Ramucirumab Beyond Disease Progression After Paclitaxel Plus Ramucirumab in Gastric Cancer: A Phase II Trial.

BACKGROUND/AIM: Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in September 2017 and trifluridine/tipiracil in August 2019. The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of paclitaxel plus ramucirumab (PTX+RAM) as second-line chemotherapy, has been under debate. PATIENTS AND METHODS: A single-center phase II study was conducted in patients with unresectable advanced or recurrent gastric cancer previously treated with fluoropyrimidines and platinum, who received PTX+RAM as second-line therapy and irinotecan plus ramucirumab (IRI+RAM) as third-line therapy after treatment failure (UMIN000022956). RESULTS: Eleven patients were enrolled from July 2016 to July 2018. Enrolment was discontinued due to difficulties in case ascertainment because of expanded third-line treatment options (originally planned for 53 patients). The median progression-free survival (the primary endpoint) of the IRI+RAM was 3.98 months [95% confidence interval (CI)=1.78-NA]. Among secondary endpoints, the transition rate to IRI+RAM was 45%, the rate of 8-week treatment continuation for IRI+RAM was 100%, the response rate for IRI+RAM was 0%, the median overall survival (OS) for PTX+RAM was 13.53 months (95%CI=1.61-24.36), and the median OS for IRI+RAM was 9.99 months (95CI=4.5-NA). CONCLUSION: The transition rate from PTX+RAM to IRI+RAM was reasonable. Ramucirumab beyond progressive disease may be beneficial for patients who are able to transition to IRI+RAM.

Preoperative NUn score serves as a robust predictor of overall and disease-specific survivals following radical surgery for gastric cancer.

PURPOSE: Methods to preoperatively stratify oncological risks associated with gastric cancer (GC) are limited. Host inflammatory parameters, i.e., serum C-reactive protein (CRP) and albumin levels, are known to be associated with outcomes. We examined the relationships between disease-specific mortality and four CRP-albumin-based indices (CRP-albumin ratio [CAR], modified Glasgow prognostic score [mGPS], Osaka prognostic score [OPS], and NUn score) preoperatively measured in cases with resectable GC. METHODS: Survival outcomes of 1290 consecutive GC patients with oncological gastrectomy were reviewed. Predictive significances of preoperative CAR, mGPS, OPS, and NUn scores were assessed with time-dependent receiver operating characteristic curves and Cox regression analyses. RESULTS: Median follow-up was 107 months. Area under the curve for predicting overall and disease-specific survivals (OS/DSS) for the preoperative NUn score was clearly superior to those of the other parameters. On univariate Cox regression analysis, preoperative CAR, mGPS, OPS, and the NUn score all correlated significantly with OS/DSS. On multivariate Cox regression analysis, the preoperative NUn score, as a continuous variable, showed an independent relationship with OS (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.16-1.50, per 1-unit increase, P < 0.001) and even DSS (HR 1.23, 95% CI 1.02-1.49, P = 0.032). The other three markers failed to maintain independence for DSS. CONCLUSIONS: Preoperative NUn scores are stably associated with outcomes, including disease-specific mortality, possibly serving as a simple measure to define the likelihood of progression to systemic disease after meticulous surgery for GC, which may contribute to identifying patients who would benefit from additional modalities.

Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer.

We investigated the tumor immune response in gastric cancer patients receiving third-line nivolumab monotherapy to identify immune-related biomarkers for better patient selection. Nineteen patients (10 males, median age 67 years) who received nivolumab as a third- or later-line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR; objective response rate, OS; overall survival, PFS; progression-free survival) to previous trials. The immunograms of individual subjects displayed no significant changes before or early in the treatment, except for the regulatory T cell (Treg) score. Moreover, there were no consistent alterations observed among cases experiencing DCB. The intratumoral immune response was suppressed by previous treatments in most third- or later-line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in early-on-treatment tumors, but clonal replacement did not impact efficacy. High T cell/Treg ratios and a low UV-radiation-response gene signature were linked to DCB and treatment response. This study emphasizes the tumor immune response's importance in nivolumab efficacy for gastric cancer. High T cell/Treg ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. The tumor-infiltrating immune response was compromised by prior treatments in third-line therapy, implying that, to enhance immunotherapeutic outcomes, commencing treatment at an earlier stage might be preferable. Larger cohort validation is crucial to optimize immune-checkpoint inhibitors in gastric cancer treatment.

