Prognostic factors in T4b gastric cancer after surgery: A more balanced and sequential therapy for patients?

INTRODUCTION: This study aimed to evaluate the prognostic factors in T4b gastric cancer (GC) in order to improve future therapeutic strategies. METHODS: We retrospectively analyzed the medical records of 43 patients with advanced GC who underwent surgery and were surgically or pathologically diagnosed with T4b GC. The overall survival (OS) rate of patients with T4b GC was analyzed, and univariate and multivariate analyses were performed to identify clinicopathological factors that were independently associated with OS. In addition, we assessed the relationship between postoperative chemotherapy and laboratory parameters 4 weeks post-surgery. RESULTS: The proportion of patients with invasion of cancer in organs, including the pancreas, transverse colon, and liver, were 58.1%, 18.6%, and 14.0%, respectively. The proportion of patients who exhibited distant metastases was 44.2%, and R0 resection was achieved in 30.2% of patients. A total of 69.8% of patients underwent postoperative chemotherapy. The median survival rate was 12.3 months. Upon multivariate analysis, the presence of distant metastases (P = 0.01, HR; 3.48), the use of postoperative chemotherapy (P = 0.0004, HR; 0.12), and R0 resection (P < 0.0001, HR; 0.14) were significantly correlated with OS. Patients who did not undergo postoperative chemotherapy showed significantly higher levels of inflammatory parameters and lower levels of nutritional parameters 4 weeks after surgery than those who did. CONCLUSIONS: We evaluated that the presence of distant metastases was significantly associated with a poor prognosis, and the use of postoperative chemotherapy and R0 resection was significantly associated with a better prognosis in patients with T4b GC. It would be more important for a T4b GC treatment to balance between therapeutic tolerance for postoperative chemotherapy and surgical therapeutic effect.

Glycogen synthase kinase 3ß: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.

The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3ß in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3ß in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3ß as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3ß in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3ß has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.

Effects of adoptive T-cell immunotherapy on immune cell profiles and prognosis of patients with unresectable or recurrent cholangiocarcinoma.

The identification of immune cell profiles (ICP) involved in anti-tumor immunity is crucial for immunotherapy. Therefore, we herein investigated cholangiocarcinoma patients (CCA) who received adoptive T-cell immunotherapy (ATI). Eighteen unresectable or recurrent CCA received ATI of αß T cells alone or combined with chemotherapy. ICP were evaluated by flow cytometry. There were 14 patients with intrahepatic cholangiocarcinoma (iCCA) and four with distal cholangiocarcinoma (dCCA). After one course of treatment, nine iCCA and four dCCA had progressive disease (PD), while five iCCA had stable disease (SD). Median overall survival (OS) was prolonged to 21.9 months. No significant differences were observed in OS between the PD and SD groups of iCCA. The frequency of helper T cells (HT) in iCCA decreased from 70.3% to 65.5% (P = .008), while that of killer T cells (KT) increased from 27.0% to 30.6% (P = .005). dCCA showed no significant changes of immune cells. OS was prolonged in iCCA with increased frequencies of CD3+ T cells (CD3) (P = .039) and αß T cells (αß) (P = .039). dCCA showed no immune cells associated with OS. The frequencies of CD3+ T cells and αß T cells in the PD group for iCCA decreased from 63.5% to 53% (P = .038) and from 61.6% to 52.2% (P = .028), respectively. In the SD group, the frequency of HT decreased from 65.8% to 56.9% (P = .043), whereas that of KT increased from 30.1% to 38.3% (P = .043). In conclusions, ATI affected ICP and prolonged OS. Immune cells involved in treatment effects differed according to the site of cholangiocarcinoma.

Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

A case of anaplastic carcinoma of the pancreas with intrasplenic huge mass formation.

