Multi-phasic gene profiling using candidate gene approach predict the capacity of specific antibody production and maintenance following COVID-19 vaccination in Japanese population.

Background: Vaccination against severe acute respiratory syndrome coronavirus type 2 is highly effective in preventing infection and reducing the severity of coronavirus disease (COVID-19). However, acquired humoral immunity wanes within six months. Focusing on the different tempo of acquisition and attenuation of specific antibody titers in individuals, we investigated the impact of genetic polymorphisms on antibody production after COVID-19 vaccination. Methods: In total 236 healthcare workers from a Japanese municipal hospital, who received two doses of the vaccine were recruited. We employed a candidate gene approach to identify the target genetic polymorphisms affecting antibody production after vaccination. DNA samples from the study populations were genotyped for 33 polymorphisms in 15 distinct candidate genes encoding proteins involved in antigen-presenting cell activation, T cell activation, T-B interaction, and B cell survival. We measured total anti-SARS-Cov2 spike IgG antibody titers and analyzed the association with genetic polymorphisms at several time points after vaccination using an unbiased statistical method, and stepwise logistic regression following multivariate regression. Results: Significant associations were observed between seven SNPs in NLRP3, OAS1, IL12B, CTLA4, and IL4, and antibody titers at 3 weeks after the first vaccination as an initial response. Six SNPs in NLRP3, TNF, OAS1, IL12B, and CTLA4 were associated with high responders with serum antibody titer > 4000 BAU/ml as boosting effect at 3 weeks after the second vaccination. Analysis of long-term maintenance showed the significance of the three SNPs in IL12B, IL7R, and MIF for the maintenance of antibody titers and that in BAFF for attenuation of neutralizing antibodies. Finally, we proposed a predictive model composed of gene profiles to identify the individuals with rapid antibody attenuation by receiver operating characteristic (ROC) analysis (area under the curve (AUC)= 0.76, sensitivity = 82.5%, specificity=67.8%). Conclusions: The candidate gene approach successfully showed shifting responsible gene profiles and initial and boosting effect mainly related to the priming phase into antibody maintenance including B cell survival, which traces the phase of immune reactions. These gene profiles provide valuable information for further investigation of humoral immunity against COVID-19 and for building a strategy for personalized vaccine schedules.

Effect of abdominal aortic calcification on the prognosis and recurrence of colorectal cancer stages II-III: A retrospective cohort study.

PURPOSE: Abdominal aortic calcification (AAC) is a well-known risk marker for cardiovascular disease. However, its clinical effect on patients who underwent radical surgery for colorectal cancer (CRC) stages II-III is unclear. This study aimed to analyze the associations between AAC and prognosis of patients with stage II-III CRC. METHODS: To evaluate the effect of AAC on clinical outcomes, prognosis, and metastatic patterns of CRC, we analyzed 362 patients who underwent radical surgery for stage II-III CRC between 2010 and 2018. RESULTS: The high AAC group had significantly worse overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) after propensity score matching to adjust for differences in baseline characteristics of patients and tumors. In the multivariate Cox regression analyses, a high AAC was an independent risk factor for poor OS (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.23-4.59; p = 0.01), poor CSS (HR, 5.22; 95% CI, 1.74-15.6; p < 0.01), and poor RFS (HR, 1.83; 95% CI, 1.19-2.83; p < 0.01). A high AAC was not associated with a risk of lung metastasis or local or peritoneal recurrence, but a risk for liver metastasis of CRC. CONCLUSION: A high AAC showed a strong relationship with poor OS, CSS, and RFS after curative resection for stage II-III CRC. A high AAC was also associated with a risk for liver metastasis, which may worsen the prognosis in stage II-III CRC. AAC could be a new clinical tool for predicting the prognosis for patients in stage II-III CRC.

Prediction of anastomotic leakage after left-sided colorectal cancer surgery: a pilot study utilizing quantitative near-infrared spectroscopy.

BACKGROUND: Anastomotic leakage (AL) occurs with some frequency in all types of colorectal cancer surgery and is associated with increased morbidity, mortality and recurrence rates. Complications might be prevented by monitoring intra-operative bowel perfusion at the anastomotic site. A pilot study concerning the objective and quantitative measurement of tissue perfusion by monitoring regional tissue saturation of oxygen (rSO2) was conducted, using the In Vivo Optical Spectroscopy (INVOS™) system (Medtronic, Minneapolis, MN, USA). METHODS: This study evaluated the ability of the INVOS™ system to predict AL after left-sided colorectal cancer surgery. rSO2 measurements of the oral side of the site of bowel anastomosis were taken before anastomosis in 73 patients. Clinical factors, including rSO2, were analyzed to identify risk factors for AL. RESULTS: Among 73 patients, 6 (8.2%) experienced AL. The rSO2 values of the oral anastomotic site were significantly lower in AL patients than in non-AL patients. In the multivariate analysis, the rSO2 value of the oral anastomotic site was an independent risk factor for AL. CONCLUSION: Monitoring the rSO2 at the anastomotic site enabled the prediction of AL. A prospective study to evaluate the efficacy of the INVOS™ system for monitoring intestinal rSO2 is in progress.

