The usefulness of indocyanine green fluorescence imaging for intestinal perfusion assessment of intracorporeal anastomosis in laparoscopic colon cancer surgery.

PURPOSE: The purpose of this study was to clarify the usefulness of indocyanine green fluorescence imaging (ICG-FI) in the assessment of intestinal vascular perfusion in patients who receive intracorporeal anastomosis (IA) in colon cancer surgery. METHODS: This was a single-center, retrospective study using propensity score matching. We compared the surgical outcomes of colon cancer patients who underwent laparoscopic colonic resection with IA or external anastomosis (EA) with the intraoperative evaluation of anastomotic perfusion using ICG-FI from January 2019 to July 2021. The detection rate of poor anastomotic perfusion by ICG-FI was examined. RESULTS: A total of 223 patients were enrolled. After matching, 69 patients each were classified into the IA and EA groups. There were no significant differences in age, sex, body mass index, tumor localization, or progression between the two groups. The operation time was similar (172 min vs. 171 min, p = 0.62) and the amount of bleeding was significantly lower (0 ml vs. 2 ml, p = 0.0023) in the IA group. The complication rates (grade ≥ 2) of the two groups were similar (14.5% vs. 11.6%, p = 0.59). ICG-FI identified four patients (5.8%) with poor anastomotic perfusion in the IA group, but none in the EA group (p = 0.046). All four patients with poor perfusion in the IA group underwent additional resection; none of these patients developed postoperative complications. CONCLUSION: Poor anastomotic perfusion was detected in 5.8% of cases who underwent laparoscopic colon cancer surgery with IA. ICG-FI is useful for evaluating anastomotic perfusion in IA in order to prevent AL.

Redo laparoscopic colorectal resection: a retrospective analysis with propensity score matching.

PURPOSE: Reports of redo laparoscopic colorectal resection (Re-LCRR) are scarce. In order to evaluate the safety and short-term outcomes of Re-LCRR, we performed a matched case-control analysis of patients who underwent this procedure for colorectal cancer. METHOD: This was a retrospective, monocentric study that included patients who underwent Re-LCRR for colorectal cancer between January 2011 and December 2019 at our institution. The patients were compared to a 2:1 matched sample. Matching was conducted based on age, sex, BMI, surgical procedure, and clinical stage. RESULT: Twenty-nine patients underwent Re-LCRR (RCRR group) and were compared to 58 patients selected by matching who underwent LCRR as primary resection (PCRR group). The median of age of the 29 patients of RCRR group was 75 (IQR 56-81) years and the RCRR group included 14 males. The median operative time of the RCRR group was 167 (IQR 126-232) minutes, and the median intraoperative blood loss was 5 (IQR 2-35) ml. In the RCRR group, there were no cases that required conversion to laparotomy. The short-term outcomes of the two groups did not differ to a statistical extent with respect to operative time (p = 0.415), intraoperative blood loss (p = 0.971), rate of conversion to laparotomy (p = 0.477), comorbidity (p = 0.215), and postoperative hospital stay (p = 0.809). No patients in either group experienced postoperative anastomotic leakage or required re-operation due to postoperative complications, and there was no procedure-related death. However, in terms of oncological factors, although there was no difference in the number of cases with a positive radical margin between the two groups (p = 1.000), the number of harvested lymph nodes in the RCRR group was significantly lower than that in the PCRR group (p = 0.015) and the RCRR group included 10 cases with less than 12 harvested lymph nodes. CONCLUSION: Re-LCRR is associated with good short-term results and can be safely performed; however, the number of harvested lymph nodes is significantly reduced in comparison to primary resection cases, and further studies are needed to evaluate its long-term prognosis.

The effect of preoperative endoscopic tattooing using India ink on lymph node yield in laparoscopic colectomy for stage I right-sided colon cancer.

