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.

Pancreatic ductal adenocarcinomas concomitant with intraductal papillary mucinous neoplasms of the pancreas: A investigation of those clinicopathological features by analyzing 48 patients who underwent surgery for those lesions.

BACKGROUND: Differences between pancreatic ductal adenocarcinomas (PDACs) concomitant with intraductal papillary mucinous neoplasm (IPMN) (C-PDACs), those without IPMN (NC-PDACs) and invasive cancers derived from IPMN (IC-Ds) have not been fully clarified. METHODS: Forty-eight patients with C-PDAC were included to investigate the differences in 1) clinicopathological features and 2) post-operative courses among the three invasive cancer groups. RESULTS: 1) Characteristics of C-PDACs were mostly similar to those of NC-PDACs; whereas, between C-PDACs and IC-Ds, the rate of mucinous carcinoma (2%/25%, p = 0.003) and pathological stage (IA, 15%/36%, p = 0.033; III, 31%/4%, p = 0.015) significantly differed. Most C-PDACs coexisted with small, multifocal IPMNs without mural nodules. 2) Cumulative 5-year recurrence-free survival (RFS) rate related to extra-pancreatic recurrence was significantly worse in C-PDACs than in IC-Ds (35%/69%, p = 0.008) and was not significantly different between C-PDACs and NC-PDACs (35%/18%). This related to intra-pancreatic recurrence tended to be poor in the order of IC-Ds, C-PDACs, and NC-PDACs (69%/82%/93%). CONCLUSIONS: Because characteristics of IPMNs remarkably differed between C-PDACs and IC-Ds, another algorithm specific to the early detection of C-PDACs is necessary. Appropriate post-operative managements according to the two types of recurrences may contribute to the improvement in the prognoses of C-PDACs/IC-Ds.

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.

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.

A modified MethyLight assay predicts the clinical outcomes of anti-epidermal growth factor receptor treatment in metastatic colorectal cancer.

DNA methylation status correlates with clinical outcomes of anti-epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti-EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low-methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor-derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression-free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild-type mCRC who were refractory or intolerable to oxaliplatin- and irinotecan-based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti-EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.

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.

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.

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.

[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.

[Synchronous double primary cancers of a mixed adenoneuroendocrine carcinoma of the distal bile duct and a carcinoma in situ in the perihilar bile duct].

We report the rare case of a 69-year-old man who underwent resection of a mixed adenoneuroendocrine carcinoma (MANEC) of the distal bile duct and a carcinoma in situ in the perihilar bile duct. The patient was admitted to our hospital for obstructive jaundice. Imaging studies revealed a mass in the distal bile duct, and an abnormal epithelium was detected in the perihilar bile duct using peroral cholangioscopy. Bile cytology and transpapillary biopsy of the tumor revealed adenocarcinoma. We diagnosed this patient with distal cholangiocarcinoma with extensive intraepithelial progression toward the perihilar bile duct and performed a subtotal stomach-preserving pancreaticoduodenectomy and left hepatectomy. According to the histological examination of the resected specimens, we found a MANEC in the distal bile duct and a carcinoma in situ in the perihilar bile duct. Together, they were diagnosed as synchronous double primary cancers due to the lack of pathological transition between them.

[Detection of small pancreatic cancer during surveillance of the main pancreatic duct stenosis].

An 83-year-old man with main pancreatic duct (MPD) stenosis in the pancreatic body had undergone surveillance with semiannual imaging studies for 3 years. During surveillance, magnetic resonance cholangiopancreatography revealed gradual enlargement of a small cyst near the MPD stenosis and contrast-enhanced computed tomography revealed locally progressive atrophic parenchyma in the pancreatic body. On endoscopic retrograde pancreatography, the MPD stenosis was more severe than it had been at diagnosis 3 years earlier. Endoscopic ultrasonography (EUS) showed a 10-mm hypoechoic mass adjacent to the MPD stenosis. The mass was pathologically diagnosed as an adenocarcinoma using EUS-guided fine needle aspiration, and distal pancreatectomy was performed. On histopathological examination, the resected specimen was found to be a moderately differentiated 9-mm invasive ductal carcinoma. Additionally, multiple high-grade pancreatic intraepithelial neoplasms (i.e., carcinoma in situ) were detected in the MPD and branch ducts near the invasive carcinoma.