Anaplastic carcinoma of the pancreas (ACP) is an aggressive pancreatic tumor that grows rapidly, and its clinical characteristics are poorly defined because of its rarity. Thus, preoperative diagnosis is difficult and most definitive diagnoses are generally made by surgery, highlighting the importance of collecting more cases of ACP. We report a case of a 79-year-old woman with ACP that was difficult to diagnose preoperatively. Abdominal enhanced computed tomography revealed a large and expansive tumor in the spleen containing multilocular cystic and solid components. The first preoperative diagnosis was splenic angiosarcoma, and the tumor could be resected by distal pancreatectomy, total gastrectomy and partial transverse colectomy. ACP was first diagnosed based on postoperative histopathological findings. ACP that spreads to the spleen and forms an intrasplenic mass is rare. However, ACP should be included in the differential diagnosis of such patients, and further research of ACP is essential for a favorable prognosis.

Recurrent malignant peritoneal mesothelioma treated by a second resection: A case report.

Key Clinical Message: Malignant peritoneal mesothelioma, a rare and poor prognosis disease, is seldom treated surgically, especially for recurrence. However, early diagnosis and aggressive treatment of primary and recurrent tumors can achieve long-term patient survival. Abstract: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive tumor, and rarely indicated for surgery, especially for recurrence. In the present case, we report a rare case who could survive long-term after two surgeries in 4 years for MPM.

[A case of acalculous gangrenous cholecystitis due to artery dissection].

A 62-year-old male presented with right intercostal muscle pain. Clinical examination revealed muscular defense in the same area. Abdominal ultrasonography revealed a distended gallbladder and ascites effusion, but no gallstones or polyps were present. Contrast-enhanced computerized tomography was performed, which revealed luminal obstruction due to arterial dissection of the celiac artery and intrinsic hepatic artery. This finding suggested gangrenous cholecystitis; thus, urgent cholecystectomy was performed. Only a few cases of celiac artery dissection and only one case of gangrenous cholecystitis without stones have been reported. We report here an extremely rare case of celiac artery dissection.

Intra-tumoral FGFR2 Expression Predicts Prognosis and Chemotherapy Response in Advanced HER2-positive Gastric Cancer Patients.

BACKGROUND/AIM: This study aimed to evaluate the relationship between clinical outcomes and intra-tumoral fibroblast growth factor receptor 2 (FGFR2) expression in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients who had undergone HER2-targeted chemotherapy. PATIENTS AND METHODS: A retrospective analysis was performed in 22 patients with HER2-positive GC, who had undergone systemic chemotherapy. We performed immunohistochemistry staining of FGFR2 expression using surgically resected specimens or biopsied samples and evaluated clinicopathological characteristic and overall survival (OS) in the FGFR2-negative and -positive GC groups. RESULTS: A total of 8 and 14 patients were placed in the FGFR2-negative and -positive group, respectively. The median OS rates were 56.2 and 16.0 months in the FGFR2-negative and -positive groups, respectively. The FGFR2-negative group had a significantly better prognosis after HER2-targeted chemotherapy [p=0.027 (log-rank test)]. The univariate analysis revealed that performing gastrectomy, response to combination chemotherapy with trastuzumab, and FGFR2 positivity were significantly correlated with OS. In a multivariate analysis, the response to combination chemotherapy with trastuzumab (p=0.008) was significantly correlated with OS. In addition, the proportions of patients who showed CR or PR in response to chemotherapy were 87.5 and 42.9% in the FGFR2-negative and -positive groups, respectively (p=0.031). CONCLUSION: HER2-positive GC patients, without overexpression of FGFR2, exhibited an improved prognosis and response rate to trastuzumab combination chemotherapy. Assessment of intra-tumoral FGFR2 expression could be helpful in predicting the prognosis and response to trastuzumab in HER2-positive GC patients.

Hyaluronic Acid May Be a Predictive Biomarker for Thrombocytopenia and Liver Dysfunction After Oxaliplatin-based Chemotherapy.

