Neural-net-based cell deconvolution from DNA methylation reveals tumor microenvironment associated with cancer prognosis.

DNA methylation is a pivotal epigenetic modification that defines cellular identity. While cell deconvolution utilizing this information is considered useful for clinical practice, current methods for deconvolution are limited in their accuracy and resolution. In this study, we collected DNA methylation data from 945 human samples derived from various tissues and tumor-infiltrating immune cells and trained a neural network model with them. The model, termed MEnet, predicted abundance of cell population together with the detailed immune cell status from bulk DNA methylation data, and showed consistency to those of flow cytometry and histochemistry. MEnet was superior to the existing methods in the accuracy, speed, and detectable cell diversity, and could be applicable for peripheral blood, tumors, cell-free DNA, and formalin-fixed paraffin-embedded sections. Furthermore, by applying MEnet to 72 intrahepatic cholangiocarcinoma samples, we identified immune cell profiles associated with cancer prognosis. We believe that cell deconvolution by MEnet has the potential for use in clinical settings.

Use of current automatic smoke evacuation system in flexible gastrointestinal endoscopy: Its feasibility and potential usefulness.

Objectives: Flexible endoscopy does not have a system that can automatically evacuate surgical smoke generated in the gastrointestinal lumen. We aimed to investigate the feasibility and potential usefulness of automatic smoke evacuation systems in flexible endoscopy. Methods: [Bench] After surgical smoke generated in the stomach was evacuated by the evacuator, the degree of residual smoke and gastric luminal collapse were evaluated to optimize the evacuator settings. [Animal] Insufflation, suction, and total operation time to complete the protocol of 10 cauterizations of the gastric mucosa were measured in three groups: "manual suction only," "manual suction with automatic evacuation (50% force)," and "manual suction with automatic evacuation (70% force)." The stability of endoscopic visualization and operability was evaluated by 10 endoscopists blinded to those suction settings, and the number of manual suctions, insufflations, and total operation time were measured. Results: [Bench] The degree of residual smoke and gastric luminal collapse were inversely correlated. [Animal] When the automatic evacuator was partially used, there was no difference in the insufflation time, but the suction time (vs 50%; p = 0.011, vs. 70%; p = 0.011) and total operation time (vs. 50%; p = 0.012, vs. 70%; p = 0.036) were significantly reduced compared to manual operation only. Furthermore, manual suction with automatic evacuation (50% force) significantly improved the stability of endoscopic visualization and operability compared to manual operation only (p = 0.041, p = 0.0085). Conclusions: The automatic smoke evacuation in flexible gastrointestinal endoscopy was potentially feasible and useful by improving the device setting.

Serum NY-ESO-1 and p53 antibodies as useful tumor markers in gastric cancer.

Purpose: The NY-ESO-1 antigen is highly immunogenic and often spontaneously induces an immune response in patients with cancer. We conducted a large-scale multicenter cohort study to investigate the utility of serum NY-ESO-1 and p53 antibodies as predictive markers for the postoperative recurrence of gastric cancer. Here, we examined the usefulness of pre-treatment NY-ESO-1 and p53 antibodies as tumor markers for the diagnosis of gastric cancer in combination with carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Methods: A total of 1031 patients with cT3-4 gastric cancer were enrolled in the study. NY-ESO-1 and p53 antibodies were assessed prior to treatment. The positivity of NY-ESO-1 and p53 antibodies, CEA, and CA19-9 was evaluated before treatment. Results: Serum NY-ESO-1 and p53 antibodies were positive in 12.6% and 18.1% of the patients, respectively. Positive NY-ESO-1 antibody response was correlated with male gender, higher cStage, and upper tumor location. However, a positive p53 antibody response was not associated with tumor factors. The combination of NY-ESO-1 or p53 antibody response with CEA and CA19-9, or the 4-factors, was positive in 45.1%, 49.6%, and 53.8% of patients, respectively. Moreover, the 4-factor combination was able to detect >60% of cStage III-IV diseases, which was 14% higher than that with the combination of CEA and CA19-9. Conclusion: The combination of NY-ESO-1 and p53 antibody responses to CEA and CA19-9 increases the diagnostic accuracy of gastric cancer. Serum NY-ESO-1 and p53 antibodies may be useful tumor markers for gastric cancer.

Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial.

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or

Risk stratification of oesophageal squamous cell carcinoma using change in total lesion glycolysis and number of PET-positive lymph nodes.

BACKGROUND: The efficacy of neoadjuvant chemotherapy (NACT) correlates with patient survival in oesophageal squamous cell carcinoma (OSCC), but optimal evaluation of the treatment response based on PET-CT parameters has not been established. METHODS: We analysed 226 OSCC patients who underwent PET-CT before and after NACT followed by surgery. We assessed SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) for the primary tumour and the number of PET-positive lymph nodes before and after NACT to predict patient survival. RESULTS: In a stepwise analysis, we defined 60%, 80%, and 80% as the optimal cut-off values for SUVmax, MTV, and TLG reduction, respectively, to distinguish responders and non-responders to NACT. In the ROC analysis, the TLG reduction rate was the best predictor of recurrence among PET-CT parameters. The TLG responders achieved significantly more favourable prognoses than non-responders (2-year progression-free survival [PFS] rate: 64.1% vs. 38.5%; P = 0.0001). TLG reduction rate (HR 2.58; 95% CI 1.16-5.73) and the number of PET-positive lymph nodes after NACT (HR 1.79; 95% CI 1.04-3.08) were significant independent prognostic factors. CONCLUSIONS: TLG reduction is the best predictor of prognosis. Preoperative PET-CT evaluation of both the primary tumour and lymph nodes could accurately stratify risk in OSCC patients.

The tissue-resident marker CD103 on peripheral blood T cells predicts responses to anti-PD-1 therapy in gastric cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Since clinical benefits are limited to a subset of patients, we aimed to identify peripheral blood biomarkers that predict the efficacy of the anti-programmed cell death protein 1 (PD-1) antibody (nivolumab) in patients with gastric cancer. METHODS: We collected peripheral blood samples from gastric cancer patients (n = 29) before and after treatment with nivolumab and investigated the relationship between the frequency of surface or intracellular markers among nivolumab-binding PD-1+CD8+ T cells and treatment responses using multicolor flow cytometry. The tumors, lymph nodes, and peripheral blood of gastric cancer patients who underwent gastrectomy following nivolumab treatment were collected, and nivolumab-binding PD-1+CD8+ T cells in these tissue samples were characterized. RESULTS: Patients with a high frequency of CD103 among PD-1+CD8+ T cells in peripheral blood 2 weeks after the start of treatment had significantly better progression-free survival than the low group (P = 0.032). This CD103+PD-1+CD8+ T cell population mainly consisted of central memory T cells, showing the high expression of Ki-67 and few cytotoxic granules. In contrast, effector memory T cells were more frequently observed among CD103+PD-1+CD8+ T cells in tumors, which implied a change in the differentiated status of central memory T cells in lymph nodes and peripheral blood to effector memory T cells in tumors during the treatment with ICIs. CONCLUSIONS: A high frequency of CD103 among PD-1+CD8+ T cells 2 weeks after nivolumab treatment in patients with advanced gastric cancer may be a useful biomarker for predicting the efficacy of anti-PD-1 therapy.

A novel, simple, and dedicated device for endoscopic mucosal defect closure.

Objectives: Endoscopic submucosal dissection (ESD) has become popular, but complications such as postoperative bleeding remain an issue. Although some methods of closing a mucosal defect with a snare and clips have been reported to be effective and safe, the snare is not a dedicated device, and the procedure is difficult and time-consuming. We aimed to find an alternative method for defect closure after ESD by developing a dedicated device. Methods: We have improved five prototypes. The load on the stopper when starting to tighten and loosen a loop and the maximum load on the stopper and the movement distance of the thread when sliding the stopper were measured five times for each prototype. With the 5th prototype, we finalized the design and named it FLEXLOOP. Additionally, the material and shape of the outer tube were improved. Then, the usability of FLEXLOOP was evaluated in pigs. The operation time for closing mucosal defects with the snare or FLEXLOOP was measured five times. Results: We made FLEXLOOP, which had a lower load when sliding and a higher load when loosening than the snare. The improvement of the outer tube significantly reduced the load on the sheath when sliding it. We confirmed the feasibility of mucosal defect closure with FLEXLOOP in pigs. The median operation time was 563 s (range 340-679 s) with the snare and 355 s (range 303-455 s) with FLEXLOOP (p = 0.047). Conclusions: FLEXLOOP can be a promising option for defect closure after ESD.

