Prognosis of Elderly Patients with Gastric Cancer Treated with the Best Supportive Care.

BACKGROUND: The prognosis of gastric cancer has gradually improved as treatments have evolved. However, curative treatments might be difficult when gastric cancer is detected in the elderly or individuals with multiple comorbidities. This study investigated the prognosis of elderly patients with gastric cancer who received best supportive care (BSC). METHODS: This single-center observational study retrospectively reviewed medical records from elderly patients (>65 years-old) diagnosed with gastric cancer between 2014 and 2019 who received BSC. RESULTS: Data were obtained from 39 patients with a median age of 90 years. Median follow-up period was 207 days. Median survival time for all causes was 508 days for stage 0, 1026 days for stage I, 319 days for stage II, 317 days for stage III, and 43 days for stage IV. Median survival time for cancer-specific deaths was 1987 days for stage 0, 1280 days for stage I, 331 days for stage II, 371 days for stage III, and 43 days for stage IV. Univariate analyses identified 'stage' and performance status as risk factors for both overall and cancer-specific mortality. In multivariate analyses, 'stage' was an independent risk factor predicting overall mortality (HR=3.71, 95%CI=1.73-7.98, P < 0.001) and both 'stage' and performance status were independent risk factors predicting cancer-specific mortality (HR=4.06 and 8.95, 95%CI=1.13-14.51 and 3.00-26.67, P = 0.031 and P < 0.001, respectively). CONCLUSION: This result will help clarify the natural history of elderly patients with gastric cancer and provide useful information when choosing treatments in the future.

Association of serum superoxide dismutase activity and the incidence of colorectal cancer in a nested case-control study.

BACKGROUND: Superoxide dismutase (SOD) is an antioxidant enzyme that degrades superoxide, a major causative factor in carcinogenesis. We assessed associations between serum SOD activities and incidence of colorectal carcinoma (CRC) in a case-control study nested in the Japan Collaborative Cohort (JACC) study. METHODS: At baseline, 39,242 subjects donated serum samples. Participants diagnosed with CRC during follow-up were regarded as cases. Odds ratios (ORs) for CRC incidence associated with SOD were evaluated with conditional logistic regression models. In the current study, 176 cases and 524 controls were analyzed. RESULTS: For the overall cohort, a decreasing trend in risk of CRC with increasing SOD was observed (P for trend=0.054) and the fourth quartile of SOD level showed the lowest risk compared to the first (OR=0.52, 95% confidence interval [CI]=0.29-0.93). This was significant in men (P for trend=0.001), with the fourth quartile of SOD level showing the lowest risk compared to the first (OR, 0.23; 95%CI, 0.09-0.60). It was also exclusively observed for rectal cancer and left-sided CRC (P for trend, 0.037 and 0.020, respectively), with the fourth quartile again showing the lowest risk compared to the first (OR, 0.28 and 0.38; 95%CI, 0.09-0.84 and 0.16-0.91, respectively). Limiting subjects to those followed-up over 2 years, all trends remained unchanged. CONCLUSIONS: Our findings suggest that serum SOD activity correlates inversely with risk of CRC, particularly in men and individuals with rectal cancer/left-sided CRC.

Serum Soluble Fas Levels and Incidence of Liver Cancer in Nested Case-Control Study.

BACKGROUND: Soluble Fas (sFas) plays various roles in carcinogenesis and tumor dissemination by preventing apoptosis via binding to Fas ligand. We analyzed associations of serum sFas levels with the incidence of liver cancer in a prospective case-control study nested in the Japan Collaborative Cohort Study. METHODS: A baseline survey was conducted from 1988, with blood samples obtained from 39,242 subjects. Patients diagnosed with liver cancer were regarded as cases. Two or three controls were selected and matched for sex, age, and geographic area. Conditional logistic regression was used to estimate ORs for cancer incidence associated with sFas. RESULTS: This study contained 86 cases and 249 controls. After controlling for alcohol intake, body mass index, smoking, and hepatitis viral infection, participants with high sFas showed elevated risk of cancer (Ptrend = 0.003) and the third tertile of sFas showed a higher risk compared with the first tertile [OR, 3.53; 95% confidence interval (CI), 1.28-9.69]. In hepatocellular carcinoma, high sFas was associated with elevated risk (Ptrend < 0.001). In men and the elderly, subjects in the highest tertiles showed higher cancer risk. Limiting subjects to those followed for 3 years, high sFas was related to liver cancer risk (Ptrend = 0.033) and the third tertile showed a higher risk compared with the first (OR, 2.94; 95% CI, 0.94-9.14). CONCLUSIONS: High serum sFas may be related to future risk of liver cancer. IMPACT: Our findings highlight this biomarker for further analysis in pooled investigations with different/larger prospective cohorts.

