Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo.

Exosomes, the smallest extracellular vesicles, have gained significant attention as key mediators in intercellular communication, influencing both physiological and pathological processes, particularly in cancer progression. A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes, with a focus on the origin from which exosomes derive. If information about the mechanisms for delivering exosomes to specific cells is incorporated, the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

[A Case of Five Years Recurrence-Free Survival after Successful Multidisciplinary Treatment for Simultaneous Brain Metastasis and Heterochronic Small Intestinal Metastasis from Lung Cancer].

The patient was a 54-year-old male at the time of initial examination. He was aware of numbness and weakness in the left hemisphere of his body and came to see the hospital. He was diagnosed with brain metastasis of lung cancer and started treatment(cT2N0M1[Brain]). He underwent gamma knife for the head lesion and nivolumab for the lung lesion. The patient's lesions shrank with the success of the medical treatment, but recurred with small intestinal metastasis. He underwent a partial resection of the small intestine and was treated again with nivolumab, which resulted in a complete response. He is currently alive without recurrence. We have experienced a very rare case of recurrence-free survival after treatment for brain metastasis and small intestinal metastasis of lung cancer.

Liver lobe-specific hydrodynamic gene delivery to baboons: A preclinical trial for hemophilia gene therapy.

Hydrodynamics-based gene transfer has been successfully employed for in vivo gene delivery to the liver of small animals by tail vein injection and of large animals using a computer-assisted and image-guided protocol. In an effort to develop a hydrodynamic gene delivery procedure clinically applicable for gene therapy, we have evaluated the safety and effectiveness of a lobe-specific hydrodynamic delivery procedure for hepatic gene delivery in baboons. Reporter plasmid was used to assess the gene delivery efficiency of the lobe-specific hydrodynamic gene delivery, and plasmid-carrying human factor IX gene was used to examine the pattern of long-term gene expression. The results demonstrated liver lobe-specific gene delivery, therapeutic levels of human factor IX gene expression lasting for >100 days, and the efficacy of repeated hydrodynamic gene delivery into the same liver lobes. Other than a transient increase in blood concentration of liver enzymes right after the injection, no significant adverse events were observed in animals during the study period. The results obtained from this first non-human primate study support the clinical applicability of the procedure for lobe-specific hydrodynamic gene delivery to liver.

An adenocarcinoma in an inverted Meckel's diverticulum with intussusception.

BACKGROUND: Adenocarcinoma in an inverted Meckel's diverticulum with intussusception has not been reported to date. We discuss the clinical issues concerning this rare condition and review the relevant literature. CASE PRESENTATION: A 71-year-old Japanese female was referred to our hospital for further investigation of severe anemia. Computed tomography revealed a tumorous lesion in the terminal ileum. Capsule endoscopy did not provide detailed images. Exploratory laparoscopy revealed intussusception in the terminal ileum. An intraluminal tumor 70 cm proximal to the ileocecal valve was observed to be the lead point. Partial resection including the tumor was performed. Macroscopically, a polypoid tumor at the tip of an inverted diverticulum-like structure was observed. The tumor was histologically composed of adenocarcinoma accompanied by gastric and pyloric gland metaplasia in the background mucosa, which was confirmed by immunohistochemical staining. Based on these characteristics, this tumor is considered to have developed from the ectopic gastric mucosa in a Meckel's diverticulum. CONCLUSIONS: When we encounter patients with unfamiliar lesions in the small bowel, we need to differentiate Meckel's diverticulum related disease. Meckel's diverticulum can invert into the lumen of the small bowel and cause an intussusception, and has potential of malignant transformation.

Hydrodynamic Delivery: Characteristics, Applications, and Technological Advances.

The principle of hydrodynamic delivery was initially used to develop a method for the delivery of plasmids into mouse hepatocytes through tail vein injection and has been expanded for use in the delivery of various biologically active materials to cells in various organs in a variety of animal species through systemic or local injection, resulting in significant advances in new applications and technological development. The development of regional hydrodynamic delivery directly supports successful gene delivery in large animals, including humans. This review summarizes the fundamentals of hydrodynamic delivery and the progress that has been made in its application. Recent progress in this field offers tantalizing prospects for the development of a new generation of technologies for broader application of hydrodynamic delivery.

