Renal Dysfunction after Rectal Cancer Surgery: A Long-term Observational Study.

Objectives: Despite the high incidence of urinary dysfunction (UD) after rectal surgery, it remains questionable whether UD causes future chronic kidney disease (CKD). This study aimed to clarify the long-term trends in renal function and risk factors for future CKD after rectal resection. Methods: For comparison, patients who underwent rectal resection (n = 129) and colectomy (n = 127) between 2006 and 2017 were identified. The estimated glomerular filtration rate (eGFR) ratio was calculated as the ratio to the baseline. "eGFR ratio < 0.75 at 3-year" was adopted as a surrogate indicator of future CKD. Results: eGFR ratio significantly decreased in the rectal cohort compared with the colon cohort at 1.5 years (0.9 vs. 0.95, p = 0.008) and at 3 years (0.85 vs. 0.94, p < 0.001). Although the preoperative prevalence of CKD was lower in the rectal than the colon cohort (13.9% vs. 23.6%, p = 0.055), it was similar at 3 years (29.5% vs. 30.7%). In multivariate analysis, females, and cT4 were independent risk factors for future CKD, but UD itself was not. Conclusions: Postoperative eGFR significantly decreased after rectal cancer surgery compared to colectomy. The prevalence of CKD more than doubled at 3 years after rectal resection. The female sex and cT4 tumor, instead of the UD, were independent risk factors for future CKD.

Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding.

G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP), and cholecystokinin (CCK). Although GPR120 signaling in adipose tissue and macrophages has been reported to ameliorate obesity and insulin resistance in a high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in the intestine, we generated intestine-specific GPR120-knockout (GPR120int-/-) mice. In comparison with floxed GPR120 (WT) mice, GPR120int-/- mice exhibited reduced GIP secretion and CCK action without change of insulin, GLP-1, or peptide YY (PYY) secretion after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed a mild reduction of body weight and substantial amelioration of insulin resistance and fatty liver. Moreover, liver and white adipose tissue (WAT) of GPR120int-/-mice exhibited increased Akt phosphorylation and reduced gene expression of suppressor of cytokine signaling (SOCS) 3, which inhibits insulin signaling. In addition, gene expression of inflammatory cytokines in WAT and lipogenic molecules in liver were reduced in GPR120int-/- mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding.NEW & NOTEWORTHY We generated novel intestine-specific GPR120-knockout (GPR120int-/-) mice and investigated the metabolic effect of GPR120 in the intestine. GPR120int-/- mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed mild improvement in obesity and marked amelioration of insulin resistance and hepatic steatosis. Our results indicate an important role of intestinal GPR120 on insulin resistance and hepatic steatosis.

Impact of combined resection of the internal iliac artery on loss of volume of the gluteus muscles after pelvic exenteration.

PURPOSE: To clarify the influence of additional internal iliac artery (IIA) resection on the loss of the gluteus muscle volume after pelvic exenteration (PE). METHODS: The subjects of this retrospective analysis were 78 patients who underwent PE with or without IIA resection (n = 44 and n = 34, respectively) between 2006 and 2018. The areas of gluteal muscles (GMs) and psoas muscles (PSMs) were calculated using CT images before and 6 months after PE, and the difference was compared. RESULTS: The volumes of the GMs and PSMs were significantly reduced after PE (P < 0.001 and P = 0.005, respectively). In the IIA resection group, the GMs were significantly reduced after surgery, but the PSMs were not. The maximum GM (Gmax) was the most atrophied among the GMs. Multivariable analysis revealed that complete IIA resection was an independent promotor of the loss of volume of the Gmax (P = 0.044). In 18 patients with unilateral IIA resection, the downsizing rate of the Gmax was significantly greater on the resected side than on the non-resected side (P = 0.008). CONCLUSIONS: The GMs and PSMs were significantly smaller after PE. Complete IIA resection reduced the Gmax area remarkably. Preservation of the superior gluteus artery is likely to help maintain Gmax size, suggesting a potential preventative measure against secondary sarcopenia.

Current status of transanal total mesorectal excision for rectal cancer and the expanding indications of the transanal approach for extended pelvic surgeries.

