Impact of Oophorectomy on Survival and Improving Nutritional Status in Ovarian Metastasis from Colorectal Adenocarcinoma.

INTRODUCTION: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer. METHODS: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient's symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5-109) months. RESULTS: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p < 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110-2,607) preoperatively and 6,095.2 (1,612.3-14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis. CONCLUSIONS: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients' symptoms and nutritional status and may result in improved prognosis.

Short-term outcomes of laparoscopic and robotic distal gastrectomy for gastric cancer: Real-world evidence from a large-scale inpatient database in Japan.

BACKGROUND AND OBJECTIVES: Robotic distal gastrectomy (RDG) has been widely performed throughout Japan since it became insured in 2018. This study aimed to evaluate the short-term outcomes of RDG and laparoscopic distal gastrectomy (LDG) for gastric cancer using real-world data. METHODS: A total of 4161 patients who underwent LDG (n = 3173) or RDG (n = 988) for gastric cancer between April 2018 and October 2022 were identified through the Japanese Diagnosis Procedure Combination Database, which covers 42 national university hospitals. The primary outcome was postoperative in-hospital mortality rate. The secondary outcomes were postoperative complication rates, time to diet resumption, and postoperative length of stay (LOS). RESULTS: In-hospital mortality and postoperative complication rates in the RDG group were comparable with those in the LDG group (0.1% vs. 0.0%, p = 1.000, and 8.7% vs. 8.2%, p = 0.693, respectively). RDG was associated with a longer duration of anesthesia (325 vs. 262 min, p < 0.001), similar time to diet resumption (3 vs. 3 days, p < 0.001), and shorter postoperative LOS (10 vs. 11 days, p < 0.001) compared with LDG. CONCLUSIONS: RDG was performed safely and provided shorter postoperative LOS, since it became covered by insurance in Japan.

Lymphocyte-to-Monocyte Ratio Is a Predictive Biomarker of Response to Treatment with Nivolumab for Gastric Cancer.

INTRODUCTION: Patients with unresectable or recurrent gastric cancer who have an objective response (OR) to nivolumab monotherapy are expected to have a good long-term prognosis. However, the OR rate for nivolumab treatment is low at 11%, and there is a need for biomarkers to predict the treatment response. This study aimed to analyze the significance of systemic inflammation-related variables and clinicopathologic characteristics as predictive markers of response to nivolumab monotherapy in patients with advanced gastric cancer. METHODS: In this retrospective cohort study, we enrolled 71 consecutive patients who received nivolumab monotherapy for unresectable or recurrent gastric cancer. Receiver operating characteristic curve analysis was performed to determine the cutoff values of systemic inflammation-related variables, predictors of treatment response, and other prognostic factors related to nivolumab therapy. We focused on systemic inflammation-related variables measured before nivolumab induction and 2 weeks after its first administration and performed multivariate analysis to assess whether they could be used as prognostic factors. RESULTS: Multivariate analysis revealed that a lymphocyte-to-monocyte ratio (LMR) of ≤3.28 after 2 weeks of initial nivolumab treatment (2wLMR) is a statistically significant predictor of treatment response (p = 0.012). The progression-free survival (PFS) rate of patients with liver metastasis was significantly worse than that of the other patients (1-year PFS: 0.0 vs. 24.4%, respectively; p = 0.005). The overall survival (OS) of patients with a low 2wLMR was significantly longer than that in patients with a high 2wLMR (1-year OS: 37.4 vs. 18.9%, respectively; p = 0.022). CONCLUSIONS: Thus, the 2wLMR could be a useful biomarker to predict response to nivolumab treatment and the prognosis of unresectable and recurrent gastric cancer.

The Combination of Preoperative Skeletal Muscle Quantity and Quality is an Important Indicator of Survival in Elderly Patients Undergoing Curative Gastrectomy for Gastric Cancer.