Perioperative Ghrelin Administration Attenuates Postoperative Skeletal Muscle Loss in Patients Undergoing Esophagectomy for Esophageal Cancer: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: Ghrelin has been reported to reduce postoperative weight loss by improving appetite and food intake in patients undergoing upper gastrointestinal surgery. OBJECTIVE: We aimed to investigate whether growth hormone induction, another essential effect of ghrelin, may attenuate skeletal muscle loss in patients during postoperative starvation. METHODS: Esophageal cancer patients were randomized to receive a continuous intravenous infusion of high-dose ghrelin (HD; 0.5 µg/kg/h), low-dose ghrelin (LD; 0.25 µg/kg/h), or placebo for 7 days after surgery. During this period, oral feeding was not introduced but the patients received the same parenteral and enteral nutrition. We investigated the effects of ghrelin on body weight, skeletal muscle mass, nutritional status, and hormone levels. RESULTS: Overall, 73 patients were enrolled in this study. The rate of weight loss on postoperative day (POD) 7 relative to that before surgery was significantly lower in the HD group than in the placebo group (HD vs. placebo: -0.61% vs. 1.8%, p = 0.030). The rate of muscle loss in the erector spinae muscle on POD 7 in the HD and LD groups was significantly lower than that in the placebo group (HD vs. placebo: 2.8% vs. 8.5%, p < 0.001; LD vs. placebo: 4.9% vs. 8.5%, p = 0.028). The levels of growth hormone on PODs 1, 3, and 7, and insulin-like growth factor 1 on PODs 3, 7, and 14 were significantly higher in patients who received ghrelin. CONCLUSION: Continuous ghrelin administration could attenuate skeletal muscle loss in esophageal cancer patients during postoperative starvation.

Neutropenia is an indicator of outcomes in metastatic colorectal cancer patients treated with FTD/TPI plus bevacizumab: a retrospective study.

PURPOSE: Trifluridine/tipiracil (FTD/TPI) improves the overall survival (OS) of metastatic colorectal cancer (mCRC) patients. Additionally, FTD/TPI plus bevacizumab (BEV) has demonstrated promising efficacy for mCRC patients who are refractory to standard chemotherapy. Chemotherapy-induced neutropenia (CIN) has been reported to be an indicator of efficacy for FTD/TPI. This study investigated whether CIN was an indicator of efficacy for FTD/TPI plus BEV. METHODS: We reviewed chemo-refractory mCRC patients who were treated with FTD/TPI alone (monotherapy) or FTD/TPI plus BEV (combination) at our institution and compared the safety and efficacy of the two. Progression-free survival (PFS) and OS were analyzed using Kaplan-Meier curves. We also investigated correlations between CIN and outcomes. RESULTS: In total, 56 patients received FTD/TPI, among whom 24 and 32 were treated with monotherapy and combination therapy, respectively. The median PFS was 1.8 and 4.7 months for the monotherapy and combination arms, respectively (hazard ratio [HR]: 0.28; 95% confidence interval [CI]: 0.15-0.51; P < 0.001). The median OS was 6.3 and 11.7 months for the monotherapy and combination arms, respectively (HR 0.25; 95% CI 0.13-0.48; P < 0.001). CIN (Grade 3 or worse) developed in five (20.8%) and 17 (53.1%) patients from the monotherapy and combination arms, respectively (P = 0.030). Patients with CIN in the combination arm had improved PFS and OS compared with non-CIN patients (P = 0.033 and P = 0.045, respectively). CONCLUSIONS: FTD/TPI plus BEV prolonged PFS and OS and had tolerable toxicity compared with FTD/TPI alone. CIN is an indicator of patients who will benefit from FTD/TPI plus BEV.