PURPOSE: The purpose of this study is to evaluate the effect of preoperative endoscopic tattooing using India ink (ETI) on the number of retrieved lymph nodes (LNs) dissected during laparoscopic surgery for stage I right-sided colon cancer (RCC). METHODS: This single-center, retrospective study included stage I RCC patients who underwent laparoscopic surgery between January 2010 and December 2021. The clinicopathological background and number of LNs retrieved were compared between patients managed with and without ETI. A multiple linear regression analysis was used to examine the effect of independent variables on the LN yield. RESULTS: A total of 169 patients were enrolled. Of these, 89 patients (52.7%) were classified into the ETI group, and 80 (47.3%) were classified into the no-ETI group. There were no significant differences in age, sex, body mass index, or tumor progression between the two groups. A univariate analysis showed that the number of LNs retrieved was significantly higher in female (26 vs. 24, p = 0.026), with tumor localization in the ascending or transverse colon (20 in the cecum, 26 in the ascending colon, 27 in the transverse colon, p < 0.001), and with preoperative ETI (28 vs. 21, p < 0.001). In a multivariate linear regression analysis, female sex (p = 0.0011), D3 lymphadenectomy (p = 0.046), and preoperative ETI (p = 0.012) were independently associated with the LN yield. CONCLUSION: In laparoscopic surgery for stage I RCC, preoperative ETI increased the number of LNs retrieved and allowed for appropriate staging.

Role of the Intramural Vascular Network of the Extrahepatic Bile Duct for the Blood Circulation in the Recipient Extrahepatic Bile Duct Used for Duct-to-Duct-Biliary-Anastomosis in Living Donor Liver Transplantation.

A duct-to-duct-biliary-anastomosis is the preferred biliary reconstruction technique in liver transplantation; biliary complications remain the major concerns for the technique. We examined the significance of the intramural vascular network of the extrahepatic bile duct (EBD) and its relevant vessels. We microscopically examined the axial sections of the EBD with 5 mm intervals of 10 formalin-fixed deceased livers. The luminal-areas of the 3 and 9 o'clock arteries correlated significantly and positively with the distance from the bifurcation of the right and left hepatic ducts (the 3 o'clock artery, r = 0.42, p < 0.001; the 9 o'clock artery, r = 0.39, p < 0.001); the ratios of the numbers of the intramural vessels to the areas of the corresponding sections of the EBD significantly correlated positively with the distance from the bifurcation of the right and left hepatic ducts (total vessels, r = 0.78, p < 0.001; arterioles, r = 0.52, p < 0.001; venules, r = 0.45, p < 0.001). This study demonstrated that there is a significant locoregional distributional heterogeneity of the intramural vessels among the EBD. The hepatic arteries neighboring the EBD primarily supply the blood flow to the EBD; thus, when the broader isolation of the EBD from the neighboring arteries is necessary, this locoregional distributional heterogeneity of the intramural vessels may render the EBD likely to suffer ischemia of the anastomotic site.

Prognostic Factors Affecting Short- and Long-Term Outcomes of Gastrectomy for Gastric Cancer in Older Patients.

INTRODUCTION: The benefits of surgery in older patients with gastric cancer are controversial. This single-institution retrospective study in Japan aimed to evaluate the impact of gastrectomy in older patients with gastric cancer. METHODS: A series of 234 patients aged ≥80 years with histologically confirmed gastric cancer had indications for surgical treatment at the Gastroenterological Center, Yokohama City University Medical Center, between April 2002 and December 2018. Patients who were lost to follow-up (n = 27), had tumors not eligible for surgery (n = 14), and could not achieve R0 resection (n = 7) were excluded from this retrospective study. The remaining 186 patients were included. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were evaluated. RESULTS: The incidence of postoperative complications with Clavien-Dindo grade ≥ II was observed in 61 patients (32.8%). The 5-year relapse-free survival and overall survival (OS) rates were 84.2% and 63.4%, respectively. Multivariate analysis showed that geriatric nutritional risk index (<98) (odds ratio, 1.97; p = 0.047), neutrophil/lymphocyte ratio (>2.36) (odds ratio, 1.94; 95% confidence interval, 1.02-3.67; p = 0.043), and total gastrectomy (TG) (odds ratio, 1.97; p = 0.042) significantly predicted postoperative complications. Moreover, TG (hazard ratio, 1.91; p = 0.036) was an independent prognostic factor of OS. CONCLUSIONS: Poor immunonutritional status and TG led to worse short-term outcomes. Moreover, TG was an independent prognostic factor of OS in older patients with gastric cancer. It is necessary to provide effective perioperative care, including nutritional support, to clarify whether short-term outcomes would be improved.

Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

PURPOSE: Few studies have reported the impact of chemoradiotherapy (CRT) on the objective response of patients with locally advanced unresectable esophageal squamous cell carcinoma (ESCC). We evaluated the factors predicting therapeutic effectiveness and the short- and long-term outcomes in patients with T4b ESCC treated with CRT. METHODS: We included 155 patients with T4b ESCC who underwent CRT at the Department of Surgery, Gastroenterological Center, Yokohama City University, between January 2000 and December 2018. Responders were defined as patients who demonstrated a complete response (CR) or partial response (PR). Multivariate analysis for objective response was performed using a logistic regression model, and prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: Among the 155 patients included, 20 and 84 patients demonstrated a CR and PR, respectively, resulting in a response rate of 67.1%. The median overall survival (OS) was 15.2 months, and the 3-year survival rate was 32.1%. High Glasgow prognostic score (GPS) and advanced N-category independently predicted the objective response to CRT. GPS and objective response were independent prognostic factors for OS. There was no significant difference in the long-term survival of responders who received subsequent chemotherapy or salvage surgery. CONCLUSIONS: High GPS and advanced N-category predicted a poor objective response to CRT in patients with T4b ESCC. Therefore, chemotherapeutic regimens with a higher efficacy are required. The indications for salvage surgery for responders should be carefully considered, with care taken to avoid complications. To confirm this, prospective randomized controlled studies are necessary.

[Long-Term Survival after Surgical Resection for Small Cell Neuroendocrine Carcinoma of the Gallbladder].

A 60-year-old woman was not accompanied by any symptom. She had a gallstone which was identified 20 years prior. Ultrasonography performed by a local doctor revealed that the gallbladder was filled with small stones, and the patient was referred to our department for further examination and treatment for gallbladder stone. Tumor markers are elevated. Contrast- enhanced CT revealed gallbladder stones and thickening in the gallbladder body. PET-CT showed abnormal accumulation of FDG-PET with SUVmax 3.6 in the body of the gallbladder. With a diagnosis of gallbladder cancer, extended cholecystectomy and gallbladder bed resection with regional lymph node dissection were performed. The tumor was diagnosed histologically as small cell type neuroendocrine carcinoma of the gallbladder(pT2a[SS], pN0, pStage ⅡA; Japanese society of hepato-biliary-pancreatic surgery, the 7th edition). The postoperative course was uneventful. This patient has been followed up for 8 years without obvious signs of recurrence. R0 resection and lack of lymph node metastasis can allow long- term survival.

Feasibility of esophagectomy for esophageal cancer in elderly patients: a case-control study.

PURPOSE: Surgery in elderly patients with esophageal cancer is challenging due to high mortality and limited survival. This study aimed to evaluate the safety and effectiveness of curative esophagectomy in elderly patients with esophageal cancer. METHODS: This study included 77 and 112 patients with esophageal cancer aged ≥ 70 and 40-64 years, respectively, who underwent R0 esophagectomy between January 1998 and December 2016. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were compared. RESULTS: The proportions of comorbid diseases (85.7% vs. 57.1%; P < 0.001), the American Society of Anesthesiologists score (1/2/3; 2.6%/94.8%/2.6% vs. 42.9%/57.1%/0%; P < 0.001), the preoperative systemic inflammation score (SIS) (0/1/2; 20.8%/48.1%/31.2% vs. 38.4%/38.4%/23.2%; P = 0.036), and postoperative complications (Clavien-Dindo grade ≥ III) (33.8% vs. 20.5%; P = 0.041) were significantly higher in the elderly group than those in the non-elderly group. However, long-term overall survival (OS) and relapse-free survival were not significantly different between the groups. On multivariate analysis, SIS (hazard ratio, 3.06; P = 0.037) and severe postoperative complications (hazard ratio, 2.01; P = 0.039) were significantly correlated with OS in the elderly group. CONCLUSIONS: As SIS and severe postoperative complications lead to poor prognosis after R0 esophagectomy in elderly patients, selecting appropriate patients for esophagectomy and preventing severe postoperative complications is essential.

Real-World Therapeutic Outcomes of S-1 Adjuvant Chemotherapy for pStage II/III Gastric Cancer in the Elderly.

BACKGROUND: The predictive factors for discontinuation of S-1 administration and prognostic factors in elderly patients with pStage II/III gastric cancer receiving S-1 adjuvant chemotherapy remain unclear. METHODS: Between January 2004 and December 2016, 80 elderly gastric cancer patients (≥70 years) undergoing curative D2 gastrectomy were enrolled in this study. Predictive factors for completion of S-1 administration over 1 year, adverse events due to S-1 administration, and prognostic factors for overall survival (OS) and relapse-free survival (RFS) were evaluated. RESULTS: Twenty-eight patients (35%) completed 8 courses of S-1. The median relative dose intensity was 82.1% (IQR 31.1-100%). The incidence rates of hematological and nonhematological adverse events were acceptable. Distal gastrectomy was an independent predictive factor for completion of S-1 administration (odds ratio [OR] 0.364; 95% confidence interval [CI] 0.141-0.939; p = 0.037). Higher postoperative neutrophil count/lymphocyte count (N/L) ratio and more advanced stage adversely influenced OS. Multivariate analysis revealed that a higher postoperative N/L ratio and more advanced stage adversely affected RFS. CONCLUSION: To complete adjuvant S-1 administration to elderly patients with pStage II/III gastric cancer, total gastrectomy should be avoided if possible. A new regimen for elderly gastric cancer patients with higher postoperative N/L ratios and more advanced stage should be established.

Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma.

AIMS: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. METHODS: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription-polymerase chain reaction (PCR). RESULTS: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor-node-metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528-5.071; P = 0.0008). CONCLUSION: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.

Microphthalmia-associated transcription factor ensures the elongation of axons and dendrites in the mouse frontal cortex.

Long interspersed element-1 (LINE-1) is a mammalian transposable element, and its genomic insertion could cause neurological disorders in humans. Incidentally, LINE-1 is present in intron 3 of the microphthalmia-associated transcription factor (Mitf) gene of the black-eyed white mouse (Mitfmi-bw allele). Mice homozygous for the Mitfmi-bw allele show the white coat color with black eye and deafness. Here, we explored the functional consequences of the LINE-1 insertion in the Mitf gene using homozygous Mitfmi-bw mice on the C3H background (C3H-bw mice) or on the C57BL/6 background (bw mice). The open-field test showed that C3H-bw mice moved more irregularly in an unfamiliar environment during the 20-min period, compared to wild-type mice, suggesting the altered emotionality. Moreover, C3H-bw mice showed the lower serum creatinine levels, which may reflect the creatine deficiency. In fact, morphologically abnormal neurons and astrocytes were detected in the frontal cortex of bw mice. The immunohistochemical analysis of bw mouse tissues showed the lower intensity for expression of guanidinoacetate methyltransferase, a key enzyme in creatine synthesis, in neurons of the frontal cortex and in glomeruli and renal tubules. Thus, Mitf may ensure the elongation of axons and dendrites by maintaining creatine synthesis in the frontal cortex.

Dysregulated Expression of MITF in Subsets of Hepatocellular Carcinoma and Cholangiocarcinoma.

Cholangiocarcinoma represents the second most common primary liver tumor after hepatocellular carcinoma. Mahanine, a carbazole alkaloid derived from Murraya koenigii (Linn.) Spreng, has been used as folk medicine in Thailand, where the liver fluke-associated cholangiocarcinoma is common. The expression of microphthalmia-associated transcription factor (MITF) is maintained at immunohistochemically undetectable levels in hepatocytes and cholangiocytes. To explore the regulation of MITF expression in the liver, we immunohistochemically analyzed the MITF expression using hepatocellular carcinoma and cholangiocarcinoma specimens of the human liver cancer tissue array. MITF immunoreactivity was detected in subsets of hepatocellular carcinoma (6 out of 38 specimens; 16%) and cholangiocarcinoma (2/7 specimens; 29%). Moreover, immunoreactivity for glioma-associated oncogene 1 (GLI1), a transcription factor of the Hedgehog signaling pathway, was detected in 55% of hepatocellular carcinoma (21/38 specimens) and 86% of cholangiocarcinoma (6/7 specimens). Importantly, MITF was detectable only in the GLI1-positive hepatocellular carcinoma and cholangiocarcinoma, and MITF immunoreactivity is associated with poor prognosis in patients with hepatocellular carcinoma. Subsequently, the effect of mahanine was analyzed in HepG2 human hepatocellular carcinoma and HuCCT1 and KKU-100 human cholangiocarcinoma cells. Mahanine (25 µM) showed the potent cytotoxicity in these hepatic cancer cell lines, which was associated with increased expression levels of MITF, as judged by Western blot analysis. MITF is over-expressed in subsets of hepatocellular carcinoma and cholangiocarcinoma, and detectable MITF immunoreactivity is associated with poor prognosis in patients with hepatocellular carcinoma. MITF expression levels may be determined in hepatic cancer cells by the balance between the Hedgehog signaling and the cellular stress.

Induction of MITF expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine, an inhibitor of the Hedgehog signaling.

Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU-100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100 cells, suggesting that MITF expression may be down-regulated in some liver cancer cases.