BACKGROUND: The diagnosis of sarcopenia emphasizes both, the quantity and quality of skeletal muscle. However, the impact of the combination of muscle quantity and quality on long-term survival remains unclear. This study aimed to assess the impact of the combination of skeletal muscle quantity and quality on long-term outcomes in patients with gastric cancer who underwent curative resection. METHODS: We retrospectively assessed 242 patients aged ≥ 65 ears who underwent curative gastrectomy between 2006 and 2015. The psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) were measured on preoperative computed tomography as skeletal muscle quantity and quality, respectively. The sarcopenia stage was classified by the combination of preoperative skeletal muscle quantity and quality (non-sarcopenia, sarcopenia, and severe sarcopenia). Prognostic factors for the 5-year overall survival (OS), non-cancer-specific survival (non-CSS), and cancer-specific survival (CSS) were evaluated by multivariable Cox regression. RESULTS: The median follow-up period was 63.2 months. The non-sarcopenia, sarcopenia, and severe sarcopenia groups comprised 88, 121, and 33 patients (36.4%, 50.0%, and 13.6%), respectively. The severe sarcopenia group was older, and had a greater depth of invasion, than the non-sarcopenia group. Multivariable analysis revealed severe sarcopenia as an independent predictive indicator of OS (hazard ratio [HR] 4.01; 95% confidence interval [CI] 1.75 to 9.22) and non-CSS (HR 3.27; 95% CI 1.61 to 6.67), but not CSS. CONCLUSIONS: The combination of preoperative skeletal muscle quantity and quality was useful for predicting survival, especially death from other diseases, in elderly patients who underwent gastrectomy for gastric cancer.

Impact of barometric pressure on adhesive small bowel obstruction: a retrospective study.

BACKGROUND: Adhesive small bowel obstruction (ASBO) is one of the most common causes of postoperative morbidity. According to Boyle's law, decreased barometric pressure expands the volume of intestinal gas. We aimed to elucidate the relationship between barometric pressure and ASBO. METHODS: We divided 215 admissions of 120 patients with ASBO into three groups: the fasting group, which responded to fasting (n = 51); the decompression group, which was successfully treated with gastrointestinal decompression (n = 104); and the surgery group which required emergency or elective surgery to treat ASBO (n = 60). We compared and examined clinical backgrounds, findings on admission, and barometric pressure during the peri-onset period (29 days: from 14 days before to 14 days after the onset of ASBO). RESULTS: There were significant differences among the three groups regarding gender, history of ASBO, hospital length of stay, and barometric pressure on the onset day of ASBO. Barometric pressure on the onset day was significantly higher in the fasting group than in the decompression group (p = 0.005). During pre-onset day 5 to post-onset day 2, fluctuations in the barometric pressure in the fasting and decompression groups showed reciprocal changes with a symmetrical axis overlapping the median barometric pressure in Matsumoto City; the fluctuations tapered over time after onset. In the fasting group, the barometric pressure on the onset day was significantly higher than that on pre-onset days 14, 11, 7, 4, 3, and 2; post-onset days 3 and 10; and the median pressure in Matsumoto City. Conversely, in the decompression group, the barometric pressure on the onset day was lower than that on pre-onset days 14, 5-2; post-onset days 1, 2, 7, 8, 11, 13, and 14; and the median pressure in Matsumoto City. In the surgery group, the barometric pressure on the onset day was equivalent to those on the other days. CONCLUSIONS: ASBO with response to conservative treatment is vulnerable to barometric pressure. Additionally, ASBO that is successfully treated with fasting and decompression is associated with a different barometric pressure on the onset day and reciprocal fluctuations in the barometric pressure during the peri-onset period.

[Two Cases of Fournier's Gangrene That Occurred during Chemotherapy for Rectal Cancer].

