Robotic versus open and laparoscopic pelvic exenterations for pelvic cancer: a multicenter propensity-matched analysis in Japan.

BACKGROUND: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors. METHODS: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias. RESULTS: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002). CONCLUSION: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Is frequent measurement of tumor markers beneficial for postoperative surveillance of colorectal cancer?

PURPOSE: To determine whether frequent measurement of tumor markers triggers early detection of colorectal cancer recurrence. METHODS: Of 1,651 consecutive patients undergoing colorectal cancer surgery between 2010 and 2016, 1,050 were included. CEA and CA 19-9 were considered to be postoperative tumor markers and were measured every 3 months for 3 years, and then every 6 months for 2 years. Sensitivity analysis of elevated CEA and CA19-9 levels and multivariate analysis of factors associated with elevated CEA and CA19-9 levels were performed. The proportion of triggers for detecting recurrence was determined. RESULTS: The median follow-up period was 5.3 years. After applying the exclusion criteria, 1,050 patients were analyzed, 176 (16.8%) of whom were found to have recurrence. After excluding patients with persistently elevated CEA and CA19-9 levels before and after surgery from the 176 patients, 71 (43.6%) of 163 patients had elevated CEA levels and 35 (20.2%) of 173 patients had elevated CA19-9 levels. Sensitivity/positive predictive values for elevated CEA and CA19-9 levels at recurrence were 43.6%/32.3% and 20.2%/32.4%, respectively. Lymph node metastasis was a factor associated with both elevated CEA and CA19-9 levels at recurrence. Of the 176 patients, computed tomography triggered the detection of recurrence in 137 (78%) and elevated tumor marker levels in 13 (7%); the diagnostic lead interval in the latter 13 patients was 1.7 months. CONCLUSION: Tumor marker measurements in surveillance after radical colorectal cancer resection contribute little to early detection, and frequent measurements are unnecessary for stage I patients with low risk of recurrence.

Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). Conclusions and Relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. Trial Registration: ClinicalTrials.gov Identifier: NCT02394795.

Multicenter, single-arm, phase II study of the continuous use of panitumumab in combination with FOLFIRI after FOLFOX for RAS wild-type metastatic colorectal cancer: Exploratory sequential examination of acquired mutations in circulating cell-free DNA.

This multicenter single-arm, phase II study evaluated the efficacy and safety of uninterrupted panitumumab usage combined with cytotoxic doublets for unresectable/metastatic colorectal cancer (mCRC). Additionally, clinical value of the RAS/BRAF mutation status in circulating cell-free DNA (ccfDNA) was evaluated; this evaluation was measured independently of the protocol treatment. Eligible patients with RAS wild-type mCRC who had received the first-line panitumumab plus FOLFOX treatment were recruited and administered continuous panitumumab combined with FOLFIRI. Progression-free survival (PFS) at 6 months was the primary endpoint, with threshold and expected values of 35% and 50%, respectively. In total, 54 patients were enrolled between October 2017 and October 2019. The crude 6-month PFS rate was 37.0%, with a 4.8-month median PFS. The response rate and disease control rate were 16.7% and 50.0%, respectively. Notably, of the 54 participants, 17 showed RAS/BRAF mutations until the end of the protocol treatment and of the 22 patients with progressive disease as their best response, 10 possessed RAS/BRAF mutations in their plasma ccfDNA at baseline. The median PFS significantly differed among patients harboring tumors with BRAF and RAS mutations and those with wild-type tumors. In conclusion, our study failed to show the expected efficacy of the continuous panitumumab use in the second-line treatment. Liquid biopsy discriminated the duration of PFS according to the mutation status. The effectiveness of continuous treatment with panitumumab should be evaluated in patients with RAS/BRAF wild-type mCRC determined by liquid biopsy at the start of the second-line treatment.

The necessity of intensive surveillance colonoscopy for patients with a remaining right colon after resection of colorectal cancer: a retrospective cohort study.

