Background The roles of infiltrating macrophages within the tumor microenvironment are complex because of their functional variety. The aim of this study is to examine the role and prognostic ...significance of tumor-associated macrophages (TAMs) that have an M2 polarized function in pancreatic cancer. Materials and Methods Formalin-fixed, paraffin-embedded blocks were obtained from 76 patients with pancreatic head cancer. All patients underwent macroscopic curative resection. We assessed the number of infiltrating macrophages within the tumor invasive front by not only CD68 but also by CD163 and CD204, which are specific receptors on M2-polarized macrophages. Furthermore, to evaluate lymphangiogenesis, we measured the density of lymphatic vessels in the tumor invasive front by using D2-40. Results High incidence of lymph node metastasis was shown in cases with a high number of CD163- or CD204-positive macrophages. Significantly increased lymphatic vessel density (LVD) was shown in cases with lymph node metastasis compared with cases without lymph node metastasis ( P = 0.0094). Significantly increased LVD ( P = 0.0175) and a poor prognosis ( P = 0.0171) were shown in cases with a high number of macrophages that express CD163 or CD204, however, there was no significant difference according to the number of CD68-positive macrophages. Conclusions M2-polarized TAMs in the invasive front of pancreatic cancer are associated with a poor prognosis due to accelerated lymphatic metastasis, and inhibition of the functional interaction between M2-polarized TAMs and tumor cells may improve the prognosis.
Objective
We aimed to develop and assess the efficacy of a liver function index that combines liver enhancement and liver volume to standard liver volume (LV/SLV) ratio on gadolinium ethoxybenzyl ...diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MRI.
Methods
In all, 111 patients underwent a Gd-EOB-DTPA-enhanced MRI, including T1 mapping, before and 20 min after Gd-EOB-DTPA administration. We calculated the following Gd-EOB-DTPA-enhanced MRI-based liver function indices: relative enhancement of the liver, corrected enhancement of the liver-to-spleen ratio, LSC_N20, increase rate of the liver-to-muscle ratio, reduction rate of T1 relaxation time of the liver, ΔR1 of the liver and
K
Hep
; the indices were multiplied by the LV/SLV ratio. We calculated the correlations between an indocyanine green (ICG) clearance and the Gd-EOB-DTPA-enhanced MRI-based liver function indices multiplied by the LV/SLV ratio, by using Pearson correlation analysis.
Results
There were significant correlations between all Gd-EOB-DTPA-enhanced MRI-based liver function indices and ICG clearance (
r
= −0.354 to −0.574,
P
< 0.001). All Gd-EOB-DTPA-enhanced MRI-based liver function indices multiplied by the LV/SLV ratio (
r
= −0.394 to −0.700,
P
< 0.001) were more strongly correlated with the ICG clearance than those without multiplication by the LV/SLV ratio.
Conclusions
Gd-EOB-DTPA-enhanced MRI-based liver function indices that combine liver enhancement and the LV/SLV ratio may more reliably estimate liver function.
Key points
•
Gd-EOB-DTPA-enhanced MRI is useful for assessing liver function.
•
Liver enhancement on Gd-EOB-DTPA-enhanced MRI correlates with indocyanine green (ICG) clearance.
•
Liver volume to standard liver volume (LV/SLV) ratio correlates with ICG clearance.
•
Liver enhancement and LV/SLV ratio help to estimate liver function.
In addition to conventional cytology, liquid-based cytology (LBC) is also used for immunocytochemistry and gene analysis. However, an appropriate method to obtain high quality DNA for next-generation ...sequencing (NGS) using LBC specimens remains controversial. We determined the optimal conditions for fixation with an alcohol-based fixative for LBC and DNA extraction using cultured cancer cell lines and clinical specimens. The extracted DNA was processed for NGS after the DNA quality was confirmed based on the DNA concentration and degree of degradation. The optimal conditions for cultured cells to obtain high quality DNA were to fix the cells at a density of 6 × 103 or 2 × 104 cells/mL and to use the magnetic bead-based DNA extraction method. Even after storing the fixed cells for 90 days, DNA extracted using the above and other extraction kits, including membrane-based methods, did not undergo degradation. Furthermore, 5-year-old residual LBC samples demonstrated high DNA quality that was suitable for NGS. Furthermore, a cancer genome panel analysis was successfully performed with DNA extracted from cultured cells fixed at 6 × 103 cells/mL for 90 days, and with DNA from residual LBC samples even after 1 year of storage. Residual LBC samples may be a useful source of DNA for clinical NGS to promote genome-based cancer medicine.
