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Abstract The influence of pulmonary dysfunction on postoperative outcomes in older patients with gastric cancer was assessed. In this retrospective study, 352 older patients (age ≥ 75 years) with gastric cancer who underwent preoperative spirometry and curative gastrectomy were enrolled. Of these patients, 200 underwent laparoscopic gastrectomy. Restrictive and obstructive pulmonary dysfunction were defined as percentage of vital capacity (%VC)

Breast cancer (BC) is the most common cancer in women, and therapeutic strategies for it are based on the molecular subtypes of luminal BC, HER2 BC, and triple-negative BC (TNBC) because each subtype harbors different unique genetic aberrations. Recently, features of the tumor microenvironment (TME), especially cancer-associated fibroblasts (CAFs), have been demonstrated to play a critical role in BC progression, and we would like to understand the molecular features of BC CAFs for novel therapeutic strategies. In a recent study, 115 CAF-associated genes (CAFGs) were identified in a public database of microdissection and microarray data (GSE35602) from 13 colorectal cancer (CRC) tumors. Using a public database (GSE10797) of 28 BC tumors, a similar analysis was performed. In BC, 59 genes from the 115 CAFGs identified in CRC (CRC CAFGs) were also closely associated with a CAFs marker, SPARC (R = 0.6 or beyond), and POSTN was of particular interest as one of the BC CAFGs with the highest expression levels and a close association with SPARC expression (R = 0.94) in the cancer stroma of BC tumors. In BC stroma, POSTN was followed in expression levels by DKK3, MMP2, PDPN, and ACTA2. Unexpectedly, FAP and VIM were not as highly associated with SPARC expression in the cancer stroma of BC tumors and exhibited low expression. These findings suggested that ACTA2 might be the most relevant conventional CAFs marker in BC, and ACTA2 was actually correlated in expression with many CRC CAFGs, such as SPARC. Surprisingly, the SE ratio values of the BC CAFGs were much lower (average SE = 3.8) than those of the CRC CAFGs (SE = 10 or beyond). We summarized the current understanding of BC CAFs from the literature. Finally, in triple-negative BC (TNBC) (n = 5), SPARC expression uniquely showed a close association with COL11A1 and TAGLN expression, representing a myofibroblast (myCAFs) marker in the cancer stroma of the BC tumors, suggesting that myCAFs may be molecularly characterized by TNBC in contrast to other BC phenotypes. In summary, CAFs could have unique molecular characteristics in BC, and such TME uniqueness could be therapeutically targeted in BC.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.

Abstract Background Myopenia and myosteatosis are reported to be long‐term prognostic factors in patients with colorectal cancer (CRC). However, the established parameters are unsuitable for the Japanese population because their body composition is different from that of the Western population. Objective We aimed to elucidate the effect of skeletal muscle changes among Japanese adults, measured using preoperative computed tomography (CT) as a prognostic factor in patients with stage III CRC. Patients We retrospectively analyzed 341 patients diagnosed with stage III CRC. The cross‐sectional area (skeletal muscle index: SMI) and mean radiodensity of skeletal muscle (skeletal muscle radiodensity: SMR) were measured using preoperative CT. The optimal sex‐specific cutoff value, which was used to divide the patients according to the risk of recurrence, was set for SMI and SMR. Univariate and multivariate analysis were performed to determine the prognostic factors for recurrence‐free survival (RFS). Results The cutoff values of SMI for men and women were set as 48.5 and 41.4, respectively, and those of SMR were 35.0 and 21.7, respectively. Univariate analysis identified low SMI and SMR in men and low SMR in women as the worst prognostic factors for RFS. Multivariate analysis identified low SMI in men and low SMR in women as independent poor prognostic factors for RFS (hazard ratio [HR] = 1.87, 95% confidence interval [CI], 1.08–3.47, P = .03 and HR = 2.49, CI, 1.21–4.95, P = .01). Conclusion Low SMI in men and low SMR in women were the independent prognostic factors for patients with stage III CRC.

Background CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. Methods Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. Results (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (pConclusion Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.

Abstract 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.

