CAF-associated genes putatively representing distinct prognosis by in silico landscape of stromal components of colon cancer.

Comprehensive understanding prognostic relevance of distinct tumor microenvironment (TME) remained elusive in colon cancer. In this study, we performed in silico analysis of the stromal components of primary colon cancer, with a focus on the markers of cancer-associated fibroblasts (CAF) and tumor-associated endothelia (TAE), as well as immunological infiltrates like tumor-associated myeloid cells (TAMC) and cytotoxic T lymphocytes (CTL). The relevant CAF-associated genes (CAFG)(representing R index = 0.9 or beyond with SPARC) were selected based on stroma specificity (cancer stroma/epithelia, cS/E = 10 or beyond) and expression amounts, which were largely exhibited negative prognostic impacts. CAFG were partially shared with TAE-associated genes (TAEG)(PLAT, ANXA1, and PTRF) and TAMC-associated genes (TAMCG)(NNMT), but not with CTL-associated genes (CTLG). Intriguingly, CAFG were prognostically subclassified in order of fibrosis (representing COL5A2, COL5A1, and COL12A1) followed by exclusive TAEG and TAMCG. Prognosis was independently stratified by CD8A, a CTL marker, in the context of low expression of the strongest negative prognostic CAFG, COL8A1. CTLG were comprehensively identified as IFNG, B2M, and TLR4, in the group of low S/E, representing good prognosis. Our current in silico analysis of the micro-dissected stromal gene signatures with prognostic relevance clarified comprehensive understanding of clinical features of the TME and provides deep insights of the landscape.

Early administration of postoperative BCAA-enriched PPN may improve lean body mass loss in gastric cancer patients undergoing gastrectomy.

BACKGROUND: It has been reported that weight loss or lean body mass (LBM) loss after gastrectomy for gastric cancer is associated with prognosis and nutritional support alone is insufficient to prevent LBM loss. Branched-chain amino acids (BCAA) play an important role in muscle catabolism, however their clinical effects on suppression of LBM loss in gastric cancer patients undergoing gastrectomy remains elusive. In this current study, we investigated the effect of our original PPN regimen including BCAA (designated to BCAA-regimen) on LBM loss. METHODS: We conducted a randomized controlled trial (RCT) at a single institution where patients undergoing gastrectomy were assigned to either receive a five-day early postoperative course of the BCAA-regimen (BCAA group) or conventional nutrition. The primary endpoint was the % reduction in LBM at postoperative day 7. The secondary endpoints included the % reduction in LBM at 1 and 3 months postsurgery. RESULTS: At postoperative day 7, LBM loss in the BCAA group tended to be lower than in the control group (0.16% vs. 1.7%, respectively; P = 0.21), while at 1 month postsurgery, LBM loss in the BCAA group was significantly different to that of the control group (- 0.3% vs. 4.5%, respectively; P = 0.04). At 3 months postgastrectomy, however, LBM loss was similar between the BCAA and the control groups. CONCLUSION: Our RCT clinical trial clarified that early administration of the postoperative BCAA regimen improved LBM loss at 1 month after surgery in gastric cancer patients undergoing gastrectomy.

Pancreas-contactless gastrectomy for gastric cancer prevents postoperative inflammation.

BACKGROUND: Pancreas-related complications after laparoscopic gastrectomy (LG) for gastric cancer can be fatal. We developed a gastrectomy procedure with no pancreas contact to prevent such complications and herein report the surgical outcomes. METHODS: We retrospectively reviewed 182 consecutive patients with gastric cancer who underwent LG at Kitasato University Hospital from January 2017 to January 2020. These patients were divided into a pancreas-contact group (C group) and pancreas-contactless group (CL group) for comparison of postoperative complications, and inflammatory parameters such as body temperature (BT) and C-reactive protein (CRP). RESULTS: Postoperative complications of CDc grade ≧ IIIa were significantly fewer in the CL group than in the C group [0/76 (0%) vs. 6/106 (5.7%), P = 0.035]. The median drain amylase (drain-AMY) on postoperative day 1 (POD1) was significantly lower in the CL group than in the C group (641 vs. 1162 IU/L, P = 0.02), as was BT at POD1 (37.4 °C vs. 37.7 °C, P = 0.04), the patient group with a BT above 37.5 °C at POD3 [5/76 (6.5%) vs. 18/106 (17%), P = 0.037], and those showing a CRP above 20.0 mg/dL at POD3 [5/76 (6.5%) vs. 20/106 (19%), P = 0.018]. CONCLUSIONS: Our technique to prevent pancreas contact during supra-pancreatic lymph node dissection during LG could minimize the inflammatory response and prevent further postoperative complications. Further large-scale, prospective studies are now required.