Antitumoral RNA-targeted oligonucleotide therapeutics: The third pillar after small molecule inhibitors and antibodies.

Oligonucleotide therapeutics, drugs consisting of 10-50 nucleotide-long single- or double-stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or proteins, include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and decoys. These oligonucleotide therapeutics could potentially become the third pillar of drug development. In particular, ASOs and siRNAs are advanced tools that are widely used to silence gene expression. They are used in clinical trials, as they have high specificity for target mRNAs and non-coding RNAs and limited toxicity. However, their clinical application remains challenging. Although chemotherapy has benefits, it has severe adverse effects in many patients. Therefore, new modalities for targeted molecular therapy against tumors, including oligonucleotide therapeutics, are required, and they should be compatible with diagnosis using next-generation sequencing. This review provides an overview of the therapeutic uses of ASOs, siRNAs, and miRNAs in clinical studies on malignant tumors. Understanding previous research and development will help in developing novel oligonucleotide therapeutics against malignant tumors.

Genomic analysis of an aggressive case with metastatic intrahepatic mucinous cholangiocarcinoma.

Intrahepatic mucinous cholangiocarcinoma (IHMC) is rare and behaves notoriously; however, the details of the clinicopathological characteristics of IHMC remain unknown. A 70-year-old man was admitted for examination of the hepatic mass in the S1 segment. He underwent extended left hepatic lobectomy. Histopathological evaluation demonstrated mixed papillary carcinoma that comprised well to moderately differentiated tubular adenocarcinoma and signet-ring cell carcinoma with large amounts of mucus lakes. Tumor was relapsed 9 months after surgery. Although he received chemotherapy with the combination of gemcitabine and cisplatin, he had renal failure and discontinued the chemotherapy. He received palliative radiotherapy for metastasis in the cervical spine. Then, the patient treated with S-1, however, he died 16 months after the initial diagnosis. The autopsy findings showed multiple nodules in the lungs, pleura, kidneys, adrenal glands, stomach, pancreas, and lymph nodes. Histological examination revealed that all nodules were IHMC. Next-generation sequencing revealed that somatic mutations in ADGRB3, TAF1L and EPHA3 may affect carcinogenesis, and those in TAF1, EPHA3, PIK3C2B, FN1, ERBB3, BRIP1, SYNE1 and TGFBR2 may affect metastasis. Molecular carcinogenesis of IHMC may be distinct from that of ordinary cholangiocarcinoma. Further studies are needed to elucidate the genetic mutations and their functions in IHMC.

Glycoprotein 2 in health and disease: lifting the veil.

In 2020, we discovered glycoprotein 2 (GP2) variants associated with pancreatic cancer susceptibility in a genome-wide association study involving the Japanese population. Individuals carrying a missense coding variant (rs78193826) in the GP2 gene resulting in a p.V432M substitution had an approximately 1.5-fold higher risk of developing pancreatic cancer than those without this variant. GP2 is expressed on the inner surface of zymogen granules in pancreatic acinar cells, which are responsible for the sorting, storage and secretion of digestive enzymes. Upon neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of zymogen granules and then secreted into the pancreatic duct and intestinal lumen. While the functions of GP2 remain poorly understood, emerging evidence suggests that it plays an antibacterial role in the gastrointestinal tract after being secreted from pancreatic acinar cells. Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa. In this review article, we summarize the role of GP2 in health and disease, emphasizing its functions in the gastrointestinal tract, as well as genetic variations in the GP2 gene and their associations with disease susceptibility. We hope that its robust genetic associations with pancreatic cancer, coupled with its emerging role in gastrointestinal mucosal immunity, will spur renewed research interest in GP2, which has been understudied over the past 30 years compared with its paralog uromodulin (UMOD).

Pilomatrical carcinosarcoma in the very elderly: A case report.

Pilomatrical carcinosarcomas are very rare tumors. To the best of our knowledge, only nine cases diagnosed with pilomatrical carcinosarcomas have been reported. The present study reported on a case of pilomatrical carcinosarcoma in the posterior part of the left auricle of a 100-year-old male patient. The tumor histologically comprised the following two components: Pilomatrical carcinoma and undifferentiated spindle cell sarcoma. The pilomatrical carcinoma comprised atypical basaloid cells and shadow cells. The basaloid cells had basophilic cytoplasm, clear nucleoli and deeply stained nuclear chromatin. The undifferentiated spindle cell sarcoma comprised atypical spindle cells. Both components contained numerous mitotic cells. The boundary area between the carcinoma and sarcoma smoothly transitioned into each other. The carcinoma cells and a portion of the sarcoma cells were positive for ß-catenin in the cytoplasm with or without the nuclei. These results suggested that the two components developed from the same origin.