Two cases of Fournier's gangrene occurred during chemotherapy for advanced rectal cancer. Patients were treated using surgical debridement and antibiotic therapy. Case 1: A 66-year-old man had advanced rectal cancer with para-aortic and inguinal lymph node metastases. He received a sigmoid colostomy and chemotherapy(capecitabine, oxaliplatin, bevacizumab). Due to progression of the rectal mass, we performed radiotherapy(30 Gy)and chemotherapy(irinotecan, S-1, bevacizumab). After 14 days, he was hospitalized with a diagnosis of Fournier's gangrene with anal pain and fever. Case 2: A 63-year-old man had mucinous rectal carcinoma with sacrum invasion. He received a sigmoid colostomy and chemotherapy. Sixteen days after regorafenib therapy, as a fifth-line of chemotherapy, he was hospitalized with a diagnosis of Fournier's gangrene with hip pain, swollen perineum, and fever. There have been no reports of Fournier's gangrene occurring during chemotherapy for rectal cancer. We report 2 cases with a review of literature.

2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor.

New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.

Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model.

A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display.

G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca(2+) in vitro (IC(50) = approximately 10 µM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs.

Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation.

Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.

Goblet cell adenocarcinoma of the appendix: A case report of three cases.

INTRODUCTION AND IMPORTANCE: Appendiceal goblet cell adenocarcinoma is in 0.3-0.9 % of appendectomy specimens. There is still controversy regarding whether surgery with dissection or additional resection is necessary for goblet cell adenocarcinoma and whether adjuvant chemotherapy is practical. We present three cases of goblet cell adenocarcinomas. CASE PRESENTATION: Case 1: A 30-year-old woman was diagnosed with appendicitis and underwent appendicectomy. Histopathological evaluation revealed a malignant neoplasm with goblet-like cells and tumour infiltration into the subserosa. The patient underwent laparoscopic ileocecal resection, and the main lymph nodes at the root of the feeding vessels were removed. Case 2: A 50-year-old man was diagnosed with appendicitis and underwent appendicectomy. Histopathological evaluation revealed a malignant neoplasm with goblet-like cells; malignant cells were found at the surgical resection margins. The patient underwent laparoscopic ileocolic resection. Case 3: A 60-year-old man undergoing treatment for malignant melanoma. He was diagnosed with appendicitis associated with an appendiceal tumour, and emergency laparoscopic caecal resection was performed and diagnosed as goblet cell adenocarcinoma. We decided to prioritize treatment for malignant melanoma, and the patient is under follow-up for goblet cell adenocarcinoma and no metastasis was detected. CLINICAL DISCUSSION: We performed additional resection in two case of goblet cell adenocarcinoma. Diagnosing appendiceal goblet cell adenocarcinoma is difficult, and the prognosis of patients with positive lymph nodes is poor. Surgical treatment should be considered for the advanced stages of this disease. CONCLUSION: Goblet cell adenocarcinoma, diagnosed after appendectomy, additional resection including lymph node dissection may provide a long-term prognosis.

Gastric glomus tumor resection using laparoscopic endoscopic cooperative surgery: A case report.

Gastric glomus tumors are rare submucosal mesenchymal neoplasms that are difficult to diagnose preoperatively. We present a case of a 60-year-old woman who was diagnosed with a gastric glomus tumor using endoscopic ultrasonography-guided fine-needle aspiration biopsy. The tumor was successfully resected with laparoscopic endoscopic cooperative surgery (LECS). LECS could be an effective method for the resection of gastric glomus tumors.

Importance of intraoperative indocyanine green imaging in the management of non-occlusive mesenteric ischemia: a case report.