[Liver Resection after Chemotherapy for Simultaneous Liver Metastasis of Cecal Cancer-A Case Report].

A 78-year-old male patient was referred to another hospital for cecal cancer and metastatic liver tumor. After open ileocecal resection, he was referred to our hospital for treatment of liver lesions. CT scan showed a lesion with contrast effect of approximately 60 mm in S8, and the patient was judged to be resectable by right lobe resection. However, considering his age and the possibility of latent disease, it was decided to introduce preoperative chemotherapy. After 4 courses of XELOX, although the ICG worsened from 9% to 18% after chemotherapy, the tumor was reduced to approximately 30 mm. The patient underwent an open anterior segment resection of the liver. Colorectal cancer guidelines recommend that surgical resection is the first-line treatment for resectable liver metastases and that preoperative adjuvant chemotherapy should not be given to patients. In this report, we describe a case in which a liver metastasis was safely resected with chemotherapy.

Gravity assistance enables liver stiffness measurements to detect liver fibrosis under congestive circumstances.

BACKGROUND: As survival has been prolonged owing to surgical and medical improvements, liver failure has become a prognostic determinant in patients with congestive heart diseases. Congestive hepatopathy, an abnormal state of the liver as a result of congestion, insidiously proceed toward end-stage liver disease without effective biomarkers evaluating pathological progression. Regular measurements of shear wave elastography cannot qualify liver fibrosis, which is a prognosticator in any type of chronic liver disease, in cases of congestion because congestion makes the liver stiff without fibrosis. We hypothesized that the effects of congestion and fibrosis on liver stiffness can be dissociated by inducing architectural deformation of the liver to expose structural rigidity. AIM: To establish a strategy measuring liver stiffness as a reflection of architectural rigidity under congestion. METHODS: Two-dimensional shear wave elastography (2dSWE) was measured in the supine (Sp) and left decubitus (Ld) positions in 298 consecutive cases as they were subjected to an ultrasound study for various liver diseases. Regions of interest were placed at twelve sites, and the median and robust coefficient of variation were calculated. Numerical data were compared using the Mann-Whitney U or Kruskal-Wallis test followed by Dunn's post-hoc multiple comparisons. The inferior vena cava (IVC) diameters at different body positions were compared using the Wilcoxon matched pairs signed rank test. The number of cases with cardiothoracic ratios greater than or not greater than 50% was compared using Fisher's exact test. A correlation of 2dSWE between different body positions was evaluated by calculating Spearman correlation coefficients. RESULTS: The IVC diameter was significantly reduced in Ld in subjects with higher 2dSWE values in Ld (LdSWE) than in Sp (SpSWE) (P = 0.007, (average ± SD) 13.9 ± 3.6 vs 13.1 ± 3.4 mm) but not in those with lower LdSWE values (P = 0.32, 13.3 ± 3.5 vs 13.0 ± 3.5 mm). In 81 subjects, SpSWE was increased or decreased in Ld beyond the magnitude of robust coefficient of variation, which suggests that body postural changes induced an alteration of liver stiffness significantly larger than the technical dispersion. Among these subjects, all 37 with normal SpSWE had a higher LdSWE than SpSWE (Normal-to-Hard, SpSWE - LdSWE (∆2dSWE): (minimum-maximum) -0.74 - -0.08 m/sec), whereas in 44 residual subjects with abnormal SpSWE, LdSWE was higher in 27 subjects (Hard-to-Hard, -0.74 - -0.05 m/sec) and lower in 17 subjects (Hard-to-Soft, 0.04 - 0.52 m/sec) than SpSWE. SpSWE was significantly correlated with ∆2dSWE only in Hard-to-Soft (P < 0.0001). ∆2dSWE was larger in each lobe than in the entire liver. When Hard-to-Hard and Hard-to-Soft values were examined for each lobe, fibrosis-4 or platelet counts were significantly higher or lower only for Hard-to-Soft vs Normal-to-Hard cases. CONCLUSION: Gravity alters the hepatic architecture during body postural changes, causing outflow blockage in hepatic veins. A rigid liver is resistant to structural deformation. Stiff-liver softening in the Ld position suggests a fibrous liver.

