Prognostic value of clinical and radiomic parameters in patients with liver metastases from uveal melanoma.

Approximately every second patient with uveal melanoma develops distant metastases, with the liver as the predominant target organ. While the median survival after diagnosis of distant metastases is limited to a year, yet-to-be-defined subgroups of patients experience a more favorable outcome. Therefore, prognostic biomarkers could help identify distinct risk groups to guide patient counseling, therapeutic decision-making, and stratification of study populations. To this end, we retrospectively analyzed a cohort of 101 patients with newly diagnosed hepatic metastases from uveal melanoma by using Cox-Lasso regression machine learning, adapted to a high-dimensional input parameter space. We show that substantial binary risk stratification can be performed, based on (i) clinical and laboratory parameters, (ii) measures of quantitative overall hepatic tumor burden, and (iii) radiomic parameters. Yet, combining two or all three domains failed to improve prognostic separation of patients. Additionally, we identified highly relevant clinical parameters (including lactate dehydrogenase, thrombocyte counts, aspartate transaminase, and the metastasis-free interval) at first diagnosis of metastatic disease as predictors for time-to-treatment failure and overall survival. Taken together, the risk stratification models, built by our machine-learning algorithm, identified a comparable and independent prognostic value of clinical, radiological, and radiomic parameters in uveal melanoma patients with hepatic metastases.

Presence of Fusobacterium nucleatum in relation to patient survival and an acidic environment in oesophagogastric junction and gastric cancers.

BACKGROUND: Fusobacterium nucleatum inhabits the oral cavity and affects the progression of gastrointestinal cancer. Our prior findings link F. nucleatum to poor prognosis in oesophageal squamous cell carcinoma via NF-κB pathway. However, its role in oesophagogastric junction and gastric adenocarcinoma remains unexplored. We investigated whether F. nucleatum influences these cancers, highlighting its potential impact. METHODS: Two cohorts of EGJ and gastric adenocarcinoma patients (438 from Japan, 380 from the USA) were studied. F. nucleatum presence was confirmed by qPCR, FISH, and staining. Patient overall survival (OS) was assessed based on F. nucleatum positivity. EGJ and gastric adenocarcinoma cell lines were exposed to F. nucleatum to study molecular and phenotypic effects, validated in xenograft mouse model. RESULTS: In both cohorts, F. nucleatum-positive EGJ or gastric adenocarcinoma patients had notably shorter OS. F. nucleatum positivity decreased in more acidic tumour environments. Cancer cell lines with F. nucleatum showed enhanced proliferation and NF-κB activation. The xenograft model indicated increased tumour growth and NF-κB activation in F. nucleatum-treated cells. Interestingly, co-occurrence of F. nucleatum and Helicobacter pylori, a known risk factor, was rare. CONCLUSIONS: F. nucleatum can induce the NF-κB pathway in EGJ and gastric adenocarcinomas, leading to tumour progression and poor prognosis.

Angiopoietin-Like Protein 2 Expression in Tumor Cells Supports Tumor-Associated Macrophage-Induced Tumor Progression in Esophageal Cancer.

BACKGROUND: Tumor-associated macrophages (TAM), a major component of the tumor microenvironment, play key roles in tumor formation and progression; however, mechanisms underlying TAM-induced tumor progression are complex and not well known. We previously reported that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. METHODS: We examined ANGPTL2 expression in paraffin-embedded tumor samples from resected specimens of 221 patients with esophageal cancer. Patients were subdivided into four groups based on immunohistochemistry scores described above: ANGPTL2-low/TAM-low, ANGPTL2-low/TAM-high, ANGPTL2-high/TAM-low, and ANGPTL2-high/TAM-high groups. Gene expression datasets of esophageal cancer cell lines were obtained from the cancer cell line encyclopedia public database. RESULTS: In this study, we demonstrate that TAM infiltration is associated with poor prognosis in patients with esophageal cancer whose tumor cells show relatively higher ANGPTL2 expression levels; however, TAM infiltration did not affect prognosis in patients with ANGPTL2-low-expressing esophageal cancer, suggesting that ANGPTL2 expression in esophageal cancer cells is required for TAM-induced tumor progression. Our analysis of public datasets indicates a potential positive correlation of ANGPTL2 expression levels with that of transforming growth factor (TGF)-ß, a TAM-activating factor, in esophageal cancer cell lines. CONCLUSION: We conclude that ANGPTL2 signaling in tumor cells supports TAM-induced tumor progression and contributes to poor prognosis in patients with esophageal cancer. These findings overall provide novel insight into pro-tumor ANGPTL2 functions and illustrate the essential role of cancer cell/TAM crosstalk in cancer progression.