PURPOSE: To clarify how often postoperative surveillance colonoscopy should be undertaken based on the risk factors for the development of metachronous cancer (MC) and advanced adenoma (AA) after surgery for colorectal cancer. METHODS: We collected data of consecutive patients who underwent curative resection for primary colorectal cancer between 2005 and 2012, with preoperative colonoscopy and surveillance colonoscopy at 1 year after surgery (406 patients, mean age: 69 years, 59% male). The detection rates of AA (with villous features, > 10 mm or high-grade dysplasia) and MC by surveillance colonoscopy were the primary outcomes. RESULTS: At 5 years, colonoscopy was performed as postoperative surveillance an average of 3.2 times. AA and MC were detected in 57 (14.0%) and 18 patients (4.4%), respectively. Both lesions were more common in the right colon (n = 43) than in the left colon (n = 28). The detection rate did not differ to a statistically significant extent according to the number of colonoscopies performed for surveillance (p = 0.21). However, after left-sided colectomy, both types of lesions were more commonly detected in those who received ≥ 3 colonoscopies than in those with one or two colonoscopies (p = 0.04). CONCLUSION: A remaining right colon after left-sided colectomy was associated with a higher risk of developing AA and MC. Physicians should consider performing surveillance colonoscopy more frequently if the right colon remains after surgery.

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study).

LESSONS LEARNED: A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. BACKGROUND: TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2 /day on days 1-5 and 8-12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. METHODS: Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1-5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). RESULTS: From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2 /day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%-56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). CONCLUSION: Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

[Appendiceal Goblet Cell Carcinoid Successfully Treated with Bevacizumab plus mFOLFOX6 Regimen-A Case Report].

A 67-year-old man presented with abdominal distention and vomiting.Computed tomography revealed bowel obstruction due to a cecal tumor.We performed laparoscopic ileocecal resection after decompression with an ileus tube. Intraoperative findings included multiple disseminated nodules on the mesenterium surrounding the cecal tumor.The histopathologic diagnosis was poorly differentiated adenocarcinoma, which consisted of glandular proliferation of atypical epithelial cells and dispersed infiltration of goblet cells. Immunohistochemistry showed positively stained neuroendocrine markers, such as CD56, chromogranin, and synaptophysin.The patient was diagnosed with goblet cell carcinoid of the appendix and treated with combination chemotherapy of bevacizumab, fluorouracil, folinic acid, and oxaliplatin.He remained free from progression for over 1 and half years with this treatment.Subsequent chemotherapy was ineffective, and he passed away.There is no established chemotherapy regimen for goblet cell carcinoid, which has the aspects of both adenocarcinoma and neuroendocrine tumors.However, the present case suggested the efficacy of the mFOLFOX6 regimen in combination with bevacizumab for appendiceal goblet cell carcinoid.

The utility of longitudinal slicing method for rectal specimen: pathological analysis of circumferential resection margin of intersphincteric resection for low-lying rectal cancer.

The pathological assessment of the resection margin of rectal cancer is important to predict clinical outcome. The transverse slicing method of rectal specimens is recommended in Western countries. However, in Japan the longitudinal slicing method is traditionally advocated. The aim of this study was to assess the advantages of the longitudinal slicing method. The subjects were 197 consecutive patients with primary rectal cancer who underwent curative intersphincteric resection from 2000 to 2013. The resected rectal specimens were cut into 12 slices in the direction of the long axis. Resection margin was considered positive when it was less than or equal to 1 mm. Resection margin was positive in 23 patients (12%). They were classified into two groups, namely the DEEP group (n = 16, 70%), when the resection margin corresponded to the deepest tumor invasion area, and the ENTRY group (n = 7, 30%), when resection margin was around the initial cutting point of the anal canal. It was shown that resection margin tends to be positive not only in the deepest tumor invasion area but also in the entry area of the anal canal. The longitudinal slicing method may have some advantages for accurate assessment of resection margin especially in low-lying rectal cancer.