Improved anastomotic technique for esophagojejunal anastomosis using circular stapler.

PURPOSE: In total gastrectomy, Roux-en-Y reconstruction with esophagojejunal anastomosis has been widely used in gastrointestinal reconstruction. In the case of anastomotic leakage of RY reconstruction, esophagojejunal anastomosis should be paid attention, and esophageal fragility is considered the reason for the leakage. Here, we introduce an atraumatic and innovative technique for esophagojejunostomy. METHODS: We prospectively performed routine novel esophagojejunal anastomosis using circular stapler device and reviewed the records of 14 consecutive patients with gastric cancer who underwent open total gastrectomy at Kitasato University Hospital from April 2019 to March 2020. By placing about 10 stay sutures around the entire esophageal stump, the esophageal stump can be opened to the maximum diameter. The forceps grasping the tissue was not necessary for these procedures, consequently preventing either tears the esophageal stump tissue or narrowing the esophageal lumen. RESULTS: These 14 cases were far advanced cases of gastric cancer, 6 cases of splenectomy and 3 cases of distal pancreatectomy. No technical problems such as esophageal tear were observed in all cases. Postoperative complications were observed in 6 patients (42.9%), and their contents varied. However, they all improved conservatively. Regarding anastomotic complications, anastomotic leakage of Clavien-Dindo-II was observed in one case, but it improved conservatively. CONCLUSION: Our new atraumatic anastomosis technique could abolish problems such as tear of esophagus wall due to introduce a larger-sized anvil, trauma of esophageal wall by grasping with forceps such as Alice or Babcock. Consequently, the atraumatic and innovative technique might make the esophagojejunostomy safe. This method might prevent anastomotic leakage and other complications effectively.

Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis.

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.

Laparoscopic and endoscopic cooperative surgery for advanced gastric cancer as palliative surgery in elderly patients: a case report.

BACKGROUND: The number of elderly patients with gastric cancer is increasing, with the very elderly often refusing radical gastrectomy with lymph node dissection. Such a patient presented to us and we proposed a palliative surgery involving gastric local resection using laparoscopy endoscopy cooperative surgery (LECS). CASE PRESENTATION: An 89-year-old woman presented to our hospital with progressing anemia. She had an aortic arch replacement for aortic dissection 6 months previously and was taking antithrombotic drugs for atrial fibrillation. She was diagnosed with advanced gastric cancer, and we presented a radical resection treatment plan involving distal gastrectomy with lymph node dissection. However, she strongly refused undergoing radical gastric cancer resection. We believed that at least local control of the tumor could be effective in preventing future bleeding or stenosis due to tumor progression. Therefore, we proposed a local gastrectomy with LECS as an optional treatment, and she agreed to this treatment. The surgery was performed with minimal blood loss, and no postoperative complications were observed. Histopathological examination revealed a 45 × 31-mm, Type 2, poorly differentiated adenocarcinoma (pT4a, ly0, v1a), and the resected margin was negative. The patient was alive 2 years after surgery without apparent recurrence or other illness. In addition, her weight was maintained, together with her daily activity. CONCLUSION: Local resection of gastric cancer with LECS might be an option for the palliative treatment of patients who refuse radical resection of gastric cancer.

Preoperative chemotherapy could modify recurrence patterns through postoperative complications in patients with gastric cancer.

PURPOSE: Postoperative infectious complications have a negative impact on survival outcomes in patients with gastric cancer. It is recently reported that preoperative chemotherapy may eliminate this negative impact. This study aimed to confirm whether preoperative chemotherapy can eliminate the negative impact of postoperative infectious complications (IC) on survival outcomes and elucidate the association between postoperative infectious complications and recurrence patterns. METHODS: We retrospectively reviewed data of 86 patients who received preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by R0 gastrectomy at the Kitasato University between 2006 and 2016. Patients who developed grade II or higher infectious complications during hospitalization were grouped into the IC group, while others were grouped into the non-IC (NIC) group. Survival outcomes and recurrence patterns were analyzed between the two groups. RESULTS: Infectious complications with Clavien-Dindo classification of grade II or higher were found in 12 patients (14.0%, IC group). The median observational period was 61 months. Overall survival and progression-free survival were similar in the IC and NIC groups. Recurrence occurred in 39 patients. The proportions of peritoneal and lymph node recurrences were not significantly different between the two groups. However, the proportion of distant metastasis in the IC group was significantly higher than that in NIC group (3/4 [75%] vs. 9/35 [17%], p = 0.04). CONCLUSIONS: Pathological stage after neoadjuvant therapy plays a stronger role in recurrence than postoperative complications. Lymph node and peritoneal metastasis may be suppressed by preoperative chemotherapy.