Abstract Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first‐line chemotherapy consists of multidrug regimens including oral 5‐FU agents such as S1/Xeloda and platinum preparations, as well as Trastuzumab, which is effective in HER2‐positive cases. Second‐ and third‐line chemotherapy regimens include taxanes, Ramucirumab (R‐mab), and Nivolumab (N‐mab), which have different mechanisms of action from first‐line chemotherapy. R‐mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5‐FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.

Abstract Postoperative pancreatic fistula is one of the most severe complications after gastric cancer surgery, and can cause critical patient conditions leading to surgery‐related death. Fortunately, the incidence of postoperative pancreatic fistula after gastrectomy seems to be decreasing with changes in operative procedures. The rate was reported at about 30% after open gastrectomy with Appleby's method in 1997, but lately has improved below 1% for robotic gastrectomy in 2019. For the diagnosis of postoperative pancreatic fistula, drain amylase concentration has been demonstrated to be beneficial and some reports have proposed the optimal cut‐off values of drain amylase to predict major postoperative pancreatic fistula. There have been many reports identifying risk factors for postoperative pancreatic fistula, including overweight patients, pancreatic anatomy, blunt trauma from compression of the pancreas, and thermal injuries caused by the continuous use of energy devices. And importantly, laparoscopic gastrectomy has been shown to be more often associated with postoperative pancreatic fistula than open gastrectomy in the prospective national clinical database in Japan. Hence, further sophistication of surgical techniques to reduce pancreas compression would have great promise in reducing postoperative pancreatic fistula after laparoscopic gastrectomy.

Abstract Minimally invasive esophagectomy (MIE) has been reported to reduce postoperative complications especially pulmonary complications and have equivalent long‐term survival outcomes as compared to open esophagectomy. Robot‐assisted minimally invasive esophagectomy (RAMIE) using da Vinci surgical system (Intuitive Surgical, Sunnyvale, USA) is rapidly gaining attention because it helps surgeons to perform meticulous surgical procedures. McKeown RAMIE has been preferably performed in East Asia where squamous cell carcinoma which lies in more proximal esophagus than adenocarcinoma is a predominant histological type of esophageal cancer. On the other hand, Ivor Lewis RAMIE has been preferably performed in the Western countries where adenocarcinoma including Barrett esophageal cancer is the most frequent histology. Average rates of postoperative complications have been reported to be lower in Ivor Lewis RAMIE than those in McKeown RAMIE. Ivor Lewis RAMIE may get more attention for thoracic esophageal cancer. The studies comparing RAMIE and MIE where recurrent nerve lymphadenectomy was thoroughly performed reported that the rate of recurrent nerve injury is lower in RAMIE than in MIE. Recurrent nerve injury leads to serious complications such as aspiration pneumonia. It seems highly probable that RAMIE is beneficial in performing recurrent nerve lymphadenectomy. Surgery for esophageal cancer will probably be more centralized in hospitals with surgical robots, which enable accurate lymph node dissection with less complications, leading to improved outcomes for patients with esophageal cancer. RAMIE might occupy an important position in surgery for esophageal cancer.

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.

Objective To validate the relationship between residual walking ability and monthly care cost as well as long-term care insurance (LTCI) certification level in elderly patients after surgical treatment for hip fractures in Japan. Methods Elderly patients aged >75 years who underwent surgical treatment for hip fractures in our hospital were included. The preand post-surgical (6-month) walking ability and LTCI certification and the presence or absence of dementia was determined from medical records and questionnaires. Walking ability was classified into 6 levels used in our daily medical practice. Based on these data, we correlated the relationship between walking ability and the LTCI certification level. Further, based on the official statistics pertaining to the average monthly costs per person at each LTCI certification level, we evaluated the relationship between walking ability and monthly care cost. Results A total of 105 cases (mean age, 80.2 years; 16 men; 39 patients with dementia) were included. The correlation between walking ability and average monthly cost per person as well as LTCI certification level at 6 months postoperatively (r=0.58) was demonstrated. The correlation was found in both groups with and without dementia. Conclusion The ability to walk reduced the cost of care in elderly patients who experienced hip fracture, regardless of the presence of dementia.