BACKGROUND: Non-obstructive intestinal ischemia (NOMI) is caused by intestinal vascular spasm and has a poor prognosis if not diagnosed and treated early. Indocyanine green (ICG) fluorescence imaging has been reported to be useful for the intraoperative assessment of the extent of intestinal resection required for NOMI. Few reports have described massive intestinal bleeding after conservative management of NOMI. We report a case of NOMI with massive postoperative bleeding from the site of an ICG contrast defect found before the initial surgery. CASE PRESENTATION: A 47-year-old woman with hemodialysis-dependent chronic kidney disease presented complaining of severe abdominal pain. A computed tomography scan showed portal gas and dilation of the small intestine, leading to a diagnosis of NOMI and subsequent emergency surgery. At the time of initial surgery, the contrast effect of ICG was slightly reduced, showing a granular distribution in the ascending colon to cecum (fine grain pattern) and significantly reduced in parts of the terminal ileum except around blood vessels (perivascular pattern). However, there was no obvious gross necrosis of the serosal surface, and the intestinal tract was not resected. The acute postoperative course was uneventful; however, the patient went into shock on the 24th postoperative day due to massive, small intestinal bleeding, and emergency surgery was performed. The bleeding originated from the section of the ileum that had complete loss of ICG contrast effect before the initial surgery. A right hemicolectomy with the terminal ileum resection was performed, and an ileo-transverse anastomosis was performed. The second post-operative course was uneventful. CONCLUSIONS: We report a case of delayed hemorrhage of the ileum shown to have poor blood flow on ICG imaging at the initial surgery. Intraoperative ICG fluorescence imaging is useful in assessing the degree of intestinal ischemia for NOMI. When patients with NOMI are followed up without surgery, complications such as bleeding should be noted.

Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRASG12D Inhibitor, in Colorectal Cancer Treatment.

BACKGROUND/AIM: Kirsten Rat Sarcoma viral oncogene homolog (KRAS) has remained undruggable for decades. KRAS has predominantly been used to evaluate the applicability of anti-Epidermal Growth Factor Receptor (EGFR) antibody drugs. However, various KRAS inhibitors have recently emerged. Unfortunately, KRAS inhibitors have not been effective against colorectal cancer. Therefore, this study aimed to determine the effects of MRTX1133, a novel KRASG12D inhibitor, in combination with an anti-EGFR antibody, cetuximab, on signal transduction and cell proliferation. MATERIALS AND METHODS: The KRASG12D-mutated LS513 and KRAS wild-type CACO-2 human colon cancer cell lines were utilized. The KRASG12D mutation was stably transduced into the CACO-2 cells using a retrovirus. We evaluated the effects of the drugs using the CCK-8 assay and assessed the activity of proteins related to the MAPK pathway using western blotting. RESULTS: We demonstrated that the administration of MRTX1133, a novel KRASG12D inhibitor, to KRASG12D-mutated colorectal cancer cells led to feedback activation of the ERK pathway via EGFR activation, inducing drug resistance. Intriguingly, when MRTX1133 was used in combination with cetuximab, KRASG12D-mutant colorectal cancer growth was effectively inhibited, both in vitro and in vivo. CONCLUSION: The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRASG12D mutation. KRASG12D is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients.

Comparison of Short-term Outcomes Between Esophageal Bypass Surgery and Self-expanding Stent Insertion in Esophageal Cancer: A Propensity Score-matched Analysis Using a Large-scale Inpatient Database.

BACKGROUND: Advanced esophageal cancer is occasionally accompanied by difficulty swallowing owing to esophageal stenosis or tracheoesophageal fistula formation. Esophageal bypass surgery and stent insertion are considered feasible palliative management options. The aim of this study was to evaluate the short-term outcomes of these palliative treatments. MATERIALS AND METHODS: Patient data were obtained from a large-scale inpatient database of 42 National University Hospitals in Japan. Patients with advanced esophageal cancer who underwent esophageal bypass surgery or stent insertion between April 2016 and March 2021 were included in this study. One-to-one propensity score matching of patients who underwent bypass surgery or stent insertion was performed. The primary outcomes were time to diet resumption and length of hospital stay after surgery. The secondary outcome was the incidence of postoperative complications. RESULTS: In 43 propensity score-matched pairs, the incidence of postoperative respiratory complications was significantly higher in the bypass group than in the stent group (32.6% vs. 9.3%, P = 0.008). Postoperative length of hospital stay was longer in the bypass group than in the stent group (24 vs. 10 d, P < 0.001). Logistic regression analysis revealed that stent insertion was associated with a decreased risk of respiratory complications (odds ratio 0.077, P < 0.007). Among patients who underwent the interventions (bypass surgery or stent insertion) and subsequently underwent anticancer therapy (chemotherapy/radiotherapy) during hospitalization, the interval between the intervention and anticancer therapy was longer in the bypass group than in the stent group (25 vs. 7 d, P = 0.003). CONCLUSIONS: Esophageal stent insertion provides better short-term outcomes than bypass surgery in patients with advanced unresectable esophageal cancer.