Prospective study to validate the clinical utility of DNA diagnosis of peritoneal fluid cytology test in gastric cancer.

The clinical efficacy of DNA cytology test (CY) in gastric cancer (GC) has been retrospectively proposed using cancer-specific methylation of cysteine dioxygenase type 1 (CDO1). We confirmed the clinical utility of DNA CY in a prospective cohort. Four hundred GC samples were prospectively collected for washing cytology (UMIN000026191), and detection of the DNA methylation of CDO1 was assessed by quantitative methylation-specific PCR in the sediments. Endpoint was defined as the match rate between conventional CY1 and DNA CY1 (diagnostic sensitivity), and the DNA CY0 rate (diagnostic specificity) in pStage IA. DNA CY1 was detected in 45 cases (12.5%), while CY1 was seen in 31 cases (8.6%) of 361 chemotherapy-naïve samples, where the sensitivity and specificity of the DNA CY in the peritoneal solutions were 74.2% and 96.5%, respectively. The DNA CY was positive for 3.5/0/4.9/11.4/58.8% in pStage IA/IB/II/III/IV, respectively (P < .01). In the multivariate analysis, DNA CY1 was independently correlated with pathological tumor depth (pT) (P = .0012), female gender (P = .0099), CY1 (P = .0135), P1 (P = .019), and carcinoembryonic antigen (CEA) (P = .036). The combination of DNA CY1 and P factor nearly all covered the potential peritoneal dissemination (P1 and/or CY1 and/or DNA CY1) (58/61:95.1%). DNA CY1 had a significantly poorer prognosis than DNA CY0 in GC patients (P < .0001). DNA CY1 detected by CDO1 promoter DNA methylation has a great value to detect minimal residual disease of the peritoneum in GC clinics, representing poor prognosis as a novel single DNA marker.

Patient selection for salvage surgery after definitive chemoradiotherapy in esophageal squamous cell carcinoma.

PURPOSE: With the widespread use of definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC), salvage surgery for recurrence/residual patients became prevalent. However, survival impact of salvage surgery remains obscure at present. METHODS: The updated clinical outcomes of salvage surgery were investigated to know its survival impact. Of the 155 ESCC patients who underwent dCRT between 2009 and 2016, we included 85 patients with recurrence or residual disease. The median follow-up was 65 months. RESULTS: Of the 85 patients with progression disease, there were 42 and 43 patients of recurrence and residual disease, respectively. Salvage surgery was performed in 27 patients after dCRT, including 15 patients who underwent salvage esophagectomy. The 5-year overall survival (OS) of salvage surgery and otherwise patients was 66.1% and 14.5%, and the patients with salvage surgery had a significantly better prognosis (p < 0.0001). In the 15 patients who underwent salvage esophagectomy, residual disease, lymph node metastasis-positive (ycN+) after dCRT, and pathological lymph node metastasis-positive (ypN+) were significantly associated with poor prognosis (p = 0.0492, p = 0.0006, p = 0.0276), and the 5-year OS rates for the ycN/ypN combinations were 90%, 33.3%, and 0% in ycN-/ypN-, ycN+/ypN-, and ycN+/ypN+ patients, respectively (p = 0.0026). In a multivariate analysis, ycN+ was an independent poor prognostic factor (HR 13.6, 95% CI 1.65-286.8, p = 0.0154). CONCLUSIONS: Survival impact of salvage surgery after dCRT is robust, and lymph node metastasis after dCRT may help determine the indication for salvage esophagectomy.

Neoadjuvant chemotherapy plus surgery for high-risk advanced gastric cancer: long-term results of KDOG1001 trial.

