Subcutaneous incision of the fistula tract and internal sphincterotomy (SIFT-IS): a novel surgical procedure for transsphincteric anal fistula.

AIM: The aetiology of anal fistula has not been fully clarified. One of the causes of anal fistulas may be the markedly deep crypts that characterize the primary openings. We developed subcutaneous incision of the fistula tract and internal sphincterotomy (SIFT-IS) to eradicate these deep crypts. The aim of this study was to evaluate outcomes in patients with anal fistula treated with SIFT-IS. METHOD: A retrospective study was performed over a 2-year period. Patients with transsphincteric anal fistula who underwent SIFT-IS were enrolled. The primary endpoint was the anal fistula healing rate at 16 weeks postoperatively. The secondary endpoints were healing time, postoperative complications and clinical continence status. RESULTS: One hundred and fifty one patients were enrolled. Primary healing was accomplished in 129 patients (85%). There were 17 patients (11%) with a remnant fistula and five (3%) with a recurrence. The remnant fistulas healed spontaneously at more than 16 weeks postoperatively in seven patients. The median healing time was 6 (3-96) weeks. Surgical intervention was required in seven patients with a remnant fistula and four with recurrence. At the final follow-up, the wounds had healed in 148 patients (98%). No significant postoperative complications or incontinence were observed. CONCLUSION: Subcutaneous incision of the fistula tract and internal sphincterotomy is a promising surgical option for transsphincteric anal fistulas, with a satisfactory healing rate.

Even a partial pathological response is associated with lower relapse rates in patients with operable rectal cancer undergoing neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy to treat locally advanced rectal cancer is an effective therapeutic strategy for the prevention of local recurrence and distant organ metastasis after surgery. OBJECTIVES: To assess the prognostic significance of histopathological tumor response in rectal cancer patients undergoing neoadjuvant chemotherapy. METHODS: This study included patients with operable rectal cancer who received neoadjuvant chemotherapy using the FOLFOX regimen (5-fluorouracil, l-leucovorin, and oxaliplatin) in a hospital between February 2012 and November 2017. The main outcome measure was disease-free survival with respect to histopathological response to neoadjuvant chemotherapy in resected specimens. RESULTS: The median follow-up was 32 months. Of 48 patients treated with neoadjuvant FOLFOX, 24 (50%) were classified as responders, which included two patients with pathological complete response and 22 patients with partial response. The remaining 24 patients (50%) were classified as nonresponders. Responders had a significantly better 3-year disease-free survival than nonresponders (86% vs. 62%, p = .02). CONCLUSIONS: Patients whose surgical specimens show a pathological complete response or partial response have good oncologic outcomes.

Emerging RAS, BRAF, and EGFR mutations in cell-free DNA of metastatic colorectal patients are associated with both primary and secondary resistance to first-line anti-EGFR therapy.

Oncogenic RAS mutations are negative biomarkers of response to epidermal growth factor receptor (EGFR) blockade. RAS mutations are usually detected in biopsies of primary colorectal tumors. However, the genomic profiles of primary tumors and metastases are not always concordant, and chemotherapeutic agents can alter the tumor molecular landscape. Cell-free DNA (cfDNA) is a novel tool to detect molecular heterogeneity. This study evaluated the clinical utility of cfDNA to predict primary or secondary resistance to EGFR blockade in patients with metastatic colorectal cancer. Thirty metastatic colorectal cancer patients without RAS and BRAF mutations were prospectively enrolled and treated with cytotoxic agents and EGFR blockade as first-line therapy. cfDNA was analyzed for the presence of RAS, BRAF, and EGFR (S492R) point mutations before initiating chemotherapy and every 2 months during chemotherapy. The analysis was performed in 223 plasma samples from all 30 patients. Of the 30 patients, five had RAS mutations in their cfDNA before starting chemotherapy and did not respond. Twenty-four of the remaining 25 patients without cfDNA RAS mutations had a response. Twenty of the 24 responders developed secondary resistance and cfDNA RAS mutations were found in 17 of the 20. cfDNA BRAF mutations were found in seven, and EGFR mutations were found in eight of the 20 patients. Emerging RAS, BRAF, and EGFR mutations occurred in patients with primary and secondary resistance to EGFR blockade. The detection of these mutations in cfDNA is a promising approach to predict treatment response and secondary resistance.

Analysis of colorectal cancer-related mutations by liquid biopsy: Utility of circulating cell-free DNA and circulating tumor cells.

