Association of severity in the grading of microvascular invasion with long-term oncological prognosis after liver resection for early-stage hepatocellular carcinoma: a multicenter retrospective cohort study from a hepatitis B virus-endemic area.

BACKGROUND: The presence of microvascular invasion (MVI) is a significant malignant pathological feature related to recurrence and survival after liver resection for hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between the severity in the grading of MVI and long-term oncological outcomes in patients with early-stage HCC. METHODS: A retrospective study was conducted on a prospectively maintained multicenter database on patients who underwent curative resection for Barcelona Clinic Liver Cancer stage 0/A HCC between 2017 and 2020. Patients were classified into three groups according to the severity in the grading of MVI: M0 (no MVI), M1 (1-5 sites of MVI occurring ≤1 cm away from the tumor), and M2 (>5 sites occurring ≤1 cm and/or any site occurring >1 cm away from the tumor). Recurrence-free survival (RFS) and overall survival (OS) were compared among the groups. RESULTS: Of 388 patients, M0, M1, and M2 of the MVI gradings were present in 223 (57.5%), 118 (30.4%), and 47 (12.1%) patients, respectively. The median OS and RFS in patients with M0, M1, and M2 were 61.1, 52.7, and 27.4 months; and 43.0, 29.1, and 13.1 months (both P <0.001), respectively. Multivariable analyses identified both M1 and M2 to be independent risk factors for OS [hazard ratio (HR): 1.682, P =0.003; and HR: 3.570, P <0.001] and RFS (HR: 1.550, P =0.037; and HR: 2.256, P <0.001). CONCLUSION: The severity in the grading of MVI was independently associated with recurrence and survival after HCC resection. Patients with the presence of MVI, especially those with a more severe MVI grading (M2), require more stringent recurrence surveillance and/or active adjuvant therapy against recurrence.

Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity.

Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chemical agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compounds are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death.

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway.

Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Diagnostic value of endobronchial ultrasound guided transbronchial needle aspiration in superior vena cava syndrome.

BACKGROUND: The pathological diagnosis is of critical importance to the subsequent treatment for the pathients with superior vena cava syndrome (SVCS). The aim of this study is to report our experience in the diagnosis of SVCS by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). METHODS: The data of 520 patients who underwent EBUS-TBNA from September 2009 to May 2012 at our institution were reviewed. Of these, there were 14 males and 6 females (mean age of 59.1 years) with SVCS who received EBUS-TBNA that were included in the analysis. RESULTS: The mean short axis diameter of the paratracheal lesions was (3.32 ± 1.79) cm (range, 1.69 to 9.50 cm) and 6 cases also had subcarinal lymph node enlargement with a mean short axis diameter of (2.14 ± 0.49) cm (range, 1.73 to 3.01 cm). An average of 4.3 punctures was performed per lesion. Malignancy was confirmed in 16 cases (10 small cell carcinomas, 4 adenocarcinomas, 1 squamous cell carcinoma and 1 Hodgkin lymphoma). In two patients, pathological examination of tissue revealed no evidence of malignancy and for 13 to 24 months of follow-up. One patient from whom adequate tissue was not obtained refused further surgical biopsy since he had undergone endovascular stenting of the SVC. One patient in whom a diagnosis was not obtained by EBUS-TBNA underwent thoracoscopic biopsy and the final diagnosis was B cell non-Hodgkin's lymphoma. The diagnosis accuracy of EBUS-TBNA in SVCS was 18/20 patients. CONCLUSION: EBUS-TBNA is a highly effective and safe procedure for the diagnosis of SVCS.

[Preliminary comparison research of thoracoscopy and thoracotomy lobectomy for clinical N0 and post-operatively pathological N2 non-small cell lung cancer].