Microphthalmia-associated transcription factor is expressed in projection neurons of the mouse olfactory bulb.

Microphthalmia-associated transcription factor (Mitf) is a key regulator for differentiation of the neural crest-derived melanocytes. Mitf consists of multiple isoforms, including melanocyte-specific Mitf-M and widely expressed Mitf-A and Mitf-H. Mitf mRNAs are also expressed in the brain, although the identity of Mitf-expressing cells remains unknown. We therefore aimed to identify Mitf-expressing cells in the brain. By the immunohistochemical analysis, we detected Mitf-expressing cells only in the olfactory bulb of the C57BL/6 mouse. The Mitf-expressing cells were then identified as projection neurons, mitral cells and tufted cells, both of which receive the signal from the olfactory neurons and transmit the information to the olfactory cortex. Real-time RT-PCR analysis showed the expression level of Mitf-M mRNA was comparable to the expression levels of Mitf-A and Mitf-H mRNAs in the olfactory bulb. We then analyzed Mitf-expressing neurons in the olfactory bulb of the homozygous black-eyed white (Mitf(mi-bw)) mouse that is characterized by the lack of melanocytes. Mitf was expressed in mitral cells and tufted cells in the olfactory bulb of the Mitf(mi-bw) mouse, thereby excluding the contribution of melanocytes to the detected expression of Mitf-M. In conclusion, Mitf, including Mitf-M, is expressed in mitral cells and tufted cells of the olfactory bulb.

Impact of Postoperative Morbidity on Long-Term Survival After Resection for Colorectal Liver Metastases.

BACKGROUND: Although correlation of postoperative morbidity with long-term survival is recognized to influence long-term survival after other cancer surgery, little information exists about the impact of postoperative morbidity on patient outcomes following liver resection for colorectal metastases. METHODS: We studied the impact of postoperative morbidity on long-term survival after liver resection for colorectal cancer metastases using data from 312 patients with curative hepatectomy. RESULTS: Among all 312 patients evaluated, 98 complications occurred, affecting 80 patients (26%). The 80 patients with morbidity had a lower disease-free rate (P = 0.03), resulting in poor overall survival (P = 0.02) compared with the group with no morbidity (n = 232). Decreases in disease-free and overall survival also were associated with severity of postoperative complications. When patients were divided according to extent of metastases, little impact of morbidity on overall survival (P = 0.10) and disease-free rate (P = 0.35) was demonstrated in patients whose metastases were less advanced. However, a negative impact of morbidity compared with no morbidity on disease-free rate (P < 0.01) and overall survival (P < 0.01) was confirmed in patients with aggressive or advanced metastases. CONCLUSIONS: Postoperative morbidity had a negative impact on long-term survival, especially for aggressive or advanced metastases or severe complications.

Significance of Vascular Resection and Reconstruction in Surgery for Hilar Cholangiocarcinoma: With Special Reference to Hepatic Arterial Resection and Reconstruction.

PURPOSE: The aim of this study was to assess the efficacy of combined resection and reconstruction (CRR) of the hepatic artery (HA) in surgery for hilar cholangiocarcinoma (HC). MATERIALS AND METHOD: Among 172 patients who underwent surgical resection for HC, the following three groups were defined according to the type of vascular reconstruction: VR(-) group, in which neither CRR of the portal vein (PV) nor HA was performed (n = 74); VR-PV group, in which only CRR of the PV was required (n = 54); and VR-A group, in which CRR of the HA was performed either with or without CRR of the PV (n = 44). Clinicopathological variables and clinical outcomes were compared among the three groups. RESULTS: Although the VR-A group showed significantly more advanced disease than other groups, the R0 resection rate was comparable among the three groups (VR(-), 74 %; VR-PV, 80 %; VR-A, 80 %). The 5-year disease-specific survival rate was also comparable among the three groups (VR(-), 45.6 %; VR-PV, 51.2 %; VR-A, 22.3 %), but tended to be worse in the VR-A group than in the other groups. A similar trend was observed in morbidity rate. Lymph node metastasis was more frequent in the VR-A group (59 %) than in the other groups (VR(-), 33.8 %; VR-PV, 50 %). In the VR-A group, lymph node metastasis (p = 0.004) and adjuvant chemotherapy (p = 0.006) were determined to represent independent prognostic factors for survival according to multivariate analysis. CONCLUSION: CRR of the HA was considered efficacious in selected patients; however, long-term outcomes of the VR-A group seem unsatisfactory. Treatments additional to surgery may be necessary in cases requiring CRR of the HA.

