Long-term Results of a Phase II Study of Neoadjuvant SOX for Advanced Gastric Cancer.

BACKGROUND/AIM: This study aimed to evaluate the long-term survival outcomes from our previous study: a phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for cT4 or N2-3 advanced gastric cancer. PATIENTS AND METHODS: The patients with clinical T4 and/or N2 or more lymph nodes received two cycles (3 weeks per cycle) of neoadjuvant chemotherapy with S-1 plus oxaliplatin (oxaliplatin at 130 mg/m2 on day 1 and S-1 at 80-120 mg/day on days 1 to 14), followed by gastrectomy with D2 lymphadenectomy. The final preplanned analysis of long-term outcomes, including overall and relapse-free survival, was performed. This trial has been completed and registered with the University Hospital Medical Information Network Clinical Trials Registry under number UMIN 000024656. RESULTS: Between May 2016 and March 2019, 30 patients were enrolled. All patients completed the protocol. After a median follow-up of 50 months for surviving patients, the 3-year overall and recurrence-free survival rates were 80.0% and 76.7%, respectively, at the last follow-up in March 2023, whereas the 5-year overall and recurrence-free survival rates were 72.7% and 73.0%, respectively. CONCLUSION: The administration of two cycles of neoadjuvant chemotherapy with S-1 plus oxaliplatin, followed by D2 gastrectomy, was associated with relatively good long-term oncologic outcomes for patients with high-risk gastric cancer.

Dysregulation of the progranulin-driven autophagy-lysosomal pathway mediates secretion of the nuclear protein TDP-43.

The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.

A Case of Pathologically Complete Response After Nivolumab Combined with Chemotherapy in a Gastric Cancer Patient with Virchow's Lymph Node Metastasis.

Gastric cancer with Virchow's lymph node metastasis (LNM) is not indicated for initial curative surgery. Although there have been some case reports of curative resections after pre-operative treatment, including immune checkpoint inhibitors (ICIs), there is no consensus regarding the optimal timing of surgery. We describe a rare case of initially unresectable gastric cancer treated preoperatively with nivolumab combined chemotherapy, which achieved a pathologically complete response. An 82-year-old man was referred for gastric cancer treatment. Contrast-enhanced computed tomography revealed stomach wall thickening and swollen left supraclavicular LN. This gastric cancer was assessed as unresectable due to the presence of Virchow's LNM; therefore, chemotherapy and ICI using S-1 plus oxaliplatin plus nivolumab were administered. After three courses of treatment, the primary tumor and Virchow's LN showed a marked reduction in size. The patient underwent Virchow's LNM resection as a preliminary step to determine indications for curative surgery. A pathological examination revealed no viable cancer cells were found inside the resected LN. The patient underwent distal gastrectomy. Pathological examination revealed complete degeneration of the primary tumor and regional LN without residual carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for one year after the initial treatment.

Tumor Depth Prediction of Gastric Cancer With a T4 Score.

BACKGROUND/AIM: Peritoneal metastases are often found at surgery of pT4 gastric cancers, preventing R0 resection. In the event of successful R0 resection, distant metastases still occur in a sizeable proportion of patients. Estimation of the depth of invasion has a relatively low accuracy (57%-86%) compared with pathological findings. This study sought to develop a clinical score to distinguish between pathological stage T4 (pT4) and pT1-3 gastric cancer. PATIENTS AND METHODS: Reviewing the data of 2,771 patients who had undergone gastrectomy at our hospital from January 1996-December 2016, we assessed demographic factors plus tumor markers, diameter, location, histology, and macroscopic type according to the fifth edition (2019) of the WHO classification. Significant factors on multivariate analysis were used to develop a pT4 gastric cancer depth prediction score (T4 score). RESULTS: Multivariate analysis revealed that the clinical factors associated with pT4 disease were CA19-9 elevation, tumor diameter ≥50 mm, poorly cohesive type adenocarcinoma, mucinous adenocarcinoma, and WHO macroscopic types 2-4. The T4 score was obtained by weighing these factors according to the ß-coefficient. The optimum cutoff value of the T4 score was 4 points. A total of 79.4% of cases with a T4 score ≥4 points were stage pT4. A total of 93.9% of cases with a T4 score <4 points were stage pT1-3, with 91.1% sensitivity, 85.3% specificity, 79.4% positive predictive value, and 93.9% negative predictive value. CONCLUSION: T4 scoring can differentiate pT4 gastric cancer from pT1-3 gastric cancer.

