Postoperative Carbohydrate Antigen 19-9 Level as a Good Indicator of Ineffective Response to the Currently Recommended S-1 Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma: A Single-Center, Retrospective Study.

PURPOSE: The intensity of adjuvant treatment for pancreatic ductal adenocarcinomas (PDACs) has not been stratified according to the risk after resection. This study was designed to identify patients with PDACs in whom the current S-1 adjuvant treatment is ineffective. METHODS: This single-center, retrospective study included patients who underwent pancreatectomy for PDACs from 2009 to 2020 at Sendai Open Hospital and were receiving S-1 adjuvant treatment. The independent risk factors for recurrence and survival were determined by using a Cox proportional hazards regression model. The effects of S-1 adjuvant treatment and detailed patterns of recurrence were evaluated in patients with high-risk factors. RESULTS: Overall, 118 patients with PDAC received S-1 adjuvant treatment. Postoperative nonnormalized carbohydrate antigen (CA19-9) was a predictive risk factor for recurrence (p < 0.010; hazard ratio [HR], 3.87; 95% confidence interval [CI], 2.26-6.62) and survival (p = 0.008; HR, 2.25; 95% CI, 1.24-4.11) after S-1 adjuvant treatment. In 24 patients with nonnormalized postoperative CA19-9, S-1 monotherapy was ineffective in preventing recurrence, even during the treatment period, compared with that noted in patients who did not receive adjuvant treatment. The recurrence rate during adjuvant treatment was 41.7%; in all cases, recurrence was caused by distant metastasis. The total recurrence rate was up to 95.8%, and distant recurrence was especially frequent. CONCLUSIONS: The current S-1 adjuvant treatment regimen is ineffective for patients with postoperative nonnormalized CA19-9. The postoperative CA19-9 level may be a good indicator for further aggressive treatment. This study may lead to further discussions on intensity stratification of adjuvant treatments for PDAC.

Isolation and whole-genome sequencing analysis of Escherichia fergusonii harboring a heat-labile enterotoxin gene from retail chicken meat in Okinawa, Japan.

This study aimed to reveal the prevalence of heat-labile enterotoxin (LT) gene-positive Escherichia fergusonii in retail chicken meat and genetically characterize these strains. E. fergusonii harboring LT gene was isolated from 6 out of 60 (10%) retail chicken samples in Okinawa, Japan. Whole-genome sequencing analysis revealed that LT gene-positive E. fergusonii from chicken meat and feces contain an IncFII plasmid harboring elt1AB, and suggested to spread clonally to retail chicken through fecal contamination. Additionally, it was found that these strains harbor multidrug-resistant genes on their plasmids. Their pathogenicity and continuous monitoring are required for confirmation.

A decreased preoperative platelet-to-lymphocyte ratio, systemic immune-inflammation index, and pan-immune-inflammation value are associated with the poorer survival of patients with a stent inserted as a bridge to curative surgery for obstructive colorectal cancer.

PURPOSE: Inflammation is one of the hallmarks of cancer, and inflammation-based markers that are calculated easily from laboratory results have shown predictive abilities. We investigated the prognostic values of the preoperative platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in patients with non-metastatic obstructive colorectal cancer (OCRC) and a self-expandable metallic stent inserted as a bridge to curative surgery. METHODS: The subjects of this retrospective study were 86 patients with pathological stage I to III OCRC. We examined the associations of these biomarkers with short- and long-term outcomes. RESULTS: Multivariate analyses revealed that a preoperative PLR < 149, SII < 597, and PIV < 209 were independently associated with poorer relapse-free survival (RFS) (P = 0.007, P < 0.001, and P = 0.002, respectively) and that a PIV < 209 was independently associated with poorer cancer-specific survival (P = 0.030). A platelet count < 240 was significantly associated with worse RFS, whereas the lymphocyte count was not. Pre-stenting PLR < 221 was an independent poor prognostic factor for RFS (P = 0.045). CONCLUSION: This study showed that decreased preoperative PLR, SII, PIV, and pre-stenting PLR were associated with poorer RFS, contrary to the findings of most previous studies. Our results suggest that platelets and obstruction contributed primarily to the opposite relationships, which might provide new insight into the possible pathophysiology of platelet-tumor interactions generated in the OCRC environment.

