OCR showed a significant negative correlation with maximum clenching force in the ND group. The OCR of the PD group was significantly greater than that of the CD group, although the difference in maximum clenching force was not significant between both groups. These results suggest that the aerobic ability of masseter muscle in complete denture wearers is relatively greater than in partial denture wearers with same age level.

Which infertile women should be indicated for sonohysterography?

OBJECTIVE: To evaluate the indications for transvaginal saline contrast sonohysterography (TV-SCSH) in endometrial screening by transvaginal sonography in infertile women. METHODS: The study involved 850 consecutive infertile women presenting to an outpatient clinic. Using transvaginal ultrasound endometrial images were evaluated in the proliferative phase. Abnormal images were classified as follows: rugged (R), hyperechoic (H), waved (W), or thick (T). Clinical symptoms such as hypermenorrhea, dysmenorrhea and abnormal uterine bleeding were also recorded. Abnormal endometrial images were further evaluated on TV-SCSH. Age-matched women with normal endometrial images underwent TV-SCSH as controls. RESULTS: The endometrial pattern was abnormal in 111 patients (13.1%). Lesions that had been identified by TV-SCSH including endometrial polyps (44 cases), submucosal myomata (29 cases), and intramural myomata with mucosal extension (24 cases) were largely associated with the R and/or the H pattern, the W or the T pattern, and the W pattern, respectively. Sensitivity and specificity of the abnormal endometrial image for any lesion were 100% and 91.5%, respectively. Sixty-four patients (59.3%) were asymptomatic despite an abnormal endometrial image. CONCLUSIONS: TV-SCSH should be performed on selected patients following assessment of endometrial images on transvaginal sonography in order to diagnose intra- and pericavitary lesions in infertile women.

Two amino acid substitutions in acetylcholinesterase associated with pirimicarb and organophosphorous insecticide resistance in the cotton aphid, Aphis gossypii Glover (Homoptera: Aphididae).

The complete coding sequences of two acetylcholinesterase (AChE) genes, Ace1 (orthologous to Drosophila Ace) and Ace2 (paralogous to Ace), from the cotton aphid (Aphis gossypii) were identified and sequences from carbamate resistant and susceptible strains compared. No change in the amino acid sequences was found in Ace1, while two amino acid substitutions, Ser431Phe and Ala302Ser, were detected between resistant and susceptible strains in Ace2. The position of Ser431Phe corresponds to one of fourteen aromatic residues lining the active site gorge and is located in the acyl pocket. Ala302Ser is located at one of the three residues which form the oxyanion hole in the active site of AChE. The Ser431Phe and Ala302Ser substitutions may play a role in pirimicarb and organophosphate resistance, respectively.

Mexiletine carbonyloxy beta-D-glucuronide: a novel metabolite in human urine.

1. The study was performed to isolate and characterize a glucuronic acid conjugate of mexiletine that releases mexiletine on acid hydrolysis from urine samples obtained from healthy volunteers following a single oral dose of mexiletine. 2. The [M-H]- ion of the isolated metabolite was observed at m/z 398 in the negative electrospray ionization mass spectrum. This mass number was 44 higher than that of the product generated when mexiletine is subjected to direct glucuronidation. In positive-ion mode, collision-induced dissociation of the quasimolecular ion [M+NH4]+, m/z 417, gave product ions at m/z 224, 180 and 58. These mass spectral data indicated that the metabolite contained a carbonyloxy moiety in its structure in addition to mexiletine and a glucuronic acid moiety. 3. The presence of this carbonyloxy moiety was further supported by the following chemical reactions. When the metabolite was hydrolysed with an aqueous solution of 1 M sodium hydroxide at room temperature, mexiletine was released, whereas the N-methoxycarbonyl derivative of mexiletine was obtained after treatment of the metabolite with methanolic sodium hydroxide solution. 4. The results indicated that the structure of the isolated metabolite was the N-carbonyloxy beta-D-glucuronic acid conjugate of mexiletine.