Xanthogranulomatous appendicitis with elevated tumor marker misdiagnosed as cecal cancer: a case report.

Xanthogranulomatous inflammation is an uncommon chronic inflammatory disease that develops most often in the kidneys and gallbladder. However, xanthogranulomatous appendicitis 45eXA is rare. Herein, we present a case of XA, with an elevated tumor marker, misdiagnosed as cecal cancer. A 76-year-old woman was referred to our hospital. Carbohydrate antigen 19-9 (CA 19-9) levels were elevated. By computed tomography and magnetic resonance imaging, we diagnosed as suspected cecal cancer and performed laparoscopic-assisted ileocecal resection. The pathological diagnosis was XA. Her CA19-9 level decreased to within normal limits. XA is a condition that results from an unusual healing pattern of appendicitis. However, the underlying mechanisms are still unclear. This is the first case of XA with elevated CA 19-9 levels. In this case, XA may have had the potential for malignancy. Our case report can aid in the understanding of these rare cases and, as a result, improve their prognosis.

Phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for gastric cancer clinical T4 or N2-3.

In Japan, the standard treatment for stage II or III gastric cancer is D2 gastrectomy followed by administration of S-1 for one year. However, patients with stage III disease have unsatisfactory survival rates. The purpose of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy consisting of S-1 and oxaliplatin for advanced gastric cancer. Patients with cT4 or cN2-3 gastric cancer were scheduled to receive two courses of chemotherapy (130 mg/m2 oxaliplatin on Day 1, 80 mg/m2 S-1 per day twice daily for 14 days) followed by surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were rates of completion of protocol treatment, pathological response, and adverse events; and 3-year overall survival, 5-year overall survival, and 5-year recurrence-free survival. Between May 2016 and March 2019, 30 patients were enrolled in the study, all of whom completed the protocol treatment. The R0 resection rate (primary endpoint) was 93.3% (95% confidence interval: 77.9-99.2). The pathological response rate was 63.3%. Grade 3-4 toxicities included anemia (3.3%), anorexia (6.7%), and fatigue (3.3%). Relative dose intensities were 91.2% and 94.2% for S-1 and oxaliplatin, respectively. Neoadjuvant S-1 and oxaliplatin is highly effective, achieving an acceptable R0 resection rate with relatively few severe toxicities and good compliance.Trial registration: Registry name: A prospective intervention study on the availability of preoperative SOX therapy for T4 or N2-3 gastric cancer. Trial ID: UMIN: UMIN000024656. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R00002836.

Rapid Flow Cytometry of Gastrointestinal Stromal Tumours Closely Matches the Modified Fletcher Classification.

AIM: We aimed to develop a rapid, simple procedure and an algorithm for quantitative analysis and classification of the metastatic risk of gastrointestinal stromal tumours (GIST) for clinical use. MATERIALS AND METHODS: Eighteen specimens from laparoscopic local gastrectomy were assessed by flow cytometry. We devised a new risk classification for GIST by combining flow cytometry parameters with tumour size and evaluated whether the combined parameters correlated with the modified Fletcher risk classification. RESULTS: We found a significant correlation between clinical prognostic factors (mitotic count and Ki-67 labelling index) and the flow cytometry parameters DNA ploidy, DNA index and S-phase fraction. The combined parameters established from tumour size and the flow cytometry parameters showed a high correlation with the modified Fletcher risk classification (p=0.0064). Flow cytometry had to be performed for approximately 10 minutes to determine the metastatic risk. CONCLUSION: Rapid flow cytometry parameters can classify risk without the need for histological analysis.

Intrahepatic cholangiocarcinoma with gastric infiltration misdiagnosed as gastric submucosal tumor.