Background/Aim: Following oxaliplatin-based chemotherapy, approximately half of all colorectal cancer patients develop sinusoidal obstruction syndrome (SOS). SOS can be monitored by measuring splenic volume; however, obtaining this measurement is not a simple process. In this study, we evaluated changes in hyaluronic acid (HA) concentrations as a simpler marker of SOS. Patients and Methods: We measured splenic volume and laboratory data, including hyaluronic acid concentration, liver enzymes, and platelet counts, in 34 patients with colorectal cancer who underwent radical resection and who received capecitabine plus oxaliplatin (CapeOx) chemotherapy. Results: A strong correlation was identified between ≥30% increase in splenic volume and significantly elevated HA concentrations. Affected patients also had persistent thrombocytopenia and liver dysfunction compared to patients without elevated HA concentration. Conclusion: HA concentration may predict SOS in patients who receive CapeOx adjuvant chemotherapy.

Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model.

Sinusoidal obstruction syndrome (SOS) is a type of fatal hepatic injury, which predominantly occurs following exposure to drugs, such as oxaliplatin, or bone marrow transplantation. Extravasated platelet aggregation (EPA) plays an important role in the development of SOS in rat and mouse models. Furthermore, platelets invading the space of Disse adhere to hepatocytes and are phagocytized in patients with SOS. Aging platelets and platelets in patients with sepsis are phagocytized by hepatocytes through Ashwell­Morell receptors, and thrombopoietin (TPO) is produced by the JAK2­STAT3 signaling pathway. The purpose of the present study was to examine the significance of TPO as a biomarker of SOS. SOS was induced in Crl:CD1(ICR) female mice by intraperitoneal administration of monocrotaline (MCT). TPO levels were measured in the serum and liver tissue. Pathological and immunohistochemical studies of the liver were performed to analyze the expression levels of TPO. TPO mRNA expression levels were measured using reverse transcription­quantitative PCR. In the SOS model, the platelet counts in peripheral blood samples were significantly decreased at 24 and 48 h after MCT treatment as compared with that at 0 h. In addition, a pathological change in hepatic zone 3 was observed in the SOS model group. Furthermore, the protein levels of TPO in liver tissue were significantly increased in the SOS model group compared with those in the control group, which was confirmed by immunohistochemistry. By contrast, serum TPO protein levels were significantly decreased in the SOS model group compared with those in the control group. These results indicated that EPA may induce sinusoidal endothelial fenestration in a mouse model of SOS, preventing TPO from translocating into the blood. In conclusion, serum TPO levels may be reduced in a mouse model of SOS owing to the accumulation in hepatocytes, suggesting that TPO could be a useful biomarker of SOS.

Preoperative diagnosis of gallbladder torsion by magnetic resonance cholangiopancreatography: A case report.

Gallbladder torsion is a rare and potentially fatal condition presenting with acute abdominal pain. Gallbladder torsion requires early diagnosis and treatment; however, preoperative diagnosis is difficult. In the present case, magnetic resonance cholangiopancreatography provided definitive imaging findings and was very useful in making the preoperative diagnosis.

Conservative management of spontaneous isolated superior mesenteric artery dissection: A case report.

Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare and potentially fatal cause diagnosis presenting with acute abdominal; however, because of its rarity, the pathogenic factors of SISMAD remain unknown and no clear cause has been found. Moreover, there is a lack of evidence-based treatment guidelines.

Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis.

Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett's esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.

Laparoscopic intraperitoneal mesh repair of a large incisional hernia in a kidney transplantation patient: A case report.

A 73-year-old woman presented to our hospital because of painful bulging in the right lower abdomen, and developed a 17 × 12 cm incisional hernia after kidney transplantation using right oblique incision. Laparoscopic intraperitoneal onlay mesh (IPOM) repair was performed. Since a transplanted kidney is close to the abdominal wall defect, the space between the transplanted kidney and the abdominal wall was peeled off to secure enough space for the mesh to be place. After that the fascial defect was detected precisely, and the polypropylene-polyglycolic acid composite mesh was fixed with 3 cm overlapping of the hernia ring by non-absorbable tacks. The patient was discharged 9 days after surgery. In general, abdominal incisional hernias after kidney transplantation are relatively large with boundary defect of abdominal wall ensuing between the abdominal and allograft. However, laparoscopic IPOM repair of incisional hernia after kidney transplantation can be performed safely and effectively.