PURPOSE: The purpose of this study is to evaluate the long-term survival outcomes of KDOG1001 trial after a minimum follow-up of 3 years. METHODS: Patients with bulky N2 lymph nodes, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy plus adjuvant S-1 therapy for 1 year. The final preplanned analysis of long-term outcomes including overall survival and relapse-free survival was conducted after minimum follow-up of 3 years. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN 000003642, and has been completed. RESULTS: From May 2010 through January 2017, 40 patients were enrolled. All included patients underwent neoadjuvant chemotherapy with DCS followed by gastrectomy with D2 lymphadenectomy, and 32 (80%) completed adjuvant S-1 therapy for 1 year. After a median follow-up for surviving patients of 68 months at the last follow-up in January 2020, 3-year overall survival rate was 77.5% (95% confidence interval 62.1-87.9%), while 3-year relapse-free survival rate was 62.5% (95% confidence interval 46.8-76.0%). CONCLUSION: Neoadjuvant chemotherapy with 4 cycles of DCS followed by D2 gastrectomy plus adjuvant S-1 was associated with relatively good long-term oncologic outcomes for patients with the high-risk gastric cancer.

Prevention of intra-thoracic recurrent laryngeal nerve injury with robot-assisted esophagectomy.

PURPOSE: Transthoracic esophagectomy for esophageal cancer is one of the most invasive procedures in surgery for gastrointestinal cancer. Serious complications sometimes occur after esophageal cancer surgery, including recurrent laryngeal nerve injury and pneumonia. The purpose of this study was to access the possibility of robot-assisted thoracoscopic esophagectomy for esophageal cancer in terms of preventing recurrent laryngeal nerve injury. METHODS: Operations in thoracic part were performed in prone position with bilateral ventilation. During dissection of the recurrent laryngeal nerve lymph nodes, thin blood vessels were coagulated with Maryland bipolar forceps in the left hand and then dissected with monopolar scissors in the right hand. Especially when dissecting left recurrent laryngeal nerve lymph nodes, the nerve was left unisolated from the vascular sheath that involves the aortic arch. Short-term outcomes including operative time, estimated blood loss, and postoperative complications including recurrent laryngeal nerve injury were accessed. RESULTS: From November 2018 to January 2020, 20 patients underwent robot-assisted thoracoscopic esophagectomy for esophageal cancer. Thoracic operative time was 242 min, estimated blood loss in the thoracic part was minimal, the number of dissected mediastinal lymph nodes was 19 (all median), and the incidence rates of recurrent laryngeal nerve injury and pneumonia were 10% (2 case) and 10% (2 cases), respectively. CONCLUSION: Robot-assisted thoracoscopic esophagectomy for esophageal cancer has the possibility of reducing recurrent laryngeal nerve injury even in the introductory period. Randomized controlled trials are required to confirm this advantage of the robotic surgery.

A phase I study of docetaxel/oxaliplatin/S-1 (DOS) combination neoadjuvant chemotherapy for patients with locally advanced adenocarcinoma of the esophagogastric junction.

BACKGROUND: The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG). METHODS: Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m2, day 1), oxaliplatin (mg/m2, day 1), and S-1 (mg/day, days 1-14) were: 50/100/80-120 at level 1, and 60/100/80-120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210). RESULTS: We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen. CONCLUSION: Recommended doses of docetaxel (mg/m2), oxaliplatin (mg/m2), and S-1 (mg/day) were 60/100/80-120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.

[A Case of Advanced Neuroendocrine Cell Carcinoma of the Stomach Treated with S-1 and Cisplatin Chemotherapy].

A 69-year-old man presented to our hospital because of epigastric pain. A type 2 lesion was seen in the lesser curvature of the antrum of the stomach. A moderately differentiated adenocarcinoma(human epidermal growth factor receptor 2-negative) was diagnosed by biopsy. Abdominal computed tomography showed a mass shadow 52mm in diameter in the pyloric region invading the surrounding organs, but no evidence of distant metastasis. Chemotherapy with S-1 and cisplatin(SP therapy)was initiated because of a diagnosis of locally advanced gastric cancer. After 2 courses of chemotherapy, the tumor shrinkage rate was 70%, confirming that treatment was effective. However, severe skin disorders developed, precluding the continuation of chemotherapy. Staging laparoscopy showed no evidence of peritoneal dissemination, but invasion into the superior mesenteric vein was noted. The tumor was resected by pancreaticoduodenectomy with partial resection of the venous wall. Pathological examination of the resected specimens provided a definite diagnosis of neuroendocrine cell carcinoma. As of 1 year and 7 months after surgery, there has been no observation of metastasis or recurrence. SP therapy was suggested to be a useful regimen for preoperative chemotherapy in patients with locally advanced neuroendocrine cell carcinoma.