Intrahepatic cholangiocarcinomas (ICC) are rare primary liver tumors. In few cases, they may invade nearby organs and present as extrahepatic growths, leading to poor prognosis. We report a case of a 78-year-old man who presented with fatigue. An upper gastrointestinal endoscopy was performed to find a cause for his anemia, which showed a submucosal tumor with delle at the lesser curvature of the gastric cardia. A computed tomography revealed a low-density tumor of diameter 70 mm at the cardia. It appeared to infiltrate the liver directly. We performed lateral hepatectomy, proximal gastrectomy and lymphadenectomy. The pathological findings revealed an ICC with gastric infiltration. Although adjuvant chemotherapy was administered, 12 months postoperatively, the patient developed pain and multiple bone metastases for which palliative radiation was initiated. The guidelines for lymphadenectomy and adjuvant chemotherapy in such cases are unclear. Appropriate regional lymphadenectomy and adjuvant chemotherapy can improve the prognosis of such patients.

Leiomyosarcoma arising from the right ovarian vein.

Leiomyosarcomas (LMS) of the ovarian vein are extremely rare and have a poor prognosis. Only 10 cases have been reported since 1977. The patient is a 69-year-old woman presented with right abdominal pain. Computed tomography showed a regularly shaped tumor, 80 mm in diameter in the retroperitoneum, adjacent to the descending part of the duodenum. Intraoperatively, the right ovarian vein was found to run through the tumor and was, therefore, resected together with the tumor. Pathological examination revealed a LMS of the right ovarian vein. Nine months postoperatively, multiple lung metastases were detected and chemotherapy was initiated. Delayed diagnosis is associated with high mortality. It is important that the diagnosis of LMS should be made preoperatively when you have already diagnosed a tumor to better direct the surgical approach. Multimodal therapy may improve prognosis.

Staging of gastric cancer with the Clinical Stage Prediction score.

BACKGROUND: Chemotherapy with or without surgery is the first-line treatment for stage III/IV gastric cancer, while surgery is the first-line treatment for stage I/II gastric cancer. Accordingly, it is important to distinguish between stage III/IV and stage I/II gastric cancer, but clinical staging is less accurate than pathological staging. This study was performed to develop a clinical score that could distinguish stage III/IV gastric cancer from stage I/II gastric cancer. METHODS: We reviewed 2722 patients who underwent gastrectomy at our hospital from January 1996 to December 2015. As pretreatment factors potentially related to tumor stage, we assessed age, sex, tumor markers, tumor diameter, tumor location, tumor histology, and macroscopic type. Factors showing significance on multivariate analysis were used to develop the Clinical Stage Prediction score (CSP score), and a cutoff value for the score was determined by receiver operating characteristics analysis. RESULTS: According to multivariate analysis, clinical factors associated with stage III/IV disease were elevation of the carcinoembryonic antigen level, tumor diameter ≥ 60 mm, circumferential gastric involvement, esophageal infiltration, mucinous adenocarcinoma, and macroscopic types 2-4. The CSP score was obtained by weighting these factors according to the non-standardized ß-coefficient. Receiver operating characteristics analysis indicated that the optimum cutoff value of the CSP score was 17 points. Among 1042 patients with a CSP score ≥ 17 points, 820 patients (78.7%) had stage III/IV gastric cancer. Conversely, among 1680 patients with a CSP score < 17 points, 1547 patients (92.1%) had stage I/II gastric cancer. When discrimination of stage III/IV gastric cancer from stage I/II gastric cancer by the CSP score was assessed, the sensitivity was 78.7%, specificity was 92.1%, positive predictive value was 86.0%, and negative predictive value was 87.5%. CONCLUSIONS: The CSP score can be helpful for differentiating stage III/IV gastric cancer from stage I/II gastric cancer based on pretreatment clinical factors.

Successful conversion surgery for unresectable gastric cancer with giant para-aortic lymph node metastasis after downsizing chemotherapy with S-1 and oxaliplatin: a case report.