Laparoscopic and endoscopic cooperative surgery as palliative treatment for elderly patients with gastric cancer.

Oncological gastrectomy, despite remaining a mainstay of gastric cancer treatment, is reportedly associated with high morbidity and mortality in elderly patients. Less invasive modalities suitable for senior gastric cancer patients with insufficient surgical tolerance are thus needed. We adopted laparoscopic and endoscopic cooperative surgery as an alternative for elderly gastric cancer cases unsuitable for aggressive gastrectomy. To date, we have experienced three cases (80-86 years old) undergoing palliative laparoscopic and endoscopic cooperative surgery. Postoperative courses were uneventful in two cases, while sutural leakage occurred in the other, which was managed conservatively. Postoperative loss of body weight and skeletal muscle mass appeared to be minimal according to bioelectrical impedance analyses. No gastric cancer recurrence was detected in any of our three cases. As to the balance between radicality and safety, laparoscopic and endoscopic cooperative surgery is potentially a viable option for geriatric gastric cancer patients in whom conventional gastrectomy is contraindicated.

Prevalence of preoperative asymptomatic deep vein thrombosis in patients undergoing elective general surgery for benign disease.

Background: The systemic inflammatory response following surgery as well as that of malignant disease itself is associated with a hypercoagulable state, and thromboprophylaxis is thus recommended during postoperative management of cancer patients. However, limited information is available on the prevalence of preoperative deep vein thrombosis (DVT) and its risk factors in surgical candidates, especially those receiving operations for benign diseases. Methods: This is a retrospective observational study with data of all patients scheduled for elective general surgery between January 2011 and September 2020, undergoing lower extremity venous ultrasonography as preoperative screening for DVT. The prevalence of preoperative asymptomatic DVT was estimated and its associations with clinical variables were evaluated. Results: Among 1512 patients included in the study, 161 (10.6%) had asymptomatic DVT before surgery. DVT prevalence was 13.7% in patients with malignant disease, while it was 8.6% in those with benign disease. The site of the thrombus was distal type in 141 (87.6%) patients, most commonly in the soleal vein. Advanced age (>70 years), female sex, and decreased hemoglobin level were significantly associated with preoperative asymptomatic DVT by multivariate analysis. The odds ratio for advanced age was the highest and rose as age increased. Malignant disease was not an independent risk factor for preoperative DVT. Conclusion: This study showed the prevalence of asymptomatic DVT to be equal in patients with and without malignant disease undergoing elective general surgery. Preoperative DVT assessment is necessary regardless of the disease indicated for surgery, especially in patients with the risk factors identified in this study.

Prior treatment with oxaliplatin-containing regimens and higher total bilirubin levels are risk factors for neutropenia and febrile neutropenia in patients with gastric or esophagogastric junction cancer receiving weekly paclitaxel and ramucirumab therapy: a single center retrospective study.

BACKGROUND: Weekly paclitaxel + ramucirumab (wPTX + RAM) therapy is recommended as the standard second-line chemotherapy regimen for unresectable advanced/recurrent gastric cancer (GC) or esophagogastric junction cancer. Recent subgroup analysis of the RAINBOW trial revealed a higher frequency of severe neutropenia due to wPTX + RAM in Japanese compared to Western patients. However, no risk factors for severe neutropenia have been identified. METHODS: This retrospective observational study included patients with advanced/unresectable gastric or esophagogastric junction cancer who received wPTX + RAM after failure to respond to platinum and fluoropyrimidine doublet chemotherapy between June 2015 and April 2020. We conducted multivariable logistic regression analyses to identify the risk factors associated with grade 4 neutropenia and febrile neutropenia (FN). In addition, we investigated the relationship between the number of risk factors and overall survival (OS) and progression-free survival (PFS). RESULTS: Among 66 patients who met the inclusion criteria, grade 4 neutropenia and FN occurred in 21 (31.8%) and 12 (18.2%) patients, respectively. Prior treatment with oxaliplatin-containing regimens was identified as an independent risk factor for developing grade 4 neutropenia (odds ratio (OR) 20.034, 95% confidence interval (95% CI) 3.216-124.807, P = 0.001). Total bilirubin of > 1.5 mg/dL (OR 31.316, 95% CI 2.052-477.843, P = 0.013) and prior treatment with oxaliplatin-containing regimen (OR 12.502, 95% CI 1.141-137.022, P = 0.039) were identified as independent risk factors for developing FN. Next, we classified patients with 0, 1, 2 risk factor(s) as RF-0, RF-1, and RF-2 subgroups, respectively, and compared the PFS and OS among the three subgroups. PFS was not significantly different among the three subgroups, whereas OS was significantly shorter in the RF-2 subgroup (median 1.4 month, 95% CI 0.0-5.3 month) than in the RF-0 subgroup (median 10.2 month, 95% CI 6.8-13.5 month, P < 0.01 vs RF-2) and RF-1 subgroup (median 13.3 month, 95% CI 10.9-15.7 month, P < 0.01 vs RF-2). CONCLUSIONS: Careful monitoring for grade 4 neutropenia and FN is needed for patients receiving wPTX + RAM therapy who have a history of treatment with oxaliplatin-containing regimens and higher total bilirubin levels.

