Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory.

Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8+ Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8- CCR8+ tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8+ effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.

BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.

BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.

Removal of gemcitabine-induced senescent cancer cells by targeting glutaminase1 improves the therapeutic effect in pancreatic ductal adenocarcinoma.

Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated ß-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.

Fat and proteolysis due to methionine, tryptophan, and niacin deficiency leads to alterations in gut microbiota and immune modulation in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is one of the intractable diseases. Nutritional components associated with IBD have been identified, and it is known that excessive methionine intake exacerbates inflammation, and that tryptophan metabolism is involved in inflammation. Analysis of the gut microbiota has also progressed, where Lactobacillus regulate immune cells in the intestine and suppress inflammation. However, whether the methionine and tryptophan metabolic pathways affect the growth of intestinal Lactobacillus is unknown. Here we show how transient methionine, tryptophan, and niacin deficiency affects the host and gut microbiota in mouse models of colitis (induced by dextran sodium sulfate) fed a methionine-deficient diet (1K), tryptophan and niacin-deficient diet (2K), or methionine, tryptophan, and niacin-deficient diet (3K). These diets induced body weight decrease and 16S rRNA analysis of mouse feces revealed the alterations in the gut microbiota, leading to a dramatic increase in the proportion of Lactobacillus in mice. Intestinal RNA sequencing data confirmed that the expression of several serine proteases and fat-metabolizing enzymes were elevated in mice fed with methionine, tryptophan, and niacin (MTN) deficient diet. In addition, one-carbon metabolism and peroxisome proliferator-activated receptor (PPAR) pathway activation were also induced with MTN deficiency. Furthermore, changes in the expression of various immune-related cytokines were observed. These results indicate that methionine, tryptophan, and niacin metabolisms are important for the composition of intestinal bacteria and host immunity. Taken together, MTN deficiencies may serve as a Great Reset of gut microbiota and host gene expression to return to good health.

RNA methylation in inflammatory bowel disease.

RNA modifications, including the renowned m6A, have recently garnered significant attention. This chemical alteration, present in mRNA, exerts a profound influence on protein expression levels by affecting splicing, nuclear export, stability, translation, and other critical processes. Although the role of RNA methylation in the pathogenesis and progression of IBD and colorectal cancer has been reported, many aspects remain unresolved. In this comprehensive review, we present recent studies on RNA methylation in IBD and colorectal cancer, with a particular focus on m6A and its regulators. We highlight the pivotal role of m6A in the pathogenesis of IBD and colorectal cancer and explore the potential applications of m6A modifications in the diagnosis and treatment of these diseases.

KLK10 derived from tumor endothelial cells accelerates colon cancer cell proliferation and hematogenous liver metastasis formation.

Tumor endothelial cells (TECs), which are thought to be structurally and functionally different from normal endothelial cells (NECs), are increasingly attracting attention as a therapeutic target in hypervascular malignancies. Although colorectal liver metastasis (CRLM) tumors are hypovascular, inhibitors of angiogenesis are a key drug in multidisciplinary therapy, and TECs might be involved in the development and progression of cancer. Here, we analyzed the function of TEC in the CRLM tumor microenvironment. We used a murine colon cancer cell line (CT26) and isolated TECs from CRLM tumors. TECs showed higher proliferation and migration than NECs. Coinjection of CT26 and TECs yielded rapid tumor formation in vivo. Immunofluorescence analysis showed that coinjection of CT26 and TECs increased vessel formation and Ki-67+ cells. Transcriptome analysis identified kallikrein-related peptide 10 (KLK10) as a candidate target. Coinjection of CT26 and TECs after KLK10 downregulation with siRNA suppressed tumor formation in vivo. TEC secretion of KLK10 decreased after KLK10 downregulation, and conditioned medium after KLK10 knockdown in TECs suppressed CT26 proliferative activity. Double immunofluorescence staining of KLK10 and CD31 in CRLM tissues revealed a significant correlation between poor prognosis and positive KLK10 expression in TECs and tumor cells. On multivariate analysis, KLK10 expression was an independent prognostic factor in disease-free survival. In conclusion, KLK10 derived from TECs accelerates colon cancer cell proliferation and hematogenous liver metastasis formation. KLK10 in TECs might offer a promising therapeutic target in CRLM.

