ACE2 and TMPRSS2 immunolocalization and oral manifestations of COVID-19.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the host cells depends on the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). We investigated the distribution of ACE2- and TMPRSS2-expressing cells in various oral tissues to identify the underlying mechanism of oral manifestations in patients with coronavirus disease 2019. SUBJECTS: We analyzed the expression patterns of ACE2 and TMPRSS2 in the oral mucosa (tongue, palate, and buccal mucosa), trigeminal ganglion, vessels, and salivary glands of 9 Sprague-Dawley rats using immunohistochemistry and immunofluorescence. RESULTS: ACE2 and TMPRSS2 were strongly expressed in the intermediate layer of the squamous epithelia of tongue papillae and buccal mucosa. ACE2- and TMPRSS2-positive cells were observed in the taste buds of the tongue. Additionally, ACE2 and TMPRSS2 were co-expressed in the ductal epithelium and acinar cells of salivary glands. Furthermore, both ACE2 and TMPRSS2 were stained in the neuronal cell body of trigeminal ganglia, but not in Schwann cells. Moreover, ACE2 and TMPRSS2 were expressed in capillaries, but not in venules/arterioles. CONCLUSIONS: SARS-CoV-2 can spread the suprabasal area of squamous epithelia of the oral mucosa, invades taste bud, trigeminal nerve, parotid gland, and microvessel, resulting in oral manifestations.

Relationship between 18F-FDG uptake and heat shock protein 90α expression in colorectal cancer.

OBJECTIVE: We investigated whether heat shock protein 90α (HSP90α) expression is associated with fluorine-18-labeled fluoro-2-deoxy-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography/computed tomography (PET/CT) can be used to predict the status of HSP90α expression in colorectal cancer (CRC). SUBJECTS AND METHODS: The medical records and preoperative 18F-FDG PET/CT studies of 51 patients with newly diagnosed CRC who underwent surgical treatment were retrospectively reviewed. The maximum standardized uptake value (SUVmax) of the primary tumor was calculated from the level of 18F-FDG uptake. HSP90α expression was determined by immunohistochemistry. The relationship between SUVmax and HSP90α expression was analyzed. RESULTS: Colorectal cancer with high HSP90α expression had significantly higher SUVmax than CRC with low HSP90α expression (18.88±10.06 vs. 12.38±5.04, P=0.003). There was a significant correlation between HSP90α expression and 18F-FDG uptake (r=0.354, P=0.011). The highest accuracy for determining HSP90α status (68.6%) was obtained with a SUVmax cut-off of 15.4. Maximum SUV was the only predictor of HSP90α expression on multivariate logistic regression analysis (Odds Ratio=5.384, P=0.016). CONCLUSION: The expression status of HSP90α was significantly related to 18F-FDG uptake in CRC.

Clinically Node-Negative Parotid Gland Cancers: Prognostic Factors of Survival and Surgical Extent.

OBJECTIVE: Conservative parotidectomy is known to reduce morbidity, but has been rarely examined in patients with clinically node-negative (cN0) parotid cancers. We evaluated the clinicopathological variables influencing the outcomes of these patients and the efficacy of conservative parotidectomy. METHODS: We reviewed the clinical and pathological data of 256 patients with cN0 parotid carcinomas who underwent curative surgery at our institution. Of these, 110 and 146 underwent conservative and total parotidectomy, respectively, with 83 undergoing elective neck dissection and 135 receiving postoperative radiotherapy. Univariate and multivariate analyses of variables predicting recurrence-free survival (RFS) and overall survival (OS) were performed. Morbidity, survival, and recurrence rates were compared between the conservative and total parotidectomy groups. RESULTS: The 5-year RFS and OS rates in all patients were 85.7 and 91.4%, respectively. Multivariate analysis showed that advanced T classification, positive resection margin, and high-histologic grade were independent prognostic factors for both RFS and OS. Among the 201 patients with low- or intermediate-grade parotid cancers, those who underwent total parotidectomy had a greater chance of facial nerve paralysis than those who underwent conservative parotidectomy (p < 0.001). The 5-year RFS and OS after conservative parotidectomy (93.7 and 100%, respectively) were not worse than those after total parotidectomy (85.5 and 90.9%, respectively). CONCLUSION: Patients with cN0 parotid cancers may be stratified by histological grade and T classification. Conservative parotidectomy may be suitable for early T1-2 low- or intermediate-grade tumors if a resection margin is secured.

