Prognosis after curative resection for stage IA gastric cancer in elderly patients: endoscopic submucosal dissection versus surgery.

PURPOSE: To establish whether gastrectomy for early gastric cancer (EGC) in elderly patients is related to poor survival. METHODS: The subjects of this retrospective study were patients aged ≥ 75 years with primary stage IA EGC, who underwent curative resection with endoscopic submucosal dissection (ESD) or surgery. RESULTS: We analyzed data on 365 patients who underwent ESD and 170 patients who underwent surgery. Overall survival (OS) was not significantly different for the ESD group vs. the surgery group (5-year cumulative rates, 81.5% vs. 79.7%; log-rank test, P = 0.506). Multivariate analysis revealed that treatments; namely, ESD or surgery, were not associated with OS (hazard ratio 1.09, 95% confidence interval 0.77-1.51). Similar results were observed even in the subgroups with worse conditions, such as age > 80 years, Eastern Cooperative Oncology Group performance status 2-3, Charlson comorbidity index ≥ 2, and prognostic nutritional index ≤ 46.7. Using propensity score matching, we selected 88 pairs of patients who underwent ESD or surgery with baseline characteristics matched and found that OS was not different between the two groups (log-rank test, P = 0.829). CONCLUSION: OS was comparable for elderly patients who underwent ESD and those who underwent surgery for EGC. Surgical invasiveness did not worsen the prognosis, even for elderly patients.

[Traumatic Neuroma Mimicking Lymph Node Metastasis of Pancreatic Neuroendocrine Neoplasms Developed after Pancreatoduodenectomy-A Case Report].

A traumatic neuroma is a benign tumor consisting of a non-neoplastic growth of injured nerves as a result of trauma or surgery. It is rarely found in an abdominal cavity, but some reports showed that it occurred around the bile duct. We report a case of a 72-year-old man who underwent subtotal stomach-preserving pancreatoduodenectomy for pancreatic neuroendocrine neoplasms 4 years ago. An abdominal contrast-enhanced CT follow-up examination revealed a growing nodule on the dorsal surface of the portal vein. The lesion showed a mild increase in fluorodeoxyglucose uptake in FDG-PET⊘CT. A lymph node metastasis of pancreatic neuroendocrine neoplasms was suspected. Nodule resection was performed for purpose of diagnosis and treatment. The final pathological diagnosis was traumatic neuroma with no evidence of recurrence. Traumatic neuromas developed after pancreatoduodenectomy have not been reported. Postoperative masses around the bile ducts should also be considered traumatic neuromas.

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.

[Two Cases of Stevens-Johnson Syndrome after Nivolumab Therapy for Gastric Cancer].

Case 1: A 51-year-old man with advanced gastric cancer and peritoneal metastasis was referred to our hospital. He received fourth-line chemotherapy with nivolumab, but it became PD. Next, he received S-1 plus docetaxel therapy as fifth- line therapy. After 2 courses of S-1 plus docetaxel, erythema and blisters appeared on his limbs, with erosions of the oral mucosa and penis. We diagnosed Stevens-Johnson syndrome(SJS)based on the clinical and pathological findings. He received steroid treatment, but the cutaneous symptoms persisted; therefore, it was impossible to continue the chemotherapy because of the SJS. Case 2: A 75-year-old woman with recurrence of peritoneally disseminated gastric cancer received third-line chemotherapy with nivolumab. After 1 course of nivolumab, erythema appeared on her body and limbs, with erosion of the lips and oral mucosa. We diagnosed SJS based on the clinical findings. She received steroid treatment, but the cutaneous symptoms persisted; therefore, it was impossible to continue chemotherapy because of the SJS. It should be noted that the onset of serious irAEs, such as SJS, might make continuous chemotherapy difficult.

[Laparoscopic Left Hemicolectomy-It Is Confirmed That the Accessory Middle Colonic Artery Branched from the Splenic Artery Showed by Preoperative 3D-CT].