OBJECTIVE: To evaluate the safty, thoroughness and efficacy of the video-assisted thoracoscopic surgery compared with open thoracotomy, in treatment of patients with the preoperative staging of lymph node negative and postoperative pathological mediastinal lymph node positive (cN0-pN2) locally advanced non-small cell lung cancer(NSCLC). METHODS: We performed a retrospective review of 616 patients who underwent either VATS lobectomy or open thoracotomy from July 2000 to December 2009. Of which 386 patients were diagnosed with preoperative staging of lymph node negative(cN0) non-small cell lung cancer. Of the 386 patients 76 were diagnosed with postoperative pathological mediastinal lymph node positive (pN2). Twenty-nine patients were operated by video-assisted thoracoscopic surgery (VATS group), 47 patients were operated by open thoracotomy(T group).The patients' preoperative and intraoperative conditions, postoperative survival and recurrence, etc. were compared. RESULTS: The two groups were similar in age, gender distribution, pulmonary function, preoperative complications and the preoperative clinical stage. VATS group was slightly lower than T group in operation time, and blood loss. The station number of mediastinal lymph nodes dissection was (3.3±1.1) vs. (3.3±1.3), P=0.959; the number of lymph nodes dissected (12.7±8.9) vs. (10.5±7.2),P=0.260; positive lymph nodes / lymph nodes dissection 28.7% vs. 32.5%, P=0.592; the postoperative proportion of single-station N2 55.2% vs. 66.0%(P=0.189) in VATS group and T group, respectively. One, three-year disease-free survival rates after operation in VATS and T group were 82.6% vs.69.2%(P=0.088) and 49.3% vs. 51.3% respectively(P=0.996); one, three-year overall survival rates were 84.9% vs. 71.2%(P=0.149) and 64.0% vs. 42.7% (P=0.121). Both groups had the similar pattern of recurrence, most of which were distant metastases. CONCLUSION: With respect to the safety,thoroughness and recent effect, VATS is not inferior to open thoracotomy in the treatment of cN0-pN2 non-small cell lung cancer.

Multiple intracranial lesions: a clinicalpathologic study of 62 cases / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicalpathologic features of intracranial multiple lesions.</p><p><b>METHODS</b>The clinical, radiologic and pathologic features of intracranial multiple lesions in 62 cases during the period from 2005 to 2009 in Xuanwu Hospital were retrospectively reviewed.</p><p><b>RESULTS</b>There were 32 males and 30 females in 62 cases. The mean age of seize onset and duration of disease were 37.4-year-old and 11.6 months, respectively. The lesions could affect cerebral hemisphere, basal ganglia, brain stem, cerebellum and other parts, most lesions were located above the tentorium. Pathological diagnosis as follows: 13 patients with glioma; metastatic tumors in 13 cases; 12 cases of central nervous system infection; immune-mediated inflammatory demyelinating disease in 8 cases; 5 cases of primary lymphoma of central nervous system; primary angiitis of the central nervous system 3 cases; mitochondrial encephalopathy 2 cases; vein thrombosis in 2 cases; Rosai-Dorfman disease in 2 cases; 2 case of radiation encephalopathy. Among them, mitochondrial encephalopathy and vein thrombosis lesions located in the cortex; metastatic tumor and blood-borne infection mainly involving junction of grey and white matter; glioma, radiation encephalopathy and demyelinating disease include white matter lesions; vascular inflammation showed cortical and subcortical white matter lesions.</p><p><b>CONCLUSIONS</b>A variety of tumor and non-neoplastic diseases can be expressed in intracranial multiple lesions, which gliomas, metastatic tumor and central nervous system infections are more common. In order to improve the diagnosis of intracranial multiple lesions, active work in the brian biopsy, study the clinical, imaging and pathological findings must be closely.</p>

Diagnostic use of D2-40 and annexin-1 in ependymal tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate the diagnostic significance of D2-40 and annexin-1 in the ependymal tumors.</p><p><b>METHODS</b>To analyses the expression of D2-40, annexin-1, EMA and Ki-67 by immunohistochemistry in 52 cases of ependymal tumors (48 cases of ependymomas, 4 cases of choroid plexus papilloma) from Xuanwu Hospital from 2005 to 2009. Ten cases of corresponding normal brain tissue were also obtained as control.</p><p><b>RESULTS</b>Thirty-two of forty-eight (66.7%) cases of ependymomas were positive for D2-40. "Dot-like" and "ring-like" structures were commonly observed in ependymomas (55.3%, 21 of 38 cases) and anaplastic ependymomas (5 of 6 cases) with D2-40 staining. There was no difference in the expression between D2-40 and Ki-67 (r(s) = -0.013, P = 0.931). For annexin-1, 87.5% (42 of 48 cases) of the ependymomas were positive. The specific "granular structures" and cilium were observed in ependymomas (1 of 4 cases of myxopapillary ependymomas and 11 of 38 cases of ependymomas respectively) for annexin-1. The difference in expression between annexin-1 and Ki-67 was statistically significant (r(s) = -0.405, P = 0.005). D2-40 in combination of EMA and annexin-1 increased the positive rate to 100% in ependymomas. Choroid plexus papillomas were all positive for D2-40 and annexin-1. The control tissue was negative for D2-40 but positive for annexin-1 in the capillaries.</p><p><b>CONCLUSIONS</b>The specific structures are valuable in diagnosing of ependymal-genetic tumors, and are highlighted by D2-40 and annexin-1. D2-40 in combination of EMA and annexin-1 is a useful diagnostic marker for ependymal tumors.</p>