Purpose: This study was designed to retrospectively analyze the safety and efficacy of chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma. Methods and materials: Eligible patients were aged 76 years or older, had a histopathologic diagnosis of esophageal squamous cell carcinoma, and were treated at the Kitasato University Hospital between January 2010 and March 2016. Chemotherapy consisted of nedaplatin in an intravenous dose of 90 mg/m2 on day 1 and 5-fluorouracil in an intravenous dose of 800 mg/m2 on days 1 to 5, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 50.4 Gy in 28 fractions for thoracic tumors and 61.2 Gy for cervical tumors. Results: Twenty-five patients were studied. Patient characteristics were as follows: median age 79 years (range, 76-85 years), clinical stage I/II/III/IV (7/8/8/2, respectively), and surgically resectable/unresectable (17/8, respectively). The completion rates of radiation therapy and chemoradiation therapy were 100% and 84%, respectively. Grade ≥3 acute toxicities included neutropenia (76%), leukopenia (72%), thrombocytopenia (32%), anemia (28%), anorexia (32%), oral mucositis (20%), febrile neutropenia (12%), and esophagitis (8%). Grade ≥3 late toxicities included esophageal stenosis (12%) and pleural effusion (4%). The complete response rate was 64%. In the median follow-up period of 18.9 months, the 1-year overall survival rate was 68%. Conclusions: Definitive chemoradiation therapy with nedaplatin and 5-fluorouracil may be a feasible treatment option for elderly patients with esophageal squamous cell carcinoma.

BackgroundThere have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer.MethodsQuantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010.Results(1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability.ConclusionsPromoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.

Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear. The aim of our study is to elucidate whether DNA methylation of the promoter region of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in SBC. The study group comprised patients with 53 patients with SBC, 107 colorectal cancer (CRC), and other rare tumors of the small intestine such as 4 malignant lymphomas, 2 leiomyosarcomas, and 9 gastrointestinal stromal tumors. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Significantly higher CDO1 methylation was observed in cancer tissues compared with non-cancerous mucosa of the small intestine (ROC = 0.96). Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09). Compared with CRC, SBC had a significantly poorer prognosis (p = 0.007) and displayed a significantly higher CDO1 methylation level (p < 0.0001). Intriguingly, especially in pStage I/II, there were robust prognostic difference between SBC and CRC (p = 0.08 / p < 0.0001), which may reflect CDO1 methylation status (p = 0.02 / p = 0.001). Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA. The CDO1 gene shows extremely cancer-specific hypermethylation, and it can be a prognostic marker in SBC.

A gastric bezoar is a mass that forms in the stomach. A giant gastric bezoar is particularly difficult to treat medically, and surgical therapy is selected. We describe our experience with a patient who had a giant gastric trichobezoar that was extracted by laparoscopic and endoscopic cooperative surgery (LECS) in accordance with the principles of LECS. The patient was a 32-year-old woman who presented at our hospital because of abdominal pain. Upper gastrointestinal endoscopy confirmed the presence of a giant gastric trichobezoar extending from the gastric cardia to the gastric angle. Because endoscopic removal was considered difficult, we extracted the giant gastric trichobezoar by LECS. The concurrent use of endoscopy was considered to allow a gastric bezoar to be extracted more safely and reliably than was previously possible.

Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC.The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1.The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively.CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.

BACKGROUND:Promoter DNA methylation of Cysteine dioxygenase type1 (CDO1) gene has been clarified as a molecular diagnostic and prognostic indicator in various human cancers. The aim of this study is to investigate the clinical relevance of CDO1 methylation in primary biliary tract cancer (BTC). METHODS:CDO1 DNA methylation was assessed by quantitative methylation-specific PCR in 108 BTC tumor tissues and 101 corresponding normal tissues. BTC was composed of extrahepatic cholangiocarcinoma (EHCC) (n = 81) and ampullary carcinoma (AC) (n = 27). RESULTS:The CDO1 methylation value in the tumor tissues was significantly higher than that in the corresponding normal tissues (p