Insulin-Like Growth Factor 2 and Incidence of Liver Cancer in a Nested Case-Control Study.

BACKGROUND: Insulin-like growth factor (IGF)2 is a potent mitogen. To elucidate the relationship between IGF2 and risk of tumorigenesis, we analyzed associations between serum levels of IGF2 and incidence of liver cancer in a prospective case-control study nested in the Japan Collaborative Cohort study. METHODS: A baseline survey was conducted from 1988 using blood samples from 39,242 subjects. Those who had been diagnosed with liver cancer by 1997 were regarded as cases. For each case, we randomly selected two or three controls matched for sex, age, and residential area. Conditional logistic regression was used to estimate ORs for cancer incidence associated with IGF2. RESULTS: This analysis included 86 cases and 294 controls. Low IGF2 was associated with risk of future liver cancer (P trend <0.001). After controlling for alcohol intake, body mass index, smoking, hepatitis viral infection, IGF1, and IGF-binding protein-3, participants with low IGF2 displayed a higher risk of liver cancer (P trend < 0.001). Individuals in quintiles 2 to 5 showed lower risk compared with quintile 1 (OR range, 0.05-0.16). In both sexes and in both nonelderly and elderly groups, subjects in the lowest quintiles showed higher risks of liver cancer. Limiting subjects to those followed for 3 years, low IGF2 was associated with cancer risk (P trend < 0.001). CONCLUSIONS: Our findings suggest that low serum IGF2 level, especially below 460 ng/mL, is related to future risk of liver cancer. IMPACT: Our findings highlight this important biomarker for further analysis in large prospective cohorts and pooled investigation with other cohorts.

Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

[A Case in Which Multiple Post-Operatively Recurring Hepatocellular Carcinomas Showed a Positive Response to Sorafenib-Hepatic Arterial Infusion Chemotherapy (HAIC)Sequential Therapy].

A male patient in his 70s underwent a right lobectomy because of a hepatocellular carcinoma(HCC)located in the right lobe(S6)of his liver. Eleven months after surgery, contrast-enhanced CT showed multiple masses in the residual liver, which were diagnosed as HCC recurrence. He was then treated with hepatic arterial infusion chemotherapy(HAIC). Ten months after the recurrence, the liver tumors progressed. Therefore, treatment was switched to sorafenib(400 mg/day orally)and HAIC(low-dose FP: 5-FU 250 mg plus CDDP 5 mg 5 days/week 4 weeks)sequential therapy. The patient received 2 cycles of sorafenib-HAIC sequential therapy for 11 months, and his liver tumors shrunk considerably. Unfortunately, 24 months after the recurrence of HCC, he died of respiratory failure. The cause of his death was officially determined to be primary lung cancer. An autopsy revealed that most tissues were necrotic, and only a small number of viable tumor cells were present in the liver tumors. This suggests that sorafenib-HAIC sequential therapy was significantly effective in targeting the multiple HCCs in this case.

Solitary synchronous gastric metastasis of renal cell carcinoma.

INTRODUCTION: There have been some reports describing metastasis to the stomach from renal cell carcinomas. However, there are few reports describing solitary synchronous gastric metastasis of renal cell carcinomas. CASE PRESENTATION: The patient was a 70-year-old woman who underwent an upper gastrointestinal endoscopy to examine her progressive weight loss. There was a submucosal tumor in the stomach, which was biopsied. The gastric tumor was pathologically proven to be a metastatic clear cell renal cell carcinoma. Furthermore, contrast-enhanced computed tomography showed right renal cell carcinoma invading the renal vein (cT3aN0M0). The patient underwent right radical nephrectomy and endoscopic resection for the treatment of the primary renal cancer and the gastric metastatic lesion, respectively. The resected specimen of the stomach had a clear resection margin. CONCLUSION: Endoscopic resection for early stage gastric metastatic lesions of renal cell carcinomas is a reasonable approach because it is a minimally invasive surgical technique.

Intraductal Papillary Mucinous Neoplasm with Pancreatogastric Fistula.