BACKGROUND: Although patients with stage IV gastric cancer who respond well to systemic chemotherapy can be treated with gastrectomy, the prognosis of patients with unresectable gastric cancer with para-aortic lymph node metastasis is poor. We herein report a case of remnant gastric cancer with para-aortic lymph node metastasis that was treated with potentially curative conversion surgery after showing a complete response to chemotherapy with S-1 and oxaliplatin (SOX). CASE PRESENTATION: An 81-year-old man was diagnosed with type 3 remnant gastric cancer with giant para-aortic lymph node metastasis, and he received SOX chemotherapy. After three courses of SOX chemotherapy, the primary tumor and para-aortic lymph node metastases markedly reduced in size, indicating a partial response. Because conversion surgery was possible, the patient underwent total remnant gastrectomy with D2 and para-aortic lymph node dissection. Histological examination revealed no residual cancer cells in the resected stomach and lymph nodes. The patient was diagnosed with a complete pathological response and was discharged on postoperative day 24. Currently, 1 year after surgery, the patient is alive and has not shown any tumor recurrence. CONCLUSION: To the best of our knowledge, this is the first case of advanced remnant gastric cancer with giant para-aortic lymph node metastasis that showed a pathological complete response and favorable outcome after SOX chemotherapy.

Relation between atlantoaxial (C1/2) and cervical alignment (C2-C7) angles with Magerl and Brooks techniques for atlantoaxial subluxation in rheumatoid arthritis.

BACKGROUND: A few studies have reported the relation between the atlantoaxial (C1/2) angle and cervical alignment (C2-C7) angle after a Magerl and Brooks (M&B) surgical procedure to treat atlantoaxial subluxation (AAS) in patients with rheumatoid arthritis (RA). However, no study has examined an optimum preoperative C1/2 angle reduction. We aimed to assess the relation between the C1/2 angle reduction and the C2-C7 angle change in patients with progressive RA who underwent the M&B procedure. METHODS: We retrospectively analyzed the relation between the preoperative C1/2 angle and C2-C7 angle in 28 consecutive RA patients using their clinical and radiological data. Differences in the preoperative and postoperative C1/2 and C2-C7 angles were detected. Correlations of these angles and the reduced degree of angles were examined. The Ranawat grading scale and Japanese Orthopaedic Association (JOA) scores were used to determine myelopathy. Pain was categorized into five categories according to severity. Clinical and X-ray evaluations were collected before surgery, at 3 and/or 6 months after surgery, and at final follow-up. RESULTS: Clinical symptoms, Ranawat grade, and JOA scores improved postoperatively, and patients achieved bony union within 3 months. We observed a strong and significant correlation between the reduced C1/2 angle and the change in the C2-C7 angle. Patients with a preoperative C1/2 angle of <20 degrees had markedly reduced cervical lordotic angle but this condition was not seen in patients with a preoperative C1/2 angle of >or=20 degrees . The optimum C1/2 angle was estimated as [20 degrees - (preoperative C1/2 angle)] in patients with a C1/2 angle <20 degrees or as an in situ angle in patients with a C1/2 angle of >or=20 degrees . CONCLUSIONS: Surgeons performing the M&B procedure need to select patients carefully and avoid complete or overreduction of the C1/2 angle to prevent serious postoperative SAS and myelopathy.

A computer simulation of human walking in persons with joint contractures.

Joint contractures decrease the patient's ability to walk, but usually other parts of the body compensate the affected joint contractures. When we restore the gait performance in paraplegic patients by means of functional electrical stimulation, however, we cannot expect complications of compensation. A computer simulation was done to clarify how the contractures affect the gait pattern when no complications of compensation were expected. A seven-segment link mechanical model was used for simulation of human walking in the sagittal plane. In turn, using a personal computer stance and swing-leg joint contractures of the ankle, knee, and/or hip were simulated. When stance-leg contracture was simulated, step length became short with increasing hip flexion contracture. The trunk was tilted backward during knee flexion or ankle plantarflexion contracture simulation. When the swing-leg contracture was simulated, step length became short with increasing knee flexion contracture. We found that hip or knee flexion contracture of < or = 15 degrees, or ankle plantarflexion contracture of < 0 degrees was required to maintain positive step length and forward movement of the center of gravity. These findings suggest that 15 degrees of hip and knee flexion contracture, and 0 degrees of ankle plantarflexion contracture are critical when gait restoration is performed by functional electrical stimulation.