Impact of Sarcopenic Obesity on Severe Postoperative Complications in Patients with Gastric Cancer Undergoing Gastrectomy.

INTRODUCTION: Several studies have indicated that sarcopenia affects the short- and long-term outcomes of cancer patients, including those with gastric cancer. In recent years, sarcopenic obesity and its effects have been reported in cancer patients. This study aimed to evaluate the impact of sarcopenic obesity on postoperative complications in patients with gastric cancer undergoing gastrectomy. METHODS: This single-center, retrospective study included 155 patients who underwent curative gastrectomy for gastric cancer from January 2015 to July 2021. Sarcopenia was defined by the psoas muscle index (<6.36 cm2/m2 in men and <3.92 cm2/m2 in women), which measures the iliopsoas muscle area at the lumbar L3 level using computed tomography. Obesity was defined by body mass index (≥25). Patients with both sarcopenia and obesity were defined as the sarcopenic obesity group and others as the non-sarcopenic obesity group. Severe postoperative complications were defined as Clavien-Dindo classification grade IIIa or higher. RESULTS: Of the 155 patients, 26 (16.8%) had sarcopenic obesity. The incidence of severe postoperative complications was significantly higher in the sarcopenic obesity group (30.8% vs. 10.9%; p = 0.014). Multivariate analysis indicated that sarcopenic obesity was an independent risk factor for severe postoperative complications (odds ratio, 3.950; 95% confidence interval, 1.390-11.200; p = 0.010). CONCLUSION: Sarcopenic obesity is an independent risk factor for severe postoperative complications.

Lymphatic flow mapping using near-infrared fluorescence imaging with indocyanine green helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer not treated with neoadjuvant chemotherapy.

BACKGROUND: Lymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for the intraoperative prediction of lymph node metastasis in esophageal or esophagogastric junction cancer. However, a consistent method that yields sufficient diagnostic quality is yet to be confirmed. This study explored the diagnostic utility of our newly established lymphatic flow mapping protocol for predicting lymph node metastasis in patients with esophageal or esophagogastric junction cancer. METHODS: We injected 0.5 mL of ICG (500 µg/mL) into the submucosal layer at four peritumoral points on the day before surgery for 54 patients. We performed lymphatic flow mapping intraoperatively using NIR imaging. After determining the NIR status and presence of metastases, evaluable lymph node stations on in vivo imaging and all resected lymph nodes were divided into four categories: ICG+meta+ (true positive), ICG+meta- (false positive), ICG-meta+ (false negative), and ICG-meta- (true negative). RESULTS: The distribution of ICG+ and meta+ lymph node stations differed according to the primary tumor site. Sensitivity and specificity for predicting meta+ lymph nodes among ICG+ ones were 50% (95% CI 41-59%) and 75% (73-76%), respectively. Predicting meta+ lymph node stations among ICG+ stations improved these values to 66% (54-77%) and 77% (74-79%), respectively. Undergoing neoadjuvant chemotherapy was an independent risk factor for having meta+ lymph nodes with false-negative diagnoses (odds ratio 4.82; 95% CI 1.28-18.19). The sensitivity of our technique for predicting meta+ lymph nodes and meta+ lymph node stations in patients who did not undergo neoadjuvant chemotherapy was 79% (63-90%) and 83% (61-94%), respectively. CONCLUSION: Our protocol potentially helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer undergoing esophagectomy who did not undergo neoadjuvant chemotherapy.

