Effect of Abdominal Aortic Calcification on Recurrence Following Initial Hepatectomy for Colorectal Liver Metastases.

BACKGROUND/AIM: The aim of the study was to analyze the association between abdominal aortic calcification (AAC) and patient prognosis following resection of colorectal liver metastases (CRLM). AAC potentially reflects intrahepatic immunity and is involved in tumor development and progression. However, the clinical effects of AAC on colorectal cancer (CRC) prognosis after curative-intent liver resection for CRLM remain unclear. PATIENTS AND METHODS: We evaluated the effect of AAC on the clinical prognosis and metastatic patterns in 99 patients who underwent hepatectomy for CRLM between 2010 and 2019. RESULTS: The high-AAC group had significantly worse overall survival (OS) and remnant liver recurrence rate (RR) after propensity score matching to adjust for differences in baseline characteristics of patients and tumors. In multivariate Cox regression analyses, high AAC volume was an independent risk factor for poor OS and liver RR, but not poor lung RR. The expression of tumor necrosis factor-related apoptosis-inducing ligand, known as an anti-tumor marker, in liver natural killer (NK) cells was lower in the high-AAC group than in the low-AAC group. CONCLUSION: High AAC volume showed a strong relationship with remnant liver RR after curative resection of CRLM. High AAC volume may be responsible for the suppression of anti-tumor activity of liver NK cells, which results in an increased risk of liver recurrence and poor prognosis.

Long-Term Follow-up Data of a Multi-Institutional Phase-2 Study of S-1/oxaliplatin and Bevacizumab Therapy in Patients with Advanced Colorectal Cancer: The HiSCO-02 Study.

Oral fluoropyrimidines (FUs) have certain advantages over intravenous FUs, such as longer intervals between outpatient visits, no requirement for central venous port (CVP) implantation, and lower incidence of neutropenia. We previously reported the efficacy of S-1/oxaliplatin (SOX) with bevacizumab therapy as a first-line treatment for advanced colorectal cancer (CRC) in a prospective phase-II multi-institutional clinical trial (HiSCO-02 study). However, our prognostic data at the time lacked a sufficient observation period. Herein, we analyze the longer-term follow-up data, focusing on the status of eventual CVP implantation via an open-label, non-randomized, multicenter study. This study enrolled 55 patients (mean age, 64 years), of whom 43 died (41 of primary cancer). The median overall survival was 22.7 months (95% CI: 20.1-34.7 months). Post-treatment regimens after failure of first-line treatment were initiated in 43 patients; CPT11-based regimens were selected in most cases, and other oral FU combinations in nine. CVP was implanted in 35 patients prior to first-line treatment; eleven of the remaining 20 patients did not require CVP implantation. In conclusion, we report here the final prognostic update of the Phase II clinical trial examining the efficacy of SOX plus bevacizumab therapy, the results of which confirm the clinical efficacy of this regimen.

C-Reactive Protein/Albumin Ratio Is an Independent Risk Factor for Recurrence and Survival Following Curative Resection of Stage I-III Colorectal Cancer in Older Patients.

BACKGROUND: The number of older patients with cancer has increased, and colorectal cancer is expected to be affected by this trend. This study aimed to compare prognostic factors, including nutritional and inflammation-based indices, between patients aged ≥ 70 and < 70 years following curative resection of stage I-III colorectal cancer. PATIENTS AND METHODS: This study included 560 patients with stage I-III colorectal cancer who underwent curative resection between May 2010 and June 2018. A retrospective analysis was performed to identify prognosis-associated variables in patients aged ≥ 70 and < 70 years. RESULTS: Preoperative low body mass index, high C-reactive protein/albumin ratio, and comorbidities were mainly associated with poor prognosis in patients aged ≥ 70 years. Tumor factors were associated with a poor prognosis in patients aged < 70 years. The C-reactive protein/albumin ratio was independently associated with poor overall survival and recurrence-free survival in those aged ≥ 70 years. The time-dependent area under the curve for the C-reactive protein/albumin ratio was superior to those of other nutritional and inflammation-based indices in most postoperative observation periods in patients aged ≥ 70 years. CONCLUSIONS: Tumor factors were associated with a poor prognosis in patients aged < 70 years. In addition to lymph node metastasis, preoperative statuses were associated with poor prognosis in patients aged ≥ 70 years. Specifically, the preoperative C-reactive protein/albumin ratio was independently associated with long-term prognosis in patients aged ≥ 70 years with stage I-III colorectal cancer after curative resection.

