Circulating cell-free DNA methylation patterns as non-invasive biomarkers to monitor colorectal cancer treatment efficacy without referencing primary site mutation profiles.

This study investigates methylation patterns in circulating cell-free DNA (ccfDNA) for their potential role in colorectal cancer (CRC) detection and the monitoring of treatment response. Through methylation microarrays and quantitative PCR assays, we analyzed 440 samples from The Cancer Genome Atlas (TCGA) and an additional 949 CRC samples. We detected partial or extensive methylation in over 85% of cases within three biomarkers: EFEMP1, SFRP2, and UNC5C. A methylation score for at least one of the six candidate regions within these genes' promoters was present in over 95% of CRC cases, suggesting a viable detection method. In evaluating ccfDNA from 97 CRC patients and 62 control subjects, a difference in methylation and recovery signatures was observed. The combined score, integrating both methylation and recovery metrics, showed high diagnostic accuracy, evidenced by an area under the ROC curve of 0.90 (95% CI = 0.86 to 0.94). While correlating with tumor burden, this score gave early insight into disease progression in a small patient cohort. Our results suggest that DNA methylation in ccfDNA could serve as a sensitive biomarker for CRC, offering a less invasive and potentially more cost-effective approach to augment existing cancer detection and monitoring modalities, possibly supporting comprehensive genetic mutation profiling.

Endoscopic Surgical Skill Qualification System: propensity-score matched cohort analysis of accredited supervisors in laparoscopic rectal cancer surgery.

BACKGROUND: The Endoscopic Surgical Skill Qualification System (ESSQS) in Japan evaluates the surgical skills required for laparoscopic surgery as an operator as well as a supervisor. This study aimed to demonstrate the benefits of an ESSQS-certified surgeon's participation in laparoscopic rectal resections as a supervisor (assistant or advisor). METHODS: We retrospectively reviewed laparoscopic resection results for cStage II and III rectal cancer performed at 56 Japanese hospitals between 2014 and 2016. We used propensity score matching to generate paired cohorts with or without an ESSQS-certified supervisor at a one-to-one ratio. The impact of ESSQS-certified supervisors' participation on short-term outcomes was assessed. In the matched cohort, multivariable logistic regression analysis and multivariable regression analysis of postoperative complication rate and intraoperative blood loss were performed to further mitigate the impact of pathological factors. RESULTS: Two groups (n = 399 each) with or without an ESSQS-certified supervisor were well matched by clinical factors. The group with an ESSQS-certified supervisor had lower blood loss (68 mL vs. 98 mL, P = 0.036) and a lower incidence of severe morbidities of Clavien-Dindo grade ≥IIIa (8.0% vs. 13.3%, P = 0.016). Multivariable logistic regression analysis and multivariable regression analysis confirmed that the attendance of ESSQS-certified supervisors reduced postoperative complication occurrence (adjusted odds ratio: 2.28, 95% confidence interval: 1.38 - 3.80, P = 0.001) and intraoperative blood loss (estimated difference: -15.7 mL, P = 0.016). CONCLUSION: This study demonstrated the educational benefits of ESSQS-certified supervisors, including assistants and advisors, evidenced by their superior short-term outcomes.

Laparoscopic Synchronous Resection for Descending Colon Cancer and Tailgut Cyst.

A 67-year-old woman underwent polypectomy for a tumor at the descending colon. Pathologically, the tumor was diagnosed as adenocarcinoma with an invasion of 2000 µm. Computed tomography showed a swollen paracolic lymph node and a mass lesion in the presacral space. Magnetic resonance imaging revealed a multio-cular cystic lesion. On diagnosis of descending colon cancer and tailgut cyst, she underwent synchronous lapa-roscopic resection. Histopathologically, the colon cancer was diagnosed as pT1bN1M0, pStage IIIa. The pre-sacral cystic lesion was diagnosed as a nonmalignant tailgut cyst with negative surgical margin. The patient is currently doing well without recurrence at 28 months.

[Successful Resection Using a Posterior Approach of a Tailgut Cyst in the Retrorectal Space].