[Long-Term Survival in a Patient with Stage â £ Gastric Cancer Successfully Treated with Multidisplinary Treatment].

A man in his 60s who had epigastric pain was referred to our hospital and diagnosed with advanced type 3 gastric cancer with multiple liver metastases, cT4acN2cN1(H1), cStage Ⅳ(HER2 3+). He underwent chemotherapy using capecitabine, cisplatin(CDDP), and trastuzumab(T-mab)(XPT). After 7 courses of XPT and 23 courses of XT, liver metastases disappeared, and we decided to perform open distal gastrectomy, D2+ #18 lymphadenectomy, and Billroth Ⅰ reconstruction as a conversion surgery. Despite adjuvant chemotherapy with S-1 plus T-mab, multiple lymph nodes recurrence occurred 3 months after the surgery. He was found to be in complete remission as assessed by CT after 5 courses of second-line CPT-11 treatment, which was discontinued after 17 courses. The patient is alive without recurrence at 57 months after the initial treatment and 22 months after the last treatment.

[A Case of Robot-Assisted Abdominoperineal Resection for Local Control for Lower Rectal Cancer with Synchronous Liver and Lung Metastases].

The patient was a 70s woman who was referred to our hospital with a complaint of bloody stool. Colonoscopy revealed type 2 tumor at a distance of 1 cm from the dentate line, without obstruction. The pathological diagnosis was adenocarcinoma. Enhanced CT revealed a tumor at the rectum below peritoneal reflection as well as swelling of the mesorectal lymph nodes. Multiple liver and lung metastases were also observed. The diagnosis was lower rectal cancer cT4aN2M1b(H2, PUL2), cStage Ⅳ. Chemotherapy was performed for disease control because of unresectable metastases. She received 7 courses of mFOLFOX plus bevacizumab. Further, as the metastatic lesion was inhibited, the primary lesion was excised for the purpose of symptom control. We judged that sphincter preservation was impossible because it was 1 cm away from the dentate line. She underwent robot-assisted abdominoperineal resection with D3 lymphadenectomy and sigmoid colostomy.

[A Resected Case of Hepatocellular Carcinoma Recurrence with Bile Duct Tumor Thrombus after RFA].

Hepatocellular carcinoma with bile duct invasion is rare, with a reported incidence of 3.4%. A 71-year-old man with hepatocellular carcinoma underwent radiofrequency ablation(RFA)(S6, S7, S8)and required readmission 22 months after the RFA for hepatocellular carcinoma recurrence detected by gadoxetic acid-enhanced magnetic resonance imaging. Enhanced abdominal computed tomography and magnetic resonance cholangiopancreatography revealed a tumor thrombus in a biliary branch and left adrenal gland metastases. We performed a right lobectomy and left adrenalectomy. The biliary thrombus was easily removed. Postoperative histopathological examination of the resected specimen showed a moderately differentiated hepatocellular carcinoma invading the biliary tract and the absence of viable cells in the liver tumor. The patient has shown no recurrence 6 months after the hepatectomy.

[A Case of Leiomyosarcoma of the Sigmoidal Mesocolon].

Leiomyosarcoma of the mesocolon is a very rare disease. Previously, there was no recommendation for chemotherapy or radiotherapy for leiomyosarcoma of the mesocolon, and only surgical resection reportedly offers a chance for cure. However, the reported cases of leiomyosarcoma of the mesocolon were not distinguished from those of gastrointestinal stromal tumor (GIST), which is the same mesenchymal tumor; thus, there is a possibility that they include cases that should be diagnosed as GIST. We report a case of leiomyosarcoma of the sigmoidal mesocolon.

[A Case of Strangulating Intestinal Obstruction Caused by Coiling of Low-Grade Appendiceal Mucinous Neoplasm to Terminal Ileum].