Long-term survival of 11 years with multidisciplinary therapy for hepatocellular carcinoma metastasis to the ovary and peritoneum: a case report.

We herein report a rare case of HCC metastases to the ovary and peritoneum in a 61-year-old female patient who has achieved 11-year survival with multidisciplinary therapy. The patient was diagnosed with HCC during balloon angioplasty performed for Budd-Chiari syndrome in 1994 and underwent partial hepatectomy twice. Five years after the second hepatectomy, allochronic recurrence of a single nodule detected in S8 was treated by radiofrequency ablation, followed by percutaneous ethanol injection therapy and stereotactic body radiotherapy. However, her α-fetoprotein level rose to 1862 ng/mL within one year and computed tomography revealed a large pelvic tumor suggesting HCC metastasis to the ovary. The subsequent laparotomy revealed one 11-cm left ovarian tumor, one small right ovarian nodule, and numerous peritoneal nodules. Bilateral salpingo-oophorectomy and peritoneal resection of as many nodules as possible were performed. Combination therapy with intravenous 5-fluorouracil plus cisplatin and ramucirumab monotherapy effectively suppressed tumor progression with maintenance of hepatic functional reserve, and she has achieved long-term survival of 11 years, illustrating that multidisciplinary therapy with favorable hepatic functional reserve maintenance can contribute to long-term survival in HCC with extrahepatic spread.

Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers.

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

[A Case of Histological Response of Grade 3 Achieved by Preoperative Chemotherapy with S-1/Oxaliplatin(SOX)].

Histological response of Grade 3 is relatively rare in gastric cancer patients but has recently been observed occasionally. We report the histological response of Grade 3 achieved by S-1/oxaliplatin(SOX)therapy. A 66-year-old man had suffered from epigastralgia when hungry. After 1 month, he visited the department of gastroenterology of our hospital. Upper gastrointestinal endoscopy revealed a type 3 tumor at the lesser curvature of middle gastric body, and poorly differentiated adenocarcinoma was detected by the biopsy examination. Abdominal/pelvic enhanced CT showed wall thickening of the lower gastric body, enlarged regional lymph nodes and para-aortic lymph nodes(No. 16b1). We diagnosed it with Stage Ⅳ. He received 4 courses of SOX therapy. After chemotherapy, upper gastrointestinal endoscopy revealed a residual tumor, although biopsy showed no cancer cells. Abdominal/pelvic enhanced CT showed significantly reduced lymph nodes despite the thickening of the gastric wall. PET-CT revealed indistinct para-aortic lymph nodes. Distal gastrectomy, D2 dissection without para-aortic lymph nodes dissection, and Billroth Ⅰ reconstruction were performed. Histological findings showed no cancer cells in the main lesion or lymph nodes, with only previous cancer cells suspected. The histological response was Grade 3. SOX therapy might be employed in the future as chemotherapy before conversion surgery for Stage Ⅳ gastric cancer.

A Superinfection of Salmonella typhi and Hepatitis E Virus Causes Biphasic Acute Hepatitis.

A 47-year-old Japanese man was referred to our hospital because of a sustained high fever with diarrhea 12 days after a flight from India. Liver enzymes were elevated with rose spots, hepatosplenomegaly, relative bradycardia, and acute cholecystitis. A liver biopsy depicted the dense infiltration of lymphocytes and Kupffer cells in sinusoids and the granulomatous formation in the parenchyma. The liver damage was initially resolved with the administration of ceftriaxone for 16 days but flared up 1 week later. Laboratory tests yielded positive reactions for Salmonella typhi and hepatitis E virus RNA. The pathophysiological presentations of concurrent typhoid and type E hepatitis are discussed.

Transcatheter Arterial Embolization Using Microspheres for Palliating Pain from Bone Metastasis in a Patient with Cholangiocellular Carcinoma.