The characteristics of residual pneumoperitoneum after laparoscopic colorectal surgery.

INTRODUCTION: Despite the popularity of laparoscopic surgery, it remains unclear whether residual pneumoperitoneum influences the patient's postoperative course. This study aimed to evaluate the characteristics of residual pneumoperitoneum. METHODS: This retrospective study included 201 Japanese patients who had undergone elective laparoscopic colorectal surgery. The patients were divided into groups, with and without anastomotic failure; the non-anastomotic failure group was further divided into subgroups, with and without residual pneumoperitoneum. Patient characteristics were compared between the various groups. RESULTS: The group with residual pneumoperitoneum included 57 patients (30.3%). Percutaneous drainage was required for one patient with residual pneumoperitoneum. Univariate analyses revealed that residual pneumoperitoneum was associated with low values for body mass index (BMI) and subcutaneous fat area (SFA). Furthermore, relative to the group with anastomotic failure, the group without anastomotic failure but with residual pneumoperitoneum had lower values for inflammatory markers. CONCLUSION: Low BMI and SFA values were identified as risk factors for residual pneumoperitoneum. Inflammatory markers may be useful as indicators for avoiding emergent surgery when it is difficult to differentiate between asymptomatic residual pneumoperitoneum and free air related to anastomotic failure.

Identification of Aggravation-Predicting Gene Polymorphisms in Coronavirus Disease 2019 Patients Using a Candidate Gene Approach Associated With Multiple Phase Pathogenesis: A Study in a Japanese City of 1 Million People.

The pathology caused by the coronavirus disease 2019 is mediated by host-mediated lung inflammation, driving severity, and mortality. Polymorphisms in genes encoding host inflammation and immune-related molecules may be associated with the development of serious pathologies, and identifying such gene polymorphisms may lead to the identification of therapeutic targets. OBJECTIVES: We attempted to identify aggravation-predicting gene polymorphisms. DESIGN: We use a candidate gene approach associated with multiple phase pathogenesis in coronavirus disease 2019 patients among a cohort in Hiroshima, a city with a population of 1 million, in Japan. DNA samples from the study populations were genotyped for 34 functional polymorphisms from 14 distinct candidate genes, which encode proteins related to viral cell entry, regulation of viral replication, innate immune modulators, regulatory cytokines, and effector cytokines. SETTING AND PARTICIPANTS: Three core hospitals providing different services for patients with coronavirus disease 2019 under administrative control. A total of 230 patients with coronavirus disease 2019 were recruited from March 1, 2020, to March 31, 2021. MAIN RESULTS AND MEASUREMENTS: Among the 14 genes, we found rs1131454 in OAS1 and rs1143627 in IL1B genes as independent genetic factors associated with disease severity (adjusted odds ratio = 7.1 and 4.6 in the dominant model, respectively). Furthermore, we investigated the effect of multiple phase pathogenesis of coronavirus disease 2019 with unbiased multifactor dimensionality reduction analysis and identified a four-gene model with rs1131454 (OAS1), rs1143627 (IL1B), rs2074192 (ACE2), and rs11003125 (MBL). By combining these polygenetic factors with polyclinical factors, including age, sex, higher body mass index, and the presence of diabetes and hypertension, we proposed a composite risk model with a high area under the curve, sensitivity, and probability (0.917, 96.4%, and 74.3%, respectively) in the receiver operating characteristic curve analysis. CONCLUSIONS AND RELEVANCE: We successfully identified significant genetic factors in OAS1 and IL1B genes using a candidate gene approach study as valuable information for further mechanistic investigation and predictive model building.

The prognostic value of organ/space surgical site infection in stage I colorectal cancer recurrence.

PURPOSE: Evidence on risk factors for postoperative recurrence in patients with colorectal cancer (CRC) confined to pathological stage I is limited. Therefore, this study aimed to identify the risk factors for recurrence in patients with stage I CRC. METHODS: Data on clinicopathological factors and blood tests of patients diagnosed with pathological stage I CRC at Hiroshima University Hospital between April 1, 2010, and December 31, 2018, were retrospectively obtained. The statistical significance between the clinical factors and postoperative recurrence was also investigated. RESULTS: A total of 244 patients were included. The median observation period was 45 months. There were 17 patients (6.6%) with a postoperative recurrence (8 local and 9 distant recurrences). In the log-lank test, rectal cancer (p = 0.004), pT2 (p = 0.020) and organ/space surgical site infection (SSI) (p = 0.008) were significantly associated with postoperative recurrence. In a multivariate analysis, rectal cancer (hazard ratio [HR] 3.678, 95% confidence interval [CI] 1.184-11.425, p = 0.024) and organ/space SSI (HR 3.137, 95% CI 1.013-9.713, p = 0.047) were independently associated with a higher recurrence rate. Among 18 patients with organ/space SSI, 4 recurrences occurred, all of which were distant metastases. CONCLUSION: Organ/space SSI significantly affects the postoperative recurrence in patients with stage I CRC.

