[Paclitaxel plus Bevacizumab Combination Therapy for Esophageal Metastasis of Breast Cancer-A Case Report].

An 80-year-old woman with a history of left breast cancer complained of dysphagia. At the age of 67 years, she had undergone a left modified radical mastectomy, chemotherapy, and endocrine therapy for left breast cancer. Six years after adjuvant therapy completion, she developed dysphagia. Chest CT showed only midesophageal stenosis. Endoscopic examination revealed whole circumferential stenosis without mucosal abnormality located 25 cm from the incisors, and a biopsy showed histologically normal mucosa. Endoscopic balloon dilatation was performed 5 times in 1 year and 3 months. Subsequently, a biopsy specimen revealed adenocarcinoma, which suggested metastasis from the previous breast cancer. One month after the initiation of tamoxifen administration, dyspnea due to pleural effusion was encountered. We treated this via pleural adhesion therapy and changed the treatment to paclitaxel plus bevacizumab combination therapy. She continued paclitaxel plus bevacizumab therapy for 1 year and 4 months without any signs of recurrence.

Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody.

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer.

An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

[Novel Therapeutic Strategy for Human Epidermal Growth Factor Receptor 2-Positive Gastric Cancer].

Trastuzumab(Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2(HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanoparticles, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanoparticles and demonstrate their efficacy for the treatment of HER2-positive, Tmabresistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanoparticles have the potential to be a novelHER2 -targeted therapeutic agent.

Granulocyte Colony-Stimulating Factor-Producing Gallbladder Cancer.

We report a case of a granulocyte colony-stimulating factor (G-CSF)-producing gallbladder tumor associated with fever in a middle-aged female. Preoperative blood analysis showed leukocytosis with elevated levels of C-reactive protein and G-CSF. We resected the liver at S4a＋S5, with regional lymph node dissection and partial resection of the duodenum. Histology revealed undifferentiated carcinoma with spindle and giant cells and papillary adenocarcinoma. Immunohistochemistry revealed Stage IIIB G-CSF-producing gallbladder cancer. Postoperatively, leukocyte and serum G-CSF levels decreased to within normal limits. Adjuvant gemcitabine chemotherapy was administered for 16 months, and she has been recurrence-free for 48 months.

[Novel HER2-Targeted Therapy Combined with Gold Nanoparticles].

Trastuzumab(Tmab)is a humanized monoclonalantibody that binds to the human epidermalgrowth factor receptor 2 (HER2). It is clinically used for HER2-positive breast and gastric cancers; however, the use of Tmab is restricted to tumors expressing high levels of HER2(accounting for only 20%of tumors), and Tmab cannot be used for tumors resistant to Tmab. Although novel HER2-targeted agents have been developed to treat Tmab-resistant tumors, none of these have shown clinical efficacy in gastric cancer patients. Recent developments in nanotechnology have had a significant impact on the field of medicine. Gold nanoparticles(AuNPs), which show characteristics such as in vivo stability and ease of surface functionalization, have been developed as therapeutic and contrast agents for medical applications. Previous studies show that AuNPs exert cytotoxic effects through autophagy and apoptosis; therefore, AuNPs in combination with tumor-targeting antibodies are attractive therapeutic agents. In this study, we developed HER2-targeted AuNPs(Tmab-AuNPs)and showed that they had a potent antitumor effect on Tmab-resistant cell lines. In addition, Tmab-AuNPs were effective against HER2-negative gastric cancer cell lines when HER2 was artificially overexpressed. Thus, our results indicate that Tmab-AuNPs may overcome the shortcomings of Tmab-based therapy.

[A case of lynch syndrome treated laparoscopically for multiple colon cancers].

Lynch syndrome is an inherited syndrome associated with the development of colorectal, endometrial, stomach, and other cancers; it is caused by defects in the mismatch repair genes. Such patients are at risk of developing multiple abdominal cancers after colectomy, and the presence of adhesions may render future abdominal surgeries difficult. We recommend that patients with Lynch syndrome should be considered good candidates for laparoscopic surgery. A 43-year-old Japanese man was admitted following a positive fecal occult blood test result. The patient was diagnosed with multiple colon cancers in the right colon. He had undergone endoscopic mucosal resection for a colon polyp when he was 24 years of age. Two people among his father's second-degree relatives had colorectal cancer, and he fulfilled the revised Bethesda guidelines. He underwent laparoscopic-assisted right hemicolectomy and D3 lymph node dissection. Microsatellite instability testing indicated the presence of MSI-H, and genetic testing demonstrated a pathogenic mutation of MLH-1.

[A case of advanced colon cancer with multiple liver metastases treated by two-stage laparoscopic surgery].

We report a case of advanced colon cancer with multiple liver metastases treated by two-stage laparoscopic surgery. An 82-year-old woman, whose main complaint was constipation, was diagnosed with stage IV sigmoid colon cancer. With the aim of decompressing the colon, a transanal decompression tube was inserted. She underwent laparoscopic-assisted sigmoidectomy and D3 lymph node dissection, and an ileostomy was created. Systemic chemotherapy was administered immediately after the operation. After 4 courses of chemotherapy, she underwent the second operation, i.e., laparoscopic- assisted partial hepatectomy and radiofrequency ablation of liver metastases. Cases of obstructive colon cancer are more advanced than cases of non-obstructive colon cancer. Systemic treatments are required after the resection of primary tumors. We aim to improve the prognosis of patients with obstructive colon cancer by the use of laparoscopic surgery.