There is a wide variety of vessel types in the transverse colon region. Among them, it is very rare that the accessory middle colonic artery(A-MCA)is branched from the splenic artery. We found a transverse colon cancer. The dominant vessel of the cancer was the A-MCA branched from the splenic artery. This vessel type was confirmed by preoperative 3D-CT. We performed a laparoscopic left hemicolectomy for the cancer. In this study, we report a case of safe laparoscopic surgery in which we separate the A-MCA branched from the splenic artery using the preoperative 3D-CT image.

[Effect on Prognosis of Immune-Related Adverse Events after Nivolumab Treatment in Gastric Cancer].

BACKGROUND: The clinical efficacy of nivolumab has been shown as a third-line treatment for advanced gastric cancer; however, nivolumab sometimes causes immune-related adverse events(irAEs). We retrospectively examined the clinical features and influence on treatment in cases of irAEs after nivolumab treatment. METHOD: We retrospectively examined 43 patients who received nivolumab treatment at our institution between October 2017 and December 2019. RESULT: The incidence of irAEs was 23.2%(10/43), and Grade 3 or higher irAEs included interstitial pneumonia, hypoadrenalism, Stevens- Johnson syndrome(SJS), and type 1 diabetes. Three patients showed long-term disease control after irAE onset. Meanwhile, SJS prevented patients from continuing treatment for gastric cancer. DISCUSSION: Nivolumab is effective in some patients with gastric cancer, while irAEs made subsequent treatment difficult. Trifluridine/tipiracil or irinotecan are also known to be effective as therapeutic drugs after third-line treatment for gastric cancer in addition to nivolumab; therefore, the choice of the third-line drug and management of irAEs owing to individual cases are considered desirable. CONCLUSION: Long-term efficacy is expected with nivolumab, but it may be necessary to recognize that the onset of serious irAEs might make subsequent treatment difficult.

[Total Pelvic Exenteration and Perineal Reconstruction with a Gracilis Myocutaneous Flap for Local Recurrence of Rectal Cancer].

The case involved a female in her 70s. Six years prior, she had undergone an abdominoperineal rectal resection for rectal cancer. Local recurrence was observed during follow-up so preoperative chemoradiotherapy was performed to shrink the tumor, followed by a total pelvic exenteration, bilateral ureterocutaneous fistula, and perineal reconstruction with a gracilis myocutaneous flap. She was discharged from hospital 39 days following surgery with no major complications. We herein report on a case of a good postoperative course due to surgery including a total pelvic exenteration and perineal reconstruction with a gracilis myocutaneous flap for postoperative local recurrence.

[Simultaneous Distal Gastrectomy, Distal Pancreatectomy, and Splenectomy Based on Remnant Gastric Blood-Flow Evaluation with Intraoperative ICG Fluorescence].

The splenic artery and vein are important to the remnant stomach after distal gastrectomy(DG). Hence, total gastrectomy is recommended when performing gastrectomy and distal pancreatectomy(DP)with splenectomy(S). In the present case, a man in his 70s was diagnosed with early gastric cancer. Abdominal CT detected a dilated main pancreatic duct. Chronic pancreatitis was suspected, but malignancy could not be completely ruled out. Thus, DG with Roux-en-Y reconstruction and DP with S were performed simultaneously. The remnant gastric blood flow was evaluated with intraoperative indocyanine green(ICG)fluorography and the blood flow was confirmed. Finally, the remnant stomach was preserved. The postoperative course was uneventful, except for the occurrence of anastomosis edema. This result suggests that ICG fluorescence is useful to evaluate remnant gastric blood flow and that it may be possible to perform DG and DP with S simultaneously depending on the case.

[A Case of Gastric Cancer with Continued Progression-Free Survival Even after Total Gastrectomy and Nivolumab Therapy].

This is a first report of gastrectomy after nivolumab immunotherapy. We describe a case in an elderly woman with gastric cancer diagnosed with cT4bN3M1(LYM), cStage ⅣB disease. Although she was administered 2 courses of SOX chemotherapy as the primary treatment, she could not continue the treatment to due to bone marrowsuppression. The second-line treatment was weekly PTX therapy, but she experienced Grade 3 neutropenia and thrombocytopenia in the first course and could not continue treatment. Nivolumab as the next treatment was effective but was discontinued for suspected druginduced pneumonia. During that time, tumor hemorrhage occurred and we performed total gastrectomy. Postoperatively, nivolumab chemotherapy was resumed. There were no adverse events and the patient has had a continued partial response for 30 courses. Gastrectomy was necessary in this case, allowing observation of the pathological findings of this highly effective case.