The patient was a 67-year-old female without a history of surgery. She presented with an abdominal pain and vomiting, and was rushed to our hospital. The abdominal pain was severe, but no peritoneal irritation sign was observed. Abdominal CT scan revealed a strangulating intestinal obstruction and accumulation of ascitic fluid. Emergency surgery was performed for diagnosis and treatment. The intraoperative finding showed serous ascitic fluid and strangulating intestinal obstruction caused by appendiceal tumor coiling around the terminal ileum, which had become ischemic with thinning of its wall. Ileocecal resection with removal of lymph nodes(D3)was performed. The postoperative course was uneventful, and the patient was discharged 13 days after the surgery. Pathological examination of the appendiceal tumor revealed a low-grade appendiceal mucinous neoplasm(LAMN)with no metastasis to the lymph nodes. We had a rare case of strangulating intestinal obstruction caused by coiling of LAMN to the terminal ileum.

[Sustained Complete Response of Hepatocellular Carcinoma with Multiple Intrahepatic Metastases following the Discontinuation of Sorafenib].

Sorafenib is an oral multi-targeted tyrosine kinase inhibitor used in cases of unresectable advanced HCC that significantly improves progression-free and overall survival. Complete response(CR)is uncommon; however, if major or complete radiological response are obtained, the issue of the discontinuation of sorafenib remains unresolved. The present study reported a case of a 75-year-old man with non-hepatitis B and C virus-related cirrhosis and multiple recurrent HCCs followingresection. In December 2010, a CT scan revealed multiple intrahepatic recurrence after TACE. Laboratory testingshowed Child-Pugh class A cirrhosis and an alpha-fetoprotein level of over 20,000 ng/mL. Sorafenib(800mg/day)was started in December 2010. The subsequent dynamic CT performed at the 6th month of therapy showed a partial response accordingto RECIST criteria and a complete response accordingto mRECIST. The AFP had decreased to within normal levels. In May 2012, the sorafenib dose was reduced(200 mgtwice daily)due to side effects(skin reaction). In December 2013, treatment was stopped after confirmation of a CR associated with shrinkage of the HCC. The patient maintained this remission until June 2018, more than 54 months after the discontinuation of sorafenib therapy. The adverse events of sorafenib were reversible. Further reportingof similar cases should help in the design of treatment strategies after CR to sorafenib therapy.

[A Resected Case of Tumorigenic Pancreatic Endocrine Cell Hyperplasia].

A 51-year-old man with a gallstone was found to have a tumor in the tail of the pancreas during preoperative examination. We performed EUS-FNA and a pancreatic neuroendocrine tumor was suspected.Therefore, laparoscopic distal pancreatectomy and cholecystectomy were performed.Pathological examination and immunohistochemistry showed that the pancreatic endocrine cells were uniformly increased and were composed of normal Langerhans islets.Therefore, the patient was diagnosed with pancreatic endocrine cell hyperplasia.Typical pancreatic endocrine cell hyperplasia does not form a tumor and is asymptomatic.However, some cases are symptomatic; therefore, when hypoglycemia or pancreatic hormone elevation are found without a clear cause, it should be distinguished.Because pancreatic tumors are difficult to diagnose definitely by imaging inspection alone, needle biopsy is necessary.However, neuroendocrine tumor and neuroendocrine cell hyperplasia are difficult to differentiate by biopsy.

[A Case of Laparoscopic Rectal Amputation Performed for Anal Gland Mucinous Carcinoma with Pagetoid Spread].

A 69-year-old man was admitted for the growing anal tumor and referred to our hospital. The tumor was about 40mm in size, and by biopsy, he was diagnosed the adenocarcinoma. Based on this diagnosis, abdominoperinealresection and edge resection were performed. Histopathologicalfindings showed mucinous carcinoma originating from analgl and with pagetoid spread. Postoperative chemotherapy was not performed, but 1 year 6 months after the surgery, inguinall ymph node recurrence was found, and lymph node dissection was performed. One year after the operation, recurrence was not found.