Diagnostic Performance of Endoscopic Ultrasound Elastography for Differential Diagnosis of Gallbladder Polyp.

BACKGROUND AND AIMS: It is difficult to differentiate between neoplastic and non-neoplastic gallbladder (GB) polyps before surgery. Endoscopic ultrasound-elastography (EUS-EG) is a non-invasive complementary diagnostic method. The utility of EUS-EG in the differential diagnosis of GB polyps has not been investigated. We aimed to investigate the diagnostic performance of EUS-EG for the differential diagnosis of GB polyps. METHODS: Patients with GB polyps were prospectively enrolled from June 2020 until November 2022. EUS-EG and semi-quantitative evaluation of the strain ratio (SR) were performed for differential diagnosis of GB polyps. Fifty-three eligible patients were divided into two groups based on the final diagnosis after surgery. Patient demographics, EUS characteristics, and SR values were compared. Receiver-operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff SR value that discriminates between neoplastic and non-neoplastic GB polyps. RESULTS: The median SR value for neoplastic polyps (32.93 [interquartile range: 22.37-69.02]) was significantly higher than for non-neoplastic polyps (5.40 [2.36-14.44]; p<0.001). There were significant differences in SR values between non-neoplastic, benign neoplastic (23.38 [13.62-39.04]), and malignant polyps (49.25 [27.90-82.00]). The optimal cut-off SR value to differentiate between neoplastic and non-neoplastic polyps was 18.4. In multivariable logistic regression, SR value >18.4 (odds ratio 33.604, 95% confidence interval 2.588-436.292) was an independent predictor of neoplastic polyps. CONCLUSIONS: EUS-EG and SR values can be used as a supplementary method for evaluating GB polyps.

Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.

Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.

Savolitinib: A Promising Targeting Agent for Cancer.

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

Interstitial Lung Abnormalities and the Clinical Course in Patients With COPD.

BACKGROUND: The presence and progression of interstitial lung abnormalities (ILAs) is known to be associated with a decline of lung function and increased risk of mortality. RESEARCH QUESTION: We aimed to elucidate the clinical course according to ILAs in patients with COPD. STUDY DESIGN AND METHODS: A retrospective study was conducted between January 2013 and December 2018 of COPD patients who underwent chest CT imaging and longitudinal pulmonary function tests. We evaluated radiologic findings, history of acute exacerbations of COPD, and lung function changes during the longitudinal follow-up. RESULTS: Of 363 patients with COPD, 44 and 103 patients had equivocal and definite ILAs, respectively. Patients with ILAs were significantly older and had lower FEV1 and FVC than patients without ILAs. During the mean follow-up period of 5.2 years, ILAs were associated significantly with the annual incidence of moderate to severe acute exacerbation of COPD (ß ± SD, 0.38 ± 0.12; P = .002) and with the risk of frequent exacerbation (adjusted OR, 2.03; P = .045). Patients with progressive ILAs showed a significantly higher rate of annual decline in FEV1 and FVC than those showing no change in, or improved, ILAs. INTERPRETATION: ILAs were associated significantly with moderate to severe acute exacerbation in patients with COPD, and the progression of ILAs was associated with an accelerated decline in lung function.

Hybrid treatment of multilevel revascularization in patients with peripheral arterial disease - a multi-centre study in Korea.

BACKGROUND: Endovascular treatment is an alternative first-line management for peripheral artery disease (PAD). Hybrid treatment (HT) is defined as a combined treatment for patients with PAD using endovascular and open surgery, simultaneously performed in an operating room. The results of HT are reportedly good for multilevel revascularization (MR) in patients with chronic limb ischaemia, and even in older high-risk patients. The goal of this study was to examine the clinical and haemodynamic outcomes of HT in patients who need MR. PATIENTS AND METHODS: Nine university hospitals in Korea participated in this multicentre study. A total of 134 patients with multilevel PAD underwent HT and MR. Patients were enrolled from July 2014 to June 2015 and were followed for 18 months. RESULTS: The mean age of the patients was 68.8 ± 9.93 years and 88.1 % were men. Patients with Rutherford category 2 to 3 and 4 to 6 comprised 59.0 % and 42.0 % of the group, respectively. The technical success rate was 100 %. The primary patency rates at 12 and 18 months were 77.6 % and 63.9 %, respectively. The primary-assisted patency rates at 12 and 18 months were both 90.0 %. The pre-operative mean ankle brachial index (0.43 ± 0.23) increased to 0.87 ± 0.23 at six months post-operatively (t-test, p < 0.05). The amputation free survival rate was 97.1 %. CONCLUSIONS: Although outcomes of multilevel PAD are reportedly poor when endovascular treatment alone is used, we have shown that HT is a feasible alternative modality for patients with multilevel PAD, with satisfactory amputation-free survival and freedom from re-intervention rates.

Analysis of multiple risk factors affecting the result of free flap transfer for necrotising soft tissue defects of the lower extremities in patients with type 2 diabetes mellitus.