Clinicopathologic characteristics of early gastric cancer according to specific intragastric location.

BACKGROUND: Although the incidence of early gastric cancer (EGC) continues to rise, there have been few studies on the intra-gastric distribution and locational characteristics of EGCs. In addition, there has been no attempt to visualize the intra-gastric distribution of EGCs using a merged tumor map. METHODS: We investigated the anatomic distribution of 644 cases of EGCs and analyzed the correlation between clinicopathologic findings and location by dividing areas of the stomach vertically and transversely. Merged tumor maps were generated using 310 surgically resected cases. RESULTS: Early gastric cancer was most commonly located in the antrum (57.5%) along the lesser curvature (37.8%). The intra-gastric distributions were similar in the merged tumor maps. Vertically, cancers of the middle third were associated with younger patient age, larger tumor size, and more frequent poorly differentiated (PD) or signet ring cell histology than cancers in other sites. Submucosal invasion was most frequently observed in the upper third. When divided transversely, tumors in the anterior or posterior wall showed more frequent PD or signet ring cell histology than those along the lesser or greater curvatures. CONCLUSIONS: EGC is the most prevalent in the antrum along the lesser curvature and has characteristic locational features, including histologic type, invasion depth, patient age, and tumor size. These results will improve the endoscopic detection rate of EGC and help to determine endoscopic resectability.

Survival Outcome of Intermediate-Grade Salivary Gland Carcinoma.

OBJECTIVE: Histological grade is the most important factor for defining treatment strategies and predicting prognosis for salivary gland carcinoma (SGC). We examined factors affecting long-term recurrence and survival among intermediate-grade SGC (IGSGC) patients to define optimal treatment modalities and outcomes. METHODS: We reviewed the clinical and pathological data on 108 IGSGC patients who underwent definitive surgery with or without postoperative radiotherapy. We compared treatment outcomes by treatment strategies such as surgical extent for the primary tumor, neck dissection, or postoperative radiotherapy. RESULTS: During a 103-month median follow-up, local, regional, and distant recurrences were detected in 14 (13.0%), 3 (2.8%), and 21 (19.4%) patients, respectively. The 10-year locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 83.1, 76.0, and 80.1%, respectively. Multivariate analyses identified a nonparotid primary site as an independent prognostic factor for LRC (p = 0.018). Adenoid cystic carcinoma and a positive pN classification were significantly unfavorable prognostic factors for DMFS (p = 0.025 and p = 0.030, respectively); overall advanced stage was an independent prognostic factor for OS (p = 0.020). Surgical extent, elective neck dissection, and postoperative adjuvant radiotherapy did not significantly affect treatment outcomes. CONCLUSION: Patients with early-stage IGSGC of parotid origin can achieve favorable treatment outcomes with conservative surgery alone.

High-level expression of Hsp90ß is associated with poor survival in resectable non-small-cell lung cancer patients.