Diagnostic accuracy of preoperative adhesion mapping by ultrasonography for laparoscopic surgery in patients with past abdominal surgery with special reference to loose adhesion.

PURPOSE: Endoscopic surgery is widely accepted for both elective and emergent abdominal surgery. This study was performed to assess the accuracy of preoperative adhesion mapping by abdominal ultrasonography (US). METHODS: Intra-abdominal intestinal adhesions on the abdominal wall in 50 patients with a history of abdominal surgery were prospectively assessed by the visceral slide test with US before laparoscopic surgery from 2019 to 2022. Adhesion was assessed in six separate abdominal zones during US. Actual adhesion on the abdominal wall was confirmed during laparoscopic surgery. RESULTS: The sliding distances in upper right, upper central, upper left, lower right, lower central, and lower left zones in patients with versus without intestinal adhesion were 4.4 versus 1.4 cm (P = .004), 3.4 versus 2.5 cm, 4.3 versus 1.3 cm (P = .011), 3.1 versus 1.5 cm (P = .0014), 3.3 versus 1.1 cm (P = .013), and 3.4 versus 0.8 cm (P = .0061), respectively. Receiver operating characteristic analysis revealed the optimal value of sliding distance as 2.5 cm and the area under the curve as 0.86. The specificity of US assessment of adhesion was lower in the central zone than in lateral zones. Loose adhesion mostly seen around the scar was attributed to either filmy tissue or omental adhesion, leading to visceral sliding during US. CONCLUSION: This study revealed the reason for insufficient accuracy of preoperative US assessment of intestinal adhesion around the scar area because of loose adhesion. The upper lateral area might be optimal for first port insertion.

Advanced Cholangiocarcinoma With High Tumor Mutation Burden Achieving Complete Response to Immune Check Point Inhibitor.

BACKGROUND/AIM: Genomic examination of tumor tissue has been clinically accepted, and the identification of actionable mutations for molecular-targeted therapy may provide substantial survival benefit for patients with advanced malignancies. CASE REPORT: A female patient in her 60s showed a stenosis of the afferent loop of the small intestine because of circumferential metastatic tumor 14 months after curative surgery for hilar cholangiocarcinoma. Chemotherapy with gemcitabine plus cisplatin was administered for 18 months. An oncopanel examination was performed during chemotherapy, and a high tumor mutation burden was revealed. At 38 months after surgery, a new recurrent tumor, 2.7 cm in size, was observed in the abdominal wall, which was histologically proven to be metastatic adenocarcinoma. Atezolizumab was administered. After three cycles of treatment, treatment was switched to pembrolizumab because of its acceptance by healthcare insurance. The recurrent tumors in the abdominal wall and small intestine disappeared 6 months after the administration of immune checkpoint inhibitor, and the patient has continued pembrolizumab, surviving for 76 months after surgery without any clinical evidence of tumor. CONCLUSION: Immune checkpoint blockade successfully prolonged the survival of a patient with advanced hilar cholangiocarcinoma with high tumor mutation burden, although the optimal number of mutations for such a successful response needs to be clarified.

Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC. METHODS: In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1-5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1-5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1-4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete. FINDINGS: A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group. INTERPRETATION: Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy. FUNDING: Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.

Final analyses of the prospective controlled trial on the efficacy of uracil and tegafur/leucovorin as an adjuvant treatment for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. METHODS: In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. RESULTS: Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. CONCLUSION: The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012).

The Success Rate Is Lower but Completion Rate of Laparoscopic Cholecystectomy Is higher in Endoscopic Transpapillary Gallbladder Drainage than Percutaneous Gallbladder Drainage for Acute Cholecystitis.