Expression and diagnostic significance of CD34 in brain tumors of patients with refractory epilepsy / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the immunohistochemical expression and diagnostic significance of CD34 in brain tumors of patients with refractory epilepsy.</p><p><b>METHODS</b>Immunohistochemical study for CD34 was performed on formalin-fixed paraffin-embedded tissue blocks of 54 cases of brain tumors occurring in patients with refractory epilepsy. The tumor types included ganglioglioma (GG, number = 21), dysembryoplastic neuroepithelial tumor (DNT, number = 8), tumors/lesions which had the transitional features that between glioneuronal hamartia and mixed neuronal-glial tumor (number = 21) and pleomorphic xanthoastrocytoma (PXA, number = 4). Cases of glioblastoma (number = 4) and oligoastrocytoma (number = 5) were used as controls.</p><p><b>RESULTS</b>Twenty of the 21 cases of GG, 1 of the 8 cases of DNT, 16 of the 21 cases of tumors/lesions which had the transitional features and 3 of the 4 cases of PXA showed cytoplasmic and membranous positivity for CD34. The adjoining brain tissues in 9 of the 18 cases of GG, 6 of the 16 cases of tumors/lesions which had the transitional features and 1 of the 3 cases of PXA also expressed CD34. In contrast, only 1 case of glioblastoma showed membranous positivity for CD34.</p><p><b>CONCLUSIONS</b>CD34 preferred to staining for GG and PXA. Which represent a valuable tool for distinguishing GG, PXA and DNT, oligoastrocytoma, glioblastoma.</p>

Brain tumors in patients with intractable epilepsy: a clinicopathologic study of 35 cases / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathologic features of brain tumors occurring in patients with medically intractable epilepsy.</p><p><b>METHODS</b>The clinical, radiologic and pathologic features of brain tumors occurring in 35 patients with intractable epilepsy encountered during the period from January, 2005 to April, 2008 in Xuanwu Hospital were retrospectively reviewed.</p><p><b>RESULTS</b>The mean age of seizure onset and duration of disease were 14.3-year-old and 8.6 years, respectively. Abnormal signals were observed in 94.3% of cases (33/35) by magnetic resonance imaging. The histologic types of brain tumors included ganglioglioma (13/35, WHO grade I and 6/35, WHO grade II), dysembryoplastic neuroepithelial tumor (3/35, WHO grade I), pleomorphic xanthoastrocytoma (3/35, WHO grade II), diffuse astrocytoma (1/35, WHO grade II), oligoastrocytoma (1/35, WHO grade II), angiocentric glioma (1/35, WHO grade I) and meningioangiomatosis (1/35). The 6 remaining cases showed features seen in between glioneuronal hamartoma and mixed neuronal-glial tumor. Most of these tumors were located in the temporal lobe (27/35) and associated with focal cortical dysplasia. Immunohistochemical study showed a remarkable expression of CD34 in gangliogliomas.</p><p><b>CONCLUSIONS</b>Brain tumors in patients with medically intractable epilepsy are almost always benign and located in the temporal lobe. Most of them represent mixed neuronal-glial tumors and some show transitional features in-between glioneuronal hamartoma and mixed neuronal-glial neoplasm. The similar morphologic pattern and biological behavior of glioneuronal hamartoma and mixed neuronal-glial tumor may suggest a common pathogenetic mechanism.</p>