[A case of adenosquamous carcinoma of lower extrahepatic bile duct].

We report a 83-year-old female with bile duct cancer who underwent subtotal stomach preserving pancreatoduodenectomy. Pathologically, her tumor was diagnosed as adenosquamous carcinoma of the lower extrahepatic bile duct with final stage IVb[pT3pN3M(-)].The prognosis of patients with adenosquamous carcinoma of the bile duct is very poor, and the reason is thought to be its tendency to invade the pancreas.Although she was an aged patient, we performed adjuvant chemotherapy using gemcitabine.No recurrence has occurred until this day, 30 months after the operation.This is thought to be an effect of the adjuvant chemotherapy, considering its poor prognosis.

Boerhaave syndrome presenting black pleural effusion: A case report.

A 55-year-old man experienced nausea and vomiting after brushing his teeth. He experienced back pain after this episode and visited our emergency department. Chest computed tomography (CT) images revealed moderate pleural fluid accumulation and mild left pneumothorax. Thoracentesis showed black pleural effusion. Thoracic drainage included food debris with black pleural effusion, and gastroscopy revealed food debris and perforation of the lower esophagus. Esophageal perforation was surgically repaired using omental implantation and pleuroclysis. Given the high mortality rate associated with black pleural effusion, prompt diagnostic procedures and corresponding management are essential.

PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer.

While the importance of programmed death-ligand 1 (PD-L1), mutation burden caused by microsatellite instability (MSI), and CD8+ tumor infiltrating lymphocytes (TILs) has become evident, the significance of PD-L1 expression on prognosis still remains controversial. We evaluated the usefulness of combined markers of PD-L1 and MSI or CD8+ TILs as a prognostic biomarker in gastric cancer. A total of 283 patients with gastric cancer were reviewed retrospectively. PD-L1 expression on >5% tumor cells was defined as PD-L1-positive. PD-L1-positive rate was 15.5% (44/283). PD-L1 positivity was significantly correlated with invasive and advanced cancer and also significantly correlated with MSI, whereas no significance was observed with CD8+ TILs. Kaplan-Meier analysis showed that PD-L1 positivity significantly correlated with a poor prognosis (p = 0.0025). Multivariate analysis revealed that PD-L1 positivity was an independent poor prognostic factor (hazard ratio [HR]: 1.97, p = 0.0106) along with diffuse histological type and lymph node metastases. Combinations of PD-L1 and MSI (HR: 2.18) or CD8+ TILs (HR: 2.57) were stronger predictive factors for prognosis than PD-L1 alone. In conclusion, combined markers of PD-L1 and MSI or CD8+ TILs may be more useful prognostic biomarkers in gastric cancer, and better clarify the immune status of gastric cancer patients.

Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system.

Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

Spontaneous rupture of a hepatic angiomyolipoma: Report of a case.

A 70-year-old female experienced sudden onset of back pain on the right side and was admitted to our hospital in December 2010. Abdominal computed tomography revealed an S7 hepatic mass measuring 7 cm in diameter accompanied by a subcapsular hematoma. Emergency angiography confirmed the diagnosis of a ruptured hepatic mass, and hemostasis was carried out by embolization of A8 and A7 of the liver. A right hepatic lobectomy was carried out 39 days following transarterial embolization. Although almost all aspects of the tumor were necrotic, residual tumor cells stained positive for HMB-45, and negative for α-SMA, S-100, CD 34, c-kit, CAM 5.2, and hepatocytes. The MIB-1 index was 2 %. Pathological diagnosis was hepatic angiomyolipoma (HAML). The patient has shown no signs of recurrence at 42 months following surgery. Here, we report on this case of spontaneous HAML rupture and discuss therapeutic strategies for HAML and ruptured hepatic tumors.

Hepatectomy in a hepatocellular carcinoma case with Dubin-Johnson syndrome and indocyanine green excretory defect.

A 77-year-old male patient with history of jaundice was referred to our hospital for treatment of hepatocellular carcinoma (HCC). He was found to have Dubin-Johnson syndrome (DJS), a clinical feature of constitutional jaundice with conjugated hyperbilirubinemia, and indocyanine green (ICG) excretory defect, both of which are rare conditions. Total bilirubin was 5.1 mg/dl and ICG retention at 15 min (ICGR15) (77.1 %). Converted ICGR15 from GSA scintigraphy was 15.9 %. Resection of the medial segment and ventral region of the anterior segment of the liver as well as cholecystectomy were performed. The background of the liver tissue was blackish yellow and consistent with DJS and chronic hepatitis. Although total bilirubin level increased to 8.2 mg/dl on the 2nd postoperative day, the patient ultimately recovered and he was discharged on the 14th day. His 1- and 2-year medical checkups indicated recurrence of HCC. He underwent transarterial chemoembolization and is presently doing well 39 months after surgery. We report here on evaluation and treatment of patients with such disorders.