PD-L1 and HLA-class I expression status and their therapeutic implication in oesophageal small-cell carcinoma.

AIMS: Oesophageal small-cell carcinoma is a rare and highly aggressive subtype of oesophageal cancer with a dismal prognosis. To explore the potential applicability of immunotherapy, we investigated the expression status of programmed death ligand 1 (PD-L1) and human leukocyte antigen (HLA)-class I and the degree of tumour-infiltrating lymphocytes (TILs) in oesophageal small-cell carcinoma. METHODS AND RESULTS: PD-L1 and HLA-class I expression levels were evaluated in 10 pure small-cell carcinomas and five mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). The combined positive score (CPS) and tumour proportion score (TPS) were used for PD-L1 assessment. Immunohistochemistry for mismatch repair (MMR) proteins was also performed. PD-L1 immunohistochemistry demonstrated CPS ≥1 in nine (60%), CPS ≥10 in five (33%), and TPS ≥1 in five (33%) cases. Overall survival was significantly longer in patients with CPS ≥1 than in those with CPS <1. HLA-class I deficiency (>50% tumour cells) was noted in five cases (33%), with no significant correlation with PD-L1 expression status. Among the five MiNENs, HLA-class I expression was decreased in the small-cell carcinoma component of three cases. HLA-class I deficiency was significantly associated with higher TNM stage and reduced TIL levels. MMR deficiency was not observed in any case. CONCLUSION: Given that a significant subset (40%) exhibited PD-L1 CPS ≥1 with preserved HLA-class I expression and high levels of TIL, the PD-1/PD-L1 pathway is a potential therapeutic target for oesophageal small-cell carcinoma.

Loss of viral genome with altered immune microenvironment during tumour progression of Epstein-Barr virus-associated gastric carcinoma.

Epstein-Barr virus (EBV) is one of the major drivers of gastric carcinogenesis. EBV infection is established before tumour initiation and is generally maintained throughout tumour development; however, the significance of EBV in tumour maintenance and progression remains to be elucidated. Here, we report eight cases of EBV-associated gastric carcinoma (EBVaGC) with intratumoural heterogenous expression of EBV-encoded small RNA (EBER), a highly expressed latent gene of EBV, and demonstrate clinicopathological characteristics of these rare cases. By performing detailed histological assessment of EBER-positive and -negative components of each case, detection of EBV genome in tumour cells by fluorescence in situ hybridisation, TP73 methylation analysis, whole exome sequencing, and targeted gene panel sequencing, we identified tumours in two patients to be collision tumours of different origins. In the other six patients, some genetic/epigenetic alterations were shared between EBER-positive and -negative components, suggesting that EBV was eliminated from tumour cells during progression. Interestingly, in both tumour types, programmed death ligand 1 and intratumoural infiltration of CD8+ T lymphocytes were lower in EBER-negative than in EBER-positive components, suggesting an immunogenic role of EBV. To the best of our knowledge, this study is the first to demonstrate the detailed histological features and genetic/epigenetic alterations in EBVaGC with heterogenous EBER expression; the loss of EBV may benefit tumour progression and immune evasion and might be clinically important for selecting treatment strategies for such cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adenocarcinoma of the stomach and esophagogastric junction with low DNA methylation show poor prognoses.

