Visualization of cecal tumor by near-infrared laparoscopy and intraoperative colonoscopy.

BACKGROUND: In laparoscopic colorectal surgery, accurate localization of a tumor is essential for ensuring an adequate ablative margin. Therefore, a new method, near-infrared laparoscopy combined with intraoperative colonoscopy, was developed for visualizing the contour of a cecal tumor from outside of the bowel. The method was used after it was verified on a model that employed a silicone tube. CASE PRESENTATION: The patient was a 77-year-old man with a cecal tumor near the appendiceal orifice. Laparoscopy was used to clamp of the terminal ileum, and a colonoscope was then inserted through the anus to the cecum. The laparoscope in the normal light mode could not be used to identify the cecal tumor. However, a laparoscope in the near-infrared ray mode could clearly visualize the contour of the cecal tumor from outside of the bowel, and the tumor could be safely resected by a stapler. The histopathological diagnosis of the resected specimen was adenocarcinoma with an invasion depth of M and a clear negative margin. CONCLUSIONS: This is the first report of the laparoscopic detection of the contour of a cecal tumor from outside the bowel. This technique is useful and safe for contouring tumors in laparoscopic colorectal surgery and can be used in various surgeries that combine endoscopy and laparoscopy.

Robotic versus open and laparoscopic pelvic exenterations for pelvic cancer: a multicenter propensity-matched analysis in Japan.

BACKGROUND: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors. METHODS: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias. RESULTS: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002). CONCLUSION: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors.

Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers.

Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNLowPDPNLow); a PDPN-dominant group (DCNMidPDPNHigh); and a DCN-dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.

Unanticipated pathological clearance in two cases of clinical T4b dMMR/MSI-h advanced colorectal cancer: the potential of immune checkpoint inhibitors despite positive positron-emission tomography results.

BACKGROUND: The standard treatment for colorectal cancer consists of surgery and chemotherapy, which can be combined to improve outcomes. Immune checkpoint inhibitors (ICI) are a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair (dMMR). However, limited data are available about the use of ICI in the neoadjuvant and conversion settings. Here, we present two cases treated with ICI. CASE PRESENTATION: Case 1: A 75-year-old male with a large, borderline resectable rectal cancer diagnosed as cT4bN1bM0 who underwent neoadjuvant chemotherapy, followed by combination ICI consisting of ipilimumab and nivolumab. After four courses of ICI, the tumor significantly shrank, but positron emission tomography still showed a positive result and R0 resection was performed. Pathological analysis revealed no residual cancer cells. The patient has been monitored without adjuvant chemotherapy, and no recurrences have occurred after one year. Case 2: A 60-year-old male with locally advanced sigmoid colon cancer who received neoadjuvant treatment with pembrolizumab. The tumor partially shrank after three courses, and continued pembrolizumab monotherapy resulted in further tumor shrinkage which still showed positive positron emission tomography. Curative sigmoidectomy with partial resection of the ileum and bladder was performed, and the pathological outcome was pCR. There was no viable tumor in the specimen. The patient has been monitored without adjuvant chemotherapy for six months, and no recurrence has been observed. CONCLUSIONS: The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a 'watch-and-wait" strategy could be used for cases in which ICI is effective.

Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Expression of ZKSCAN3 protein suppresses proliferation, migration, and invasion of pancreatic cancer through autophagy.

Elevated autophagy activity enhances the malignancy of pancreatic cancer (PaCa), and autophagy is recognized as a novel therapeutic target. Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) is a transcription factor that suppresses autophagy, but its association with PaCa is unknown. We analyzed the function of ZKSCAN3 in PaCa and investigated whether autophagy regulation through ZKSCAN3 could become a new therapeutic target for PaCa. Using reverse transcription-quantitative polymerase chain reaction and western blotting, we observed that ZKSCAN3 expression was upregulated in several PaCa cell lines compared with normal pancreatic ductal epithelial cells. Additionally, comparing ZKSCAN3 expression with the prognosis of PaCa patients using web databases, we found that higher ZKSCAN3 expression in PaCa was associated with extended overall survival. Knocking down ZKSCAN3 promoted the proliferation of PaCa cells. Moreover, following ZKSCAN3 knockdown, PaCa cells exhibited significantly enhanced migratory and invasive properties. Conversely, overexpression of ZKSCAN3 significantly suppressed the proliferation, migration and invasion of PaCa cells. Additionally, the knockdown of ZKSCAN3 increased the expression of LC3-II, a marker of autophagy, whereas ZKSCAN3 overexpression decreased LC3-II expression. In a xenograft mouse model, tumors formed by MIA PaCa-2 cells in which ZKSCAN3 was knocked down significantly increased in size compared with the control group. In conclusion, ZKSCAN3 expression was upregulated in several pancreatic cancer cells. Additionally, it was revealed that ZKSCAN3 is negatively correlated with the malignancy of PaCa through autophagy. These results suggest that autophagy regulation via ZKSCAN3 may be a new therapeutic target for PaCa.