BACKGROUND: We investigated the success and complication rates of endoscopic transpapillary gallbladder drainage (ETGBD) and percutaneous transhepatic gallbladder drainage (PTGBD) and the outcomes of subsequent cholecystectomy for acute cholecystitis. METHODS: Patients (N=178) who underwent cholecystectomy after ETGBD or PTGBD were retrospectively assessed. RESULTS: ETGBD was successful in 47 (85.5%) of 55 procedures, whereas PTGBD was successful in 123 (100%) of 123 sessions (P<0.001). Complications related to ETGBD and PTGBD occurred in 6 (12.8%) of 47 and 16 (13.0%) of 123 patients, respectively (P=0.97). After propensity matching, 43 patients from each group were selected. Median time from drainage to cholecystectomy was 48 (14 to 560) days with ETGBD and 35 (1 to 90) days with PTGBD (P=0.004). Laparoscopy was selected more often in the ETGBD group (97.7%) than in the PTGBD group (79.1%) (P=0.007), and conversion from laparoscopy to open cholecystectomy was more common with PTGBD (41.2%) than with ETGBD (7.1%) (P<0.001). Mean operation time was significantly shorter with ETGBD (135.8±66.7 min) than with PTGBD (195.8±62.2 min) (P<0.001). The incidence of Clavien-Dindo grade ≥III postoperative complications was 9.3% with ETGBD and 11.6% with PTGBD (P=0.99). CONCLUSIONS: The success rate is lower but completion of laparoscopic cholecystectomy is more in endoscopic gallbladder drainage than percutaneous gallbladder drainage for acute cholecystitis.

Laparoscopic versus open abdominal lymph node dissection for esophageal squamous cell carcinoma: a propensity score matching analysis.

PURPOSE: To compare the short- and long-term outcomes of laparoscopic and open abdominal lymph node dissection using propensity score matching (PSM) analysis. METHODS: The subjects of this retrospective analysis were 459 patients who underwent curative resection for esophageal squamous cell carcinoma (ESCC) between May, 2005 and December, 2019, at our hospital. Patients were divided into two groups: the Laparoscopic (Lap group) and the Open (Open group). Post-PSM, 139 patients from each group were selected for the analysis to compare the short- and long-term outcomes between the groups. RESULTS: The Lap group experienced fewer Clavien-Dindo (CD) Grade ≥ 2 complications (28.1% vs. 40.3%, P = 0.04) and lower rates of abdominal surgical site infections (SSI) (2.9% vs. 7.9%, P = 0.02) than the Open group. The number of lymph nodes harvested was similar in the Lap and Open groups (14.8 ± 7.5 vs. 15.7 ± 8.6, P = 0.34). There was no significant difference in 3-year overall survival rates (81.2% vs. 69.5%, P = 0.12) or relapse-free survival rates (61.1% vs. 58.2%, P = 0.54) between the groups. CONCLUSIONS: Laparoscopic abdominal lymph node dissection for ESCC can be performed safely and appears to be beneficial.

First-line pembrolizumab plus chemotherapy for advanced/metastatic esophageal cancer: 1-year extended follow-up in the Japanese subgroup of the phase 3 KEYNOTE-590 study.

BACKGROUND: First-line pembrolizumab plus chemotherapy (pembrolizumab-chemotherapy) demonstrated improved efficacy and a manageable safety profile versus placebo plus chemotherapy (placebo-chemotherapy) in the subgroup analysis of Japanese patients with advanced/metastatic esophageal cancer in KEYNOTE-590 at a median follow-up of 24.4 months. Longer-term data from the Japanese subgroup analysis of KEYNOTE-590 are reported. METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ≤ 35 cycles plus chemotherapy (cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2/day). Endpoints included overall survival (OS) and progression-free survival (PFS; investigator-assessed per RECIST v1.1; dual primary) and safety (secondary). Early tumor shrinkage (ETS) and depth of response (DpR) were assessed post hoc. RESULTS: Overall, 141 patients were enrolled in Japan. As of July 9, 2021, median follow-up was 36.6 months (range, 29.8-45.7). Pembrolizumab-chemotherapy showed a trend toward favorable OS (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.47-1.03) and PFS (0.57; 0.39-0.83) versus placebo-chemotherapy. In the pembrolizumab-chemotherapy group, patients with ETS ≥ 20% (55/74; 74.3%) versus < 20% (19/74; 25.7%) had favorable OS (HR, 0.23; 95% CI 0.12-0.42) and PFS (0.24; 0.13-0.43). Patients with DpR ≥ 60% (31/74; 41.9%) versus < 60% (43/74; 58.1%) had favorable OS (HR, 0.37; 95% CI 0.20-0.68) and PFS (0.24; 0.13-0.43). Grade 3-5 treatment-related adverse events occurred in 55/74 patients (74.3%) with pembrolizumab-chemotherapy and 41/67 patients (61.2%) with placebo-chemotherapy. CONCLUSIONS: With longer-term follow-up of Japanese patients with advanced/metastatic esophageal cancer, efficacy continued to favor pembrolizumab-chemotherapy compared with placebo-chemotherapy, with no new safety signals observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03189719.