We present the case of a Tailgut cyst occurring in the retrorectal space that was curatively resected using a posterior approach. A 40-year-old man presented to the Kochi Health Sciences Center with the chief complaint of perineal incongruity. Pelvic magnetic resonance imaging revealed a multilocular cystic lesion in the retrorectal space, with high signal intensity on T2-weighted imaging. After diagnosing a Tailgut cyst, we performed resection of the tumor using a posterior approach. The lesion was removed en bloc with the coccyx. Histopathologically, the lesion was diagnosed as a non-malignant Tailgut cyst, and the surgical margin was negative. The patient is currently doing well without recurrence at 20 months.

The possibility of a transanal tube as an alternative to diverting stoma in terms of preventing severe postoperative anastomotic leakage after laparoscopic low anterior resection.

PURPOSE: The purpose of this study was to reveal whether a transanal tube (TAT) could act as an alternative to a diverting stoma (DS) after laparoscopic low anterior resection. PATIENTS AND METHODS: A total of 89 consecutive rectal cancer patients whose tumors were located within 15 cm from the anal verge who underwent laparoscopic low anterior resection without a DS at our institution between May 12, 2015 and August 31, 2019 were included. All patients received a postoperative Gastrografin enema study (GES) through a TAT between the 3rd and 10th postoperative day. We planned two study protocols. From May 12, 2015 to March 31, 2017, we conducted a second operation including a DS construction immediately when radiological anastomotic leakage (rAL) was detected (Group A, n=46). From April 1, 2017 to August 31, 2019, we continued TAT drainage even if rAL was detected and repeated the GES weekly until the rAL was healed (Group B, n=43). RESULTS: In Group A (n=46), 14 cases of rAL were included, 11 of which underwent stoma construction. The remaining 3 patients who refused stoma construction were treated conservatively. In Group B (n=43) rAL was encountered in 10, and 7 of these patients were treated successfully by TAT continuous drainage. The rate of DS in Group B (7.0%) was significantly lower than that in Group A (23.9%) (p=0.028). CONCLUSIONS: A TAT could act as a DS to mitigate the symptoms of anastomotic leakage after laparoscopic low anterior resection.

Effect of Neoadjuvant Chemotherapy in Patients with Colorectal Cancer Liver Metastases.

BACKGROUND: This study was performed to evaluate the relationships between potential prognostic factors and post-surgery survival in patients with colorectal cancer liver metastasis (CRLM). In particular, this study investigated the value of neoadjuvant chemotherapy as an independent predictor of cancer-specific survival. METHODS: The study participants included 147 patients who underwent resection for CRLM. Demographics, treatments, and relationships between potential prognostic factors and the survival rate were analyzed using a prospective database. RESULTS: The overall 1-, 3- and 5-year cancer-specific survival rates for post-surgery CRLM patients were 94.3%, 71.2%, and 53.5%, respectively. Multivariate analysis revealed that a positive surgical margin and extrahepatic metastasis were independent negative prognostic factors. The administration of neoadjuvant chemotherapy prior to liver surgery did not significantly improve post-surgery outcomes of patients with CRLM. In a subgroup analysis, the time to recurrence in the remnant liver after hepatectomy for CRLM was significantly less in the neoadjuvant group than in the upfront surgery group. CONCLUSIONS: Neoadjuvant chemotherapy was not predictive of cancer-specific survival. The achievement of macroscopically and microscopically negative resection remains the main aim of surgery.

[A Case of Aggressive Angiomyxoma in a 75-Year-Old Man].

Aggressive angiomyxoma is an uncommon mesenchymal tumor that mostly involves the pelvic and perineal regions in young women.We herein report an extremely rare case of aggressive angiomyxoma in a 75-year-old man. The patient had undergone follow-up for an intraductal papillary mucinous neoplasm.In September 2015, CT detected a tumor measuring 33 mm in diameter around the pelvis, and the tumor showed gradual increase in size.MRI revealed a relatively sharply marginated tumor with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.For treatment and diagnosis, we laparoscopically resected the tumor. Histopathologically, the specimen showed spindle tumor cells within a myxoid background and vascular structures.The tumor was diagnosed as aggressive angiomyxoma, and surgical margins were negative for tumor cells. The patient is currently doing well without any signs of recurrence as of 18 months postoperatively.