We recruited 56 colorectal cancer patients and compared the mutational spectrum of tumor tissue DNA, circulating cell-free DNA (ccfDNA) and circulating tumor cell (CTC) DNA (ctcDNA) to evaluate the potential of liquid biopsy to detect heterogeneity of cancer. Tumor tissue DNA, ccfDNA, and ctcDNA were extracted from each patient and analyzed using next-generation sequencing (NGS) and digital PCR. To maximize yields of CTC, three antibodies were used in the capture process. From 34 untreated patients, 53 mutations were detected in tumor tissue DNA using NGS. Forty-seven mutations were detected in ccfDNA, including 20 not detected in tissues. Sixteen mutations were detected in ctcDNA, including five not detected in tissues. In 12 patients (35.3%), mutations not found in tumor tissues were detected by liquid biopsy: nine (26.5%) in ccfDNA only and three (8.8%) in ctcDNA only. Combination analysis of the two liquid biopsy samples increased the sensitivity to detect heterogeneity. From 22 stage IV patients with RAS mutations in their primary tumors, RAS mutations were detected in 14 (63.6%) ccfDNA and in eight (36.4%) ctcDNA using digital PCR. Mutations not detected in primary tumors can be identified in ccfDNA and in ctcDNA, indicating the potential of liquid biopsy in complementing gene analysis. Combination analysis improves sensitivity. Sensitivity to detect cancer-specific mutations is higher in ccfDNA compared with ctcDNA.

Establishment and characterization of a novel neuroendocrine carcinoma cell line derived from a human ascending colon tumor.

The incidence of rare neuroendocrine tumors (NET) is rapidly increasing. Neuroendocrine carcinoma (NEC) is a NET with poorly differentiated histological features, high proliferative properties and associated poor prognoses. As these carcinomas are so rare and, thus, affect only a small number of patients allowing for few cell lines to be derived from patient biopsies, the histological, immunohistochemical, and clinical characteristics associated with colorectal NEC and NEC in other organs have yet to be clearly defined. Herein, we describe the establishment of a novel NEC cell line (SS-2) derived from a tumor resection of the ascending colon from a 59-year-old Japanese woman. The histological, electron microscopic and immunohistochemical features of chromogranin A (CgA) as well as confirmation of synaptophysin positivity in this tumor were typical of those commonly observed in surgically resected colorectal NEC. Further, the Ki-67 labeling index of the resected tumor was >20% and, thus, the tumor was diagnosed as an NEC of the ascending colon. The SS-2 cell line maintained characteristic features to those of the resected tumor, which were further retained following implantation into subcutaneous tissues of nude mice. Additionally, when SS-2 cells were seeded into ultra-low attachment plates, they formed spheres that expressed higher levels of the cancer stem cell (CSC) marker CD133 compared to SS-2 cells cultured under adherent conditions. SS-2 cells may, therefore, contribute to the current knowledge on midgut NEC biological function while providing a novel platform for examining the effects of colorectal NEC drugs, including CSC.

Liquid Biopsy for the Management of Patients with Colorectal Cancer.

BACKGROUND: Liquid biopsy is a collective term that refers to the analysis of tumor-derived biomarkers isolated from biological fluids of cancer patients. Recently, many authors reported the usefulness of liquid biopsy for the management of malignancy. Summary and Key Messages: The peripheral blood of cancer patients is a pool of cells and/or cell products derived from the primary or metastatic tumor, including circulating tumor cells (CTCs), circulating free (cf) DNA or RNA, and exosomes containing proteins, nucleic acids, and lipids. CTCs are tumor cells that can be isolated from peripheral blood. Free circulating DNA with a tumor-specific mutation is called circulating tumor DNA (ctDNA). Some patients who undergo curative surgery experience recurrent disease, which can be due to the presence of minimal residual disease (MRD). Thus, MRD indicates a high risk of relapse. Detection of ctDNA or CTC after surgery is a direct proof of MRD. Molecular volume (e.g., the number of CTCs and level of ctDNA) might reflect tumor burden, thus high molecular volume may indicate poor prognosis. The most notable application of liquid biopsy in cancer is to understand spatial and temporal heterogeneities. Heterogeneity is one of the causes of refractoriness and hampers prediction of chemotherapeutic effect. Emerging mutations that are not present in primary tumors but are found in their metastases can be detected in ctDNA. Some colorectal cancer patients with wild-type RAS do not respond to epidermal growth factor receptor blockade. In a subset of these patients, RAS mutation is detected in ctDNA, indicating heterogeneity.

[Effectiveness of Chemoradiotherapy for the Treatment of Local Recurrence in Rectal Cancer-A Case Report].

Chemoradiotherapy(CRT)for locally recurrent rectal cancer can shrink the tumor and permit R0 resection; however, its effectiveness and safety have not been established. Herein, we report a case of a 60s man with locally recurrent rectal cancer invading the surrounding organs who was administered CRT followed by R0 laparoscopic-assisted abdominoperineal resection( APR). Local recurrence was detected 11 months after laparoscopic-assisted low anterior resection(pT3N0M0, pStage Ⅱ). After tumor shrinkage by CRT(capecitabine 3,000mg/day plus 45 Gy/25 Fr), laparoscopic-assisted APR was performed. The pathological findings showed a pathological complete response(pCR). The patient had not experienced recurrent disease at 6 months after the second surgery. CRT may improve the prognosis of patients with locally recurrent rectal cancer, especially those with possibly unresectable tumors.