Prognostic significance of Ishii's sarcopenia screening score for patients undergoing curative surgery for obstructive colorectal cancer after intraluminal decompression.

PURPOSE: Sarcopenia influences the short- and long-term outcomes of various medical conditions including malignancy. Ishii's screening test estimates the probability of sarcopenia based on a score calculated by three simple variables: age, grip strength, and calf circumference. We investigated the clinical significance of Ishii's score for patients with non-metastatic obstructive colorectal cancer (OCRC) who underwent curative surgery after intraluminal decompression. METHODS: Ishii's score was calculated in 79 patients with OCRC. Muscle volume loss and decreased muscle quality were evaluated by computed tomography (CT) images as skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively. RESULTS: There were 46 men and 33 women, with a median age of 70 years old. The cutoff value for Ishii's score was 155.1 and 15 patients were in the high-score group. The high-score group was significantly associated with worse time to recurrence (TTR) and overall survival (OS), and a high Ishii's score was an independent negative prognostic factor for TTR (hazard ratio = 2.93, P = 0.015). A high Ishii's score was significantly associated with a low SMI value but not with the IMAC value. CONCLUSION: A high Ishii's score was independently associated with poorer TTR in patients with non-metastatic OCRC.

Prognostic significance of the mean corpuscular volume (MCV) and red cell distribution width (RDW) in obstructive colorectal cancer patients with a stent inserted as a bridge to curative surgery.

PURPOSE: The prognostic significance of the mean corpuscular volume (MCV) and red cell distribution width (RDW) in patients with malignancy have not been intensely investigated and are largely overlooked. We, therefore, investigated the clinical significance of MCV and RDW in non-metastatic obstructive colorectal cancer (OCRC) patients with a self-expandable metallic stent inserted as a bridge to curative surgery. METHODS: Eighty-five pathological stage II and III OCRC patients were retrospectively evaluated. The associations of the preoperative MCV and RDW values with short- and long-term outcomes were examined. RESULTS: There were 50 males and 35 females, and the median age was 71 years old. The median interval between stenting and surgery was 17 days, and the median postoperative hospital stay was 16 days. Fifty-six patients were in the MCV ≥ 87 group, and 47 were in the RDW ≥ 13.8 group. Multivariate analyses revealed the MCV ≥ 87 status to be independently associated with a poor relapse-free survival (hazard ratio [HR] = 4.70, 95% confidence interval [CI] 1.52-14.58, P = 0.007). The RDW ≥ 13.8% was an independent predictor of postoperative infectious complications (HR = 7.28, 95% CI 1.24-42.70, P = 0.028). CONCLUSION: The MCV and RDW are simple but strong predictors of postoperative outcomes in OCRC patients.

A longer interval after stenting compromises the short- and long-term outcomes after curative surgery for obstructive colorectal cancer.

PURPOSE: Intestinal decompression using self-expandable metallic colonic stents (SEMSs) as a bridge to surgery is now considered an attractive alternative to emergency surgery. However, data regarding the optimal timing of surgery after stenting are limited. METHODS: We investigated the impact of the interval between stenting and surgery on short- and long-term outcomes in 92 obstructive colorectal cancer (OCRC) patients who had a SEMS inserted and subsequently received curative surgery. RESULTS: The median age of the patients was 70.5 years, and the median interval between SEMS insertion and the surgery was 17 (range 5-47) days. There were 35 postoperative complications, including seven major postoperative complications. An interval of more than 16 days was an independent predictor of a poor relapse-free survival (hazard ratio [HR] = 3.12, 95% confidence interval [CI] 1.24-7.81, p = 0.015). An interval of more than 35 days was independently associated with major postoperative complications (HR = 16.6, 95% CI 2.21-125, p = 0.006). CONCLUSION: A longer interval between stenting and surgery significantly compromised the short- and long-term outcomes. Surgery within 16 days after stenting might help maximize the benefit of SEMS without interfering with short- and long-term outcomes.