AIMS: The aim of this study was to investigate the expression of Hsp90ß and GRP94, and elucidate the clinical significance of their expression, in patients with resectable non-small-cell lung cancer (NSCLC). METHODS AND RESULTS: Surgical tissue specimens were obtained from 208 patients with NSCLC who underwent surgical resection. The expression levels of Hsp90ß and GRP94 were assessed with tissue microarrays and immunohistochemistry. No correlations were observed between Hsp90ß or GRP94 expression and several clinicopathological factors. The high-Hsp90ß group [median overall survival (OS) 20.4 months; 95% confidence interval (CI) 0.000-40.864] showed a significant decrease in OS as compared with the low-Hsp90ß group (median OS not reached; P = 0.003). In contrast to the Hsp90ß analysis, the GRP94 analysis did not show a difference in OS. Moreover, in subgroup analyses of patients with squamous cell carcinoma histology, OS (P = 0.012) and relapse-free survival (P = 0.044) were significantly worse in the high-Hsp90ß group than in the low-Hsp90ß group. Multivariate analysis suggested that old age [hazard ratio (HR) 1.568; 95% CI 1.019-2.412; P = 0.041], advanced disease (HR 2.066; 95% CI 1.218-3.502; P = 0.007) and high Hsp90ß expression (HR 1.802; 95% CI 1.061-3.060; P = 0.029) were independent poor prognostic factors for OS. CONCLUSIONS: Hsp90ß expression might be a useful marker of poor OS, although further large prospective studies are warranted to validate our findings.

High nuclear expression of protein arginine methyltransferase-5 is a potentially useful marker to estimate submucosal invasion in endoscopically resected early colorectal carcinoma.

Protein arginine methyltransferase-5 (PRMT5), a major type II arginine methyltransferase, is an important epigenetic modifier with oncogene-like properties because of its ability to repress the expression of tumor suppressor genes. We determined the correlations between PRMT5 expression or its cellular localization and malignant progression, with special reference to invasiveness, in colorectal adenomas and early colorectal carcinomas (CRCs). We performed immunohistochemical detection of PRMT5 in 108 endoscopically resected tissue samples (6 adenomas with low-grade dysplasia, 34 adenomas with high-grade dysplasia, 30 intramucosal carcinomas, and 38 submucosal invasive carcinomas). Early CRC (55 of 68, 80.9%) showed more frequent nuclear expression of PRMT5 than adenoma (15 of 40, 37.5%) (P < 0.001). Furthermore, high (strong staining in ≥ 50% of nuclei) nuclear expression of PRMT5 was more common in submucosal invasive carcinoma (21 of 38, 55.3%) than in intramucosal carcinoma (9 of 30, 30.0%) (P = 0.037). In conclusion, our data suggests that high nuclear expression of PRMT5 is a potentially useful marker for estimating submucosal invasion of early CRC in endoscopically resected specimens.

Modified seromuscular patch flap for reinforcing an anastomosis site in hypopharyngeal reconstruction using free jejunal transfer: an anatomical and clinical study.

INTRODUCTION: Free jejunal transfer is commonly used as a reliable reconstructive method after total pharyngolaryngectomy. An anastomotic fistula is the most common complication in the early postoperative period, occurring in 5% to 35% of cases. There have been several studies regarding surgical techniques for minimizing fistula formation. Specifically, the vascularized seromuscular patch flap has been used for reinforcing the anastomosis site; however, this flap does not yield a sufficient range of motion because of traction on the vascular pedicle. METHODS: Between 2004 and 2011, 4 patients underwent vascularized seromuscular patch flaps with free jejunal transfer. A short segment of jejunum on a mesenteric pedicle is usually opened longitudinally along the antimesenteric border to make a patch flap; however, we made a longitudinal incision along 1 side of the mesenteric border. To investigate the vascular anatomy of the flap, a lead oxide-gelatin mixture was injected into the arterial system of 4 fresh cadavers. RESULTS: The flap had increased mobility without traction on the vascular pedicle and adequate circulation. In the injection study, it was shown that the modification guaranteed adequate circulation across the antimesenteric border and from the proximal to the distal end of the flap. CONCLUSION: In conclusion, an incision along 1 side of the mesenteric border produces increased mobility of the jejunal seromuscular patch flap. Angiography can demonstrate clear evidence of a reliable circulation.