[Microsatellite Instability in Gastric Cancer].

INTRODUCTION: Pembrolizumab and nivolumab are anti-programmed death receptor-1(PD-1)antibodies. The use of pembrolizumab for unresectable or metastatic cancer with microsatellite instability-high(MSI-High)has been recently approved. However, there were few clinical reports on MSI in gastric cancer. MATERIALS AND METHODS: We examined the clinicopathological features and MSI for 37 patients who underwent chemotherapy for unresectable gastric cancer in January 2019. RESULTS: MSI-High was observed in 3 patients(8.1%). Among the MSI-High patients, there was a tendency towards older age, female sex, undifferentiated type, distal-located lesions and lymphatic vessel invasions, but the differences were not significant. Eleven patients underwent chemotherapy with nivolumab, 4 of them had partial response(PR). Three out of the 4 patients (75%)were MSI-High. CONCLUSIONS: These results suggested that anti-PD-1 antibody could be effective as a secondary treatment for unresectable or metastatic gastric cancer among MSI-High patients.

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.

[Analysis of Hepatectomy for Liver Metastasis from Gastric Cancer].

INTRODUCTION: The indication of hepatectomy for liver metastasis from gastric cancer has not been definitely established. PATIENTS AND METHODS: Among 12 cases that were performed hepatectomy for liver metastasis from gastric cancer in our institute from 2008 to 2016, we analysed prognosis and the benefit of surgical resection. RESULTS: The overall 5-year survival rates of all cases were 42.3%, and median survival time was 2 years. The overall survival rates of synchronous metastasis was 59.3%and of metachronous metastasis was 0%. Recurrence rate of all cases within 1 year was 75%. There was no long-term survivor for metachronous metastasis because of its early recurrence though it was solitary liver tumor. CONCLUSION: We should carefully indicate surgical resection for liver metastasis from gastric cancer.

Training system for laparoscopy-assisted distal gastrectomy.

PURPOSE: Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes. METHODS: We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically. RESULTS: Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with ≤10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that >10 operator cases were the most important factor for achieving good-quality operations. CONCLUSION: These results show that our current LADG procedure and training system are appropriate and effective.

[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.

[Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease].

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.However, the cancer relapsed in a single para-aortic LN and he was treated with RT to the lesion followed by chemotherapy.Although it completely regressed, later, lung metastasis was observed.The lung lesions were well suppressed by switching to docetaxel; however, the cancer relapsed again in a mediastinal LN, and it was not responsive to docetaxel.The growing mediastinal lesion was irradiated again, which resulted in stable disease.The patient has been treated for 4 years and 7 months with all lesions being well-managed, and chemotherapy is being continued.Recurrent gastric cancer after surgery tends to present as multiple lesions; therefore, the principle therapy is systemic chemotherapy and RT is unlikely to be suitable.However, especially in cases of a solitary lesion that is chemo-resistant, RT could be an optimal option and contribute to long-term survival even in patients with recurrent gastric cancer.

[A Case of Duodenal Invasive Advanced Gastric Cancer in Which the Primary Tumor Achieved pCR, but Viable Cancer Cells Remained in Lymph Node No.13 after Neoadjuvant Chemotherapy].

A woman approximately 70-years-old with duodenal invasive advanced gastric cancer was referred to our hospital. Meta- stasis to lymph node(LN)No.13 was suspected based on FDG/PET-CT. For better curability, we selected neoadjuvant chemotherapy( NAC)with S-1 plus oxaliplatin(SOX therapy). After 3 courses of SOX, distal gastrectomy with D2(+No.13) lymphadenectomy was performed. Upon pathological evaluation, no viable cancer cells were found in the primary tumor, but viable cancer cells were identified in LN No.6 and 13. LN No.13 was defined as M1 according to the current Japanese classification of gastric carcinoma. On the other hand, the 2014 Japanese gastric cancer treatment guidelines(ver. 4)mentioned that D2(+No.13)lymphadenectomy may be an option in potentially curative gastrectomy for tumors invading the duodenum. This case suggests that No.13 lymphadenectomy is necessary as a curative operation for duodenal invasive advanced gastric cancer, even if the primary tumor has achieved pCR after NAC.