[Sigmoid Colon Cancer with Lateral Lymph Node Metastasis That Presented with Gastric Perforation].

A 74-year-old man visited his local clinic complaining of abdominal pain that persisted for three days. He was diagnosed with diffuse peritonitis and was transported to our hospital. Contrast computed tomography(CT)showed gastric perforation and a tumor in the sigmoid colon with left obturator lymph node metastasis. He was diagnosed with diffuse peritonitis resulting from gastric perforation and performed emergent surgery. As the size of the gastric perforation was large, we performed distal gastrectomy and transverse colostomy. He was discharged without any complications, and a total of 6 courses of SOX with a bevacizumab regimen were administered postoperatively. CT following chemotherapy showed shrinkage of the lesion. He was admitted again for sigmoidectomy with left lateral lymph node resection and discharged from the hospital on postoperative day 8. We administered 2 courses of SOX regimen after the surgery. He remains alive with no recurrence 27months after the first surgery.

The feasibility and efficacy of pure laparoscopic repeat hepatectomy.

BACKGROUND: Repeat hepatectomy is often required for hepatocellular carcinoma and metastatic tumors. However, this procedure is technically challenging, so laparoscopic repeat hepatectomy (LRH) has not been widely adopted. The aim of this study was to evaluate the feasibility and efficacy of LRH compared with open repeat hepatectomy (ORH) and laparoscopic primary hepatectomy (LPH). METHODS: We introduced laparoscopic hepatectomy at our institution in April 2014. We performed 127 LPH (LPH group) and 33 LRH procedures (LRH group) from April 2014 to April 2017; 37 patients underwent ORH from January 2010 to April 2017 (ORH group). This study retrospectively compared the patient characteristics and short-term outcomes of the LRH and ORH groups as well as the LRH and LPH groups. RESULTS: There were no conversions to open surgery in the LRH group. In comparing the LRH and ORH groups, there were no significant differences in patient characteristics except for the type of approach to the previous hepatectomy (p = 0.004) and indocyanine green retention rate at 15 min (median 12.5 vs. 8.75%, p = 0.026). The LRH group had less blood loss (median 30 mL vs. 652 mL; p < 0.001), less intraoperative transfusion (6.1 vs. 32.4%; p = 0.006), and shorter postoperative hospital stays (median 6.5 days vs. 9.0 days; p < 0.001). There were no differences with regard to operation time, severe postoperative complications, and mortality. In comparing the LRH and LPH groups, there was a significant difference only in past history of abdominal surgery (100 vs. 61.4%; p < 0.001). In the short-term outcomes, the postoperative hospital stay was significantly shorter in the LRH group (median 6.5 days vs. 7 days; p = 0.033), and the other results were comparable between the two groups. CONCLUSIONS: LRH is feasible and useful for repeat hepatectomy, achieving good short-term outcomes.

Laparoscopic radical antegrade modular pancreatosplenectomy for left-sided pancreatic cancer using the ligament of Treitz approach.