Transanal total mesorectal excision (taTME) has been rapidly accepted as a promising surgical approach to the distal rectum. The benefits include ease of access to the bottom of the deep pelvis linearly over a short distance in order to easily visualize the important anatomy. Furthermore, the distal resection margins can be secured under direct vision. Additionally, a two-team approach combining taTME with a transabdominal approach could decrease the operative time and conversion rate. Although taTME was expected to become more rapidly popularized worldwide, enthusiasm for it has stalled due to unfamiliar intraoperative complications, a lack of oncologic evidence from randomized trials, and the widespread use of robotic surgery. While international registries have reported favorable short- and medium-term outcomes from taTME, a Norwegian national study reported a high local recurrence rate of 9.5%. The characteristics of the recurrences included rapid, multifocal growth in the pelvis, which was quite different from recurrences following traditional transabdominal TME; thus, the Norwegian Colorectal Cancer Group reached a consensus for a temporary moratorium on the performance of taTME. To ensure acceptable baseline quality and patient safety, taTME should be performed by well-trained colorectal surgeons. Although the appropriate indications for taTME remain controversial, the transanal approach is extremely important as a means of goal setting in difficult TME cases and as an aid to the transabdominal approach in various types of extended pelvic surgeries. The benefits in transanal lateral lymph node dissection and pelvic exenteration are presented herein.

Triphenylbismuth dichloride inhibits human glyoxalase I and induces cytotoxicity in cultured cancer cell lines.

Organobismuth compounds, i.e., organic-inorganic hybrid molecules composed of an organic structure and bismuth metal, have been reported to induce cytotoxicity in cancer cells; however, the target proteins associated with this cytotoxicity have not been elucidated. Herein, we investigated the inhibitory effect of five organobismuth compounds on human glyoxalase I (hGLO I), a promising target candidate for cancer therapy. Among these compounds, triphenylbismuth dichloride (Bi-05) exerted a strong inhibitory effect on hGLO I. Indeed, Bi-05 inhibited hGLO I in a dose-dependent manner with an IC50 value of 0.18 µM. Bi-05 also induced cytotoxicity in human leukemia HL-60 cells and human lung cancer NCI-H522 cells, both of which exhibit high expression levels of GLO I. However, the hGLO I-inhibiting and cytotoxic effects of Bi-05 disappeared when the bismuth atom was replaced with an antimony or phosphorus atom. Bismuth(III) nitrate had little inhibitory effect on hGLO I activity and only slightly reduced the viability of cancer cells. In the culture medium of Bi-05-treated HL-60 cells, the concentration of the GLO I substrate methylglyoxal was markedly elevated. In addition, Bi-05 treatment more strongly inhibited human lung cancer NCI-H522 cell (exhibiting high GLO I expression) proliferation than human lung cancer NCI-H460 cell (exhibiting low GLO I expression) proliferation. Furthermore, the cytotoxicity of Bi-05 was significantly decreased by pre- and co-treatment with the methylglyoxal scavengers N-acetyl-L-cysteine and aminoguanidine. Overall, these results suggest that Bi-05 treatment leads to the accumulation of methylglyoxal via GLO I inhibition, resulting in cytotoxic effects in cancer cells.

Noninvasive Evaluation of GIP Effects on ß-Cell Mass Under High-Fat Diet.

Pancreatic ß-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased ß-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.

Minimum radial margin in pelvic exenteration for locally advanced or recurrent rectal cancer.

PURPOSE: The aim of this study was to clarify the suitable radial margin (RM) for favourable outcomes after pelvic exenteration (PE), focusing on the discrepancy between the concepts of circumferential resection margin (CRM) and traditional R status. METHODS: Seventy-three patients with locally advanced (LARC, n = 24) or locally recurrent rectal cancer (LRRC, n = 49) who underwent PE between 2006 and 2018 were retrospectively analysed. Patients were histologically classified into the following 3 groups; wide RM (≥1 mm, n = 45), narrow RM (0-1 mm, n = 10), and exposed RM (n = 18). The analysis was performed not only in the entire cohort but also in each disease group separately. RESULTS: The rates of traditional R0 (RM > 0 mm) and wide RM were 75.3% and 61.6%, respectively, resulting in the discrepancy rate of 13.7% between the two concepts. Preoperative radiotherapy was given in 12.3%. In the entire cohort, the local recurrence and overall survival (OS) rates for narrow RMs were significantly worse than those for wide RMs (p < 0.001 and p = 0.002), but were similar to those for exposed RMs. In both LARC and LRRC, RM < 1 mm resulted in significantly worse local recurrence and OS rates compared to the wide RMs. Multivariate analysis showed that RM < 1 mm was an independent risk factor for local recurrence in both LARC (HR 15.850, p = 0.015) and LRRC (HR 4.874, p = 0.005). CONCLUSIONS: Narrow and exposed RMs had an almost equal impact on local recurrence and poor OS after PE. Preoperative radiotherapy might have a key role to ensure a wide RM.

Role of resection for extrahepatopulmonary metastases of colon cancer.