Survival outcomes of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: the HiSCO-04 prospective cohort study.

BACKGROUND: The efficacy of adjuvant chemotherapy in elderly patients aged ≥ 80 years with stage III colorectal cancer remains unclear. In parallel with a multicenter prospective phase II trial evaluating the efficacy of uracil-tegafur and leucovorin as adjuvant chemotherapy (HiSCO-03), we conducted a prospective observational study of these patients to assess survival outcomes, including those ineligible for chemotherapy. METHODS: This multi-institutional prospective cohort study included 17 institutions in Hiroshima, Japan. Patients aged ≥ 80 years with stage III colorectal cancer who underwent curative resection were enrolled. The primary endpoint was 3-year disease-free survival, and the secondary endpoints were 3-year overall and relapse-free survival. Propensity score matching was used to assess the effects of adjuvant chemotherapy on survival outcomes. RESULTS: A total of 214 patients were analyzed between 2013 and 2018, including 99 males and 115 females with a median age of 84 years (range 80-101 years). Recurrence occurred in 58 patients and secondary cancers were observed in 17. The 3-year disease-free, overall, and relapse-free survival rates were 63.3%, 76.9%, and 62.9%, respectively. Adjuvant chemotherapy was administered to 65 patients with a completion rate of 52%. In a study of 80 patients that adjusted for background factors using propensity score matching, patients who completed the planned treatment showed improved disease-free survival (3-year disease-free survival: completed, 80.0%; not received, 65.5%; and discontinued, 56.3%; p = 0.029). CONCLUSIONS: Completion of adjuvant chemotherapy may improve the prognosis of patients with colorectal cancer aged ≥ 80 years, although the number of patients who would benefit from it is limited.

Association between social background and implementation of postoperative adjuvant chemotherapy for older patients undergoing curative resection of colorectal cancers, sub-analysis of the HiSCO-04 study.

PURPOSE: Adjuvant chemotherapy is recommended following colorectal cancer resection based on risk of recurrence. In older patients, treatment decisions should consider recurrence rates and tolerability, as well as functional prognosis, residual disease, and social factors. This study aims to investigate factors, including social background, influencing implementation of postoperative adjuvant chemotherapy in older patients undergoing curative resection for colorectal cancer. METHODS: This multi-institutional prospective cohort study included 15 institutions belonging to the Hiroshima Surgical study group for Clinical Oncology. We analyzed 159 older patients aged ≥ 80 years, who underwent curative resection for stage III colorectal cancer between December 2013 and June 2018, as sub-analysis of the HiSCO-04 study. RESULTS: In total, 62 (39.0%) patients underwent postoperative adjuvant chemotherapy. Four factors were significantly associated with its implementation: performance status < 2, Charlson Comorbidity Index < 2, prognostic nutritional index ≥ 40, and presence of a spouse or siblings as lifestyle supporters. No significant difference was found in the backgrounds between complete and incomplete postoperative adjuvant chemotherapy patients. CONCLUSION: Performance status, Charlson Comorbidity Index, nutritional status, and presence of a spouse or siblings as lifestyle supporters are possible factors influencing the implementation of postoperative adjuvant chemotherapy in older patients. To select appropriate treatment options, including postoperative adjuvant chemotherapy, it is essential to consider physical condition and comorbidities of older patients, thoroughly explain the situation to their families, and establish a support system to enhance understanding of the available treatment options.

Laparoscopic excision of a retroperitoneal pseudocyst using a modified medial approach: A case report.

INTRODUCTION: Retroperitoneal pseudocysts of non-pancreatic origin are rare. Although the laparoscopic approach has been used for their treatment, laparotomy remains the mainstream strategy for these lesions. PRESENTATION OF CASE: We report the case of an asymptomatic 51-year-old male patient who was incidentally diagnosed with a retroperitoneal pseudocyst. Computed tomography showed a 3 × 3 cm cystic lesion in the retroperitoneum, localized between the third part of the duodenum and the inferior vena cava. The patient underwent complete laparoscopic excision using a modified right-sided colonic resection procedure (modified medial approach), and histopathological examination revealed a non-pancreatic retroperitoneal pseudocyst. The patient was discharged without any complications, and no postoperative recurrence was detected. DISCUSSION: Complete excision is of great significance in the treatment of retroperitoneal cysts. There have been few studies on the laparoscopic approach for retroperitoneal pseudocysts. A laparoscopic procedure is less invasive and helps identify the correct tissue planes to ensure complete resection and prevent inadvertent injury to adjacent vital structures. We detached the retroperitoneal lesion from the duodenum and safely removed it without damaging the surrounding organs by a modified medial approach. CONCLUSIONS: Retroperitoneal pseudocysts can be resected laparoscopically by identifying the correct tissue planes and adjacent vital structures.