BACKGROUND: Laparoscopic distal pancreatectomy (Lap-DP) for benign lesions or those with low malignant potential has been proven safe and effective, and its performance is now widespread [1-3]. Lap-DP for left-sided pancreatic cancer (PC) is also being increasingly performed. According to some reports, Lap-DP has superior short-term outcomes (blood loss, postoperative hospital stay) and comparable oncological outcomes and overall survival with those of open distal pancreatectomy (Op-DP) [4-6]. PC has highly malignant potential; thus, complete resection and sufficient regional lymphadenectomy with tumor-free margins are very important. Radical antegrade modular pancreatosplenectomy (RAMPS) is an accepted standard Op-DP technique for PC and is reportedly useful for achieving R0 resection and radical lymphadenectomy [7-10]. However, laparoscopic RAMPS (Lap-RAMPS) is not yet popular because of its technical difficulty and lack of adequate evidence. Few reports have described the detailed surgical technique of Lap-RAMPS [11-13]. We employ Lap-RAMPS using the ligament of Treitz approach with the benefit of a laparoscopic view and herein describe the usability of this laparoscopic procedure with a video. METHODS: Our indication for Lap-RAMPS is left-sided PC located ≥1 cm away from the origin of the splenic artery (SPA) without invasion of the superior mesenteric artery (SMA), celiac artery (CA), common hepatic artery (CHA), or portal vein (PV). We apply either anterior or posterior RAMPS to achieve tumor-free margins. Therefore, the left adrenal gland and the nerve plexus around the SMA and CA are resected depending on the extent of the cancer. Three patients underwent Lap-RAMPS for left-sided PC using the ligament of Treitz approach from April to December 2016. This video shows our Lap-RAMPS procedure performed in a 67-year-old man with pancreatic body cancer who was being followed up for autoimmune pancreatitis. The tumor was suspected to have invaded the SPA, splenic vein, and retroperitoneum but was not close to the SMA, CA, CHA, or PV. The patient was put in the supine position with his legs opened, and the operation was performed using five trocars. Early in the operation, we incised the retroperitoneum just beside the ligament of Treitz, and the inferior vena cava and left renal vein (LRV) were exposed with resection of Gerota's fascia under a good laparoscopic view. The left adrenal gland was resected in this case to obtain sufficient tumor-free margins. The origin of the SMA was easily identified above the LRV. The most posterior dissection was carried out early in the operation, making it easy and safe to determine the resected margin and enabling curative resection with sufficient regional lymphadenectomy. After division of the pancreas with a linear stapler, the lymph nodes around the SMA and CA were safely removed. RESULTS: The operative time was 358 min, and the estimated blood loss was 1 ml. The postoperative course was uneventful, and the patient was discharged on postoperative day 10. Pathological examination revealed invasive ductal carcinoma (stage III, T3N1M0 according to the 7th edition of the Union for International Cancer Control system) with tumor-free margins. In all three patients, the median operative time and blood loss were 358 (328-451) min and minimal (minimal to 1 ml). One patient underwent anterior RAMPS and the other two patients, including the case mentioned above, underwent posterior RAMPS. One patient developed a grade B pancreatic fistula according to the International Study Group for Pancreatic Fistula (ISGPF) classification, but he recovered promptly with conservative treatment. No life-threatening complications occurred. The median postoperative hospital stay was 14 (10-16) days. CONCLUSIONS: Lap-RAMPS using the ligament of Treitz approach is feasible and extremely helpful in performing minimally invasive, curative resection for well-selected left-sided PC.

The Impact of Anastomotic Leakage on Anal Function Following Intersphincteric Resection.

BACKGROUND: Data regarding anastomotic leakage (AL) following intersphincteric resection (ISR) are lacking. We aimed to evaluate the effect of AL on anal function in a retrospective review of patients who developed AL following ISR. METHODS: We evaluated 341 consecutive patients who underwent ISR between 2000 and 2012. Patients were classified into three groups: anastomotic dehiscence (AD), major AL (Clavien-Dindo grade III+), or control (

Anal Function after Surgery for Low-Lying Rectal Cancer: Comparison of Mechanical and Hand-Sewn Coloanal Anastomosis.

BACKGROUND/AIMS: Mechanical coloanal anastomosis (MCAA) or hand-sewn coloanal anastomosis (HCAA) are used in anus-preserving surgery for low-lying rectal cancer. Either method can be used if the lower edge of the tumor is 4-6 cm from the anal verge. The goal of this study was to evaluate differences in the anal function after MCAA or HCAA. METHODS: The subjects were 305 consecutive patients with primary rectal cancer tumors situated 4-6 cm from the anal verge who underwent curative anus-preserving surgery between 2004 and 2013. Functional assessment was performed using a questionnaire at 3, 6, 12, and 24 months after stoma closure. RESULTS: Of the 305 patients, 145 underwent MCAA and 160 underwent HCAA. The median distance of the tumor from the anal verge was 6.0 cm (range 4.0-6.0) in the MCAA group and 4.5 cm (range 4.0-6.0) in the HCAA group (p < 0.001). A total of 192 patients (73%) responded to the 1-year questionnaire. The median Wexner score was 6 (range 0-17) in the MCAA group and 11 (range 0-20) in the HCAA group (p < 0.001). CONCLUSIONS: Retention of anal function is feasible after both MCAA and HCAA. MCAA may contribute to better postoperative anal function compared to HCAA.

Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer.

Tumors can create a heterogenetic tumor microenvironment. We recently identified the pathologically unique cancer microenvironment formed by peritoneal invasion (CMPI), and revealed that subperitoneal fibroblasts (SPFs) within peritoneal tissue play a crucial role in tumor progression through their interaction with cancer cells. Therefore, the genes in SPFs altered by cancer stimulation may include some biologically important factors associated with patient prognosis. In this study, we aimed to identify new biomarkers using genes specifically upregulated in SPFs by cancer-cell-conditioned medium (CCCM) stimulation (SPFs CCCM response genes; SCR genes) in colon cancer (CC). We constructed two frameworks using SCR gene data: a publicly released microarray dataset, and validation cases with freshly frozen CC samples to identify genes related to short recurrence-free survival (RFS). In the first framework, we selected differentially expressed genes between the high and low SCR gene expression groups. In the second framework, genes significantly related to short RFS were selected by univariate analysis using all SCR genes, and multivariate analysis was performed to select robust genes associated with short RFS. We identified CTGF, CALD1, INHBA and TAGLN in the first framework, and PDLIM5, MAGI1, SPTBN1 and TAGLN in the second framework. Among these seven genes, high expression of three genes (CALD1, TAGLN and SPTBN1) showed a poor prognosis in our validation cases. In a public microarray dataset, SCR gene expression was associated with the expression of ECM component, EMT, and M2-macrophage associated genes, which was concordant with the pathological features of CMPI. Thus, we successfully identified new prognostic factors.

Spread of tumor microenvironment contributes to colonic obstruction through subperitoneal fibroblast activation in colon cancer.

We evaluated the influence of the cancer microenvironment formed by peritoneal invasion (CMPI) on clinical findings in colon cancer patients. In addition to the association with poor prognosis, we discovered a relationship with bowel obstruction. Detailed analysis revealed that clinical findings related to bowel obstruction occurred more frequently in patients with an elevated type tumor, which had peritoneal elastic laminal elevation to the tumor surface, compared to those with non-elevated type tumors among those with elastic laminal invasion (ELI). Lateral tumor spread and increase of tumor annularity rate in ELI-positive elevated type cases suggested the morphological progression from ELI-positive non-elevated type to elevated type. In addition, α-smooth muscle actin expression was the highest in ELI-positive elevated type, and prominent expressions were found not only in the deep tumor area but also in the shallow tumor area. Furthermore, contraction assays revealed the robust contractile ability of subperitoneal fibroblasts stimulated by cancer cell-conditioned medium. Our findings suggest that CMPI spread into the luminal side of the colonic wall along with tumor progression, which caused bowel obstruction through the activation of subperitoneal fibroblasts. However, although the clinical outcome was not different between the two types, the clinical findings were affected by the spread of CMPI. We are the first to explore how the alteration of the tumor-promoting microenvironment, along with tumor progression, contributes to the development of clinical findings.

Patterns and treatment of recurrence following pulmonary resection for colorectal metastases.