We herein report a rare case of intraductal papillary mucinous neoplasm with a pancreatogastric fistula in an elderly Japanese man admitted to our hospital. The pancreatogastric fistula was confirmed using endoscopic retrograde pancreatography via a cannulated guidewire placed in the stomach. Six months after admission, the patient was diagnosed with intraductal papillary mucinous carcinoma. A pancreatogastric fistula is generally a rare complication of intraductal papillary mucinous neoplasm. It was caused by mechanical penetration in this case. Interestingly, we also observed endoscopic and histochemical mucosal changes in the fistula.

A rare case of Helicobacter pylori-uninfected intramucosal poorly differentiated adenocarcinoma that occurred in the gastric fornix.

We report a rare case of undifferentiated-type intramucosal gastric cancer that occurred in the fornix of the stomach without Helicobacter pylori infection, which consisted mainly of poorly differentiated adenocarcinoma. A 49-year-old man visited our hospital for a follow-up endoscopic examination of a small depressed lesion of the gastric fornix detected by surveillance esophagogastroduodenoscopy. On magnifying endoscopy with blue laser imaging, the depressed lesion (approximately 10 mm in diameter) was regarded as undifferentiated-type early gastric cancer that proved to be a poorly differentiated adenocarcinoma by histological examination of biopsied specimens. The cancerous lesion was successfully treated with endoscopic submucosal dissection and microscopically showed an intramucosal cancer that invaded the whole mucosal layer with predominant growth of a poorly differentiated adenocarcinoma component. The patient status was verified as Helicobacter pylori-naïve according to the strict diagnostic criteria, thereby confirming this case as an undifferentiated-type Helicobacter pylori-uninfected gastric cancer. Helicobacter pylori-uninfected intramucosal poorly differentiated adenocarcinoma occurring in the gastric fornix has not been previously reported.

Long-term outcomes of incidental gallbladder carcinoma without additional resection: A single institution experiment.

Incidental gallbladder carcinoma (IGC), defined as unexpected malignancy identified in the surgical gallbladder specimen of a cholecystectomy performed for a benign diagnosis, can be difficult to suspect preoperatively. Furthermore, there are valid clinical reasons to defer reoperation for additional resection, particularly in elderly patients. The present study aimed to determine the long-term outcomes and prognostic factors associated with recurrence in patients with IGC. The medical records of 678 patients who underwent cholecystectomy at Toyooka Hospital between September 2011 and November 2017 were reviewed. The cases identified to be IGC were retrospectively analyzed to determine patient and histopathological characteristics, surgical details, long-term outcomes and factors associated with cancer recurrence. A total of 22 patients were diagnosed with gallbladder carcinoma following cholecystectomy by histopathological examination, and 12 of these were identified to be IGC. The median age was 80 years (range 70-89 years). Although 6 of the 12 patients with IGC had stage pT2 or pT3 tumors, only 1 patient underwent additional resection. Recurrence occurred in 3 of the 8 patients who did not undergo additional resection and were available for long-term follow-up. Recurrence was not associated with the extent of tumor invasion but may be associated with other histopathological findings, preoperative treatment history and risk factors for recurrence. Furthermore, long-term survival was observed in patients with pT2 and pT3 tumors who did not undergo additional resection. Recurrence was not associated with the extent of tumor invasion but may be associated with other histopathological findings, preoperative treatment history, and risk factors for recurrence. Furthermore, long-term survival was observed in patients with pT2 and pT3 tumors who did not undergo additional resection. Even if it is a progressive IGC case, appropriate preoperative treatment or cholecystectomy without persistence of the carcinoma cell, based on a preoperative image evaluation and a postoperative histopathological examination, may greatly influence the long-term prognosis of IGC.

[Coexistence of IgG4-related autoimmune hepatitis and inflammatory pseudotumors of the liver:a case report].

IgG4-related autoimmune hepatitis (IgG4-AIH) is characterized by hepatic inflammation and is considered an IgG4-related disease. Several inflammatory pseudotumors (IPTs) are also considered as IgG4-related diseases;however, there have been no reports of cases wherein both diseases occurred concurrently. An older adult with liver dysfunction was admitted to the hospital and was diagnosed with IgG4-AIH following a liver biopsy;IgG4-positive plasma cell infiltration in the portal tract and high serum IgG4 concentration were detected. A few months following biopsy, imaging studies revealed two IPTs in the liver. The patient was diagnosed with cryptogenic organized pneumonia several months after imaging and was treated with steroids in a different hospital. Her liver dysfunction improved, and one of the two IPTs disappeared in response to steroid treatment. The following is an account of a rare case of IgG4-AIH with IPTs of the liver.