Tumor suppressive role of the epigenetic master regulator BRD3 in colorectal cancer.

Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.

High N6-methyladenosine-activated TCEAL8 mRNA is a novel pancreatic cancer marker.

N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their malignant transformation. In this study, we analyzed gene expression and m6A modification in cancer tissues, ducts, and acinar cells derived from pancreatic cancer patients using MeRIP-seq. We found that dozens of RNAs highly modified by m6A were detected in cancer tissues compared with ducts and acinar cells. Among them, the m6A-activated mRNA TCEAL8 was observed, for the first time, as a potential marker gene in pancreatic cancer. Spatially resolved transcriptomic analysis showed that TCEAL8 was highly expressed in specific cells, and activation of cancer-related signaling pathways was observed relative to TCEAL8-negative cells. Furthermore, among TCEAL8-positive cells, the cells expressing the m6A-modifying enzyme gene METTL3 showed co-activation of Notch and mTOR signaling, also known to be involved in cancer metastasis. Overall, these results suggest that m6A-activated TCEAL8 is a novel marker gene involved in the malignant transformation of pancreatic cancer.

Serum NY-ESO-1 antibody as a predictive biomarker for postoperative recurrence of gastric cancer: a multicenter prospective observational study.

BACKGROUND: No reliable marker has been identified to predict postoperative recurrence of gastric cancer. We designed a clinical trial to investigate the utility of serum NY-ESO-1 antibody responses as a predictive marker for postoperative recurrence in gastric cancer. METHODS: A multicenter prospective study was conducted between 2012 and 2021. Patients with resectable cT3-4 gastric cancer were included. Postoperative NY-ESO-1 and p53 antibody responses were serially evaluated every 3 months for 1 year in patients with positive preoperative antibody responses. The recurrence rate was assessed by the positivity of antibody responses at 3 and 12 months postoperatively. RESULTS: Among 1001 patients, preoperative NY-ESO-1 and p53 antibody responses were positive in 12.6% and 18.1% of patients, respectively. NY-ESO-1 antibody responses became negative postoperatively in non-recurrent patients (negativity rates; 45% and 78% at 3 and 12 months, respectively), but remained positive in recurrent patients (negativity rates; 9% and 8%, respectively). p53 antibody responses remained positive in non-recurrent patients. In multivariate analysis, NY-ESO-1 antibody positivity at 3 months (P < 0.03) and 12 months (P < 0.001) were independent prognostic factors for a shorter recurrence-free interval. CONCLUSIONS: Serum NY-ESO-1 antibodies may be a useful predictive marker for postoperative recurrence in gastric cancer. CLINICAL TRIAL REGISTRATION: UMIN000007925.

Results of a Randomized Clinical Study of Gemcitabine Plus Nab-Paclitaxel Versus Gemcitabine Plus S-1 as Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma (RCT, CSGO-HBP-015).

BACKGROUND: The optimal neoadjuvant chemotherapy (NAC) regimen for patients with localized pancreatic ductal adenocarcinoma (PDAC) remains uncertain. This trial aimed to evaluate the efficacy and safety of two neoadjuvant chemotherapy (NAC) regimens, gemcitabine plus nab-paclitaxel (GA) and gemcitabine plus S-1 (GS), in patients with resectable/borderline-resectable (R/BR) PDAC. PATIENTS AND METHODS: Treatment-naïve patients with R/BR-PDAC were enrolled and randomly allocated. They received two cycles (2 months) of each standard protocol, followed by radical surgery for those without tumor progression in general hospitals belonging to our intergroup. The primary endpoint was to determine the superior regimen on the basis of achieving a 10% increase in the rate of patients with progression-free survival (PFS) at 2 years from allocation. RESULTS: A total of 100 patients were enrolled, with 94 patients randomly assigned to the GS arm (N = 46) or GA arm (N = 48). The 2-year PFS rates did not show the stipulated difference [GA, 31% (24-38%)/GS, 26% (18-33%)], but the Kaplan-Myer analysis showed significance (median PFS, GA/GS 14 months/9 months, P = 0.048; HR 0.71). Secondary endpoint comparisons yielded the following results (GA/GS arm, P-value): rates of severe adverse events during NAC, 73%/78%, P = 0.55; completion rates of the stipulated NAC, 92%/83%, P = 0.71; resection rates, 85%/72%, P = 0.10; average tumor marker (CA19-9) reduction rates, -50%/-21%, P = 0.01; average numbers of lymph node metastasis, 1.7/3.2, P = 0.04; and median overall survival times, 42/22 months, P = 0.26. CONCLUSIONS: This study found that GA and GS are viable neoadjuvant treatment regimens in R/BR-PDAC. Although the GA group exhibited a favorable PFS outcome, the primary endpoint was not achieved.