Parkinson's disease, the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. FBXO7 (F-box protein only 7) (PARK15) mutations cause ...early-onset Parkinson's disease. FBXO7 is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its neuronal relevance and function have not been elucidated. To determine its function in neurons, we generated neuronal cell-specific FBXO7 conditional knockout mice (FBXO7
: Nestin-Cre) by crossing previously characterized FBXO7 floxed mice (FBXO7
) with Nestin-Cre mice (Nestin-Cre). The resultant Fbxo7
: Nestin-Cre mice showed juvenile motor dysfunction, including hindlimb defects and decreased numbers of dopaminergic neurons. Fragmented mitochondria were observed in dopaminergic and cortical neurons. Furthermore, p62- and synuclein-positive Lewy body-like aggregates were identified in neurons. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system that includes the ubiquitin-proteasome system, in controlling intracellular inclusion body formation. These data indicate that the pathologic processes associated with the proteolytic and mitochondrial degradation systems play a crucial role in the pathogenesis of PD.
Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid ...condition, LBC specimens are suitable for genetic analyses.
Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues.
A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases.
These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.
Background
This study aimed to examine the prognostic relevance of glucose transporter type 1 (GLUT-1), which is a key regulator of the glucose metabolism. In particular, the study aimed to examine ...the association between GLUT-1 expression and the therapeutic effect of chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC).
Methods
Patients with PDAC were enrolled in the study. Patients with distant metastases and those who received only chemotherapy as treatment were excluded from the study. Specimens for immunohistochemical evaluations were obtained through surgical resection and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the primary tumor before any treatment.
Results
This study included 197 patients. Of these 197 patients, 100 underwent upfront surgery, and 97 received neoadjuvant CRT (NACRT), which was performed mainly for patients with locally advanced tumors. Of the 97 patients who received NACRT, 21 later underwent surgical resection. For the patients who underwent upfront surgery, low GLUT-1 expression was an independent factor for a better prognosis. For the patients who underwent NACRT, low GLUT-1 expression was significantly associated with greater tumor size reduction, a higher resection rate, and a better prognosis. Additionally, GLUT-1 expression was significantly increased after NACRT treatment.
Conclusions
Among the patients with PDAC, those with low GLUT-1 expression in the primary tumor had a better prognosis those with high GLUT-1 expression. Moreover, the patients with low GLUT-1 expression displayed a better therapeutic response to NACRT.
Purpose
To investigate the differences in nutritional status 1 year after pancreaticogastrostomy (PG) using vertical suturing (VS) vs. twin square horizontal mattress (HMS) suturing in patients ...undergoing pancreaticoduodenectomy (PD).
Methods
The subjects of this study were 134 patients who underwent PD, followed by PG, which was closed by VS in 52 and by HMS in 82. We evaluated the peri- and postoperative factors, nutritional parameters, diameter of the remnant main pancreatic duct, and glucose intolerance 1 year postoperatively.
Results
Forty-five (87%) patients from the VS group and 75 (91%) patients from the HMS group survived for more than 1 year. The incidences of intraabdominal abscess and pancreatic fistula were significantly lower in the HMS group than in the VS group (19.2% vs. 6.6% and19.2% vs. 2.6%, respectively). There were no significant changes in the total protein, serum albumin, and HbA1c levels 1 year postoperatively. The postoperative expansion ratio of the main pancreatic duct diameter was significantly smaller in the HMS group than in the VS group. The strongest risk factor for body weight loss 1 year postoperatively was a non-soft pancreas texture.