Preemptive Bundle Therapy for Subclinical Pulmonary Hypertension After Liver Transplant.

OBJECTIVES: After liver transplant, veno-occlusive disease and infectious complications may result from subclinical pulmonary hypertension. In this retrospective study, we investigated whether our preemptive bundle therapy was effective for subclinical pulmonary hypertension and extrasinusoidal platelet aggregation after liver transplant. MATERIALS AND METHODS: After January 2014, nutrition therapy with glutamine, synbiotics, phosphodiesterase 3 inhibitors, prostaglandin E1, prostaglandin I2, closedloop artificial pancreas, and sivelestat has been used to reduce bacterialtranslocation, vascular endothelial cell damage, and extrasinusoidal platelet aggregation, which is administered as preemptive bundle therapy for all livertransplantrecipients. In this study, we evaluated the prognosis of 84 liver transplant recipients who underwent liver transplants through 2018. Subclinical pulmonary hypertension was evaluated in 49 adult liver transplant recipients with an evaluable main pulmonary artery trunk cross-sectional area using enhanced computed tomography in the acute phase after transplant, with 14 of these patients receiving preemptive bundle therapy. RESULTS: Subclinical pulmonary hypertension was reduced in the preemptive bundle therapy group (n = 14) compared with the nontherapy group (n = 35). The preemptive bundle therapy group showed more rapid recovery of platelet, prothrombin time, and bilirubin levels afterlivertransplant compared with the nontherapy group. The prognosis of patients in the preemptive bundle therapy group was significantly better than in the nontherapy group. Extrasinusoidal platelet aggregation was significantly lower in the preemptive bundle therapy group than in the nontherapy group. CONCLUSIONS: Preemptive bundle therapy reduced sinusoidal endothelial cell injury, extrasinusoidal platelet aggregation, and subclinical pulmonary hypertension after liver transplant, resulting in good posttransplant recovery.

nPTD classification: an updated classification of gastric cancer location for function preserving gastrectomy based on physiological lymphatic flow.

BACKGROUND: The correlation between tumor location and lymphatic flow distribution in gastric cancer has been previously reported, and PTD (Proximal - Transitional - Distal) classification was proposed. Our group updated and developed the nPTD classification. METHOD: We retrospectively studied gastric cancer patients who underwent the dye method sentinel node biopsy from 1993 to 2020. The inclusion criteria were a single lesion type 0 cancer of ≤5 cm in the long axis, clinically node-negative, and invasion within the proper muscle layer pathologically. In this study, the distribution of dyed lymphatic flow was evaluated for each occupied area of the tumor. RESULTS: We included 416 patients in this study. The tumors located in the watershed of the right and left gastroepiploic arteries near greater curvature had extensive lymphatic flow; therefore, a newly circular region with a diameter of 5 cm is set on the watershed of the greater curvature between P and T zone as the 'n' zone. In addition, for cancers located in the lesser P curvature, lymphatic flow to the greater curvature was not observed. Therefore, the P zone was divided into two: the lesser curvature side (PL) and the greater curvature side (PG). CONCLUSIONS: The advantage of the nPTD classification is that it provides not only proper nodal dissection but also adequate function-preserving gastrectomy. If the tumor is localized within the PL, the proximal gastrectomy resection area can be further reduced. In contrast, for cancers located in the 'n' zone, near-total gastrectomy is required because of the extensive lymphatic flow.

Relationship between fatty liver change and nutritional status after total gastrectomy in gastric cancer patients: a retrospective study.