[Clinical Outcome of Hepatectomy of Liver Metastasis of Duodenal Ampullary Cancer].

We evaluated the clinical outcome and assessed the indication of hepatectomy for liver metastasis of duodenal ampullary cancer. We analyzed 42 cases of duodenal ampullary cancer and 4 patients who underwent hepatectomy for liver metastasis. Eleven(50%)of 22 cases with recurrence of duodenal ampullary cancer had liver metastasis. Four cases were solitary and 7 cases were multiple. Four patients underwent hepatectomy didn't had other organ metastasis. Three of 4 cases with solitary liver metastases and one of 7 cases with multiple metastasis underwent hepatectomy. One of 3 cases of solitary liver metastasis died of lung and bone metastases without liver recurrence 2 years and 8 months after hepatectomy. Other 2 cases are long surviving without recurrence 8 years and 8 months and 4 years and 9 months after hepatectomy respectively. One case of multiple liver metastases died of early liver recurrence 10 months after hepatectomy. The indication of hepatectomy for liver metastasis was restrictive. However the prognosis of patients with solitary liver metastasis was relatively favorable. Therefore hepatectomy could be indicated for solitary liver metastasis of duodenal ampullary cancer.

[A Case of Anaplastic Carcinoma Spindle Cell Type of the Pancreas].

Anaplastic carcinoma spindle cell type is an extremely rare disease and its prognosis is very poor. We herein report a case of anaplastic carcinoma spindle cell type of the pancreas. A 50-year-old man complaining of epigastralgia was found to have a pancreatic body-tail tumor by abdominal US and CT studies. Abdominal CT showed an irregular poorly-enhanced 33mm tumor containing a cystic component. ERCP revealed the main pancreatic duct was cut off at the tumor. Cytology of the pancreatic fluids did not indicate malignancy. A pancreatic tumor with a cystic component similar to pancreatic neoplasms containing cystic degeneration or a mass-forming pancreatitis concomitant with pancreatic pseudocyst was suspected. Therefore, we performed distal pancreatectomy. Histological findings showed the center of the tumor was severely necrotized and oval or spindle dysplastic cells proliferated around the peripheral area. According to the immunohistological staining pattern, the patient was diagnosed as having anaplastic carcinoma spindle cell type. He was administered oral S-1 for 6 months and is now recurrence-free, surviving for 15 months after pancreatectomy. Reports of long-term survival cases that also demonstrated R0 resection should be indicated in the treatment of anaplastic carcinoma spindle cell type despite the poor prognosis.

[A Case of Mixed Hepatocellular and Primary Hepatic Neuroendocrine Carcinomas with Remnant Liver Recurrence and Rapid Exacerbation].

The patient was a 77-year-old man with a 4.0 cm hepatictumor in hepaticsegment 4. Plain computed tomography(CT) showed the tumor with low density. On dynamicexamination, the tumor showed heterogeneous enhancement during the arterial phase. Magneticresonanc e imaging showed the tumor as a low intensity area in the hepatobiliary phase in hepatic segments 4, 6, and 8. A month later, CT showed an enlarged tumor in segment 4 measuring 7.0 cm. We diagnosed the tumor as primary liver cancer and suspected it to be hepatocellular carcinoma(HCC)preoperatively. We performed extended medial segmentectomy and partial hepatectomy of segment 6. The histopathological diagnosis was mixed HCC and primary hepatic neuroendocrine carcinoma(PHNEC). Three months after hepatectomy, the patient died of multiple intrahepatic recurrences. In most of the reported cases of mixed HCC and PHNEC, only the PHNEC component has been detected in the biopsy of the metastatic lesions. This fact might suggest that PHNEC has a higher proliferative activity and malignant potential than HCC. Standard treatment for mixed HCC and PHNEC is unclear; therefore, development of multidisciplinary treatment strategies combining surgical treatment and systemic chemotherapy is required.

Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion.

A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.