Long-Term Effects of Oral Nutritional Supplements After Gastrectomy for Gastric Cancer: A Survival Analysis from a Multicenter, Open-Label, Randomized Controlled Trial.

BACKGROUND: Weight loss (WL) after gastrectomy for gastric cancer is associated with both decreased compliance with adjuvant chemotherapy and impaired survival. This study examined the effects of administering oral nutritional supplements (ONS) for 3 months after gastrectomy in terms of compliance with adjuvant chemotherapy and survival outcomes. METHODS: This large-scale, multicenter, open-label, randomized controlled trial enrolled 1,003 gastric cancer patients undergoing curative gastrectomy. Patients were assigned to the control group (n = 503) or ONS group (n = 500). In the ONS group, 400 kcal/day of ONS was recommended in addition to a regular diet for 3 months after gastrectomy. Compliance with adjuvant chemotherapy and survival outcomes were compared between the two groups. RESULTS: Compared with the control group, the ONS group showed significantly decreased WL at 3 months after gastrectomy (8.6 ± 6.1 vs. 7.2 ± 5.7%, respectively, P = 0.0004). The control and ONS groups did not differ regarding the induction rate of adjuvant chemotherapy (84.9 vs. 82.8%, respectively, P = 0.614) or the continuation rate at 3 months postoperatively (75.3 vs. 76.6%, respectively, P = 0.809). Oral nutritional supplements for 3 months showed no survival benefit; the 3- and 5-year overall survival (OS) rates were 91.3% and 87.6% in the control group and 89.6% and 86.4% in the ONS group, respectively, indicating no significant difference (P = 0.548). Subgroup analysis could not detect a population in which ONS administration increased OS. CONCLUSIONS: Administration of ONS for 3 months after gastrectomy was not associated with increased compliance with adjuvant chemotherapy or with improved prognosis.

Skeletal Muscle-Derived Irisin Enhances Gemcitabine Sensitivity and Suppresses Migration Ability in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: High skeletal muscle mass might be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC); however, the underlying reason is unclear. We hypothesized that myokines, which are cytokines secreted by the skeletal muscle, function as suppressors of PDAC. We specifically examined irisin, a myokine, which plays a critical role in the modulation of metabolism, to clarify the anticancer mechanisms. METHODS: First, the effect of the conditioned medium (CM) from skeletal muscle cells and from irisin-knockdown skeletal muscle cells on PDAC cell lines was evaluated. We then investigated the effects and anticancer mechanism of irisin in PDAC cells, and evaluated the anticancer effect of recombinant irisin in a PDAC xenograft mouse model. Finally, patients undergoing pancreatic resection for PDAC were divided into two groups based on their serum irisin level, and the long-term outcomes were evaluated. RESULTS: The CM enhanced gemcitabine sensitivity by inducing apoptosis and decreasing cell migration by inhibiting epithelial-mesenchymal transition (EMT) in PDAC cell lines. The CM derived from irisin-knockdown skeletal muscle cells did not affect the PDAC cell lines. The addition of recombinant irisin to PDAC cell lines facilitated sensitivity to gemcitabine by inhibiting the mitogen-activated protein kinase (MAPK) pathway, and decreased migration by inhibiting EMT via the transforming growth factor-ß/SMAD pathway. Xenografts injected with gemcitabine and recombinant irisin grew slower than the xenografts injected with gemcitabine alone. The overall survival was prolonged in the high-irisin group compared with that in the low-irisin group. CONCLUSIONS: Skeletal muscle-derived irisin may affect PDAC by enhancing its sensitivity to gemcitabine and suppressing EMT.