[Two Successful Cases of Surgical Treatment of Reconstructed Gastric Tube-Bronchial Fistula after Esophagectomy for Esophageal Cancer by Pedunculated Latissimus Dorsi Flap].

We herein report 2 cases of successful surgical treatment of reconstructed gastric tube-bronchial fistulas caused by leakage after esophagectomy for esophageal cancer. One patient was a 56-year-old man who developed a reconstructed gastric tube-bronchial fistula, and the fistula was closed by conservative treatment. However, he developed pneumonia on postoperative day 117, and the reconstructed gastric tube-bronchial fistula was found to have recurred. Fibrin glue was endoscopically injected into the fistula, but this treatment was unsuccessful. The other patient was a 60-year-old man who developed a reconstructed gastric tube-bronchial fistula and severe pneumonia, and his condition did not improve by conservative treatment. We performed a reoperation for both patients using a pedunculated latissimus dorsi flap, and both patients recovered well.

[A Case of Intra-Abdominal Desmoid Tumor with Abacterial Peritonitis].

A woman in her 50s visited our hospital in February 2015 with a complaint of dull abdominal pain in the right lower quadrant. She had a medical history of appendectomy for appendicitis in her 20s. Computed tomography(CT)revealed a tumor 90 mm in diameter near the ileocecum. Elective surgery was planned under the suspicion of gastrointestinal tumor, malignant lymphoma, or ileal cancer. She was emergently hospitalized 1 day earlier than scheduled because of high fever and severe abdominal pain. CT revealed that the tumor had increased to 120 mm in diameter without free air. Her white blood cell count was not elevated, and her symptoms improved readily with medical treatment. Thus, we performed the operation as scheduled. A tumor with a dark red recess on the surface had invaded the transverse colon intraoperatively, and a small amount of purulent ascites was present at the pouch of Douglas. We performed ileocecal resection with partial transverse colectomy. Histopathological examination led to the diagnosis of desmoid tumor in the mesentery of the terminal ileum. The surgical margins were negative for tumor cells. The tumor surface around the recess showed peritonitis, and the ascites showed no bacteria or tumor cells. The patient had been doing well without recurrence after discharge. Some cases of desmoid tumor with peritonitis have been reported, but most were caused by tumor penetration into the intestinal tract. We report herein a rare case of intra-abdominal desmoid tumor with abacterial peritonitis.

The rare BRAF VK600-601E mutation as a possible indicator of poor prognosis in rectal carcinoma ­ a report of a case.

BACKGROUND: The BRAF V600E mutation is reportedly associated with inferior survival among colon cancer patients. Here we report a patient with rectal cancer who carried the novel BRAF mutation VK600-601E, which has analogous molecular functions to those of the conventional BRAF mutation V600E, and may have potential as a prognostic marker for colorectal cancer (CRC). CASE PRESENTATION: The present 65-year-old male patient was diagnosed with recurrent rectal adenocarcinoma (stage II by AJCC TNM staging 7th edition) 14 months after surgery and was treated with modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin), radiation, and FOLFIRI (fluorouracil, leucovorin, and irinotecan). The tumor progressed before further treatment could be initiated, resulting in death after 15 months. This survival period was similar to the median overall survival among patients with metastatic CRC and BRAF mutations who were treated with the FOLFIRI regimen with or without cetuximab. CONCLUSIONS: Thus, the BRAF VK600-601E mutation may lead to an aggressive clinical course in CRC patients suffering from rapid progression and potential resistance to multiple therapeutic modalities.

A Case-matched Comparative Study of Laparoscopic and Open Total Proctocolectomy for Ulcerative Colitis.