BACKGROUND: Gastric cancer (GC) is characterized by unique DNA methylation epigenotypes (MEs). However, MEs including adenocarcinomas of the esophagogastric junction (AEG) and background non-neoplastic columnar mucosae (NM) remain to be clarified. METHODS: We analyzed the genome-wide DNA MEs of AEG, GC, and background NM using the Infinium 450 k beadarray, followed by quantitative pyrosequencing validation. Large-scale data from The Cancer Genome Atlas (TCGA) were also reviewed. RESULTS: Unsupervised two-way hierarchical clustering using Infinium data of 21 AEG, 30 GC, and 11 NM revealed four DNA MEs: extremely high-ME (E-HME), high-ME (HME), low-ME (LME), and extremely low-ME (E-LME). Promoter methylation levels were validated by pyrosequencing in 146 samples. Non-inflammatory normal mucosae were clustered into E-LME, whereas gastric or esophagogastric junction mucosae with chronic inflammatory changes caused by either Helicobacter pylori infection or reflux esophagitis were clustered together into LME, suggesting that inflammation status determined DNA MEs regardless of the cause. Three cases of Barrett's-related adenocarcinoma were clustered into HME. Among 94 patients whose tumors could be clustered into one of four MEs, 11 patients with E-LME cancers showed significantly shorter overall survival than that in the other MEs, even with the multivariate Cox regression estimate. TCGA data also showed enrichment of AEG in HME and a poorer prognosis in E-LME. CONCLUSIONS: E-LME cases, newly confirmed in this study, form a unique subtype with poor prognosis that is not associated with inflammation-associated elevation of DNA methylation levels. LME could be acquired via chronic inflammation, regardless of the cause, and AEG might preferentially show HME.

Current status of gastrectomy and reconstruction types for patients with proximal gastric cancer in Japan.

BACKGROUND: Surgical procedures for proximal gastric cancer remain a highly debated topic. Total gastrectomy (TG) is widely accepted as a standard radical surgery. However, subtotal esophagectomy, proximal gastrectomy (PG) or even subtotal gastrectomy, when a small upper portion of the stomach can technically be preserved, are alternatives in current clinical practice. METHODS: Using a cohort of the PGSAS NEXT trial, consisting of 1909 patients responding to a questionnaire sent to 70 institutions between July 2018 and December 2019, gastrectomy type, reconstruction method, and furthermore the remnant stomach size and the anti-reflux procedures for PG were evaluated. RESULTS: TG was the procedure most commonly performed (63.0%), followed by PG (33.4%). Roux-en-Y was preferentially employed following TG irrespective of esophageal tumor invasion, while jejunal pouch was adopted in 8.5% of cases with an abdominal esophageal stump. Esophagogastrostomy was most commonly selected after PG, followed by the double-tract method. The former was preferentially employed for larger remnant stomachs (≧3/4), while being used slightly less often for tumors with as compared to those without esophageal invasion in cases with a remnant stomach 2/3 the size of the original stomach. Application of the double-tract method gradually increased as the remnant stomach size decreased. Anti-reflux procedures following esophagogastrostomy varied markedly. CONCLUSIONS: TG is the mainstream and PG remains an alternative in current Japanese clinical practice for proximal gastric cancer. Remnant stomach size and esophageal stump location appear to influence the choice of reconstruction method following PG.

Clinical practice guidelines for duodenal cancer 2021.

Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

Combining nutritional status with TNM stage: a physiological update on gastric cancer staging for improving prognostic accuracy in elderly patients.

BACKGROUND: The tumor-node-metastasis (TNM) staging system does not take the patient's physiological status into consideration, reportedly making it insufficient for predicting survival outcomes in frail cancer patients. We assessed the prognostic values of several nutrition- and inflammation-based markers in combination with pTNM stage in gastric carcinoma (GC) patients. METHODS: In total, 1166 patients undergoing GC surgery were studied. The prognostic capabilities of 3 nutritional and 3 systemic inflammatory parameters were examined. We developed new staging systems by adding these markers, individually, to the pTNM stage. We then compared the prognostic capabilities of our new systems with that of pTNM stage alone. We also assessed the prognostic values of these systems by dividing our patient cohort into elderly (≥ 65 years) and non-elderly groups. RESULTS: Our novel staging systems had greater predictive capabilities for overall survival (OS) than pTNM alone. Most notably, survival discrimination was significantly increased for pTNM when it was combined with albumin-based nutritional indices (geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI)). Our new staging systems incorporating GNRI or PNI into pTNM had significantly better predictive capability for OS, especially non-GC mortality, than pTNM alone in elderly GC patients. In the non-elderly patients, the predictive capabilities of the new staging systems for OS differed minimally from that of pTNM. CONCLUSIONS: The predictive capability of pTNM stage was particularly enhanced when this parameter was combined with nutritional markers. Our new approach aids in predicting survival outcomes, especially non-GC-related death, in elderly GC patients.

Sphingosine 1-phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids.