BACKGROUND: The limb-threatening large soft tissue defects that occur on the feet of type 2 diabetic patients have complex causes and are less likely to be corrected by free flap reconstruction compared to those in non-diabetic patients. We retrospectively analysed factors affecting the success of free flap transfer for necrotising soft tissue defects of the lower extremities in patients with type 2 diabetes. METHODS: This study included 33 diabetic patients whose feet were treated with free flap transfers. All patients had limb-threatening large soft tissue defects with tendon or bone exposure. The operative results were divided into three groups at 1 month post-operatively: the complete healing group, and the complication group, with either partial necrosis requiring additional simple procedures or flap failure with total necrosis. Nine preoperative factors were analysed: (1) ankle brachial index, (2) HbA1c, (3) BMI, (4) the smoking factor, (5) atherosclerotic calcifications (6) serum creatinine levels (>1.28 mg dL(-1) vs. <1.28 mg dL(-1)), (7) GFR, (8) wound infection and (9) wound defect size. RESULTS: Of the 33 patients, 15 showed complete healing and 18 showed complications of the free flap (eight partial necrosis and 10 flap failure). No atherosclerotic calcifications were found in the patients in the complete healing group, although they were found in 12 patients in the complication group, and this difference was significant (p = 0.002). Patients with serum creatinine levels >1.28 mg dL(-1) had significantly higher free flap transfer complication rates than those with serum creatinine levels <1.28 mg dL(-1) (p = 0.038). CONCLUSIONS: This study analysed the risk factors of free flap reconstruction for limb-threatening large soft tissue defects on the feet of type 2 diabetic patients. Serum creatinine levels >1.28 mg dL(-1) and atherosclerotic calcifications were confirmed as risk factors for flap survival.

Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer.

Cancers and tissue stem cells (SCs) share similar molecular pathways for their self-renewal and differentiation. The race is on to identify unique pathways to specifically target the cancer, while sparing normal SCs. Here, we uncover the transcription factor Runx1/AML1, a known haematopoietic and leukaemia factor, albeit dispensable for normal adult SC homeostasis, as being important for some mouse and human epithelial cancers. We implicate Runx1 as a SC-intrinsic gene in mouse hair follicle and oral epithelia by genetic lineage tracing in adulthood. Runx1-expressing SCs, but not other cells that ectopically upregulate Runx1 by injury and inflammation, are at the skin tumour origin. Runx1 loss impairs tumour initiation and maintenance and the growth of oral, skin, and ovarian epithelial human cancer cells. Runx1 stimulates Stat3 signalling via direct transcriptional repression of SOCS3 and SOCS4 and this is essential for cancer cell growth. Thus, Runx1 is a broader epithelial SC and cancer factor than previously recognized, and qualifies as an attractive potential target for both prevention and therapy of several epithelial cancers.

Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel.

Lymphedema is a manifestation of lymphatic system insufficiency. It arises from primary lymphatic dysplasia or secondary obliteration after lymph node dissection or irradiation. Although improvement of swelling can be achieved by comprehensive non-operative therapy, treatment of this condition requires lifelong care and good compliance. Recently molecular-based treatments using VEGF-C have been investigated by several researchers. We designed the present study to determine whether the therapeutic efficacy of implanted human adipose-derived stem cells (hADSCs) could be improved by applying a gelatin hydrogel containing VEGF-C (VEGF-C hydrogel) to the site of tissue injury in a lymphedema mouse model. Four weeks after the operation, we evaluated edema and determined lymphatic vessel density at various post-operative time points. Mice treated with hADSCs and VEGF-C hydrogel showed a significantly decreased dermal edema depth compared to the groups of mice that received hADSCs only or VEGF-C hydrogel only. Immunohistochemical analysis also revealed that the hADSC/VEGF-C hydrogel group showed significantly greater lymphatic vessel regeneration than all the other groups. hADSCs were detected in the implantation sites of all mice in the hADSC/VEGF-C group, and exhibited a lymphatic endothelial differentiation phenotype as determined by co-staining PKH-labeled hADSCs for the lymphatic marker LYVE-1. Our results suggest that co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis.

Laparoscopic resection of nonadrenal retroperitoneal tumors.