The aim of this single-institution, retrospective, observational case-control study was to evaluate the safety and feasibility of laparoscopic proctocolectomy (PC) for ulcerative colitis (UC), by comparing it with a case-control series of open PC. Twenty UC patients who underwent laparoscopic PC were retrospectively compared with the open PC group of 12 patients matched for age, sex, and urgency of the operation. In the laparoscopic PC group, the operative time was significantly longer, but the amount of blood loss was significantly smaller. The open PC patients underwent an intraoperative blood transfusion significantly more often, and the serum C-reactive protein level on the first postoperative day was significantly higher in the open PC group. In the laparoscopic PC group, the rate of severe postoperative morbidities, grades 3 and 4 on the Clavien-Dindo classification, was significantly lower, and the median length of hospital stay was significantly shorter. Laparoscopic PC for patients with UC showed superior perioperative outcomes to open PC, except for longer operative time.

Aggressive multimodality treatment for advanced rectal cancer.

A case of advanced rectal cancer treated by aggressive local and systemic treatment who has survived more than 7 years from initial recurrence is presented. A 55-year-old woman was diagnosed with advanced lower rectal cancer and underwent a low anterior resection with complete removal of all regional lymph nodes and total mesorectal excision. The tumor was diagnosed as a moderately differentiated adenocarcinoma, pStage IIIB (T3, N2a, M0). Twenty-six months after the initial surgery, local recurrence in the pelvis was detected by computed tomography, and total pelvic exenteration with distal sacrectomy (TPES) was performed after systemic chemotherapy with a molecular-targeted drug. Six months after the TPES, multiple lung metastases were detected. Consequently, the patient underwent radiofrequency ablation (RFA) and chemotherapy. The disease has since been controlled for 38 months. As volume control is essential for cancer treatment, it may be important to combine appropriate local therapy with systemic therapy to metastatic or recurrent sites in order to achieve much longer disease control.

[A case of appendix cancer treated as cancer of unknown primary origin].

A 57-year-old man initially presented with chief complaints of abdominal distension and anorexia. Positron emission tomography- computed tomography (PET-CT) scan showed ascites and multiple peritoneal metastases with abnormal uptake of fluorodeoxyglucose (FDG). The patient underwent endoscopy, biopsy, and cytology and was diagnosed with adenocarcinoma of unknown primary origin. He was treated with systematic chemotherapy, including carboplatin/paclitaxel (CBDCA/ PTX) and gemcitabine regimens. However, progressive disease (PD) complicated by intestinal obstruction was indicated. He was referred to our department for management. We performed surgery to resolve the intestinal obstruction and confirm the diagnosis. Appendix cancer was diagnosed intraoperatively. He was administered a modified fluorouracil plus Leucovorin and oxaliplatin(mFOLFOX6) /panitumumab regimen following surgery. The tumor had a good response to treatment, and the primary lesion was resected. After resection , the tumor was controlled by systemic chemotherapy for six months. However, the patient unfortunately died owing to arrhythmia. Most patients with cancer of unknown primary origin have a very poor prognosis because it is difficult to select appropriate treatment. Laparotomy can be effective in making a definitive diagnosis, as in the case described here.

[A successful multimodality therapy for a case of recurrent rectal cancer with KRAS mutation].

A man in his 50s underwent high anterior resection for rectosigmoid cancer in January 2010. The primary tumor was diagnosed as a moderately differentiated adenocarcinoma with KRAS mutation, pStage III a. In May 2011, the patient had a recurrent lung tumor detected by computed tomography(CT); the tumor was resected using video-assisted thoracoscopic surgery. However, additional recurrent lung tumors arose, and radiofrequency ablation (RFA) was performed to treat these in February 2012. After RFA therapy, capecitabine was administered as adjuvant chemotherapy. Unfortunately, 10 months later, positron emission tomography (PET) /CT suggested a new recurrence in a left lateral lymph node. Although the pelvic lymph node was surgically removed immediately, a new lung recurrence was found on CT three months after the surgery. RFA was again used to treat this lung lesion. After the second RFA, the patient is doing well without any evidence of recurrence. We describe a case of recurrent rectal cancer successfully treated with multimodality therapy. The combination of appropriate local therapy with systemic chemotherapy is an essential strategy to treat advanced colorectal cancer, especially in patients with KRAS mutation when anti-EGFR antibodies are not effective.