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.

Protocadherin B9 Is Associated with Human Esophageal Squamous Cell Carcinoma Progression.

INTRODUCTION: Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC. METHODS: PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference. RESULTS: High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells. CONCLUSION: These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC.

Essential Roles of TDO2 in Gastric Cancer: TDO2 Is Associated with Cancer Progression, Patient Survival, PD-L1 Expression, and Cancer Stem Cells.

INTRODUCTION: Tryptophan metabolism has been shown to be involved in tumor development. Two main tryptophan-degrading enzymes, tryptophan 2,3-dioxygenase (TDO2) and indoleamine 2,3-dioxygenase 1 (IDO1), may potently promote cancer cell survival and distant metastasis in diverse types of cancer, such as lung and breast cancer. IDO1 overexpression is an independent prognosticator in gastric cancer (GC). This work aimed to uncover the expression of TDO2 and its clinicopathologic significance in GC. METHODS: TDO2 expression was evaluated in public data of The Cancer Genome Atlas cohort STAD and in two different GC cohorts. Correlation between TDO2 and immune cell infiltrates as well as PD-L1 tumor staining was investigated. The biofunction of TDO2 was examined with MTT, colony formation, and spheroid formation assays by RNA interference. RESULTS: TDO2 expression was correlated with both progressive disease and clinical outcome, and its expression was an independent predictor of prognosis in GC. TDO2 expression was correlated with infiltration of immune cells and tumor expression of PD-L1. Inhibition of TDO2 expression suppressed cell proliferation, colony formation, and cell invasion of GC cells. Additionally, suppression of TDO2 expression inhibited spheroid body-formation and viability of GC organoids. CONCLUSION: Our data show that TDO2 might be a crucial marker for predicting prognosis and targeted therapy in GC.

Protocadherin B9 Is Associated with Tumorigenesis and Cancer Progression in Colorectal Cancer.

BACKGROUND: Genes encoding transmembrane proteins expressed specifically in cancer cells may be ideal therapeutic targets or biomarkers for diagnosis. METHODS: In the present study, we investigated the expression and function of PCDHB9, which encodes transmembrane protein protocadherin B9 in colorectal cancer (CRC). RESULTS: Immunohistochemical analysis showed that 39 (26%) of 148 CRC cases were positive for protocadherin B9. Expression of protocadherin B9 correlated with lymphatic invasion, venous invasion, and T classification and was weakly detected in adenomas by immunohistochemistry. Although PCDHB9 knockdown did not change cell growth and invasion activity in CRC cell lines, cell adhesion to fibronectin was significantly reduced by PCDHB9 knockdown. Expressions of ITGA3, ITGA4, ITGA5, ITGB1, and ITGB6 were significantly reduced by PCDHB9 knockdown. In addition, the number of spheres was significantly decreased by PCDHB9 knockdown. CONCLUSION: These results suggest that protocadherin B9 might be associated with colorectal tumorigenesis and cancer progression in CRC.

Overexpression of aldolase, fructose-bisphosphate C and its association with spheroid formation in colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The spheroid colony formation assay is a useful method to identify cancer stem cells (CSCs). Using the DLD-1 and WiDr CRC cell lines, we performed microarray analyses of spheroid body-forming and parental cells and demonstrated that aldolase, fructose-bisphosphate C (ALDOC) was overexpressed in the spheroid body-forming cells of both lines. Cells transfected with small interfering RNA against ALDOC demonstrated lower proliferation, migration, and invasion compared with negative control cells. Both the number and size of spheres produced by the CRC cells were significantly reduced by ALDOC knockdown. Additionally, inhibition of ALDOC reduced lactate production. Immunohistochemistry was used to analyze ALDOC protein expression in tissues from 135 CRC patients and revealed that 66 (49%) cases were positive for ALDOC. The ALDOC-positive cases were associated with higher T and M grades and, as determined by Kaplan-Meier analysis, a poorer prognosis. Univariate and multivariate analyses indicated that ALDOC expression was an independent prognostic factor for CRC patients. Furthermore, ALDOC expression was associated with CD44 expression. These results suggest that ALDOC contributes to CRC progression and plays an important role in CSCs derived from 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.