Poorly differentiated mucinous carcinoma of the ascending colon complicated by bilateral ovarian mature cystic teratomas in a 17-year-old female patient: a case report.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and screening colonoscopy has led to a decreasing incidence rate. However, the incidence of CRC is increasing among young people, especially adolescents and young adults (AYAs) who are not routinely screened. Although CRC is the fourth most common cancer among AYAs, it is extremely rare. In younger patients, CRC is often diagnosed later, and the proportion of patients with advanced CRC is higher than that in older patients. We herein present a case of poorly differentiated mucinous carcinoma of the ascending colon complicated by bilateral ovarian mature cystic teratomas (MCTs) in an AYA. CASE PRESENTATION: A 17-year-old female patient presented with a chief complaint of abdominal pain and diarrhea that had persisted for more than 3 years. Colonoscopy revealed circumferential wall thickening of the ascending colon, and colonic biopsy revealed a mucous mass and findings of adenocarcinoma, predominantly signet ring cell carcinoma. Abdominal computed tomography (CT) and pelvic magnetic resonance imaging (MRI) showed bilateral ovarian tumors. Laparoscopic right hemicolectomy and enucleation of bilateral ovarian tumors were performed. Although the ascending colon cancer formed a large mass, there were no signs of peritoneal dissemination or direct invasion to the surrounding organs. Microscopically, the ascending colon was a poorly differentiated mucinous carcinoma with signet ring cell carcinoma and lymph node metastasis (9/42). The ovarian tumors were diagnosed as MCTs without any malignant components. The pathological diagnosis was ascending colon cancer (pT4aN2bM0, pStage IIIC) and bilateral ovarian MCTs. Microsatellite instability (MSI) testing was negative, and there were no gene mutations in either RAS or BRAF. Postoperative adjuvant chemotherapy with oxaliplatin and 5-FU was started. CONCLUSIONS: We presented a case of locally advanced ascending colon cancer in a 17-year-old female patient. CRC rarely occurs in AYAs. However, the incidence has gradually increased in recent years. It should be considered as a differential diagnosis for young patients with long-term abdominal symptoms of unknown cause.

The relationship between the treatment course and prognosis of oligometastasis after esophageal squamous cell carcinoma resection.

PURPOSE: The concept of oligometastasis, which represents limited metastatic disease, has recently gained interest, accompanied by a more detailed classification. This study aims to investigate the relationship between the treatment course and prognosis in patients with a recurrence of esophageal squamous cell carcinoma (ESCC) after curative esophagectomy. METHODS: 126 patients with ESCC recurrence after curative resection were enrolled in this study. Oligometastasis was defined as fewer than five recurrences in a single organ. Patients were classified as having oligometastatic recurrence (OLR) or polymetastatic recurrence (PLR). Patients were further classified into four subgroups according to lesion progression: persistent oligorecurrence (PER-OLR), converted polyrecurrence (CON-PLR), induced oligorecurrence (IND-OLR), and persistent polyrecurrence (PER-PLR). We analyzed the relationship between the recurrence patterns and prognosis according to the progression of oligometastatic lesions. RESULTS: OLR was identified in 58 (46%) of 126 patients with recurrence. Patients with OLR had a significantly better prognosis than those with PLR (P < 0.0001). A further subgroup analysis revealed that patients who underwent IND-OLR had a similar prognosis to those who underwent PER-OLR. CONCLUSIONS: This study suggests that OLR is a prognostic factor after recurrence following resection of ESCC and that PLR can be converted to OLR by therapeutic intervention to achieve a long-term survival.

RAC1-mediated integrin alpha-6 expression in E-cadherin-deficient gastric cancer cells promotes interactions with the stroma and peritoneal dissemination.