Evaluation of YD MolecuTech Real HPV Assay in Comparison with Roche Cobas HPV Assay and BD Onclarity HPV Assay for Detection of HPV Infection.

OBJECTIVE: Human papillomavirus (HPV) is a double-stranded DNA virus that belongs to the papillomavirus family. High-risk (HR) genotypes of HPV are associated with cervical cancer. The combination of molecular HPV testing and cytology results in an increased detection of high-grade cervical lesions. This study compares the performance of a newly developed MolecuTech Real HPV 16/18/HR assay to that of the cobas HPV assay and Onclarity HPV Assay in Korea. METHODS: A SurePath liquid-based cytology device (BD diagnostics, NC, USA) was used to prospectively collect cervical swab specimens. Onclarity HPV Assay (Onclarity; BD diagnostics), Cobas 4800 HPV Test (Cobas; Roche, Rotkreuz, Switzerland), and MolecuTech Real HPV 16/18/HR (MolecuTech; YD, Yongin, Korea) were performed to detect HPV genotypes. RESULTS: Of the 438 cervical specimens, 13.7% showed the HR-HPV genotype. The concordance rates between Onclarity and MolecuTech, cobas and MolecuTech, and Onclarity and Cobas were 94.9% (kappa=0.754), 95.7% (kappa=0.768), and 95.5% (kappa=0.791), respectively. Moreover, no statistically significant differences in HPV genotyping results were observed in the cytology-positive specimens. CONCLUSIONS: The MolecuTech Real HPV 16/18/HR assay showed good agreement in the detection of HR HPV genotypes, and similar analytical performance for the detection of HR HPV genotypes in samples with abnormal cytological findings.

Tailored radiation dose according to margin width for patients with ductal carcinoma in situ after breast-conserving surgery.

A 2 mm resection margin is considered adequate for ductal carcinoma in situ (DCIS). We assessed the effectiveness of a tailored radiation dose for margins < 2 mm and the appropriate margin width for high-risk DCIS. We retrospectively evaluated 137 patients who received adjuvant radiotherapy after breast-conserving surgery for DCIS between 2013 and 2019. The patients were divided into three- positive, close (< 2 mm), and negative (≥ 2 mm) margin groups. Radiation dose to the tumor bed in equivalent dose in 2 Gy fractions were a median of 66.25 Gy, 61.81 Gy, and 59.75 Gy for positive, close, and negative margin groups, respectively. During a median follow-up of 58 months, the crude rates of local recurrence were 15.0%, 6.7%, and 4.6% in the positive, close, and negative margin groups, respectively. The positive margin group had a significantly lower 5-year local recurrence-free survival (LRFS) rate compared to the close and negative margin groups in propensity-weighted log-rank analysis (84.82%, 93.27%, and 93.20%, respectively; p = 0.008). The difference in 5-year LRFS between patients with the high- and non-high-grade tumors decreased as the margin width increased (80.4% vs. 100.0% for margin ≥ 2 mm, p < 0.001; 92.3% vs. 100.0% for margin ≥ 6 mm, p = 0.123). With the radiation dose tailored for margin widths, positive margins were associated with poorer local control than negative margins, whereas close margins were not. Widely clear margins (≥ 2 mm) were related to favorable local control for high-grade DCIS.

Mutant pattern of p53 predicts local recurrence and poor survival rate in gastric cancer.