BACKGROUND: In addition to potent agonist properties for sphingosine 1-phosphate (S1P) receptors, intracellularly, S1P is an intermediate in metabolic conversion pathway from sphingolipids to glycerolysophospholipids (glyceroLPLs). We hypothesized that this S1P metabolism and its products might possess some novel roles in the pathogenesis of cancer, where S1P lyase (SPL) is a key enzyme. METHODS: The mRNA levels of sphingolipid-related and other cancer-related factors were measured in human hepatocellular carcinoma (HCC), colorectal cancer, and esophageal cancer patients' tumours and in their adjacent non-tumour tissues. Phospholipids (PL) and glyceroLPLs were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In-vitro experiments were performed in Colon 26 cell line with modulation of the SPL and GPR55 expressions. Xenograft model was used for determination of the cancer progression and for pharmacological influence. RESULTS: Besides high SPL levels in human HCC and colon cancer, SPL levels were specifically and positively linked with levels of glyceroLPLs, including lysophosphatidylinositol (LPI). Overexpression of SPL in Colon 26 cells resulted in elevated levels of LPI and lysophosphatidylglycerol (LPG), which are agonists of GPR55. SPL overexpression-enhanced cell proliferation was inhibited by GPR55 silencing. Conversely, inhibition of SPL led to the opposite outcome and reversed by adding LPI, LPG, and metabolites generated during S1P degradation, which is regulated by SPL. The xenograft model results suggested the contribution of SPL and glyceroLPLs to tumour progression depending on levels of SPL and GPR55. Moreover, the pharmacological inhibition of SPL prevented the progression of cancer. The underlying mechanisms for the SPL-mediated cancer progression are the activation of p38 and mitochondrial function through the LPI, LPG-GPR55 axis and the suppression of autophagy in a GPR55-independent manner. CONCLUSION: A new metabolic pathway has been proposed here in HCC and colon cancer, SPL converts S1P to glyceroLPLs, mainly to LPI and LPG, and facilitates cancer development.

Impact of Tumor Location on the Quality of Life of Patients Undergoing Total or Proximal Gastrectomy.

PURPOSE: Most studies have investigated the differences in postgastrectomy quality of life (QOL) based on the surgical procedure or reconstruction method adopted; only a few studies have compared QOL based on tumor location. This large-scale study aims to investigate the differences in QOL between patients with esophagogastric junction cancer (EGJC) and those with upper third gastric cancer (UGC) undergoing the same gastrectomy procedure to evaluate the impact of tumor location on postoperative QOL. METHODS: The Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45) questionnaire was distributed in 70 institutions to 2,364 patients who underwent gastrectomy for EGJC or UGC. A total of 1,909 patients were eligible for the study, and 1,744 patients who underwent total gastrectomy (TG) or proximal gastrectomy (PG) were selected for the final analysis. These patients were divided into EGJC and UGC groups; thereafter, the PGSAS-45 main outcome measures (MOMs) were compared between the two groups for each type of gastrectomy. RESULTS: Among the post-TG patients, only one MOM was significantly better in the UGC group than in the EGJC group. Conversely, among the post-PG patients, postoperative QOL was significantly better in 6 out of 19 MOMs in the UGC group than in the EGJC group. CONCLUSIONS: Tumor location had a minimal effect on the postoperative QOL of post-TG patients, whereas among post-PG patients, there were definite differences in postoperative QOL between the two groups. It seems reasonable to conservatively estimate the benefits of PG in patients with EGJC compared to those in patients with UGC.

Optimal settings of near-infrared fluorescence imaging with indocyanine green for intraoperative detection of lymph node metastasis in esophageal cancer.

Lymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for intraoperative diagnosis of lymph node metastasis (LNM) in various cancers. Accurate prediction of LNM intraoperatively may allow minimization of the extent of lymphadenectomy. However, a consistent method and diagnostic ability, allowing application of NIR-guided lymphatic flow mapping to esophageal cancer (EC), have not been established due to the multidirectional and complex characteristics of lymphatic flow in the esophagus. Herein, we present a novel NIR-guided surgical technique for predicting lymph node stations potentially containing LNM in EC with high diagnostic accuracy derived from appropriately adjusting the ICG injection setting.

Signature and Prediction of Perigastric Lymph Node Metastasis in Patients with Gastric Cancer and Total Gastrectomy: Is Total Gastrectomy Always Necessary?