Expression of drug resistance-associated proteins in brain of patients with refractory epilepsy / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the expression of P-glycoprotein, multi-drug resistance associated protein and major vault protein in pathologic brain specimens, and to investigate their roles in the pathogenesis of refractory epilepsy.</p><p><b>METHODS</b>Immunohistochemical study was performed in pathology specimens from 18 cases of refractory epilepsy (including 5 cases of focal cortical dysplasia, 3 cases of tuberous sclerosis, 5 cases of ganglioglioma and 5 cases of dysembryoplastic neuroepithelial tumor).</p><p><b>RESULTS</b>Both the P-glycoprotein and major vault protein were localized in microvascular endothelium of the lesions. Major vault protein was also seen in balloon cells and some neuronal cells. On the other hand, multi-drug resistance associated protein was mainly localized in the neuronal component of the lesions. In general, the expression of P-glycoprotein and major vault protein in tumoral tissue was higher than that in non-tumoral tissue. The expression of multi-drug resistance associated protein and major vault protein was also different in the neoplastic glial cells of ganglioglioma and dysembryoplastic neuroepithelial tumor.</p><p><b>CONCLUSIONS</b>P-glycoprotein, multi-drug resistance associated protein and major vault protein contribute to the pathogenesis of refractory epilepsy. They may however have different roles, with different cellular localization.</p>

Research on distribution and expression of NMDA receptors and parvalbumin-positive neurons in intractable epilepsy-related focal cortical dysplasia / 中华病理学杂志

<p><b>OBJECTIVE</b>To evaluate the alteration of subunits composition in NMDA receptor and the alterations of the expression and distribution of NMDA receptors and parvalbumin (PV)-positive neurons in focal cortical dysplasia (FCD) cortices.</p><p><b>METHODS</b>Twenty cases of FCD samples (including all four subtypes of FCD) obtained during epilepsy surgery and 4 controls were analysed by immunohistochemical staining for NR1, NR2A/B and PV.</p><p><b>RESULTS</b>Increased expression of NR1 was detected in the giant neurons and dysmorphic neurons in FCD; while pronounced expression of NR2A/B was detected in immature neurons, giant neurons and dysmorphic neurons of FCD, especially in somata and processes of the immature neurons. Compared with the controls, FCD cortices showed prominent scattered arrangement of PV positive neurons and fibers, dramatically decreased number of PV positive interneurons and PV background staining, especially in foci of FCD II subtype.</p><p><b>CONCLUSION</b>There are increased expressions of NR1 and NR2A/B subunits in FCD abnormal neurons, as well as scattered and reduced expressions of PV positive neurons and fibers in FCD cortices.</p>

Quantification and distribution of white matter neurons in the temporal lobe of normal individuals / 中华神经科杂志

Objective To quantify the neurons in the temporal lobe white matter and find their distribution in the neurologically normal individuals.Methods The temporal lobe at the level of exterior geniculata body from brain autopsy samples of 14 neurologically normal individuals were made into large slice followed by quantitative analysis of neuron density,cell density,ratio and diameter of the neuronal nuclear and the distribution of white matter neurons using two-dimensional cell counting methods.Results With the depth of the white matter of the temporal lobe increasing,the neuron density decreased from 29.26 neurons/ mm~2 to 7.32 neurons/mm~2 and 0.00 neurons/mm~2,respectively;the cell density,neuron ratio and diameter of the neuronal nuclei all decreased.Conclusion There are neurons in the temporal lobe white matter of neurologically normal individuals,whose distribution of neurons is related to the depth of white matter.

Preparation of Enantiomerically Enriched (2R,3R)- or (2S,3S)-trans-2,3-Diaryloxiranes via Camphor-Derived Sulfonium Ylides.

Easily available D-(+)-camphor-derived sulfides 3, 4, 6, and 7 were employed for enantioselective epoxidation via an ylide route. When benzylated or methylated sulfides were used as reagents or mediators for benzylidene transfer, stoichiometric and catalytic epoxidations were realized, respectively. Opposite asymmetric induction was achieved only when sulfides containing exo- (3 and 4) and endo- (6 and 7) alkylthio groups were used. That is, both (+)- and (-)-trans-diaryloxiranes could be obtained in excellent yields and moderate to good ee values under extremely mild conditions from the same chiral pool-derived reagents. A nonbonded interaction between the free OH in the ylides from sulfides (3, 6, and 7) and the carbonyl group of aldehydes controls the approach of the substrates to the ylidic carbon preferentially at one specified face and therefore leads to a more efficient asymmetric induction than that in the case of the ylide from methyl-protected hydroxylated sulfides 4, which cannot cause such an interaction. The same opposite asymmetric induction was also observed in the catalytic reaction with methyl-protected hydroxylated sulfide 4b and unprotected hydroxylated sulfide 3b.