Clinical Impact of Conversion Surgery After Induction Therapy for Esophageal Cancer with Synchronous Distant Metastasis: A Multi-institutional Retrospective Study.

BACKGROUND: The standard treatment for advanced esophageal cancer with synchronous distant metastasis is systemic chemotherapy or immunotherapy. Conversion surgery is not established for esophageal cancer with synchronous distant metastasis. This study aimed to investigate the clinical impact of conversion surgery for esophageal cancer with synchronous distant metastasis after induction therapy. METHODS: This multi-institutional retrospective study enrolled 66 patients with advanced esophageal cancer, including synchronous distant metastasis, who underwent induction chemotherapy or chemoradiotherapy followed by conversion surgery between 2005 and 2021. Short- and long-term outcomes were investigated. RESULTS: Distant lymph node (LN) metastasis occurred in 51 patients (77%). Distant organ metastasis occurred in 15 (23%) patients. There were 41 patients with metastatic para-aortic LNs, and 10 patients with other metastatic LNs. Organs with distant metastasis included the lung in seven patients, liver in seven patients, and liver and lung in one patient. For 61 patients (92%), R0 resection was achieved. The postoperative complication rate was 47%. The in-hospital mortality rate was 1%, and the 3- and 5-year overall survival (OS) rates for all the patients were 32.4% and 24.4%, respectively. The OS rates were similar between the patients with distant LN metastasis and the patients with distant organ metastasis (3-year OS: 34.9% vs. 26.7%; P = 0.435). Multivariate analysis showed that pathologic nodal status is independently associated with a poor prognosis (hazard ratio, 2.43; P = 0.005). CONCLUSIONS: Conversion surgery after chemotherapy or chemoradiotherapy for esophageal cancer with synchronous distant metastasis is feasible and promising. It might be effective for improving the long-term prognosis for patients with controlled nodal status.

Prognostic Significance of Biologic Factors in Patients with a Modest Radiologic Response to Neoadjuvant Treatment for Resectable and Borderline Resectable Pancreatic Cancers: Impact of the Combination Index of Sialyl-Lewis Antigen-Related Tumor Markers.

BACKGROUND: Appropriate re-evaluation after neoadjuvant treatment (NAT) is important for optimal treatment selection. Nonetheless, determining the operative eligibility of patients with a modest radiologic response remains controversial. This study aimed to assess the prognostic significance of biologic factors for patients showing a modest radiologic response to NAT and investigate the tumor markers (TMs), CA19-9 alone, DUPAN-II alone, and their combination, to create an index that combines these sialyl-Lewis antigen-related TMs associated with treatment outcomes. METHODS: This study enrolled patients deemed to have a "stable disease" by RECIST classification with slight progression (tumor size increase rate, ≤20%) as their radiologic response after NAT. A sialyl-Lewis-related index (sLe index), calculated by adding one fourth of the serum DUPAN-II value to the CA19-9 value, was created. The prognostic significances of CA19-9, DUPAN-II, and the sLe index were assessed in relation to postoperative outcomes. RESULTS: An sLe index lower than the cutoff value (45.25) was significantly associated with favorable disease-free survival. Moreover, the post-NAT sLe index had a higher area under the curve value for recurrence within 24 months than the post-NAT levels of CA19-9 or DUPAN-II alone. Multivariable analysis showed that a post-NAT sLe index higher than 45.25 was the single independent predictive factor for recurrence within 24 months. CONCLUSIONS: Additional evaluation of biologic factors can potentially enhance patient selection, particularly for patients showing a limited radiologic response to NAT. The authors' index is a simple indicator for the biologic evaluation of multiple combined sialyl-Lewis antigen-related TMs and may offer a better predictive significance.

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma.

BACKGROUND: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). METHODS: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. RESULTS: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. CONCLUSION: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704).

BACKGROUND: The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial. METHODS: Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m2, day 1), oxaliplatin (100 mg/m2, day 1), and S-1 (80-120 mg/body, days 1-14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria. RESULTS: Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.

Apparent diffusion coefficient in intrahepatic cholangiocarcinoma diffusion-weighted magnetic resonance imaging noninvasively predicts Ki-67 expression.