Development of a simple and cost-effective gel-based duplex PCR method to identify both encapsulated and unencapsulated Neisseria meningitidis applicable under resource-limited conditions.

Tens of thousands of cases of invasive meningococcal diseases (IMD) with thousands of deaths are reported annually worldwide; however, only approximately 40 cases occur each year in Japan. Therefore, the majority of medical technologists in Japan have never performed or prepared for analyses of the causative agent, Neisseria meningitidis. Since IMD outbreaks have been reported at mass gathering events, the risk of IMD will increase in Japan in 2021 because of the Olympics. In the present study, we developed a new simple gel-based duplex PCR method that may be employed by the majority Japanese clinical laboratories. It is simple to perform and time- and cost-effectively identifies encapsulated and unencapsulated N. meningitidis by detecting the encapsulated N. meningitidis-specific ctrB and N. meningitidis-specific ggt genes. We consider this simple and cost-effective identification method to compensate for the lack of experience and resource-poor conditions in most Japanese laboratories in which N. meningitidis has rarely been examined.

The Controlling Nutritional Status (CONUT) Score as a prognostic factor for obstructive colorectal cancer patients received stenting as a bridge to curative surgery.

PURPOSE: The Controlling Nutritional Status (CONUT) Score, originally developed as a nutritional screening tool, is a cumulative score calculated from the serum albumin level, total cholesterol level, and total lymphocyte count. Previous studies have demonstrated that the score has significant prognostic value in various malignancies. We investigated the relationship between the CONUT score and long-term survival in obstructive colorectal cancer (OCRC) patients who underwent self-expandable metallic colonic stent placement and subsequently received curative surgery. METHODS: We retrospectively analyzed 57 pathological stage II and III OCRC patients between 2013 and 2019. The associations between the preoperative CONUT score and clinicopathological factors and patient survival were evaluated. RESULTS: A receiver operating characteristic curve analysis revealed that the optimal cut-off value for the CONUT score was 7. A CONUT score of ≥ 7 was significantly associated with elevated CA19-9 level (p = 0.03). Multivariate analyses revealed that a CONUT score of ≥ 7 was independently associated with cancer-specific survival (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 1.2-85.9, p = 0.03) and disease-free survival (HR = 7.1, 95% CI 2.3-21.7, p = 0.0006). CONCLUSION: The results demonstrated that the CONUT score was a potent prognostic indicator. Evaluating the CONUT score might result in more precise patient assessment and tailored treatment.

[Study of Laparoscopic Surgery for Elderly Patients with Colorectal Cancer].

The number of elderly patients and colorectal cancer patients is increasing, so laparoscopic surgery for colorectal cancer in elderly patients is suspected to increase. In 456 patients who underwent laparoscopic surgery for colorectal cancer, we investigated whether laparoscopic surgery for elderly patients with colon cancer patients could be performed equally compared to non-elderly patients. Preoperative ASA-PS was slightly poorer in elderly patients. There was no significant difference in pStage. The 5-year overall survival rate was lower in the elderly, but there were no significant differences in blood loss, operation time, postoperative hospital stays and incidence of complications of Clavien-Dindo classification grade 3 or higher. It was suggested that laparoscopic surgery for elderly patients with colorectal cancer may be safely performed compared with non-elderly patients.

Protective effect of the oral administration of cystine and theanine on oxaliplatin-induced peripheral neuropathy: a pilot randomized trial.