A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis.

Conversion of percutaneous transhepatic biliary drainage to endoscopic ultrasound-guided biliary drainage.

Introduction: Percutaneous transhepatic biliary drainage (PTBD) is a useful alternative treatment for malignant biliary obstruction (MBO) when patients have difficulty with endoscopic transpapillary drainage. We examined the feasibility of conversion of PTBD to endoscopic ultrasound-guided biliary drainage (EUS-BD) in patients with MBO unsuited for endoscopic transpapillary biliary drainage. Methods: This retrospective study included patients who underwent conversion of PTBD to EUS-BD between March 2017 and December 2019. Eligible patients had unresectable MBO, required palliative biliary drainage, and were not suited for endoscopic transpapillary drainage. Initial PTBD had been performed for acute cholangitis or obstructive jaundice in all patients. EUS-BD was performed following improvements in cholangitis. Sixteen patients underwent conversion of PTBD to EUS-BD. We evaluated technical success, procedure time, clinical success (defined as subsequent external catheter removal), adverse events (AEs), time to recurrent biliary obstruction (TRBO), and re-intervention rates. Results: Technical success was achieved in all patients (100%). The median procedure time was 45.0 minutes (interquartile range [IQR] 30.0-50.0 minutes). Clinical success was achieved in all patients (100%). There were mild early AEs in two patients (12.5%) (acute cholangitis: 1, bile peritonitis: 1), which improved with antibiotic administration alone. Recurrent biliary obstruction (RBO) occurred in six patients (37.5%). Kaplan-Meier analysis revealed a 50% TRBO of 95 days (IQR 41-246 days). Endoscopic treatment was possible in all RBO cases, and repeat PTBD was not required. Conclusions: Conversion of PTBD to EUS-BD for the management of MBO is both feasible and safe. This approach is expected to be widely practiced at centers with little experience in EUS-BD.

Stent Placement for Malignant Inferior Vena Cava Syndrome in a Patient with Recurrent Colon Cancer.

A 70-year-old man was admitted to our hospital with gait disturbance due to marked edema of the lower limbs for more than 6 months. He had been receiving systemic chemotherapy over two years for multiple recurrence after sigmoid colon cancer resection. Contrast-enhanced computed tomography demonstrated severe inferior vena cava (IVC) stenosis due to compression by lymph node metastases, i.e. IVC syndrome. As increased doses of diuretic agents failed to improve the edema, IVC stent placement was performed. This led to significant improvement of the edema and complete gait normalization. This case demonstrates the efficacy of IVC stent placement for IVC syndrome.

Primary malignant melanoma of the esophagus with multiple lymph node metastases: A case report and literature review.

RATIONALE: Primary malignant melanoma of the esophagus (PMME) is a very rare malignancy accounting for only 0.1% to 0.2% of all malignant esophageal lesions. Presently, there are no standard strategies or clear guidelines for PMME treatment. PATIENT CONCERNS: Herein, we report a patient who had PMME with multiple lymph node metastases (LNMs) who was treated successfully by esophagectomy. In March 2018, a 74-year-old man with symptoms of continuous dysphagia was referred to our hospital. DIAGNOSIS: Upper gastrointestinal endoscopic examination revealed melanin pigmentation in the middle thoracic esophagus and a pigmented polypoid mass in the lower esophagus. Histopathological examination of the endoscopic biopsy specimen revealed malignant melanoma. Contrast-enhanced computed tomography showed a 3 cm tumor lesion with several enlarged lymph nodes without distant metastasis. The preoperative diagnosis based on the TNM classification was cT2N2M0 stage III. INTERVENTIONS: The patient underwent esophagectomy with lymph node dissection. OUTCOMES: Histopathological examination showed that the tumor extended to the submucosal layer of the esophageal wall, with multiple LNMs. Although multiple LNMs were detected, computed tomography scan 15 months after surgery showed no recurrence. Additionally, we analyzed the relationship between the overall survival and the clinicopathological factors including LNMs in 48 previously reported cases of PMME that were surgically treated. LESSONS: To our knowledge, this is the first report on the effect of LNMs on the prognosis of PMME patients. The analysis revealed the prognostic value of the TNM stage. Early tumor detection and esophagectomy with lymph node dissection may play as key factors for achieving a better overall survival of PMME patients.