Transmesenteric approach for laparoscopic endoscopic cooperative surgery for a duodenal adenoma located in the third portion of the duodenum.

We report our experience in a patient with adenoma located in the horizontal part of the duodenum, which was effectively treated with the transmesenteric laparoscopic endoscopic cooperative surgery (LECS) approach. This approach, which entails incising the mesentery of the colon, simplified laparoscopic access to the horizontal part of the duodenum, which was minimally mobilized. Thus, the bulb and descending part of the duodenum were fixed to the retroperitoneum, facilitating stable handling of the endoscope and enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. This approach enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. The advantages of this method include a secure field of view, lower probability of damage to large vessels, and minimizing the defect to the intestine caused by the incision.

MEK inhibitor and anti-EGFR antibody overcome sotorasib resistance signals and enhance its antitumor effect in colorectal cancer cells.

The Kirsten rat sarcoma (KRAS) oncogene was "undruggable" until sotorasib, a KRASG12C selective inhibitor, was developed with promising efficacy. However, inhibition of mutant KRAS in colorectal cancer cells (CRC) is ineffective due to feedback activation of MEK/ERK downstream of KRAS. In this study, we screened for combination therapies of simultaneous inhibition to overcome sotorasib resistance using our previously developed Mix Culture Assay. We evaluated whether there was an additive effect of sotorasib administered alone and in combination with two or three drugs: trametinib, a MEK inhibitor, and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody. The MAPK pathway was reactivated in KRASG12C-mutated cell lines treated with sotorasib alone. Treatment with KRAS and MEK inhibitors suppressed the reactivation of the MAPK pathway, but upregulated EGFR expression. However, the addition of cetuximab to this combination suppressed EGFR reactivation. This three-drug combination therapy resulted in significant growth inhibition in vitro and in vivo. Our data suggest that reactive feedback may play a key role in the resistance signal in CRC. Simultaneously inhibiting KRAS, MEK, and EGFR is a potentially promising strategy for patients with KRASG12C-mutated CRC.

RhoA G17E/Vav1 Signaling Induces Cancer Invasion via Matrix Metalloproteinase-9 in Gastric Cancer.

BACKGROUND: RAS homolog family member A (RhoA), a member of the Rho family of small GTPases, and Vav1, a guanine nucleotide exchange factor for Rho family GTPases, have been reported to activate pathways related to the actin cytoskeleton and regulation of cell shape, attachment, and motility. The interaction between these molecules in lymphoma is involved in malignant signaling, but its function in epithelial malignancy is unknown. Here, we investigated the malignant signal of mutant RhoA in gastric cancer and demonstrated the potential of RhoA G17E/Vav1 as a therapeutic target for diffuse gastric cancer. METHODS: The RhoA mutants R5W, G17E, and Y42C were retrovirally transduced into the gastric cancer cell line MKN74. The stably transduced cells were used for morphology, proliferation, and migration/invasion assays in vitro. MKN74 cells stably transduced with ectopic wild-type RhoA and mutant RhoA (G17E) were used in a peritoneal xenograft assay. RESULTS: The RhoA mutations G17E and Y42C induced morphological changes in MKN74. G17E induced Vav1 expression at the mRNA and protein levels and promoted the migration and invasion of MKN74. An RNA interference assay of Vav1 revealed that RhoA G17E enhanced cancer cell invasion via Vav1. Furthermore, immunoprecipitation revealed that Vav1 and RhoA G17E specifically bind and function together through matrix metalloproteinase -9. In a peritoneal xenograft model of nude mice, RhoA G17E promoted peritoneal dissemination, whereas Vav1 knockdown suppressed it. CONCLUSION: Overall, our findings indicate that RhoA G17E is associated with Vav1 and promoted cancer invasion via matrix metalloproteinase -9 in gastric cancer cells. Thus, RhoA G17E/Vav1 signaling in diffuse gastric cancer may be a useful therapeutic target.