BACKGROUND: Oxaliplatin, one of the key cytotoxic drugs for colorectal cancer, frequently causes peripheral neuropathy which leads to dose modification and decreased patients' quality of life. However, prophylactic or therapeutic measures have not yet been established. Orally administered amino acids, cystine and theanine, promoted the synthesis of glutathione which was one of the potential candidates for preventing the neuropathy. The aim of this study was to determine whether daily oral administration of cystine and theanine attenuated oxaliplatin-induced peripheral neuropathy (OXLIPN). METHODS: Twenty-eight colorectal cancer patients who received infusional 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) therapy were randomly and evenly assigned to the cystine and theanine group and the control group. OXLIPN was assessed up to the sixth course using original 7-item questionnaire as well as Common Terminology Criteria for Adverse Events (CTCAE) grading scale. RESULTS: Neuropathy scores according to our original questionnaire were significantly smaller in the cystine and theanine group at the fourth (p = 0.026), fifth (p = 0.029), and sixth course (p = 0.038). Furthermore, significant differences were also observed in CTCAE neuropathy grades at the fourth (p = 0.037) and the sixth course (p = 0.017). There was one patient in each group who required dose reduction due to OXLIPN. Except for neurotoxicity, no significant differences were noted in the incidence of adverse events, and the total amount of administered oxaliplatin. CONCLUSION: The results demonstrated the daily oral administration of cystine and theanine attenuated OXLIPN.

The prognostic value of the prognostic nutritional index and inflammation-based markers in obstructive colorectal cancer.

PURPOSE: Inflammation-based markers predict long-term outcomes of various malignancies. We investigated the relationship between these markers and the long-term survival in obstructive colorectal cancer (OCRC) patients with self-expandable metallic colonic stents (SEMSs) who subsequently received curative surgery. METHODS: We retrospectively analyzed 72 consecutive pathological stage II and III OCRC patients between 2013 and 2019. The prognostic significance of the prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), and platelet-lymphocyte ratio (PLR) was evaluated. RESULTS: The overall survival (OS), cancer-specific survival, and disease-free survival (DFS) were significantly shorter in the PNI < 35 group than in the PNI ≥ 35 group (p = 0.006, p < 0.001, and p = 0.003, respectively), and multivariate analyses revealed the PNI to be the only inflammation-based marker independently associated with the survival. A PNI < 35 was significantly associated with an elevated CA 19-9 level (p = 0.04) and longer postoperative hospital stay (p = 0.03). Adjuvant chemotherapy was also significantly associated with the OS (p = 0.040) and DFS (p = 0.011) in multivariate analyses. CONCLUSION: The results showed that the PNI was a potent prognostic indicator. For OCRC patients, both systemic inflammation and the nutrition status seem to be important for predicting the prognosis, and administering adjuvant chemotherapy was very important.

Preoperative change of modified Glasgow prognostic score after stenting predicts the long-term outcomes of obstructive colorectal cancer.

PURPOSE: Inflammation-based markers predict the long-term outcomes of various malignancies. We investigated the relationship between the modified Glasgow prognostic score (mGPS) and the long-term outcomes of obstructive colorectal cancer in patients who underwent self-expandable metallic colonic stent placement and subsequently received curative surgery. METHODS: We retrospectively analyzed 63 consecutive patients with pathological stage II and III obstructive colorectal cancer from 2013 to 2018. The mGPS was calculated before stenting and surgery, and the difference of the scores was defined as the d-mGPS. RESULTS: All d-mGPS = 2 patients were > 70 years of age (p = 0.01). Postoperative complications were more common in the preoperative mGPS = 2 group (p = 0.02). The postoperative hospital stay was significantly longer in the mGPS = 2 group (p = 0.007). Multivariate analyses revealed that d-mGPS was an independent prognostic factor for overall survival (OS) (hazard ratio [HR] = 9.18, p = 0.004) and cancer-specific survival (HR = 9.98, p = 0.01). Preoperative mGPS = 2 was significantly associated with poor OS (HR = 5.53, p = 0.04). CONCLUSION: The results indicated that mGPS might serve as a valuable indicator of the immunonutritional status of preoperative patients, and a preoperative change of the status might affect the long-term outcomes of patients with obstructive colorectal cancer.