BACKGROUND: A growing number of studies suggest that the current indications for partial gastrectomy, including proximal gastrectomy and pylorus-preserving gastrectomy (PPG), may be expanded, but evidence is still lacking. METHODS: We retrospectively analyzed 300 patients with gastric cancer (GC) who underwent total gastrectomy. We analyzed the incidence of pLNMs in relation to tumor location, tumor size and T stage. We further identified predictive factors for perigastric lymph node metastasis (pLNM) in stations 1, 2, 3, 4sa, 4sb, 4d, 5, and 6. RESULTS: No patients with upper-third T1-T2 stage GC had pLNMs in stations 4sa, 4sb, 4d, 5, or 6, but 3.8% of patients with stage T3 had 4d pLNM. No patients with upper-third GC < 4 cm in diameter had pLNMs in 2, 4sa, 4d, 5, or 6, and 2.3% of patients had pLNMs in 4sb. For middle-third GCs, 2.9% of patients with T1 stage had pLNMs in 4sa and 5, but no patients with T2 stage or tumors < 4 cm had pLNMs in 2, 4sa, or 5. The shortest distance from pylorus ring to distal edge of tumor (sDPD) was a new predictive factor for pLNMs in 2, 4d, 5, and 6. CONCLUSIONS: Proximal gastrectomy may be expanded to patients with stage T1-T2 GC and/or tumor diameter < 4 cm in the upper-third stomach, whereas PPG may be expanded to include T1-T2/N0 and/or tumors < 4 cm in the middle-third stomach. A new predictive factor, sDPD, showed good predictive performance for pLNMs, especially in stations 4d, 5, and 6.

Impacts of complications after esophageal cancer surgery on health-related quality of life and nutritional status.

BACKGROUND: The long-term impacts of post-operative complications, especially pulmonary complications and anastomotic leakage, on health-related quality of life (HRQoL), nutritional status and body composition remain to be fully addressed in patients undergoing esophageal cancer surgery. METHODS: Patients who underwent esophagectomy between 2015 and 2019 and survived without recurrence were eligible. HRQoL (European Organization for Research and Treatment of Cancer QLQ-C30 and the QLQ-OES18 questionnaires), nutritional and body composition data were prospectively evaluated before and at 3, 6, 12 and 24 months after surgery. Collected data were compared between patients with post-operative complications and those without. RESULTS: In total, 88 patients were included. Overall complications, anastomotic leakage and pulmonary complications developed in 48 (54.5%), 20 (20.7%) and 18 (20.5%) patients, respectively. Patients with pulmonary complications had significantly more reflux-related symptoms (dry mouth; P = 0.03, coughing; P = 0.047), and more difficulties with eating at 24 months after surgery, as compared to those without such complications. Anastomotic leakage increased pain, speaking problems and dysphagia up to 6 months after surgery. Patients with pulmonary complications had significantly lower prealbumin levels (P = 0.01, 0.02 and 0.008 at 6, 12 and 24 months after surgery, respectively) and lower prognostic nutritional index values over time after surgery than those without these complications. In contrast, anastomotic leakage was not associated with poor nutritional status post-operatively. Body composition was not affected by the occurrence of complications. CONCLUSION: Patients who developed post-operative complications, especially pulmonary complications, had long-lasting negative HRQoL outcomes and poor nutritional status after esophagectomy.

Universal encoding of pan-cancer histology by deep texture representations.

Cancer histological images contain rich biological and clinical information, but quantitative representation can be problematic and has prevented the direct comparison and accumulation of large-scale datasets. Here, we show successful universal encoding of cancer histology by deep texture representations (DTRs) produced by a bilinear convolutional neural network. DTR-based, unsupervised histological profiling, which captures the morphological diversity, is applied to cancer biopsies and reveals relationships between histologic characteristics and the response to immune checkpoint inhibitors (ICIs). Content-based image retrieval based on DTRs enables the quick retrieval of histologically similar images using The Cancer Genome Atlas (TCGA) dataset. Furthermore, via comprehensive comparisons with driver and clinically actionable gene mutations, we successfully predict 309 combinations of genomic features and cancer types from hematoxylin-and-eosin-stained images. With its mounting capabilities on accessible devices, such as smartphones, universal encoding for cancer histology has a strong impact on global equalization for cancer diagnosis and therapies.