Validation of the Diagnostic Criteria for IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis (IgG4PA/RPF) 2018, and Proposal of a Revised 2023 Version for IgG4-Related Cardiovascular/Retroperitoneal Disease.

BACKGROUND: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

Genomic diversity of the pathogenic fungus Aspergillus fumigatus in Japan reveals the complex genomic basis of azole resistance.

Aspergillus fumigatus is a pathogenic fungus with a global distribution. The emergence of azole-resistant A. fumigatus (ARAf) other than the TR-mutants is a problem in Japan. Additionally, the genetic diversity of A. fumigatus strains in Japan remains relatively unknown. Here we show the diversity in the A. fumigatus strains isolated in Japan as well as the complexity in the global distribution of the pathogenic strains. First, we analyzed the genome sequences of 171 strains from Japan as well as the antifungal susceptibility of these strains. Next, we conducted a population analysis of 876 strains by combining the available genomic data for strains isolated worldwide, which were grouped in six clusters. Finally, a genome-wide association study identified the genomic loci associated with ARAf strains, but not the TR-mutants. These results highlight the complexity of the genomic mechanism underlying the emergence of ARAf strains other than the TR-mutants.

In vitro activity of tedizolid against 43 species of Nocardia species.

The purpose of the present study was to evaluate the in vitro activity of tedizolid against several clinically significant species of Nocardia by comparing with that of linezolid. A total of 286 isolates of Nocardia species, including 236 clinical isolates recovered from patients in Japan and 50 strains (43 species) purchased from NITE Biological Resource Center, were studied. Antimicrobial susceptibility testing was performed using the broth microdilution method. For the 286 Nocardia isolates, the minimal inhibitory concentration (MIC)50 and MIC90 values of tedizolid were 0.25 and 0.5 µg/ml, and those of linezolid were 2 and 2 µg/ml, respectively. The distribution of the linezolid/tedizolid ratios (MICs of linezolid/MICs of tedizolid) showed that tedizolid had four- to eight-fold higher activity than linezolid in 96.1% (275/286) of Nocardia isolates. Both the tedizolid and linezolid MIC90 values for Nocardia brasiliensis were two-fold higher than those for the other Nocardia species. Both tedizolid and linezolid had low MIC values, 0.25-1 µg/ml and 0.5-4 µg/ml, respectively, even against nine isolates (five species) that were resistant to trimethoprim/sulfamethoxazole. One Nocardia sputorum isolate showed reduced susceptibility to tedizolid (4 µg/ml). Bioinformatics analysis suggests different resistance mechanisms than the oxazolidinone resistance seen in enterococci and staphylococci.

Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease.

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of ß-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to ß-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

