Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal signs

To identify novel mutations causing hereditary motor and sensory neuropathy (HMSN) with pyramidal signs, a variant of Charcot‐Marie‐Tooth disease (CMT), we screened 28 CMT and related genes in four members of an affected Japanese family. Clinical features included weakness of distal lower limb muscles, foot deformity, and mild sensory loss, then late onset of progressive spasticity. Electrophysiological studies revealed widespread neuropathy. Electron microscopic analysis showed abnormal mitochondria and mitochondrial accumulation in the neurons and Schwann cells. Brain magnetic resonance imaging (MRI) revealed an abnormally thin corpus callosum. In all four, microarrays detected a novel heterozygous missense mutation c.1166A>G (p.Y389C) in the gene encoding the light‐chain neurofilament protein (NEFL), indicating that NEFL mutations can result in a HMSN with pyramidal signs phenotype.     

Endoscopic ultrasound with double-balloon endoscopy in the evaluation of small-bowel disease

Background

Double-balloon endoscopy (DBE) has become a new standard in enteroscopy. However, it may be difficult to make a diagnosis or plan treatment strategy with endoscopic visualization alone. The addition of endoscopic ultrasonography (EUS) has the potential to improve the ability to establish the diagnosis and develop a treatment strategy. The present study was conducted to assess the feasibility and usefulness of EUS with DBE.

Methods

EUS with DBE was performed in 31 of 891 patients who underwent DBE from July 2004 to March 2011 at Jichi Medical University Hospital. We analyzed the EUS findings for lesions and evaluated the usefulness of EUS considering the following three factors: qualitative diagnostic value for lesions, depth grading of lesions, and evaluation of the structure of severe strictures prior to endoscopic balloon dilation.

Results

EUS was performed for 31/32 lesions (97 %) in 31 patients. EUS findings were informative for 29/32 lesions (91 %). EUS findings were useful for establishing a qualitative diagnosis in 15/25 lesions (60 %). EUS findings for depth grading provided useful information for determining the therapeutic strategy in 11/13 lesions (85 %). EUS with DBE was useful in the evaluation of strictures for all six lesions (100 %). The overall usefulness of EUS with DBE on decision making was 72 % (23/32) in this study.

Conclusions

EUS with DBE is feasible and useful. It provides additional information on small-bowel disease and contributes to establishing a precise diagnosis and selection of an appropriate therapeutic strategy.     

Granulocyte colony-stimulating factor-producing undifferentiated carcinoma of the colon mimicking a pulmonary giant cell carcinoma: a case showing overexpression of CD44 along with highly proliferating nestin-positive tumor vessels

Granulocyte colony-stimulating factor (G-CSF)-producing tumors are known for their aggressive behavior. Only four cases of G-CSF-producing colorectal carcinoma have been previously reported. Herein, we present a case of an undifferentiated carcinoma of the descending colon showing G-CSF production and giant cell carcinoma morphology in a 93-year-old woman. A tumor with a diameter of 80 mm was identified in the descending colon via computed tomography. Descending colectomy was performed involving the abdominal wall where tumor invasion was observed. The white blood cell count, which was elevated before resection, decreased to normal levels after intervention. However, local recurrence at the resected site was detected 39 days after surgery. Upon recurrence, increased white blood cell counts and serum G-CSF were seen. The patient died because of respiratory failure 98 days after colectomy. By using immunohistochemistry, G-CSF expression was detected in tumor cells in the resected specimen, along with overexpression of CD44 and highly proliferating nestin-positive tumor vessels. The poor clinical outcome of this patient is consistent with previous reports that the expression of these three molecules predict poor prognosis. While G-CSF can be a therapeutic target considering its auto/paracrine function to induce tumor growth via the G-CSF receptor, CD44 and nestin may also be possible candidate therapeutic targets. Further studies are required to assess the efficacy of treatments targeting these three molecules.     