Case-matched comparison of the short-term outcomes between laparoscopic and open abdominoperineal resection for rectal cancer.

PURPOSE: The aim of this study was to evaluate the short-term surgical outcomes of laparoscopic abdominoperineal resection (APR) for rectal cancer, by comparing it with a case-control series of open APR. METHODS: Fourteen patients with rectal cancer who underwent laparoscopic APR between August 2004 and November 2011 were compared with the open APR group of 14 patients matched for age, gender, and surgical procedure. RESULTS: There were no cases of conversion to laparotomy in the laparoscopic APR group and no mortality in either of the groups. The median operation was longer (P = 0.002), but the median amount of blood loss was smaller (P = 0.019), in the laparoscopic APR group. The median length of hospital stay of the laparoscopic APR group was 8 days, shorter than that of the open APR group (16 days, P < 0.001). The changes of the WBC count and serum CRP level after operations were significantly smaller in the laparoscopic APR group (P < 0.05). There were no significant differences between the groups in terms of the perioperative morbidity and readmission rates within 30 days. CONCLUSION: Patients undergoing laparoscopic APR had superior perioperative outcomes to those undergoing open APR, except for the longer operation.

[False-positive local recurrences on FDG-PET/CT due to postoperative infection - a case report].

Although ¹8F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a powerful tool for detecting the recurrence of colorectal cancer, FDG uptake is not tumor specific. Herein, we report a case of a 65-year- old man who underwent emergency colectomy for perforation of colon cancer. FDG-PET/CT after surgery showed 2 tumors that were difficult to differentiate from peritoneal metastases with invasion to the spleen. Splenectomy was performed, and the histopathology revealed that the tumors in fact were abscesses. This is a clinically thought-provoking case that showed the difficulty of the differential diagnosis between early recurrence after emergent surgery of colorectal cancer and the postoperative changes.

Recurrence-free survival curve for pulmonary metastasectomy in colorectal cancer plateaus at 3 years.

Pulmonary metastasectomy in colorectal cancer (CRC) has encouraging results; however, specific criteria for lung resection and the timing of resection remain undetermined. Therefore, in this study, we aimed to examine the long-term prognosis and 10-year survival rates and analyze poor prognostic factors in patients who underwent resection of pulmonary metastases from CRC. This retrospective, single-institution study included 156 patients with controlled primary CRC and metastases confined to the lungs or liver who underwent pulmonary metastasectomy between 2005 and 2022. Statistical analyses were conducted using the X2 and two-tailed Student's t test to compare variables. The receiver operating characteristic (ROC) curve was used to determine the appropriate cut-off point for tumor size as a predictive factor of survival. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and non-parametric group comparisons were performed using log-rank tests. The 5- and 10-year OS rates were 67% and 59%, respectively. Further, there was no recurrence 38 months post-surgery, and the RFS curve plateaued. Moreover, by 88 months post-surgery, no deaths occurred, and the OS curve plateaued. Multivariate analysis revealed that a pulmonary metastatic tumor >14 mm and disease-free interval <2 years indicated poor prognosis. The RFS curve for pulmonary metastasectomy may plateau approximately 3 years after surgery. Pulmonary metastasectomy can achieve long-term survival in selected patients with CRC. Furthermore, surgical resection of recurrence after pulmonary metastasectomy may lead to better results. Thus, tumor size and disease-free interval may be independent prognostic factors.

[A case of local recurrence of rectal carcinoma 10 years after initial surgery].