Aberrant activation of Notch signaling in extrahepatic cholangiocarcinoma: clinicopathological features and therapeutic potential for cancer stem cell-like properties.

BACKGROUND: Little is known about the roles of Notch signaling in cholangiocarcinoma (CC). The expression of hairy and enhancer of split 1 (Hes-1) has not been investigated yet in resected specimens of CC. Notch signaling has been reported to be related to cancer stem cell (CSC) like properties in some malignancies. Our aim is to investigate the participation of Notch signaling in resected specimens of extrahepatic CC (EHCC) and to evaluate the efficacy of CC cells with CSC-like properties by Notch signaling blockade. METHODS: First, the expression of Notch1, 2, 3, 4 and Hes-1 was examined by immunohistochemistry in 132 resected EHCC specimens. The clinicopathological characteristics in the expression of Notch receptors and Hes-1 were investigated. Second, GSI IX, which is a γ-secretase-inhibitor, was used for Notch signaling blockade in the following experiment. Alterations of the subpopulation of CD24+CD44+ cells, which are surface markers of CSCs in EHCC, after exposure with GSI IX, gemcitabine (GEM), and the combination of GSI IX plus GEM were assessed by flow cytometry using the human CC cell lines, RBE, HuCCT1 and TFK-1. Also, anchorage-independent growth and mice tumorigenicity in the cells recovered by regular culture media after GSI IX exposure were assessed. RESULTS: Notch1, 2, 3, 4 and Hes-1 in the resected EHCC specimens were expressed in 50.0, 56.1, 42.4, 6.1, and 81.8 % of the total cohort, respectively. Notch1 and 3 expressions were associated with poorer histological differentiation (P = 0.008 and 0.053). The patients with the expression of at least any one of Notch1-3 receptors, who were in 80.3 % of the total, exhibited poorer survival (P = 0.050). Similarly, the expression of Hes-1 tended to show poor survival (P = 0.093). In all of the examined CC cell lines, GSI IX treatment significantly diminished the subpopulation of CD24+CD44+ cells. Although GEM monotherapy relatively increased the subpopulation of CD24+CD44+ cells in all lines, GSI IX plus GEM attenuated it. Anchorage-independent growth and mice tumorigenicity were inhibited in GSI IX-pretreated cells in RBE and TFK-1 (P < 0.05). CONCLUSION: Aberrant Notch signaling is involved with EHCC. Inhibition of Notch signaling is a novel therapeutic strategy for targeting cells with CSC-like properties.

Long-term outcomes after extrahepatic excision of congenital choladocal cysts: 30 years of experience at a single center.

BACKGROUND/AIMS: Congenital choladocal cysts are generally treated by resection of the dilated extrahepatic biliary duct followed by hepaticojejunostomy, but it is associated with postoperative complications, including postoperative cholangitis, intrahepatic calculi, pancreatitis, and carcinogenesis, in the remnant bile duct. We investigated the most common long-term complications and identified the factors implicated in their development. METHODOLOGY: We conducted a retrospective review and analysis of the long-term complications of 65 patients surgically treated for congenital choledochal cysts between 1978 and 2008 at one institute. The risk factors for intrahepatic calculi were identified based on the odds ratios of the implicated variables. RESULTS: Cholangitis with high fever or abdominal pain was reported in 14 patients (21.5%), intrahepatic calculi in 12 (18.5%), pancreatitis in 3 (4.6%), and cholangiocarcinoma in 3 (4.6%). Diagnosis with type IVa choledochal cysts was the most significant risk factor, followed by age ≥30 years at the time of treatment, and the presence of preoperative intrahepatic calculi. CONCLUSIONS: While precise and thorough surgical treatment is necessary to prevent the long-term development of complications after surgical excision of congenital choledochal cysts, it must be accompanied by long-term postoperative follow-up, especially of elderly patients and those with type IVa cysts.