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer that is prone to peritoneal dissemination, with poor patient prognosis. Although intercellular adhesion loss between cancer cells is a major characteristic of DGCs, the mechanism underlying the alteration in cell-to-extracellular matrix (ECM) adhesion is unclear. We investigated how DGCs progress and cause peritoneal dissemination through interactions between DGC cells and the tumour microenvironment (TME). P53 knockout and KRASG12V-expressing (GAN-KP) cells and Cdh1-deleted GAN-KP (GAN-KPC) cells were orthotopically transplanted into the gastric wall to mimic peritoneal dissemination. The GAN-KPC tumour morphology was similar to that of human DGCs containing abundant stroma. RNA sequencing revealed that pathways related to Rho GTPases and integrin-ECM interactions were specifically increased in GAN-KPC cells compared with GAN-KP cells. Notably, we found that Rac Family Small GTPase 1 (RAC1) induces Integrin Subunit Alpha 6 (ITGA6) trafficking, leading to its enrichment on the GC cell membrane. Fibroblasts activate the FAK/AKT pathway in GC cells by mediating extracellular matrix (ECM)-Itga6 interactions, exacerbating the malignant phenotype. In turn, GC cells induce abnormal expression of fibroblast collagen and its transformation into cancer-associated fibroblasts (CAFs), resulting in DGC-like subtypes. These findings indicate that Cdh1 gene loss leads to abnormal expression and changes in the subcellular localization of ITGA6 through RAC1 signalling. The latter, through interactions with CAFs, allows for peritoneal dissemination.

Age-associated reduction of sinus macrophages in human mesenteric lymph nodes.

There are numerous macrophages and dendritic cells in lymph nodes (LNs). Recent studies have highlighted that sinus macrophages (SMs) in LNs possess antigen-presenting capabilities and are related to anti-cancer immune responses. In this study, we assessed the distribution of SMs in mesenteric LNs removed during surgery for colorectal cancer. A marked reduction of SMs was noted in elderly patients, particularly those over 80 years old. We observed a disappearance of CD169-positive cells in LNs where SMs were reduced. In silico analysis of publicly available single-cell RNA sequencing data from LNs revealed that CD169-positive macrophages express numerous genes associated with antigen presentation and lymphocyte proliferation, similar to dendritic cells' functions. In conclusion, our study demonstrates that SMs, potentially crucial for immune activation, diminish in the LNs of elderly patients. This reduction of SMs may contribute to the immune dysfunction observed in the elderly.

Conversion surgery for stage IV gastric cancer with multiple liver metastases with a complete pathological response to S-1 plus oxaliplatin therapy.

Although patients with stage IV gastric cancer who respond well to systemic chemotherapy can be treated with gastrectomy, the prognosis of patients with multiple liver metastases is poor. We herein describe a patient with stage IV gastric cancer with multiple liver metastases who underwent conversion surgery after systemic treatment with S-1 plus oxaliplatin. The patient was a 62-year-old man. Upper gastrointestinal endoscopy revealed a 30-mm type 2 tumor in the greater curvature of the stomach at the anterior wall, and biopsy revealed a poorly differentiated adenocarcinoma. Imaging showed three suspected liver metastases in liver segment S8. The patient was judged to have gastric cancer, cStage IV (cT3N1M1(H)), and systemic chemotherapy was administered. He was treated with a total of six courses of chemotherapy. After re-evaluation, the primary tumor had shrunk significantly, and liver metastases could not be detected. Confirming no signs of seeding by laparoscopy, robot-assisted pylorus-preserving gastrectomy with D2 dissection and laparoscopic partial hepatic (S8) resection were performed. The patient was diagnosed with a complete pathological response. Conversion surgery is an option for stage IV gastric cancer when distant metastases are controlled with chemotherapy and when R0 resection is possible.

Clinical impact of very early recurrence after conversion surgery for stage IV gastric cancer.

Background: The development and improved response to chemotherapy has resulted in a survival benefit of conversion surgery (CS) for advanced gastric cancer (GC). However, this benefit is limited in some cases, such as in those with very early recurrence (VER). This study investigated the relationship between outcome and clinicopathological characteristics after CS for stage IV GC, and the risk factors for VER after CS. Methods: We retrospectively studied 184 patients with stage IV GC who initially underwent chemotherapy, including 36 patients who underwent CS between May 2007 and January 2022. We evaluated the long-term outcome after CS for stage IV GC and the clinicopathological characteristics of the patients who underwent CS. Results: Median survival times (MSTs) in the chemotherapy alone and CS groups were 13.4 and 36.5 months, respectively (p < 0.0001). Of the 27 patients who underwent R0 resection, 22 remained free of early recurrence and five experienced VER. MSTs in the VER and free of early recurrence groups were 15.2 and 44.1 months, respectively (p < 0.0001). Significantly more patients had liver metastasis before initial treatment in the VER group than in the FER group (p = 0.016). There were more patients with preoperative PNI <40 in the VER group (p = 0.046). Conclusion: CS is an effective treatment for stage IV GC, but VER is associated with poor prognosis. We need to carefully consider the indications for CS, especially for patients with poor nutritional status and liver metastases.