BACKGROUND: Although surgical resection for liver or lung metastases of colorectal cancer has been widely accepted, the use of this approach for extrahepatopulmonary metastases remains debatable due to the systemic nature of the disease. The aim of this study was to clarify the utility of resection along with perioperative chemotherapy for patients with extrahepatopulmonary metastases of colon cancer. METHODS: This is a retrospective single-arm study at a single institution. Forty-two patients with resectable extrahepatopulmonary metastases who underwent metastasectomy with curative intent between 2009 and 2018 at Nagoya University Hospital were retrospectively analyzed. The primary outcomes measured were overall and relapse-free survival. RESULTS: The most common metastatic site was the peritoneum (n = 31), followed by the distant lymph nodes (n = 10), ovary (n = 1) and spleen (n = 1), with overlaps. Preoperative and postoperative chemotherapies were administered to 22 and 8 patients, respectively; the remaining 14 patients received surgery alone. R0 resection was achieved in 36 patients (85.7%). The 5-year overall survival and 3-year relapse-free survival rates were 58.6% and 33.8%, respectively. In the univariate analysis, R1 resection was associated with a poor relapse-free survival rate (P = 0.02). In the multivariate analysis, the absence of perioperative chemotherapy was an independent risk factor for poor overall survival rates (P = 0.02). CONCLUSIONS: Surgical resection benefited selected patients with extrahepatopulmonary metastases with favorable long-term survival outcomes. Surgery alone without systemic chemotherapy is likely to bring poor outcome; therefore, preoperative induction might be promising to keep up with chemotherapy.

Stoma creation is associated with a low incidence of midline incisional hernia after colorectal surgery: the "fighting over the fascia" theory concerning the incision and stoma hole.

PURPOSE: Parastomal hernia (PH) develops more frequently than incisional hernia (IH) after colorectal surgery with stoma. This study evaluated our hypothesis that inward traction of the fascia when closing a midline incision widens the stoma hole and increases the incidence of PH. METHODS: A total of 795 patients who underwent colorectal resection between 2006 and 2016 were retrospectively analyzed. The risk classification was constructed from IH risk factors extracted from the non-stoma group. Then, the classification was extrapolated to the stoma group for predicting midline IH and PH. RESULTS: The incidence of IH was 5.3% in the stoma group and 12.5% in the non-stoma group (p = 0.005). PH developed in 19.6% of 97 patients with permanent stoma. The risk classification was able to predict PH without a significant difference but was well balanced in patients with permanent stoma; however, it failed to predict IH in the stoma group. CONCLUSION: The risk classification constructed from the non-stoma group was useful for predicting not midline IH but PH, suggesting that the stoma site was the most vulnerable for herniation. The "fighting over the fascia" theory between the midline incision and stoma hole may explain the causal relationship between the midline IH and PH.

The carcinoembryonic antigen ratio is a potential predictor of survival in recurrent colorectal cancer.

BACKGROUND: The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. METHODS: This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. RESULTS: Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor. CONCLUSION: The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.

Visualization of Apoptosis in Three-Dimensional Cell Aggregates Based on Molecular Beacon Imaging.

The objective of this study is to visualize cell apoptosis in three-dimensional (3D) cell aggregates based on molecular beacons (MB). Two types of MB for messenger RNA were used: caspase-3 MB as a target for apoptosis and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) MB as a control of stable fluorescence in cells. To enhance the MB internalization into cells, caspase-3 and GAPDH MB were incorporated in cationized gelatin nanospheres (cGNS), respectively (cGNScasp3 MB and cGNSGAP MB). In addition, cGNS co-incorporating caspase-3 and GAPDH MB (cGNSdual MB) were prepared to perform the dual-color imaging for the same cell aggregate. The cGNSMB were incubated with mouse mesenchymal stem cells to label with MB in the two-dimensional culture. The cell apoptosis mediated by the addition of antibody for a death receptor Fas was ratiometrically detected by the cGNSdual MB to the same extent as single MB. The cell aggregates were prepared from MB-labeled cells, and the MB fluorescence was detected from almost all the cells even in the 3D aggregates to show the homogenous distribution. In addition to the Fas-mediated apoptosis, the aggregates were treated with camptothecin of a low-molecular weight apoptosis inducer. The fluorescence of caspase-3 MB was mainly distributed at the surface surrounding site of Fas-mediated apoptotic aggregates rather than the center site, while that of GAPDH MB was detected even in the interior site. On the other hand, in the camptothecin-induced apoptotic aggregates, both caspae-3 and GAPDH MB fluorescence were detected from the interior site of aggregates as well as the surrounding site. It is likely that the MB fluorescence reflected the localization of apoptotic position caused by the different molecular sizes of apoptosis inducer and the consequent penetration into the aggregates. It is concluded that the cGMSMB are a promising system to visualize cell apoptosis in 3D cell aggregates without the destruction of aggregates.

Complexation design of cationized gelatin and molecular beacon to visualize intracellular mRNA.