Robotic resection for splenic artery aneurysm associated with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is an autosomal-dominant disease characterized by café-au-lait spots and neurofibromas, as well as various other symptoms in the bones, eyes, and nervous system. Due to its connection with vascular fragility, neurofibromatosis type 1 has been reported to be associated with vascular lesions, such as aneurysms. However, there have been few reports of abdominal visceral aneurysms associated with neurofibromatosis type 1. Furthermore, there have been no reports of robotic treatment of aneurysms associated with neurofibromatosis type 1. In this report, we describe the case of a patient with neurofibromatosis type 1 with a splenic artery aneurysm who was successfully treated with robotic surgery. CASE PRESENTATION: This report describes a 41-year-old Asian woman with a history of neurofibromatosis type 1 who was referred to our hospital for evaluation of a 28 mm splenic artery aneurysm observed on abdominal ultrasound. The aneurysm was in the splenic hilum, and transcatheter arterial embolization was attempted; however, this was difficult due to the tortuosity of the splenic artery. Thus, we suggested minimally invasive robotic surgery for treatment and resection of the splenic artery aneurysm with preservation of the spleen. The postoperative course was uneventful, and the patient was discharged on the eighth day after surgery. At 1 year of follow-up, the patient was doing well, with no evidence of recurrence. CONCLUSION: We encountered a rare case of splenic artery aneurysm in a patient with neurofibromatosis type 1 who was successfully treated with robotic surgery. There is no consensus on treatment modalities for neurofibromatosis-related aneurysms, and endovascular treatment is considered safe and effective; however, surgery remains an important treatment modality. Especially in patients with stable hemodynamic status, robotic surgery may be considered as definitive treatment. To our knowledge, this is the first successfully treated case of a splenic artery aneurysm in a patient with neurofibromatosis type 1.

The Natural Product Parthenolide Inhibits Both Angiogenesis and Invasiveness and Improves Gemcitabine Resistance by Suppressing Nuclear Factor κB Activation in Pancreatic Cancer Cell Lines.

We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa.

Compatibility of the semijailing technique with extremely soft i-ED coils for ruptured blood blister-like and dissecting aneurysms: patient series.

BACKGROUND: Optimal treatment options for ruptured blood blister-like aneurysms (BBAs) and dissecting aneurysms (DAs) have not yet been established. Endovascular treatment may achieve vessel reconstruction with the preservation of antegrade blood flow; however, securing curative hemostasis at the fragile rupture point remains a major concern. OBSERVATIONS: Two ruptured BBAs and two ruptured DAs treated by stent-assisted coiling with the semijailing technique in the last 2 years are described herein. The devices used were braided stents and i-ED coils, which are new low-memory shape and extremely soft coils. Neither rebleeding nor ischemic complications were observed. All patients had a favorable outcome and showed no recurrence after treatment. LESSONS: All aneurysms were treated without ischemic complications or rebleeding. The good compatibility of braided stents and the new concept coils in stent-assisted coiling by the semijailing technique provides insight into these intractable hemorrhagic vascular pathologies.

Improved Renal Function in Initial Treatment Improves Patient Survival, Renal Outcomes, and Glucocorticoid-Related Complications in IgG4-Related Kidney Disease in Japan.

Introduction: We aimed to clarify long-term renal prognosis, complications of malignancy, glucocorticoid (GC) toxicity, and mortality in immunoglobulin G4 (IgG4)-related kidney disease (IgG4-RKD). Methods: Reviewing the medical records of 95 patients with IgG4-RKD, we investigated clinical and pathologic features at baseline, the course of renal function, complications of malignancy, GC toxicity, and mortality during follow-up (median 71 months). The standardized incidence ratio (SIR) of malignancy and standardized mortality ratio were calculated using national statistics. Factors related to outcomes were assessed by Cox regression analyses. Results: At diagnosis, the median estimated glomerular infiltration rate (eGFR) was 46 ml/min per 1.73 m2. GC achieved initial improvement. Additional renal function recovery within 3-months of initial treatment occurred in patients with highly elevated serum IgG and IgG4 levels and hypocomplementemia. During follow-up, 68%, 17%, and 3% of the patients had chronic kidney disease (CKD), >30% eGFR decline, and end-stage renal disease (ESRD), respectively. Age-adjusted and sex-adjusted Cox regression analyses indicated that eGFR (hazard ratio [HR], 0.71) and extensive fibrosis (HR, 2.58) at treatment initiation had a significant impact on the time to CKD. Ten patients died, and the standardized mortality ratio was 0.94. The SIR of malignancy was 1.52. The incidence rate (IR) of severe infection was 1.80/100 person-years. Cox regression analyses showed that the best eGFR within 3 months after treatment initiation were associated with lower mortality (HR 0.67) and fewer severe infections (HR 0.63). Conclusion: This study suggests that more renal function recovery through early treatment initiation may improve patient survival, renal outcomes, and some GC-related complications in IgG4-RKD.