BACKGROUND: Pulmonary resection is the best therapeutic option for lung metastases from colorectal cancer (CRC) today. However, recurrences are frequent following pulmonary resection. We aimed to evaluate the recurrence pattern and treatment of initial pulmonary resection for metastases from CRC. METHODS: Data from 76 patients with recurrence after curative resection of primary CRC and lung metastases were reviewed. The primary outcome measure was overall survival (OS), defined as the interval between the date of recurrence after pulmonary resection and the date of death or last follow-up. Cox regression analyses were performed to identify the factors associated with OS. RESULTS: Recurrence sites after initial pulmonary resection were lung (n = 37), liver (n = 12), others (n = 11), and multiple (n = 16). Treatments for recurrence included surgery (n = 35), chemotherapy (n = 37), and palliative care (n = 4). Of 35 patients who underwent surgery, 22 had pulmonary resection, and 11 had hepatic resection, and 2 had other resection. The 3-year OS was 84.1 % for surgery, 38.9 % for chemotherapy, and 0 % for palliative care, respectively (p < 0.001). In the surgery group, there was no difference in survival between surgical treatments for pulmonary and hepatic recurrences (p = 0.503). Cox regression analyses identified three factors: disease-free interval (DFI) (HR 1.99, 95 % CI 1.03-3.83), surgery (HR 0.30, 95 % CI 0.12-0.72), and recurrence site (lung: HR 0.10, 95 % CI 0.04-0.28, liver: HR 0.08, 95 % CI 0.02-0.31). CONCLUSIONS: The most common recurrence site after resection of lung metastases was the lung. Although the relapse rate is high, surgery for isolated recurrences is a promising strategy, especially for patients with long DFI.

Clinical impact of elastic laminal invasion in colon cancer: elastic laminal invasion-positive stage II colon cancer is a high-risk equivalent to stage III.

BACKGROUND: Elastic laminal invasion is defined as tumor invasion beyond the peritoneal elastic lamina. It is one of the factors affecting the prognosis of patients with colon cancer. OBJECTIVE: This study aimed to investigate the clinical impact of elastic laminal invasion in colon cancer and the magnitude of the worse prognosis of elastic laminal invasion-positive, node-negative patients. DESIGN: This was a retrospective cohort study. SETTINGS: This study reviewed data from a tertiary care cancer center in Japan. PATIENTS: The records of 436 patients with pT3 or pT4a colon cancer who underwent curative resection between January 1996 and December 2006 were reviewed. MAIN OUTCOME MEASURES: The primary outcome measure was recurrence-free survival. Cox regression analyses established the factors associated with recurrence-free survival. Six groups formed by combining the factors were compared. RESULTS: Of the patients with pT3 disease, those who were positive for elastic laminal invasion had a 5-year recurrence-free survival rate of 73.8% compared with a rate of 85.0% in those who were negative for elastic laminal invasion and 53.5% in patients with pT4 disease. Three unfavorable prognostic factors were identified, including lymph node metastasis, positive elastic laminal invasion, and a lack of adjuvant chemotherapy. Log-rank analysis revealed statistically significant differences in recurrence-free survival between group 1 (node negative, elastic laminal invasion negative, and no adjuvant chemotherapy) and group 3 (node negative, elastic laminal invasion positive, and no adjuvant chemotherapy). The HR for group 1 compared with group 3 was 0.49 (95% CI, 0.27-0.90). Furthermore, the HRs for group 2 (node positive, elastic laminal invasion negative, and received adjuvant chemotherapy) and group 4 (node positive, elastic laminal invasion positive, and received adjuvant chemotherapy) vs group 3 were 0.77 (95% CI, 0.35-1.69) and 1.36 (95% CI, 0.62-2.98). LIMITATIONS: Our study has limited prediction accuracy of our prognostic stratification, and an analysis of small subgroups may not have been capable of detecting significant differences. In addition, a wide range of hematoxylin and eosin- and elastica-stained slides were examined per case. CONCLUSIONS: Elastic laminal invasion adversely influences prognosis in pT3 and pT4a colon cancer. Although elastic laminal invasion positivity does not affect prognosis in node-positive patients receiving adjuvant chemotherapy, node-negative patients with elastic laminal invasion have a similar risk of recurrence as node-positive patients.

Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.