Here, we report an extremely rare case of local recurrence of rectal cancer 10 years after initial tumor resection. A 53-year-old man underwent abdominoperineal resection for advanced rectal cancer at a local hospital. The tumor was graded as pStage II (pA, pN0, pH0, pP0, pM0, curA)as per the Japanese Classification of Colorectal Carcinoma, seventh edition, and diagnosed as a moderately differentiated adenocarcinoma on histopathological examination. Subsequently, the patient received adjuvant chemotherapy for 5 years. Although the patient lived without any recurrences after adjuvant chemotherapy, unfortunately, blood examination showed a high carcinoembryonic antigen(CEA)level 10 years after the initial surgical treatment. Computed tomography(CT)and positron emission tomography(PET)/CT revealed a perineal tumor, 40mm in size, without other distant metastases. On diagnosis of local recurrence of rectal cancer, the patient underwent surgical tumor resection at Okayama University Hospital. The tumor was determined to be a well- to moderately differentiated adenocarcinoma by histopathological examination, suggesting local recurrence of the primary rectal adenocarcinoma. Moreover, the radial margin was free of cancer. The patient is now doing well without any re-recurrence 30 months after the second surgical treatment, without any adjuvant chemotherapy.

[A case of advanced sigmoid colon cancer successfully treated with multimodality therapy].

A 61-year-old man underwent sigmoidectomy with partial cystectomy for advanced sigmoid colon cancer with unresectable multiple liver metastases at the Okayama University Hospital in June 2006. Pathological examination revealed moderately differentiated adenocarcinoma, pStage IV( pSI[ bladder], pN0, pH2, pP0, pM0), as per the Japanese Classification of Colorectal Carcinoma, seventh edition. The patient underwent systematic chemotherapy with irinotecan, 5-fluorouraci( l 5-FU), and folinic acid( FOLFIRI) and oxaliplatin, Leucovorin, and 5-FU( mFOLFOX6) for 13 months. In July 2007, hepatectomy was performed as the liver metastatic lesions had shrunk to a resectable size. Follow-up computed tomography (CT) in November 2009 revealed recurrence in the liver and lung. Subsequently, lateral segmentectomy was performed for the recurrent liver lesions, and radiofrequency ablation( RFA) was performed for the lung lesions. After having undergone RFA, the patient is doing well without any re-recurrence. We encountered a patient with advanced sigmoid colon cancer who was successfully treated with multimodality therapy. For patients with advanced or recurrent colorectal cancers, curative resection can lead to a good prognosis; however, in most patients, it is difficult to achieve curative resection by upfront surgery. Multimodality therapy could facilitate curative resection, thereby resulting in a good prognosis.

Skin and Bone Regeneration of Solid Bone Marrow Aspirate Concentrate Versus Platelet-Rich Fibrin.

Solid bone marrow aspirate concentrate (sBMAC) is harvested from bone marrow aspirate without anticoagulants by a centrifugation protocol similar to that for platelet-rich fibrin (PRF) prepared from peripheral blood. It was hypothesized that sBMAC could accelerate not only wound healing but also bone regeneration because of the abundant growth factor (GF) releases from enriched bone marrow cells. The purpose of the present study was to investigate skin wound healing and bone regenerative potential of sBMAC compared with arterial blood-derived PRF (Ar-PRF) and venous blood-derived PRF (Ve-PRF) in a skin defect and calvarial bone defect model in rabbits. GF release assays revealed significantly higher release of transforming growth factor-ß (TGF-ß), alkaline phosphatase (ALP), and osteocalcin (OCN) from sBMAC compared with PRFs for 24 h. In the skin defect animal model, sBMAC and PRFs promoted wound bed angiogenesis and re-epithelization in skin defect sites with higher collagen 1 synthesis, cytokeratin AE1/AE3, vascular endothelial growth factor (VEGF) expressions on week 1. Furthermore, a calvarial defect assay revealed that sBMAC promoted new bone formation with a sufficient bone marrow structure similar to that of intact bone in the bone defects. Ar-PRF achieved the second highest bone closure and new bone volume but yielded new bone that was thinner than the intact bone. In conclusion, sBMAC treatment might be a good option instead of PRF as an adjuvant therapy for both skin and bone tissue regeneration therapies in certain clinical situations. Impact statement Solid bone marrow aspirate concentrate (sBMAC) is new type of clot material prepared from bone marrow aspirate. The present study for the first time showed that sBMAC significantly accelerated both skin wound healing and bone formation in the defects, compared with conventional platelet-rich fibrin in rabbit experiment models.