The objective of this study is to prepare cationized gelatin-molecular beacon (MB) complexes for the visualization of intracellular messenger RNA (mRNA). The complexes were prepared from cationized gelatins with different extents of cationization and different mixing ratios of MB to cationized gelatin. The apparent size of complexes was almost similar, while the zeta potential was different among the complexes. Irrespective of the preparation conditions, the complexes had a sequence specificity against the target oligonucleotides in hybridization. The cytotoxicity and the amount of complexes internalized into cells increased with an increase in the cationization extent and the concentration of cationized gelatin. After the incubation with complexes prepared from cationized gelatin with the highest extent of cationization and at mixing ratios of 10 and 20 pmole MB/µg cationized gelatin, a high fluorescent intensity was detected. On the other hand, the complex prepared with the mixing ratio at 20 pmole/µg did not show any cytotoxicity. The complex was the most effective to visualize the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA endogenously present. In addition, even for enhanced green fluorescent protein (EGFP) mRNA exogenously transfected, the complex permitted to effectively detect it as well. It is concluded that both the endogenous and exogenous mRNA can be visualized in living cells by use of cationized gelatin-MB complexes designed.

Synthesis, Structural Characterization, and Optical Properties of Benzene-Fused Tetracyclic and Pentacyclic Stiboles.

The expectation that antimony (Sb) compounds should display phosphorescence emissions based on the "heavy element effect" prompted our interest in the introduction of antimony to a biaryl as the bridging atom in a fused heterole system. Herein, the synthesis, molecular structures, and optical properties of novel benzene-fused heteroacenes containing antimony or arsenic atoms are described. The stiboles and arsole were prepared by the condensation of dibromo(phenyl)stibane or dichloro(phenyl)arsine with dilithium intermediates derived from the corresponding dibromo compounds. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal analysis revealed that the linear pentacyclic stibole was highly symmetric in both the solution and crystal states. In contrast, the curved pentacyclic stibole adopted a helical structure in solution, and surprisingly, only M helical molecules were crystallized from the racemate. All synthesized compounds produced very weak or no emissions at room temperature or in the solid state. In contrast, the linear penta- and tetracyclic stiboles exhibited clear phosphorescence emissions in the CHCl3 frozen matrix at 77 K under aerobic conditions.

Molecular Beacon Imaging to Visualize Ki67 mRNA for Cell Proliferation Ability.

The objective of this study is to visualize the ability of cell proliferation based on molecular beacons (MB). Two types of MB to detect messenger RNA (mRNA) were used. One is a Ki67 MB of a target for cell proliferation ability. The other one is a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) MB as a control of stable fluorescence in cells. To enhance the MB internalization into cells, the MB were incorporated into cationized gelatin nanospheres (cGNS). There was no difference in the physicochemical properties and the cell internalization between the cGNSKi67 MB and cGNSGAP MB. When basic fibroblast growth factor (bFGF) was added to KUM6 cells of a mouse bone marrow-derived mesenchymal stem cell line, the expression of Ki67 and the cell proliferation increased with the bFGF concentration. After the incubation for the cell internalization of cGNS incorporating MB (cGNSMB), the cells were further incubated for 24 h with or without different concentrations of bFGF. The fluorescence of cGNSKi67 MB significantly increased with the increase of bFGF concentration, whereas that of cGNSGAP MB was constant, irrespective of the bFGF concentration. A time-lapse imaging assay revealed a fast enhancement of cGNSKi67 MB fluorescence after the bFGF addition compared with no bFGF addition. On the other hand, for cGNSGAP MB, a constant fluorescence was observed even at any time point after the bFGF addition. It is concluded that the cGNSMB system is promising for the chronological visualization of proliferation ability in living cells.

Indications for neoadjuvant treatment based on risk factors for poor prognosis before and after neoadjuvant chemotherapy alone in patients with locally advanced rectal cancer.

INTRODUCTION: The oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC. MATERIALS AND METHODS: We examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed. RESULTS: In the median follow-up duration after surgery of 60 months (3-120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32-28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27-27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01-6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06-29.93, P = 0.043). CONCLUSION: NAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.

Absence of GIP secretion alleviates age-related obesity and insulin resistance.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP-/-) and heterozygous (GIP+/-) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP-/- mice compared to that in WT and GIP+/- mice from 38 weeks of age, while there was no significant difference between WT and GIP+/- mice. Visceral and s.c. fat mass were also significantly lower in GIP-/- mice compared to those in WT and GIP+/- mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP-/- mice than those in WT and GIP+/- mice. During insulin tolerance test, GIP-/- mice showed higher insulin sensitivity than that of WT and GIP+/- mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP-/- mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.