Preoperative incremental maximum squeeze pressure as a predictor of fecal incontinence after very low anterior resection for low rectal cancer.

PURPOSE: Very low anterior resection (VLAR) is performed widely, but some patients are left with fecal incontinence (FI), which compromises their quality of life (QOL) severely. This study sought to identify the predictive factors of postoperative FI after VLAR, which remain unclear. METHODS: We evaluated the anorectal manometry data of patients who underwent VLAR to identify the risk factors for postoperative FI among the various clinicopathological factors and manometric characteristics. FI and QOL were analyzed using the Wexner score and EORTC QLQ-C30, respectively. RESULTS: The subjects of this study were 40 patients who underwent VLAR for low rectal cancer between April, 2015 and May, 2018. There were 11 (27%) patients in the major-FI group and 29 (73%) in the minor-FI group. Multivariate analysis revealed that low preoperative incremental maximum squeeze pressure (iMSP) was an independent risk factor for postoperative major-FI. Postoperative QOL tended to be worse in the major-FI group. CONCLUSIONS: Preoperative low iMSP increases the risk of major-FI and impaired QOL after VLAR. This highlights the importance of performing preoperative anorectal manometry to evaluate the patient's anal function as well as to select the most appropriate operative procedure and early multifaceted treatment such as medication, rehabilitation, and biofeedback for postoperative FI.

Rare Cases of Low-Grade Appendiceal Mucinous Neoplasm: Two Case Reports and a Literature Review.

Appendiceal mucocele (AM) is rare disease found in <1% of all appendectomy specimens. AM is often misdiagnosed as appendicitis because the most frequent symptom is right lower quadrant abdominal pain. AM should be considered in the differential diagnosis of abdominal pain. Although there are pathological classifications, surgical resection is accepted as the treatment to prevent the development of peritoneal pseudomyxoma (PP); however, the optimal surgical technique that must be used is unclear. We present two cases suspected of being AM prior to surgery that were pathologically diagnosed as low-grade appendiceal mucinous neoplasms. Each case progressed without developing PP. The surgical procedures we chose are considered appropriate for each case.

Revascularization for cavernous transformation radical lymphadenectomy in the treatment of gastric cancer: A case report.

INTRODUCTION: There are few reported cases of cavernous transformation of the portal vein (CTPV). CTPV is usually found by accident because most patients are asymptomatic at presentation. This paper reports a case of early gastric cancer with CTPV that required gastrectomy and revascularization. PRESENTATION OF CASE: A 71-year-old man diagnosed with early gastric cancer, which was classified as clinical Stage IA (T1b, N0, M0) according to the TNM classification criteria for gastric cancer, was admitted to our hospital. Preoperative computed tomography (CT) revealed portal vein stenosis, CTPV, and esophageal varix. CT angiography showed that portal flow was maintained by the left gastric vein-right gastric vein (LGV-RGV) shunt. We had to perform lymphadenectomy while maintaining the hepatic blood flow. We performed distal gastrectomy with lymph node dissection including the vessel of the lesser curvature without massive bleeding. Postoperative course was uneventful, and CT examination performed in the 7th postoperative day revealed good blood flow from the reconstructed collateral vessels. The patient had no recurrence of gastric cancer during the postoperative period of 1 year. CONCLUSION: Diseases that cause intra-abdominal inflammation, such as pancreatitis and choledocholithiasis, might cause CTPV. Thus, patients with this medical history should be carefully assessed for CTPV to avoid intraoperative complications, such as massive bleeding or ischemia. When we preform operation a case with CTPV, we must pay meticulous attention. In our case, we encountered some difficulties in the surgical procedure, especially with respect to the dissection of the regional lymph nodes for gastric cancer.

[A case of advanced sigmoid colon cancer with metastases in the liver and the paraaortic lymph nodes successfully treated with 5-FU/l-LV and FOLFOX4 followed by S-1 leading to long-term complete response].

The patient was a 70-year-old woman with sigmoid colon cancer and metastases in the liver and the paraaortic lymph nodes. We performed sigmoidectomy along with lymph node dissection. The solitary hepatic metastasis was 3 cm in diameter; however, hepatectomy was not performed because metastases in the paraaortic lymph nodes persisted. The serum carcino embryonic antigen(CEA)level was above 200 ng/mL, both preoperatively and postoperatively. After surgery, chemo- therapy was initiated. Initially, weekly 5-fluorouracil and l / -Leucovorin(5-FU/l-LV)therapy was administered 4 times. Subsequently, 5-FU/folinic acid plus oxaliplatin(FOLFOX4)therapy was administered 12 times every 2 weeks. Thereafter, S-1 therapy(orally, 40 mg twice a day, 28 days, followed by 14 days of rest)was initiated. After 3 months of chemotherapy, serum CEA levels decreased rapidly to within the normal limit. Paraaortic lymph node metastases and the hepatic metastasis disappeared after 3 months and 11 months, respectively. S-1 therapy was continued for over 7 years. Currently, it has been over 1 year since the discontinuation of S-1 therapy, and complete response has been maintained for over 9 years since the surgery.