Hepatitis B surface antigen expression impairs endoplasmic reticulum stress-related autophagic flux by decreasing LAMP2.

Background & Aims: Hepatitis B surface antigen (HBsAg) drives hepatocarcinogenesis. Factors and mechanisms involved in this progression remain poorly defined, hindering the development of effective therapeutic strategies. Therefore, the mechanisms involved in the HBsAg-induced transformation of normal liver into hepatocellular carcinoma (HCC) were investigated. Methods: Hemizygous Tg(Alb1HBV)44Bri/J mice were examined for HBsAg-induced carcinogenic events. Gene set-enrichment analysis identified significant signatures in HBsAg-transgenic mice that correlated with endoplasmic reticulum (ER) stress, unfolded protein response, autophagy and proliferation. These events were investigated by western blotting, immunohistochemical and immunocytochemical staining in 2-, 8- and 12-month-old HBsAg-transgenic mice. The results were verified in HBsAg-overexpressing Hepa1-6 cells and validated in human HBV-related HCC samples. Results: Increased BiP expression in HBsAg-transgenic mice indicated induction of the unfolded protein response. In addition, early-phase autophagy was enhanced (increased BECN1 and LC3B) and late-phase autophagy blocked (increased p62) in HBsAg-transgenic mice. Finally, HBsAg altered lysosomal acidification via ATF4- and ATF6-mediated downregulation of lysosome-associated membrane protein 2 (LAMP2) expression. In patients, HBV-related HCC and adjacent tissues showed increased BiP, p62 and downregulated LAMP2 compared to uninfected controls. In vitro, the use of ER stress inhibitors reversed the HBsAg-related suppression of LAMP2. Furthermore, HBsAg promoted hepatocellular proliferation as indicated by Ki67, cleaved caspase-3 and AFP staining in paraffin-embedded liver sections from HBsAg-transgenic mice. These results were further verified by colony formation assays in HBsAg-expressing Hepa1-6 cells. Interestingly, inhibition of ER stress in HBsAg-overexpressing Hepa1-6 cells suppressed HBsAg-mediated cell proliferation. Conclusions: These data showed that HBsAg directly induces ER stress, impairs autophagy and promotes proliferation, thereby driving hepatocarcinogenesis. In addition, this study expanded the understanding of HBsAg-mediated intracellular events in carcinogenesis. Impact and implications: Factors and mechanisms involved in hepatocarcinogenesis driven by hepatitis B surface antigen (HBsAg) are poorly defined, hindering the development of effective therapeutic strategies. This study showed that HBsAg-induced endoplasmic reticulum stress suppressed LAMP2, thereby mediating autophagic injury. The present data suggest that restoring LAMP2 function in chronic HBV infection may have both antiviral and anti-cancer effects. This study has provided insights into the role of HBsAg-mediated intracellular events in carcinogenesis and thereby has relevance for future drug development.

Combined Neutrophil-to-Lymphocyte Ratio Score Is Associated With Chemotherapeutic Response and Predicts Prognosis in Patients With Advanced Pancreatic Cancer.

BACKGROUND/AIM: Neutrophil-to-lymphocyte ratio (NLR) is a prognostic indicator for several malignancies, including pancreatic cancer. We developed a novel combined NLR score (cNLRS) based on baseline NLR and change in NLR after chemotherapy (ΔNLR), and examined its prognostic value and role in chemotherapeutic response in patients with advanced pancreatic cancer. PATIENTS AND METHODS: This study retrospectively assessed 210 advanced pancreatic cancer patients receiving chemotherapy between 2010 and 2021. The cNLRS was developed and its association with chemotherapeutic response and prognosis was investigated. RESULTS: The cNLRS consisted of baseline NLR ≥2.5 and ΔNLR ≥0, both of which were remained as independent poor predictors of prognosis adjusting for other traditional clinicopathological features. A high cNLRS served as an independent prognostic factor of reduced overall survival. Of note, the cNLRS was significantly associated with disease control rate and treatment duration not only in 1st line treatment but also in 2nd line treatment. CONCLUSION: The cNLRS established as a useful prognostic biomarker might be associated with chemotherapeutic response and could predict survival in advanced patients with pancreatic ductal adenocarcinoma treated with chemotherapy.