BACKGROUND: TP53 mutation is a poor prognostic factor for various organ malignancies such as colorectal cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, lung adenocarcinoma and clinical pathologists previously evaluated it using immunohistochemistry for p53. The clinicopathologic significance of p53 expression in gastric cancer remains unclear due to inconsistent classification methods. METHODS: Immunohistochemistry for p53 protein was performed using tissue microarray blocks generated from 725 cases of gastric cancer, and p53 expression was divided into three staining patterns using a semi-quantitative ternary classifier: heterogeneous (wild type), overexpression, and absence (mutant pattern). RESULTS: Mutant pattern of p53 expression had a male predominance, greater frequency in cardia/fundus, higher pT stage, frequent lymph node metastasis, local recurrence clinically, and more differentiated histology microscopically compared with wild type. In survival analysis, p53 mutant pattern was associated with worse recurrent-free survival and overall survival rates, and significance was maintained in subgroup analysis of early versus advanced gastric cancers. In Cox regression analysis, p53 mutant pattern was a significant predicting factor for local recurrence (relative risk (RR=4.882, p<0.001)) and overall survival (RR=2.040, p=0.007). The p53 mutant pattern remained significant for local recurrence (RR=2.934, p=0.018) in multivariate analyses. CONCLUSIONS: Mutant p53 pattern on immunohistochemistry was a significant prognostic factor for local recurrence and poor overall survival in gastric cancer.

A High-Fat Diet in the Absence of Obesity Increases Lymphangiogenesis by Inducing VEGF-C in a Murine Lymphedema Model.

BACKGROUND: Many researchers have attempted to induce lymphangiogenesis for the treatment of lymphedema. However, most previous studies had limited clinical usefulness. A high-fat diet (HFD) increases serum ß-hydroxybutyrate (ß-OHB) levels, which can stimulate lymphangiogenesis. The authors hypothesized that an HFD will ameliorate lymphedema through enhanced lymphangiogenesis. METHODS: The effects of ß-OHB on the lymphangiogenic process in human dermal lymphatic endothelial cells were analyzed. A mouse tail lymphedema model was used to evaluate the effects of an HFD on lymphedema. Experimental mice were fed an HFD (45% kcal as fat, 20% as protein, and 35% as carbohydrates) for 4 weeks. Tail volume was measured using the truncated cone formula. Biopsy specimens were taken 6 weeks after surgical induction of lymphedema. RESULTS: In human dermal lymphatic endothelial cells, treatment with 20 mM of ß-OHB increased cell viability ( P = 0.008), cell migration ( P = 0.011), tube formation ( P = 0.005), and VEGF-C mRNA and protein expression ( P < 0.001) compared with controls. HFD feeding decreased tail volume by 14.3% and fibrosis by 15.8% ( P = 0.027), and increased the lymphatic vessel density ( P = 0.022) and VEGF-C protein expression ( P = 0.005) compared with those of operated, standard chow diet-fed mice. CONCLUSIONS: The authors' findings demonstrated that ß-OHB promoted lymphatic endothelial cell function and increased VEGF-C mRNA and protein expression. When mice with tail lymphedema were fed an HFD, volume and fibrosis of the tail decreased. Therefore, the authors' findings suggest that an HFD can be a successful novel dietary approach to treating lymphedema. CLINICAL RELEVANCE STATEMENT: Lymphatic regeneration after vascularized lymph node transfer can be augmented when a high-fat diet is used in conjunction with vascularized lymph node transfer.

Peripheral Microneedle Patch for First-Aid Hemostasis.

Despite the minimized puncture sizes and high efficiency, microneedle (MN) patches have not been used to inject hemostatic drugs into bleeding wounds because they easily destroy capillaries when a tissue is pierced. In this study, a shelf-stable dissolving MN patch is developed to prevent rebleeding during an emergency treatment. A minimally and site-selectively invasive hemostatic drug delivery system is established by using a peripheral MN (p-MN) patch that does not directly intrude the wound site but enables topical drug absorption in the damaged capillaries. The invasiveness of MNs is histologically examined by using a bleeding liver of a Sprague-Dawley (SD) rat as an extreme wound model in vivo. The skin penetration force is quantified to demonstrate that the administration of the p-MN patch is milder than that of the conventional MN patch. Hemostatic performance is systematically studied by analyzing bleeding weight and time and comparing them with that of conventional hemostasis methods. The superior performance of a p-MN for the heparin-pretreated SD rat model is demonstrated by intravenous injection in vivo.