Insertion of long interspersed element-1 in the Mitf gene is associated with altered neurobehavior of the black-eyed white Mitf(mi-bw) mouse.

Microphthalmia-associated transcription factor (Mitf) is required for the differentiation of melanoblasts of the neural crest origin. The mouse homozygous for the black-eyed white (Mitf(mi-bw) ) allele is characterized by white-coat color and deafness with black eye, due to the loss of melanoblasts during embryonic development. The Mitf(mi-bw) allele carries an insertion of long interspersed element-1 (L1) in intron 3 of the Mitf gene, which may cause the deficiency of melanocyte-specific Mitf-M. Here, we show that the L1 insertion results in the generation of alternatively spliced Mitf-M mRNA species, such as Mitf-M mRNA lacking exon 3, exon 4 or both exons 3 and 4, each of which encodes Mitf-M protein with an internal deletion. Transient expression assays showed the loss of or reduction in function of each aberrant Mitf-M protein and the dominant negative effect of Mitf-M lacking exon 4 that encodes an activation domain. Thus, the L1 insertion may decrease the expression level of functional Mitf-M. Importantly, Mitf-M mRNA is expressed in the wild-type mouse brain, with the highest expression level in the hypothalamus. Likewise, aberrant Mitf-M mRNAs are expressed in the bw mouse brain. The bw mice show the altered neurobehavior under a stressful environment, suggesting the role of Mitf-M in sensory perception.

Low infiltration of peritumoral regulatory T cells predicts worse outcome following resection of colorectal liver metastases.

BACKGROUND: The tumor-infiltrating lymphocyte (TIL) count in several types of cancer, including colorectal cancer and colorectal liver metastases (CRLM), reportedly predicts survival following resection; however, the prognostic significance of the TIL counts remains controversial. METHODS: In total, 162 patients who underwent potentially curative resection for CRLM from 1992 to 2010 were immunohistochemically analyzed retrospectively. CD4, CD8, and FoxP3 were examined as markers for helper T cells, cytotoxic T cells, and regulatory T cells (Tregs), respectively. The correlation between patients' TIL composition and long-term outcome was investigated. RESULTS: The median follow-up time was 46.6 months for all patients and 46.8 months for survivors. Cancer-specific survival (CSS) at 1, 3, and 5 years was 93.2, 65.6, and 51.0 %, respectively. The 5-year disease-free survival and CSS among patients with high infiltration of peritumoral Tregs was 44.2 and 74.8 %, respectively, while those of patients with low infiltration of peritumoral Tregs was 18.9 and 40.3 %, respectively (p < 0.01 for both). Multivariate analyses indicated that synchronous liver metastases, hypoalbuminemia, and low peritumoral Treg infiltration were significant predictors of unfavorable CSS. CONCLUSIONS: Low peritumoral Treg infiltration proved to be a significant predictor of unfavorable CSS in patients undergoing resection for CRLM.

High infiltration of mast cells positive to tryptase predicts worse outcome following resection of colorectal liver metastases.

BACKGROUND: Accumulation of tumor-infiltrating mast cells (MCs) predicts poor survival in several cancers after resection. However, its effect on the prognosis of patients with colorectal liver metastases (CRLM) is not known. METHODS: Our retrospective study included 135 patients who underwent potentially curative resection for CRLM between 2001 and 2010. Expression of tryptase, MAC387, CD83, and CD31, which are markers for MCs, macrophages, mature dendritic cells, and vascular endothelial cells, respectively, was determined via immunohistochemistry of resected tumor specimens. The relationship between immune cell infiltration and long-term outcome was investigated. RESULTS: The median follow-up time was 48.4 months for all patients and 57.5 months for survivors. Overall survival (OS) rates at 1, 3, and 5 years were 91.0, 62.4, and 37.4 %, respectively. Five-year disease-free survival (DFS) and OS rates were 21.6 and 38.1 %, respectively, in patients with high MC infiltration, and 42.6 and 55.6 %, respectively, in patients with low MC infiltration (p < 0.01 for both DFS and OS). Infiltration of other types of immune cells did not correlate with survival. Multivariate analyses indicated that hypoalbuminemia and high peritumoral MC infiltration were significant predictors of unfavorable OS. CONCLUSION: High peritumoral MC infiltration predicts poor prognosis in patients who underwent hepatectomy for CRLM. The number of MCs in metastatic lesions is important for predicting the prognosis of CRLM patients and as an indication of therapy.