BACKGROUND: Laparoscopic resection of primary retroperitoneal tumors is a challenging procedure because access is difficult due to the deep, posterior location and adjacent major vessels. OBJECTIVE: To assess the safety and feasibility of laparoscopic resection of primary nonadrenal retroperitoneal tumors. Method  Data on 20 patients with a diagnosis of primary retroperitoneal tumor who underwent laparoscopic resection from August 1, 2003, to June 30, 2009 were analyzed. RESULTS: Twenty patients (12 men and 8 women; median age, 45.5 years) were included in the review. The tumor sizes ranged from 2.0 to 9.5 cm in diameter (median, 4.7 cm). In 10 patients, tumors were adherent to adjacent major vessels (ie, inferior vena cava, renal vein, superior mesenteric vein, or the splenic vessel). Postoperative examination of the samples revealed that lymphangioma (7 [35.0%]) was the most common tumor type, followed by ganglioneuroma (3 [15.0%]), schwannoma (2 [10.0%]), paragangolioma (2 [10.0%]), and Castleman disease (2 [10.0%]). The median operative time was 117.5 minutes and the median estimated blood loss was 50.0 mL. One operation (0.05%) was converted to laparotomy due to intraoperative bleeding. Postoperative complications occurred in 2 patients (10.0%), both of whom were treated conservatively. The median length of the postoperative hospital stay was 5 days. Neither tumor size nor the presence of adhesions to adjacent vessels affected the perioperative or clinical outcomes. CONCLUSION: Laparoscopic resection of retroperitoneal tumors is feasible even when a tumor is large or adheres to adjacent vascular structures if there is no evidence of malignancy based on preoperative radiologic studies.

[A case of early bile duct cancer arising from villous adenoma in choledochal cyst].

Choledochal cyst is an uncommon premalignant anomaly. The morphology and pathogenesis of the premalignant lesion of cholangiocarcinoma arising from the choledochal cyst has not been well described. Herein, we report a rare case of bile duct adenoma arising from choledochal cyst with anomalous union of pancreaticobiliary duct (AUPBD). 50-year-old woman was admitted to our hospital with the complaint of epigastric pain. She had received common bile duct (CBD) exploration and choledocholithotomy and cholecystectomy 3 months earlier under the diagnosis of multiple CBD stones. Intraoperalive cholangiogram was not remarkable except CBD dilatation at that time. Endoscopic retrograde cholangiopancreatography revealed choledochal cyst with AUPBD and round filling defect which disappeared easily on the balloon cholaniogram. On magnetic resonance cholangiopancreatography, the filling defect was confirmed as 2 cm polypoid mass attached to the distal bile duct wall. At laparotomy, a soft whitish mass was palpable on the lower CBD. On histological examination, adenoma with focal carcinoma change arising from choledochal cyst was diagnosed.

[A case of anti-LKM 1 positive autoimmune hepatitis accompanied by systemic lupus erythematosus].

Overlap of autoimmune hepatitis and systemic lupus erythematosus (SLE) is a comparatively rare condition. Although both autoimmune hepatitis and SLE can share common autoimmune features such as polyarthralgia, hypergammaglobulinemia and positive ANA, it has been considered as two different entities. We report a case of anti-LKM1 positive autoimmune hepatitis who developed SLE two years later. The presence of interface hepatitis with lymphoplasma cell infiltrates and rosette formation points to the autoimmune hepatitis rather than SLE hepatitis. Autoimmune hepatitis is infrequently accompanied by SLE, therefore, it could be recommended to investigate for SLE in patients with autoimmune hepatitis.

Delayed recurrent hemarthrosis after staple fixation of tibial avulsion fracture of the posterior cruciate ligament: a case report.

This study reports a case of unusual vascular complication related to the staple fixation for the tibial avulsion fracture of the posterior cruciate ligament (PCL). The patient, who experienced recurrent hemarthrosis 12 months after staple fixation for the avulsion fracture of the PCL, was successfully managed by removing the staple and suturing the bleeding focus of the popliteal artery. Injury to the popliteal artery by the prominent staples could be the culprit causing the recurrent hemarthrosis. This type of delayed popliteal artery injury should be kept in mind in open reduction and internal fixation for the tibial avulsion fracture of the PCL.

Gene expression of perforin by peripheral blood lymphocytes as a marker of acute rejection.

BACKGROUND: Previous findings have demonstrated that the expression of cytotoxic effector molecules is increased in acute rejection of renal allografts. In the present study, we serially examined the gene expression of perforin, granzyme B and Fas ligand (FasL) in peripheral blood lymphocytes (PBLs) of renal allograft recipients to assess the potential of their expression as a marker of acute rejection. METHODS: PBLs were isolated from blood samples taken on days 2, 4, 6, 8, 10 and 12 after transplantation. Competitive PCR was performed to evaluate the abundance of mRNA of perforin, granzyme B and FasL. The mean value + 2 SD of each molecule in the control group was set as a discriminatory level for that particular molecule. RESULTS: When all measured samples were compared, perforin expression was significantly higher in patients with acute rejection than in the control group (1.84 +/- 3.01 vs. 0.71 +/- 0.48, p = 0.01). The percentage of perforin expression exceeding the discriminatory level was also significantly higher in patients with acute rejection (p = 0.0003). Five patients in the rejection group (5/7, 71.4%) showed perforin expression exceeding the discriminatory level, while only 1 patient in the control group did so (1/8, 12.5%) (p = 0.02). Perforin expressions of days 0 and 1 of rejection crisis were the highest over the study period. No consistent pattern of granzyme B and FasL expression was identified in relation to rejection crisis. CONCLUSION: Gene expression of perforin by PBLs was upregulated in accordance with acute rejection, thus offering the possibility that it may be utilized as a marker of acute rejection.