BACKGROUND: The relationship between chronological nutritional changes and development of fatty liver after total gastrectomy (TG) in gastric cancer (GC) patients is still unclear. This study aimed to evaluate relationship between development of fatty liver and chronological changes of nutritional parameters during 12 months after TG. METHODS: We retrospectively analyzed medical records of 59 patients with GC who underwent TG at the Kanazawa Medical University Hospital between January 2009 and December 2017. We defined fatty liver change as a mean liver-to-spleen attenuation ratio (L/S ratio) of less than 1.2 in the computed tomography images at 12 months after TG and divided the patients into fatty liver (FL) and non-FL groups from the L/S ratio. We analyzed serum levels of total protein and albumin, and psoas muscle index (PMI) before TG and at 6 and 12 months after TG in the non-FL and FL groups. RESULTS: Six patients showed an L/S ratio of less than 1.2 at 12 months after TG and were included into FL group. There was no significant difference between the groups in serum parameters, L/S ratio, and PMI before TG. In the FL group, the mean levels of total protein and albumin decreased after TG and were significant lower at 6 months, compared with the non-FL group. And then, these levels in the FL group recovered at 12 months. In contrast, the mean levels of total protein and albumin in the non-FL group did not decrease below the preoperative levels throughout the year after surgery. As with laboratory parameters, all patients in the FL group showed decrease of PMI at 6 months after TG. This proportion was significantly higher than that in the non-FL group (100% vs. 40.8%, P = 0.006). CONCLUSIONS: We evaluated that the patients with fatty liver occurring after TG had significantly lower levels of serum nutritional parameters and skeletal muscle index at 6 months, not but 12 months, after TG.

Risk Factors for Overall Complications and Remote Infection After Gastrectomy in Elderly Gastric Cancer Patients.

BACKGROUND/AIM: A significant predictive factor for the occurrence of complications after gastrectomy in elderly gastric cancer patients is yet to be determined. We aimed to evaluate the clinical factors associated with overall complications including remote infection after gastrectomy in elderly gastric cancer patients. PATIENTS AND METHODS: We retrospectively analyzed data of 101 patients aged over 80 years, who underwent curative gastrectomy. We analyzed the clinicopathological factors that were independently associated with the occurrence of overall complications or remote infection by a logistic regression model. RESULTS: The overall complication rate was 24.8%. We identified pneumonia as a remote infection, and the occurrence rate of remote infections was 5.9%. On multivariate analysis, hemoglobin (<11 g/dl) and operation time (>240 min) were significantly correlated with the occurrence of overall complications. Regarding the occurrence of remote infection, performing total gastrectomy and a hemoglobin level <11 g/dl were identified as significant risk factors. CONCLUSION: Preoperative anemia and intraoperative factors, including the surgical procedure, could affect the occurrence of postoperative complications in elderly patients.

[Intestinal Care Using L‒Glutamine Supplement and Probiotics Can Induce a Strong Anti‒Tumor Immune Response through the Induction of Mature Tertiary Lymphoid Structures in Pancreatic Cancer Patients Receiving Preoperative Chemotherapy].

Most cancer patients receiving chemotherapy are accompanied by gut dysbiosis and intestinal mucosal barrier dysfunction to a greater or lesser degree. These disorders of the gut can easily cause bacterial translocation, resulting in the formation of immunothrombosis composed mainly of neutrophil extracellular traps and activated platelets in hepatic sinusoid in order to trap bacteria. At the same time, however, a lot of alarmin such as HMGB1, S100A8/S100A9 and VEGF‒A which are released from immunothrombosis, promote to recruit many myeloid‒derived suppressor cells(MDSCs)from bone marrow, leading to the strong immunosuppressive milieu in both liver and cancerous lesions. Therefore, intestinal care must be necessary for protection of intestinal barrier integrity during chemotherapy. Recently, we found that intestinal care using oral L‒glutamine‒ enriched supplement and probiotics including Lactobacillus casei Shirota supplement(Yakult®)and Clostridium butyricum MIYAIRI 588 strain(Miya‒BM®)could induce a strong anti‒tumor immune response through the induction of fully mature tertiary lymphoid structures in some pancreatic cancer patients who received 3 cycles of preoperative chemotherapy(gemcitabine 1,000 mg/m2 plus nab‒paclitaxel 125 mg/m2 on days 1, 8, and 15 of 28‒day cycle). In this review article, we discussed the role of intestinal care in the induction of fully mature tertiary lymphoid structures in cancer patients receiving chemotherapy.