Dosimetric comparison between RapidArc and HyperArc in hippocampal-sparing whole-brain radiotherapy with a simultaneous integrated boost.

The HyperArc technique is known for generating high-quality radiosurgical treatment plans for intracranial lesions or hippocampal-sparing whole-brain radiotherapy (WBRT). However, there is no reported feasibility of using the HyperArc technique in hippocampal-sparing WBRT with a simultaneous integrated boost (SIB). This study aimed to compare dosimetric parameters of 2 commercially-available volumetric-modulated arc radiotherapy techniques, HyperArc and RapidArc, when using hippocampal-sparing WBRT with a SIB to treat brain metastases. Treatment plans using HyperArc and RapidArc techniques were generated retrospectively for 19 previously treated patients (1 to 3 brain metastases). The planning target volumes for the whole brain (excluding the hippocampal avoidance region; PTVWB) and metastases (PTVmet) were prescribed 25 and 45 Gy, respectively, in 10 fractions. Each plan included homogeneous and inhomogeneous delivery to the PTVmet. Dosimetric parameters for the target (conformity index [CI], homogeneity index [HI], target coverage [D95%]), and nontarget organs at risk were compared for the HyperArc and RapidArc plans. For homogeneous delivery, dosimetric parameters, including mean CI, HI, and target coverage in PTVWB and PTVmet, were superior for HyperArc than RapidArc plans (all p < 0.01). The PTVWB and PTVmet target coverage for HyperArc plans was significantly greater than for RapidArc plans (96.17% vs 93.38%, p < 0.01; 94.02% vs 92.21%, p < 0.01, respectively). HyperArc plans had significantly lower mean hippocampal Dmax and Dmin values than RapidArc plans (Dmax: 15.53 Gy vs, 16.71 Gy, p < 0.01; Dmin: 8.33 Gy vs 8.93 Gy, p < 0.01, respectively). Similarly, inhomogeneous delivery of hyperArc produced a superior target and lower hippocampal dosimetric parameters than RapidArc, except for the HI of PTVmet (all p < 0.01). HyperArc generated superior conformity and target coverage with lower hippocampal doses than RapidArc. HyperArc could be an attractive technique for hippocampal-sparing WBRT with an SIB.

Effect of high-dose radiation therapy on positive margins after breast-conserving surgery for invasive breast cancer.

PURPOSE: Positive margins after breast-conserving surgery are associated with poor oncological outcomes and warrant additional surgery. This study aimed to evaluate the effectiveness of high-dose radiation therapy for positive margins by comparing local recurrence between patients with positive and negative margins. METHODS: We retrospectively evaluated 550 patients treated with adjuvant radiation therapy after breast-conserving surgery for invasive breast cancer between 2013 and 2019. The total equivalent dose in 2 Gy fractions (EQD2) to the tumor bed ranged from 65.81 to 66.25 Gy for positive margins and 59.31-61.81 Gy for negative margins. The differences in local recurrence between the positive and negative margin groups were analyzed. RESULTS: After a median follow-up of 58 months, the crude local recurrence rate was 7.3% in the positive margin group (n = 55) and 2.4% in the negative margin group (n = 495). Positive margins were associated with higher local recurrence without statistical significance in the entire cohort (p = 0.062). Among patients aged <60 years, those with positive margins had a significantly lower 5-year local recurrence-free survival rate than those with negative margins (89.16% vs. 97.57%, respectively; p = 0.005). In contrast, there was no significant difference in the 5-year local recurrence-free survival rate between patients with positive and negative margins among those aged ≥60 years (100.00% vs. 94.38%, respectively; p = 0.426). CONCLUSION: In this study, positive margins were not associated with poor local control in older patients after a high-dose boosts. Further prospective studies are needed to verify our findings.