[Oral Administration of Amino Acids Cystine and Theanine During Chemotherapy Can Reduce the Symptoms of Stomatitis].

INTRODUCTION: Cystine and theanine are amino acids that contribute to the production of glutathione, which is the most potent antioxidant in the body, and it has been reported that these amino acids prevent immunosuppression, has anti- inflammatory effect, and reduce invasiveness. OBJECTIVE: To evaluate the effect of oral administration of amino acids cystine and theanine on stomatitis during chemotherapy. SUBJECTS AND METHODS: For 17 patients with Grade 1(CTCAE v4.0)or worse stomatitis during chemotherapy for gastrointestinal cancer or breast cancer, cystine 700 mg and theanine 280 mg/ day were orally administered for 28 days, and the degree of stomatitis was evaluated objectively and subjectively. RESULTS: As an objective evaluation, changes in Grade showed improvement in 11 cases(64.7%), 5 cases unchanged(29.4%), and 1 case was worse(5.9%). Subjective assessment, pain was in remission(30.8%)or disappeared(61.5%)in 4 of 13 cases. Food intake increased in 5 patients(29.4%). 15 of 17 patients(88.2%)felt it was effective. CONCLUSION: Oral administration of amino acids cystine and theanine during chemotherapy can reduce the symptoms of stomatitis.

[A Case of Gastric Cancer That Pathological Completely Responded to Neoadjuvant S-1 plus Cisplatin Therapy].

A 67-year-old man with complaints of upper abdominal pain visited a clinic and was diagnosed with type 3 gastric cancer. Contrasted-enhanced CT revealed gastric wall thickening and extensive metastatic lymph nodes particularly around the celiac artery and also invasion to pancreas. He was diagnosed with cT4b, cN2, cM0, cStage ⅢB and we treated with neoadjuvant chemotherapy(NAC)consisting of 4 courses of S-1 and cisplatin regimen. After the NAC, primary cancer and metastatic lymph nodes were reduced remarkably. A curative operation could be performed and the histopathological examination showed"Grade 3, pathological complete response".

[A Case of Granulocyte-Colony Stimulating Factor Producing Ascending Colon Cancer].

A 59-year-old man with chief complaints of right-sided rib pain and fever was admitted to our hospital. A type 2 tumor in the ascending colon was revealed by total colonoscopy. Computed tomography examination revealed multiple tumors in the liver. The white blood cell count was high as 13,740/µL. Chemotherapy was planned after treatment with antibiotics, but it was not successful. Right colectomy was performed for infection control. mFOLFOX6 therapy was performed, but liver metastases progressed rapidly, and he died on the 39th postoperative day. The immunohistochemistry revealed G-CSF producing colon cancer. G-CSF producing colon cancer progresses rapidly with poor prognosis. It is necessary to think carefully about indication of surgery and chemotherapy.

Oral administration of the amino acids cystine and theanine attenuates the adverse events of S-1 adjuvant chemotherapy in gastrointestinal cancer patients.