Conclusion
HMS was superior to VS for preventing early postoperative complications and did not affect pancreatic function.
Background
Although lymph node metastasis (LNM) has been considered an important prognostic factor for intrahepatic cholangiocarcinoma (ICC), the impact of lymph node enlargement on the prognosis of ...ICC, and the accuracy of diagnosis of LNM, have not been fully clarified.
Methods
Using a chart review of 225 patients with ICC, we compared survival times between patients with and without lymph node enlargement, and we evaluated the accuracy of diagnosis of LNM. We also performed a multivariate analysis to determine the variables affecting overall survival in the study population.
Results
The survival time of patients without lymph node enlargement was significantly longer than that of patients with lymph node enlargement (median survival time MST 43.7 vs. 20.1 months;
p
= 0.007). However, in the group with enlarged lymph nodes, survival time was prolonged as a result of hepatectomy (MST 20.1 vs. 7.6 months;
p
< 0.01). The sensitivity of lymph node size and positron emission tomography–computed tomography findings for diagnosing LNM were 50.0 % (23/46) and 31.2 % (5/16), respectively, and were thus insufficient. Multivariate analysis identified the serum carcinoembryonic antigen (hazard ratio HR 1.830) and carbohydrate antigen 19-9 (HR 2.189) levels, blood transfusion (HR 1.792), intrahepatic metastasis (HR 1.988), and final stage (HR 8.684) as prognostic factors for overall survival, but lymph node enlargement was not identified as a prognostic factor.
Conclusion
Preoperative evaluation of LNM proved to be difficult, and survival time in ICC patients with lymph node enlargement was prolonged as a result of hepatectomy. Thus, ICC patients with preoperative lymph node enlargement should not be prematurely deemed non-curative cases.
The aim of this study was to identify risk factors for early recurrence and assess the prognostic benefit of neoadjuvant therapy (NAT) for resectable pancreatic cancer.
Patients with radiographically ...resectable pancreatic cancer according to the National Comprehensive Cancer Network guidelines were enrolled. We regarded recurrence within 6 months after surgery as early recurrence.
This study involved 115 patients (80 who underwent upfront surgery and 35 who received NAT). Serum carbohydrate antigen 19-9 greater than 85 U/mL and p53 expression in 0 or more than 80% of tumor cells were independent risk factors for early recurrence after upfront surgery. We classified patients into a high-risk group (1 or 2 risk factors) and a low-risk group (no risk factors). In the high-risk group, the median overall survival time of patients with NAT was significantly longer than that of patients without NAT (P = 0.028). By contrast, the median overall survival time was not different according to NAT in the low-risk group.
Serum carbohydrate antigen 19-9 and p53 expression of the primary tumor could be predictors of early recurrence in patients with resectable pancreatic cancer. The prognosis of patients with a high risk of early recurrence may be improved using NAT.
Human leukocyte antigen (HLA)-class I molecules on tumor cells have been regarded as crucial sites where cytotoxic T lymphocytes (CTL) can recognize tumor-specific antigens and are strongly ...associated with anti-tumor activity. However, the clinical impact of HLA class I expression in breast cancer has not been clarified.
A total of 212 breast cancer patients who received curative surgery from 1993 to 2003 were enrolled in the current study. HLA class I expression was examined immunohistochemically using an anti-HLA class I monoclonal antibody. The correlation between HLA class I positivity and clinical factors was analyzed.
The downregulation of HLA class I expression in breast cancer was observed in 69 patients (32.5%). HLA class I downregulation was significantly associated with nodal involvement (p < 0.05), TNM stage (p < 0.05), lymphatic invasion (p < 0.01), and venous invasion (p < 0.05). Patients with preserved HLA class I had significantly better disease-free interval (DFI) than those with loss of HLA class I (p < 0.05). However, in multivariable analysis, HLA class I was not selected as one of the independent prognostic factors of disease-free interval.
The examination of HLA class I expression is useful for the prediction of tumor progression and recurrent risk of breast cancer via the antitumor immune system.
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