Altered expression of microRNA miR-21, miR-155, and let-7a and their roles in pulmonary neuroendocrine tumors.

MicroRNA (miRNA) has a critical effect on tumorigenesis through post-transcriptional modification and is considered to be potential biomarkers for cancer diagnosis and treatment monitoring. We evaluated the expression pattern of three selected miRNAs (miR-21, miR-155, and let-7a) to evaluate their potential roles by quantitative reverse transcription-polymerase chain reaction using formalin-fixed and paraffin-embedded tissues of 63 surgically resected pulmonary neuroendocrine (NE) tumors (19 typical carcinoids (TCs), 6 atypical carcinoids (ACs), 19 large cell NE carcinomas (LCNECs), and 19 small cell lung carcinomas (SCLCs). Control amplification for U6 small nuclear RNA (U6) was performed in all samples. Normalized Ct values were calculated (Ct(Experimental miRNA) -Ct(U6) ) for each case and recorded. The expression levels of miR-21 and miR-155 were significantly higher in high-grade NE carcinomas (LCNECs and SCLCs) than in carcinoid tumors (TCs and ACs) (each P < 0.001). The expression level of miR-21 in carcinoid tumors with lymph node metastasis was significantly higher than in carcinoid tumors without lymph node metastasis (P= 0.010). To the best of our knowledge, the present study is the first to examine the expression patterns of miR-21 and miR-155 as an adjunctive diagnostic tool or clinically relevant biomarkers for pulmonary NE tumors.

Colorectal cancers with a residual adenoma component: Clinicopathologic features and KRAS mutation.

BACKGROUND/AIM: Colorectal cancer is well known for its "adenoma-carcinoma" sequential carcinogenesis. Some colorectal cancers demonstrate a residual adenoma component during progression from adenoma to invasive carcinoma. However, the clinicopathological significance of residual adenoma component remains unclear. In this study, we aimed to investigate the clinicopathologic and molecular characteristics including the KRAS mutation in colorectal cancers containing a residual adenoma component. MATERIALS AND METHODS: In this study, 498 surgically resected colorectal cancer patients were enrolled. Their detailed clinicopathologic features and results of molecular study including KRAS mutation test and microsatellite instability were analyzed. RESULTS: A residual adenoma component was identified in 42 (8.4%) patients with colorectal cancer. The presence of a residual adenoma component was associated with a high frequency of the KRAS mutation (65%, p = 0.031) as well as indolent clinicopathological features, including polypoid gross type (p < 0.001), well-differentiated histology (p < 0.001), low pT (p < 0.001) and pN stage (p = 0.003), absence of vascular invasion (p = 0.005), and a better progression-free prognosis (p = 0.029). The cases with an adenoma component had a 35.7% discordance rate on the KRAS mutation tests in their adenoma and carcinoma regions. CONCLUSION: In conclusion, colorectal cancer with a residual adenoma component showed indolent clinicopathologic features and frequent KRAS mutations. Due to the discordance in the incidence of the KRAS mutation between the adenoma and carcinoma components, the adenoma component should be documented in the pathology report, and care should be taken not to include the adenoma component when collecting samples for molecular testing.

High expression of the phosphoinositide 3-kinase p11γ isoform can predict poor prognosis of non-small cell lung cancer.

The protein p110γ is an isoform of the catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI3Ks are involved in the regulation of cell survival, growth, proliferation, and migration and have been implicated in the oncogenesis of various cancers. In this study, p110γ expression in non-small cell lung cancer (NSCLC) and its association with clinicopathological factors and patient survival were evaluated. A total of 230 NSCLC tumors were immunohistochemically stained for p110γ. Of these, 174 (75.7%) and 56 (24.3%) were placed in the low and high expression groups, respectively. The positive rate of p110γ was significantly higher in adenocarcinoma than in squamous cell carcinoma (p⟨0.001). Advanced stage NSCLCs showed higher p110γ expression than those at an early stage (p=0.002). Irrespective of the histological tumor type, the patients with high p110γ expression had significantly worse overall survival than those with low p110γ expression (p=0.004). p110γ expression was an independent poor prognostic factor in the multivariate analysis. Our results suggest that p110γ may be involved in the development and progression of NSCLC, and that p110γ has promising potential as a prognostic factor or novel therapeutic target for NSCLC.