Retinoblastoma gene-independent G1 phase arrest by flavone, phosphatidylinositol 3-kinase inhibitor, and histone deacetylase inhibitor.

In most human malignant tumors, retinoblastoma tumor-suppressor gene (RB) product is inactivated by phosphorylation. Therefore, cancer preventive agents or molecular-targeting agents can inhibit the tumor growth at G(1) phase through RB reactivation. However, little is known about the effectiveness of RB reactivating agents against malignancies with mutated RB. We report here that chemopreventive agent flavone, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) also induce G(1) phase arrest in malignant tumor cells with mutated RB. In human prostate cancer DU145 cells with mutated RB, flavone increased cyclin-dependent kinase (CDK) inhibitors p21 and p27, and reduced cdk4 and cdk6, resulting in decrement of phosphorylated RB family proteins p130 and p107. LY294002 also dephosphorylated p107 and p130 proteins, whereas TSA dephosphorylated p130, but not p107. Furthermore, flavone induced G(1) phase arrest in both mouse embryo fibroblast (MEF) wild-type and MEF RB(-/-) cells, but did not do so in RB, p107, and p130 triple-knockout MEF cells. These results suggested that p130 and p107 contributed to G(1) phase arrest by flavone in RB-mutated cells. However, flavone induced tumor suppressor microRNA miR-34a with reduction of E2F1 and E2F3, known to be downregulated by miR-34a, raising the possibility that miR-34a might partially contribute to G(1) arrest by flavone. These results raise the possibility that RB reactivating chemopreventive agents or molecular targeting agents might also be effective against a variety of malignant tumor cells with mutant RB.

Intraoperative visualization of morphological patterns of the thoracic duct by subcutaneous inguinal injection of indocyanine green in esophagectomy for esophageal cancer.

To prevent chylothorax after esophageal cancer surgery, it is important to recognize morphological patterns of the thoracic duct intraoperatively. The present study aimed to evaluate the safety and usefulness of near-infrared (NIR) fluorescence imaging with subcutaneous inguinal injection of indocyanine green (SII-ICG) to detect the thoracic duct during thoracoscopic esophagectomy for esophageal cancer. Patients (n = 16) who underwent thoracoscopic esophagectomy in the prone position with SII-ICG at Shinshu University Hospital between June 2020 and January 2022 were enrolled in the present study and retrospectively reviewed. Immediately prior to thoracoscopic esophagectomy, we injected 0.2-0.5 mg/kg ICG into the subcutaneous tissue in the bilateral inguinal region. The identification rate of the thoracic duct was 93.8% (n = 15), and the success rate of fluorescence using SII-ICG was 87.5% (n = 14). The visible thoracic ducts had four patterns: a typical pattern in 50% (n = 8), duplication pattern in 18.8% (n = 3), branching pattern in 12.5% (n = 2), and plexiform pattern in 12.5% (n = 2). In all cases, ICG fluorescence did not disappear and was visible during the thoracic surgery. No SII-ICG-related complications were observed. Intraoperative NIR fluorescence imaging of the thoracic duct using SII-ICG is a simple and safe method with very high detection sensitivity. This method can be a powerful tool for avoiding thoracic duct injuries during esophageal cancer surgery.