Influence of resting before sonographic examination on Doppler measurements of renal blood flow

Renal artery stenosis (RAS) is the most common cause of secondary hypertension, via increases in plasma renin–angiotensin–aldosterone levels. Renal artery stenosis is diagnosed from blood examinations such as renin activity and from imaging examinations such as sonography. Patients are required to lie on the bed for 30 min before and during phlebotomy, since plasma renin activity is easily altered by posture. However, no such pre‐examination rest is required for sonography. The present study therefore investigated the possible influence of resting before examination on Doppler parameters used for the diagnosis of RAS. Subjects comprised 55 healthy young adults (24 males, 31 females; mean age, 22 ± 1 years). Sonographic measurements were made shortly after subjects entered the examination room and again after 30 min of rest lying on a bed. Median peak systolic velocity in the renal artery was significantly decreased after rest (106 cm/s, interquartile range (IQR) 96–121 cm/s) compared with before rest (120 cm/s, IQR 107–135 cm/s; p < .001). Median acceleration time in the intra‐renal segmental artery was also significantly shorter after rest (49 ms, IQR 38–54 ms) compared to before rest (50 ms, IQR 38–59 ms; p = .039). The present results suggest that serious consideration should be given regarding whether pre‐examination resting is needed to accurately interpret Doppler measurements of renal blood flow when diagnosing RAS from sonography.     

Predictive model for recurrence of renal cell carcinoma by comparing pre‐ and postoperative urinary metabolite concentrations

To improve treatment outcomes in real practice, useful biomarkers are desired when predicting postoperative recurrence for renal cell carcinoma (RCC). We collected data from patients who underwent definitive surgery for RCC and for benign urological tumor at our department between November 2016 and December 2019. We evaluated the differences in pre‐ and postoperative urinary metabolites with our precise quantitative method and identified predictive factors for RCC recurrence. Additionally, to clarify the significance of metabolites, we measured the intracellular metabolite concentration of three RCC cell lines. Among the 56 patients with RCC, nine had a recurrence (16.0%). When comparing 27 patients with T1a RCC and 10 with benign tumor, a significant difference was observed between pre‐ and postoperative concentrations among 10 urinary metabolites. In these 10 metabolites, multiple logistic regression analysis identified five metabolites (lactic acid, glycine, 2‐hydroxyglutarate, succinic acid, and kynurenic acid) as factors to build our recurrence prediction model. The values of area under the receiver operating characteristic curve, sensitivity, and specificity in this predictive model were 0.894%, 88.9%, and 88.0%, respectively. When stratified into low and high risk groups of recurrence based on this model, we found a significant drop of recurrence‐free survival rates among the high risk group. In in vitro studies, intracellular metabolite concentrations of metastatic tumor cell lines were much higher than those of primary tumor cell lines. By using our quantitative evaluation of urinary metabolites, we could predict postoperative recurrence with high sensitivity and specificity. Urinary metabolites could be noninvasive biomarkers to improve patient outcome.     

Accurate quantification of urinary metabolites for predictive models manifest clinicopathology of renal cell carcinoma

Using surgically resected tissue, we identified characteristic metabolites related to the diagnosis and malignant status of clear cell renal cell carcinoma (ccRCC). Specifically, we quantified these metabolites in urine samples to evaluate their potential as clinically useful noninvasive biomarkers of ccRCC. Between January 2016 and August 2018, we collected urine samples from 87 patients who had pathologically diagnosed ccRCC and from 60 controls who were patients with benign urological conditions. Metabolite concentrations in urine samples were investigated using liquid chromatography‐mass spectrometry with an internal standard and adjustment based on urinary creatinine levels. We analyzed the association between metabolite concentration and predictability of diagnosis and of malignant status by multiple logistic regression and receiver operating characteristic (ROC) curves to establish ccRCC predictive models. Of the 47 metabolites identified in our previous study, we quantified 33 metabolites in the urine samples. Multiple logistic regression analysis revealed 5 metabolites (l ‐glutamic acid, lactate, d ‐sedoheptulose 7‐phosphate, 2‐hydroxyglutarate, and myoinositol) for a diagnostic predictive model and 4 metabolites (l ‐kynurenine, l ‐glutamine, fructose 6‐phosphate, and butyrylcarnitine) for a predictive model for clinical stage III/IV. The sensitivity and specificity of the diagnostic predictive model were 93.1% and 95.0%, respectively, yielding an area under the ROC curve (AUC) of 0.966. The sensitivity and specificity of the predictive model for clinical stage were 88.5% and 75.4%, respectively, with an AUC of 0.837. In conclusion, quantitative analysis of urinary metabolites yielded predictive models for diagnosis and malignant status of ccRCC. Urinary metabolites have the potential to be clinically useful noninvasive biomarkers of ccRCC to improve patient outcomes.