Promotion of dermal tissue engineering in a rat model using a composite 3D-printed scaffold with electrospun nanofibers and recipient-site preconditioning with an external volume expansion device.

We hypothesized that use of a composite three-dimensionally (3D) printed scaffold with electrospun nanofibers in conjunction with recipient-site preconditioning with an external volume expansion (EVE) device would enable successful dermal tissue regeneration of a synthetic polymer scaffold. Cell viability, cell infiltration, extracellular matrix deposition, scaffold contraction, and mRNA expression by dermal fibroblasts cultured on three different scaffolds, namely, 3D-printed scaffold with a collagen coating, 3D-printed scaffold with an electrospun polycaprolactone nanofiber and collagen coating, and 3D-printed scaffold with an electrospun polycaprolactone/collagen nanofiber, were measured. Before scaffold implantation, rats were treated for 2 h with an EVE device to evaluate the effect of this device on the recipient site. Cell proliferation rates were significantly higher on the 3D-printed scaffold with electrospun polycaprolactone nanofiber and collagen coating than on the other scaffolds. In cell invasion studies, the 3D-printed scaffold with electrospun polycaprolactone nanofiber and collagen coating showed better cell integration than the other scaffolds. Under stereomicroscopy, fibroblasts adhered tightly to the electrospun area, and the fibroblasts effectively produced both collagen and elastin. Rat skin treated with an EVE device exhibited increased HIF-1α protein expression and capillary neoformation compared with control skin. Invasion of CD8+ cytotoxic lymphocytes surrounding the scaffold decreased when the recipient site was preconditioned with the EVE device. The composite 3D printed scaffold with electrospun nanofibers provided a favorable environment for proliferation, migration, and extracellular matrix synthesis by fibroblasts. Recipient-site preconditioning with an EVE device allowed for scaffold incorporation with less inflammation due to improved angiogenesis.

Thyroid Hormone Ameliorates Lymphedema by Suppressing Adipogenesis in a Murine Lymphedema Model.

Background: Exogenous supplementation of thyroid hormone could inhibit excessive fat deposition in lymphedema tissue by suppressing adipogenesis. Methods and Results: Cell viability, adipogenic differentiation, and mRNA expression were measured in 3T3-L1 preadipocytes treated with L-thyroxine. Twelve mice were divided into control and L-thyroxine groups. Two weeks after lymphedema was surgically induced, the experimental mice were fed L-thyroxine for 4 weeks. Tail volume and body weight were measured, and 6 weeks after the surgery, tail skin and subcutaneous tissue were harvested for histopathologic examination and protein isolation. In 3T3-L1 cells, treatment with 10-500 µM L-thyroxine did not affect cell viability. Eight days after induction of adipogenic differentiation, lipid accumulation decreased significantly in the 50 and 100 µM L-thyroxine groups (p < 0.001). mRNA levels of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and fatty acid-binding protein 4 (FABP4) decreased significantly in the 100 µM L-thyroxine group compared with the control group (p = 0.017). Lymphedema tails treated with L-thyroxine exhibited decreased volume (p = 0.028) and thickness of dermal and subcutaneous tissue (p = 0.01) and increased vascular endothelial growth factor-C protein expression (p = 0.017) compared with the control. Conclusion: Thyroid hormone therapy inhibits the adipogenesis of 3T3-L1 cells in vitro and decreases the volume of murine lymphedema tail in vivo. These findings suggest that thyroid hormone therapy could be used to treat lymphedema.