MRI multiparametric scoring system for pial blood supply of intracranial meningiomas

Background: Meningiomas are occasionally fed by pial blood supply (PBS). It is postulated that peritumoral flow void (PTFV), peritumoral brain edema (PTBE), and absence of an arachnoid plane (AP) are useful parameters for evaluating PBS. Purpose: To determine whether conventional magnetic resonance imaging (MRI) using a multiparametric scoring system (MSS) is a useful way to predict PBS. Material and Methods: Forty-six patients were included and divided: PBS and non-PBS groups. Differences between the groups in six parameters of MR imaging were analyzed: tumor size, tumor location, PTBE grade, AP grade, PTFV, and MIB1 labeling index (MIB1-LI) grade. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis for the differentiation of both groups based on statistically significant parameters. All cases were scored as 1 (PBS) or 0 (non-PBS) for each parameter according to set thresholds. Individual scores were totaled for each case, yielding a combined score for each case to obtain a cutoff value using ROC curve analysis for the MSS. Results: Peritumoral brain edema grade, AP grade, PTFV, and MIB-LI grade were statistically associated with PBS. Receiver operating characteristic curve analyses showed that PTBE grade 3 or 4, AP grade 3 or 4, and PTFV positivity had the highest accuracy of 69%, 64%, and 68%, respectively. Regarding the MSS, a cutoff value of 2 had the highest accuracy of 71%; PBS diagnosis was indicated by at least two of the three parameters, namely, PTBE grade, AP grade, and PTFV. Conclusion: The MSS is a useful way to predict PBS in intracranial meningiomas on MRI

sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

The late-onset form of Tay-Sachs disease displays when the activity levels of human β-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp2-iminosugar glycomimetics related to GalNAc that feature a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and behave as selective nanomolar competitive inhibitors of human Hex A at pH 7 with a ten-fold lower inhibitory potency at pH 5, a good indication for pharmacological chaperoning. They increased the levels of lysosomal HexA activity in Tay-Sachs patient fibroblasts having the G269S mutation, the highest prevalent in late-onset Tay-Sachs disease.Ministerio de Ciencia e Innovación 10.13039/50110001103Fondo Europeo de Desarrollo Regional PID2019-105858RB-I00, RTI2018-097609-B-C21Junta de Andalucía P20_00166Canadian Institutes of Health Research MOP-123341Natural Sciences and Engineering Research Council of Canada RGPIN-06466Japan Society for the Promotion of Science 17K10051Universidad de Sevilla BES-2017–079676, FPU17/0314

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.España Ministerio de Economía y Competitividad (contract numbers CTQ2015-64425-C2-1-R and SAF2016-76083-R)Junta de Andalucía contract number FQM2012-146

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.Ministerio de Economía y Competitividad CTQ2015-64425-C2-1-R , SAF2016-76083-RJunta de Andalucía FQM2012-1467Japan Society for the Promotion of Science JSPS KAKENHI 17K1005

A Case of Granulocyte-Colony Stimulating Factor-Producing Hepatocellular Carcinoma Confirmed by Immunohistochemistry

Granulocyte-colony stimulating factor (G-CSF) is a naturally occurring glycoprotein that stimulates the proliferation and maturation of precursor cells in the bone marrow into fully differentiated neutrophils. Several reports of G-CSF-producing malignant tumors have been published, but scarcely any in the hepatobiliary system, such as in hepatocellular carcinoma (HCC). Here, we encountered a 69-yr-old man with a hepatic tumor who had received right hepatic resection. He showed leukocytosis of 25,450/µL along with elevated serum G-CSF. Histological examination of surgical samples demonstrated immunohistochemical staining for G-CSF, but not for G-CSF receptor. The patient survived without recurrence for four years, but ultimately passed away with multiple bone metastases. In light of the above, clinicians may consider G-CSF-producing HCC when encountering patients with leukocytosis and a hepatic tumor. More cases are needed to clarify the clinical picture of G-CSF-producing HCC

How many times can patients tolerate reoperation?

The frequency of resection for the recurrence of colorectal cancer has not been investigated in previous studies. Likewise, the related postoperative complications and the limit for indicating surgical resection has not been reported. Herein, we reported the complications of a highly frequent surgical approach for rectal cancer recurrence, i.e., exceeding three reoperations, based on our clinical experience. We included 15 cases exceeding two operations for the local recurrence of colorectal cancer from 2014 to 2019. We examined the postoperative complications classified as Clavien–Dindo IIIb. The positive rates of the complications were 0 (0.0%), 0 (0.0%), 2 (13.3%), 3 (37.5%), and 0 (0.0%) for the primary, 1st recurrent, 2nd recurrent, 3rd recurrent, and 4th recurrent operation group (p = 0.027), respectively. It is important to exercise caution in handling cases exceeding two reoperations (exceeding three reoperations including the primary operation)

Peritoneal cecal cancer metastasis to a mesh-plug prosthesis : A case report

We report the case of a 77-year-old man who presented to our hospital with cecal cancer, lung metastasis, and liver metastasis in January 2013. After four courses of modified infusional intravenous fluorouracil and levofolinate with oxaliplatin (mFOLFOX 6) + bevacizumab, there was no new metastatic lesion and lung metastasis reduction was observed. Ileocecal resection was performed in May, left lower lung lobectomy in August, and extended right posterior segmentectomy + S8 partial liver resection was performed in December. The tumor marker declined initially ; thereafter, it gradually increased. Computed tomography (CT) performed in April 2014 revealed right inguinal mass around the mesh-plug prosthesis. A positron emission tomography-CT (PET-CT) also revealed a high 2-fluoro-2-deoxy-D-glucose (FDG) uptake at the same site. Right inguinal tumor resection was performed in July. Cancer tissues were confirmed by performing intraoperative rapid pathological diagnosis, and R0 resection could be achieved. Previous studies have reported malignant tumor metastases to the mesh-plug prosthesis, and this was believed to one of the sites that cancer cells can easily engraft. In particular, in patients with a history of advanced malignant tumors, if mass formation around the artifact insertion site is observed, the possibility of peritoneal metastasis should be considered

Combined resection of re-recurrent lateral lymph nodes and external iliac vein : Case Report and Literature

Herein, we describe the operative procedure for combined resection of re-recurrent lateral lymph nodes and the external iliac vein. There is no consensus on the clinical implications of resection of locally re-recurrent colorectal tumors, as the operative procedure is extremely difficult. We present the case of a 52- year-old woman who underwent abdominoperineal resection. About one year later, we excised a recurrent lymph node in the left lateral obturator area through an extraperitoneal approach. About 18 months later, lymph node re-recurrence in the left external iliac area was observed. Re-recurrent lymph nodes directly invade the left external iliac vein.We removed the re-recurrent lymph node with combined, radical segmental resection of the left external iliac vein, left obturator artery and vein, and left obturator nerve