Overexpression of claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer.

Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan-Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.

TDO2 overexpression correlates with poor prognosis, cancer stemness, and resistance to cetuximab in bladder cancer.

BACKGROUND: Bladder cancer (BC) is the 10th most common cancer in the world. BC with muscle invasion results in a poor prognosis and is usually fatal. Cancer cell metabolism has an essential role in the development and progression of tumors. Expression of tryptophan 2,3-dioxygenase (TDO2) is associated with tumor progression and worse survival in some other cancers. However, no studies have been performed to uncover the biofunctional roles of TDO2 in BC. AIM: This study aim to investigate the clinicopathologic significance of TDO2 in BC. METHODS AND RESULTS: TDO2 expression was evaluated by qRT-PCR and immunohistochemistry in an integrated analysis with the Cancer Genome Atlas (TCGA) and other published datasets. TDO2 overexpression was significantly associated with T classification, N classification, and M classification, tumor stage, recurrence, and basal type, and with the expression of CD44 and aldehyde dehydrogenase 1 (ALDH1) in BC. High TDO2 expression correlated with poor outcome of BC patients. Using BC cell lines with knockdown and forced expression of TDO2, we found that TDO2 was involved in the growth, migration, and invasiveness of BC cells. Moreover, TDO2 was found to be crucial for spheroid formation in BC cells. Importantly, TDO2 promoted BC cells resistance to cetuximab through integration of the EGFR pathway. CONCLUSION: Our results indicate that TDO2 might take an essential part in BC progression and could be a potential marker for targeted therapy in BC.

Clinicopathologic features of TDO2 overexpression in renal cell carcinoma.

BACKGROUND: Tryptophan 2,3-dioxygenase (TDO2) is the primary enzyme catabolizing tryptophan. Several lines of evidence revealed that overexpression of TDO2 is involved in anoikis resistance, spheroid formation, proliferation, and invasion and correlates with poor prognosis in some cancers. The aim of this research was to uncover the expression and biofunction of TDO2 in renal cell carcinoma (RCC). METHODS: To show the expression of TDO2 in RCC, we performed qRT-PCR and immunohistochemistry in integration with TCGA data analysis. The interaction of TDO2 with PD-L1, CD44, PTEN, and TDO2 expression was evaluated. We explored proliferation, colony formation, and invasion in RCC cells line affected by knockdown of TDO2. RESULTS: RNA-Seq and immunohistochemical analysis showed that TDO2 expression was upregulated in RCC tissues and was associated with advanced disease and poor survival of RCC patients. Furthermore, TDO2 was co-expressed with PD-L1 and CD44. In silico analysis and in vitro knockout of PTEN in RCC cell lines revealed the ability of PTEN to regulate the expression of TDO2. Knockdown of TDO2 suppressed the proliferation and invasion of RCC cells. CONCLUSION: Our results suggest that TDO2 might have an important role in disease progression and could be a promising marker for targeted therapy in RCC. (199 words).

Tumor budding as a predictive marker for 5-fluorouracil response in adjuvant-treated stage III colorectal cancer.

BACKGROUND: Tumor budding (TB) has been described as an adverse prognostic marker for operable colorectal cancer (CRC); however, a limited number of studies have demonstrated the prognostic significance of TB in patients with drug therapy. This study was conducted to determine the predictive power of TB in stage III CRC patients who received adjuvant chemotherapy. METHODS: We retrospectively collected clinicopathological data including TB of 237 stage III colorectal cancer patients at Hiroshima University Hospital between July 1, 2006 and June 31, 2019. Differential disease-free survival (DFS) was investigated according to TB status. RESULTS: This study included 237 patients with a median age of 67 years, comprising patients who underwent surgery alone (n = 65), 5-fluorouracil (5-FU) monotherapy (n = 129), and oxaliplatin-based chemotherapy (n = 43). Overall, 81 patients developed disease recurrence, and 33 patients died of cancer-related causes. The TB status was categorized into two groups: 99 with low budding (< 5 buds) and 138 with high budding (≥ 5 buds). Overall, the low budding cases demonstrated significantly better DFS. In the 5-FU monotherapy group, low-risk patients (T1, T2, or T3 and N1) with low budding showed a remarkably higher 3-year DFS (91%) compared to high budding (55%). CONCLUSION: Our results indicate that TB could play a subsidiary role in selecting patients who could maintain a favorable prognosis with 5-FU monotherapy in stage III CRC.