Synchronous Double Bile Duct Cancers with Distinct Genetic Features.

A 69-year-old man was referred to our hospital because of appetite loss. Imaging showed a nodular tumor in the perihilar bile duct and a second flat lesion in the distal bile duct. Right hepatopancreaticoduodenectomy was performed, and the histopathological findings demonstrated that the perihilar and distal lesions were moderately and poorly differentiated adenocarcinoma, respectively, and anatomically separated. Furthermore, the resected specimens showed no pancreaticobiliary maljunction. Histological and TP53 gene analyses in a rare case of synchronous double bile duct cancers suggest that there are various genetic pathways through which bile duct cancer develops, highlighting the complexity of its pathogenesis.

[A Case of Local Remnant Esophageal Cancer after Chemotherapy Getting Complete Response by Radiotherapy].

This is a case of a 72-year-old woman who presented without anymajor complaint. An anemia was indicated during follow-up for diabetes at the internal medicine unit and an upper gastrointestinal endoscopy(GS)was performed. A type 2 tumor was detected in the middle thoracic esophagus and biopsyrevealed a squamous cell carcinoma. A tumor was detected in the middle thoracic esophagus bycervical thoracoabdominal computed tomography(CT)scan and no invasion of surrounding organs was noted. The lymph node 104R had enlarged significantlybut no distant metastasis was observed. The patient was diagnosed with advanced esophageal cancer, Mt, type 2, cT2N2M0, stage Ⅱ. For preoperative chemotherapy, CDDP plus 5-FU(FP)therapywas administered. Lung metastasis was found on CT examination and surgical resection was not indicated. Hence, 4 courses of docetaxel plus CDDP plus 5-FU(DCF)therapywere administered. Following treatment, lung and lymph node metastases disappeared on the image. However, the main tumor remained at the GS. Radiotherapy was administered as a local additional treatment. Thereafter, GS showed mucous membrane redness and white spots of the lesion. Biopsyfrom the same site showed no malignant findings. The patient has remained malignancy-free since 18 months.

[Administering Ramucirumab Safely after Inserting an Intestinal Stent, Due to Peritoneal Metastasis of Gastric Cancer-A Case Report].

The recent phase Ⅲ trials REGARD and RAINBOW have shown survival benefits and acceptable safetyprofiles of ramucirumab( RAM)alone and RAM plus paclitaxel. Based on this result, RAM is recommended as a secondarytreatment for advanced and recurrent gastric cancer bythe Japanese Gastric Cancer Association. Although the frequencyis not high, gastrointestinal perforation has been reported as a serious side effect. RAM is a human anti-vascular endothelial growth factor receptor 2(VEGFR-2)monoclonal antibodythat acts on vascular endothelial cells to inhibit angiogenesis. The detailed mechanism has not been elucidated, but it is thought that the ischemic state and delayed wound healing due to the inhibition of vascular endothelial growth factors could be the cause of perforation. Thus, the usage of angiogenesis inhibitors such as RAM while intestinal stents are placed, mayincrease the risk of gastrointestinal perforation. We report a case in which RAM was administrated with no adverse events after multiple gastrointestinal metal stents being inserted.

[Efficacy of Palliative Radiotherapy in Hemorrhage Control in Patients with Unresectable Gastric Cancer].

We report the case of an 80-year-old man with unresectable, advanced gastric cancer and pulmonary cancer because of multiple liver metastases. The serum hemoglobin level declined to 5.3 g/dL during fourth-line chemotherapy. Radiation therapy of 30 Gy was administered in 10 fractions. After radiation treatment was completed, the serum hemoglobin level increased to 8.5g/dL. No new adverse event was observed. Subsequently, the progression of anemia stopped, and oral intake became possible. Thus, palliative radiation therapy is useful for hemorrhage control in unresectable, advanced gastric cancer patients with a poor general condition and difficult surgical treatment.