BACKGROUND: Nutritional therapy is used to reduce the adverse events (AEs) of anticancer drugs. Here, we determined whether the amino acids cystine and theanine, which provide substrates for glutathione, attenuated the AEs of S-1 adjuvant chemotherapy. METHODS: Patients scheduled to receive S-1 adjuvant chemotherapy were randomized to the C/T or the control groups. The C/T group received 700 mg cystine and 280 mg theanine orally 1 week before the administration of S-1, which then continued for 5 weeks. Each group received S-1 for 4 weeks. Blood sampling was performed and AEs were evaluated (CTCAE ver. 4.0) before and after the administration of S-1. S-1 was discontinued when AEs ≥ grade 2 occurred. RESULTS: The incidences of AEs of any grade and those over grade 2 were lower in the C/T group than in the controls. The incidence of diarrhea (G ≥ 2) was significantly less (p < 0.05) in the C/T group (3.1 %) than in the controls (25.8 %). The duration and completion rate of the S-1 adjuvant chemotherapy were significantly longer (p < 0.01) and higher (p < 0.01), respectively, in the C/T group (complete ratio: 75.0 %, duration: 24.8 ± 5.8 days) than in the controls (complete ratio: 35.5 %, duration: 20.0 ± 7.7 days). CONCLUSIONS: The oral administration of cystine and theanine attenuated the AEs of S-1 adjuvant chemotherapy and increased the S-1 completion rate, suggesting that cystine and theanine is a useful supportive care for chemotherapy.

The Spread of Heat-Labile Enterotoxin-Harboring Escherichia fergusonii in Broiler Chickens and Pigs in Okinawa, Japan.

In 2012, Escherichia fergusonii harboring a heat-labile enterotoxin (LT) was isolated from healthy chickens in South Korea. However, little is known regarding the prevalence, spread, and pathogenicity of these strains in humans and animals. This study aimed to understand the public health threats, such as the distribution, antimicrobial resistance, and genetic diversity of E. fergusonii carrying LTs. E. fergusonii containing LT was isolated from 15.0% (52/346) of chicken fecal samples from all three tested chicken farms but not from 360 pig fecal samples. The antimicrobial susceptibility testing revealed that over 75% of strains were resistant to ampicillin, kanamycin, nalidixic acid, streptomycin, or tetracycline; additionally, 71.2% (37/52) of strains were resistant to all five of these antimicrobials. The 52 strains were clustered into eight pulsed-field gel electrophoresis (PFGE) types, with types V and type VI accounting for 84.6% (44/52). In the present study, multiple chicken farms harbored E. fergusonii with similar antimicrobial resistance patterns and genetic clonality. Since the pathogenicity of LT-bearing E. fergusonii in humans and animals, such as food poisoning and sporadic diarrhea via meat, the transmission of the strains, and the dissemination of antimicrobial resistance genes are unknown, additional research is required.

Antimicrobial resistance and molecular epidemiological analysis of Escherichia fergusonii harboring the mcr gene in pigs and broiler chickens in Okinawa, Japan.

The dissemination of mcr-harboring Enterobacteriaceae, e.g., Escherichia fergusonii, with resistance to colistin via animal products is a public health concern. In our previous study, E. fergusonii harboring the mcr gene were isolated from 11 pigs and 43 chickens. To understand the spread of mcr-harboring E. fergusonii in Okinawa, Japan, and to gain further insights into how they can be controlled, an antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE), a conjugation test for the transferability of mcr-harboring plasmids, and PCR-based replicon typing (PBRT) were performed using the 54 strains. According to the disk-diffusion and broth microdilution methods, 9 of the 11 strains from pigs and 9 of the 43 strains from chickens had multidrug resistance (MDR). The broth microdilution method showed that all strains were resistant to colistin, and the minimum inhibitory concentration of colistin was 4-16 µg/mL. PFGE suggested identical PFGE types were being transmitted within one pig farm, within one chicken farm, and among several chicken farms. These findings showed that some mcr-harboring E. fergusonii in Okinawa exhibited MDR, and these had spread within farms and between farms. In the mcr gene conjugation test and PBRT, a type IncI2 plasmid replicon was detected in all mcr-1-harboring transconjugants. Therefore, evidence suggests that the IncI2 plasmid is probably involved in the transmission of the mcr-1 gene. It is important to monitor the antimicrobial resistance profile and dissemination of the IncI2 plasmid in mcr-harboring E. fergusonii.