AIM: Tumor Ki-67 expression reflects prognosis and cancer grade, and biopsy-based preoperative assessment of Ki-67 expression is key to treatment. Apparent diffusion coefficient (ADC) values obtained with this imaging may noninvasively predict Ki-67 by reflecting tumor cell density and limited water molecule movement from irregular alignment. This study aimed to investigate the ability of ADC values to predict Ki-67 expression in intrahepatic cholangiocarcinoma (ICC). METHOD: We retrospectively analyzed 39 cases of ICC confirmed by surgical pathology. All patients had undergone magnetic resonance imaging, and ADC values (mean, minimum, and maximum) were calculated. Ki-67 expression was assessed by immunohistochemistry, and patients were divided into groups of high (n = 18) and low (n = 21) Ki-67 expression. To assess the diagnostic performance of the ADC values for Ki-67 expression, we used the receiver operating characteristic curve and compared the areas under the curve (AUC). RESULTS: The mean and minimum ADC values were significantly lower in the group with high Ki-67 expression. For predicting high Ki-67 expression, the AUC values were 0.701 for mean ADC, 0.818 for minimum ADC, and 0.571 for maximum ADC. The diagnostic sensitivity and specificity of the minimum ADC values were 88.9% and 76.2%, respectively. In addition, with ADC values combined, the AUC increased to 0.831. Apparent diffusion coefficient is a useful predictor of Ki-67 expression level in ICC. CONCLUSION: Apparent diffusion coefficient values, especially minimum ADC values, can noninvasively predict ICC associated with high Ki-67 expression.

Exploratory prospective, randomized phase II study of neoadjuvant transcatheter arterial chemoembolization plus surgery versus surgery alone for large hepatocellular carcinoma (CSGO-HBP-005): Clinical Study Group of Osaka University, Hepato-Biliary-Pancreatic Group.

AIM: Neoadjuvant transcatheter arterial chemoembolization (TACE) for large tumors is controversial, especially in the minimally invasive surgery era. The aim of this study was to compare features between groups treated with neoadjuvant TACE followed by surgery (TACE + surgery) or upfront surgery for hepatocellular carcinoma >5 cm. METHODS: In this exploratory, multicenter, randomized phase I study, the primary measure was 2-year disease-free survival (DFS). Secondary measures were resection rate, necrosis rate by TACE, 2-year overall survival, and site of recurrence. A total of 30 patients were randomly allocated to each arm. RESULTS: The two arms did not differ in patient characteristics. The median time to surgery from randomization was 48 days for TACE + surgery and 29 for surgery only (p < 0.001). Postoperative morbidities did not differ between arms. The 2-year DFS, overall survival, and resection rates were 56.7%, 80.0%, and 93.3%, respectively, in the TACE + surgery arm, and 56.1%, 89.9%, and 90.0% in the upfront surgery arm. Minimally invasive surgery was carried out in 35.7% in the TACE + surgery arm and in 29.6% in the upfront surgery arm. The median necrosis rate by TACE was 90.0%. In resected specimens, invasion to the hepatic vein was less with TACE + surgery (3.6% vs. 22.2%, p = 0.0380). In cases of 100% necrosis with TACE, 2-year DFS was 100%. Site of recurrence did not differ between groups. CONCLUSION: Neoadjuvant TACE did not improve 2-year DFS, and neoadjuvant TACE allowed delay of surgical treatment without increased morbidity and cancer progress. CLINICAL TRIAL REGISTRATION: UMIN: 000005241.

Clinical effectiveness of a new scope warmer/cleaner for laparoscopic and thoracoscopic surgery.

In laparoscopic and thoracoscopic surgery, maintaining clear visualization is crucial for safe and efficient operation. We have developed a new scope warmer/cleaner (Lapahot®) based on "hot-pack" technology. We used our device in 20 consecutive laparoscopic and thoracoscopic cases and compared it with the conventional warm saline method. Lens fogging was not observed in any of the cases, and the cleaning function was comparable to the warm saline method. Moreover, continuous temperature monitoring showed that Lapahot® maintained its temperature much longer than warm saline. Our novel device has the potential to become the new standard for lens defogging and cleaning.