[Consideration for Prognostic Indicators of Ovarian Metastasis of Colorectal Cancer].

Ovarian metastasis of colorectal cancer is associated with poor prognosis. Recent advances in chemotherapy may improve this prognosis. In this retrospective study, we evaluated indicators of poor prognosis for ovarian metastasis of colorectal cancer. Twenty patients, who were diagnosed with ovarian metastasis of colorectal cancer from April 2000 to December 2017, were enrolled. Oophorectomy was performed in 18 of the 20 patients. Postoperative chemotherapy was provided to 13 patients, and molecular targeting agents were administered in 5 patients. Metastases to other organs besides the ovaries, premenopausal condition, undifferentiated histologic type of the primary tumor, and no resection of ovarian metastases were identified as indicators of poor prognosis. The 3-year survival rate was 15%, and the 5-year survival rate was 0%. In conclusion, oophorectomy can improve the prognosis of patients with ovarian metastasis of colorectal cancer. However, prognostic improvement due to molecular target agents was not shown.

Oncological Assessment of Stent Placement for Obstructive Colorectal Cancer from Circulating Cell-Free DNA and Circulating Tumor DNA Dynamics.

BACKGROUND: The self-expanding metallic stent (SEMS) provides effective decompression for patients with malignant large bowel obstruction (MLBO); however, mechanical damage to malignant cells from insertion may negatively affect prognosis, similar to surgical manipulation, and its oncological safety is unclear. We examined mechanical damage from SEMS placement using circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA). METHODS: Between 1 November 2014 and 30 June 2017, 35 MLBO patients were analyzed, comprising 25 SEMS patients and 10 transanal decompression tube (TDT) patients (control). Blood samples were collected before and after decompression on days 0, 1, 3, and 7. cfDNA, ctDNA, white blood cells, C-reactive protein, and lactate dehydrogenase were analyzed. RESULTS: The clinical success rates of SEMS and TDT were 88 and 90%, respectively (p = 1.0). The cfDNA concentration on day 7 was significantly higher in the SEMS group than in the TDT group (992 vs. 308 ng/mL; p = 0.005). A significant increase in ctDNA was observed in the SEMS group compared with the TDT group (83% vs. 22%; p = 0.002). The cfDNA concentration showed strong positive correlations with ctDNA and lactate dehydrogenase (R 2 = 0.838 and 0.593, respectively), and a weak positive correlation with C-reactive protein (R 2 = 0.263). CONCLUSIONS: Despite equivalent clinical success rates, SEMS placement increased plasma levels of cfDNA and ctDNA by tumor manipulation, but TDT did not. Colonic stenting showed oncological risk in terms of molecular analysis.

Male sex and history of ischemic heart disease are major risk factors for anastomotic leakage after laparoscopic anterior resection in patients with rectal cancer.

BACKGROUND: Anastomotic leakage (AL) is the most serious and common complication of surgery for rectal cancer, and associated risk factors remain unknown despite developments in laparoscopic surgery. The present study aimed to determine risk factors for AL after laparoscopic anterior resection (AR) of rectal cancer. METHODS: This retrospective cohort study extracted information from a prospective database of all consecutive colorectal resections that proceeded at Nippon Medical School Hospital between January 2011 and December 2015 (n = 865). We identified 154 patients with rectal cancer treated by elective laparoscopic AR with anastomosis using primary double-stapling. Clinical variables and comorbidity, habits, and surgery-related variables were assessed by univariate and multivariate analyses to determine preoperative risk factors for clinical AL. RESULTS: The overall rate of clinical AL was 11.7% (18 of 154 patients), and 5 (27.8%) of 18 patients required revised laparotomy. Data from males were analyzed because AL occurred only in males. Univariate analysis of male patients (n = 100) significantly associated preoperative creatinine values (p = 0.03) and a history of ischemic heart disease (IHD) (p = 0.012) with AL. The frequency of AL tended to increase (p = 0.06) when patients had low AR (p = 0.06) and transanal drainage. Having AL significantly prolonged hospital stays compared with patients without leakage (36.2 vs. 11.1 days; p <  0.01). Multivariate analysis identified a history of IHD (odds ratio [OR], 4.73; 95% confidence interval [CI], 1.27-17.5; p = 0.025] as an independent risk factor for AL. CONCLUSIONS: Male sex and a history of IHD are possible risk factors for AL after elective laparoscopic rectal cancer surgery.

Oxaliplatin-induced increase in splenic volume; irreversible change after adjuvant FOLFOX.

BACKGROUND AND OBJECTIVES: Oxaliplatin can cause hepatic sinusoidal obstruction syndrome (SOS). SOS can cause chemotherapy-related adverse effects or morbidity after liver resection. Conventionally, SOS is diagnosed using liver biopsy. Recently, it was reported that increased splenic volume (SV) can be used to detect SOS. In this study, we evaluated the changes in SV during adjuvant chemotherapy. METHODS: We enrolled 103 consecutive patients with stage III and high-risk stage II colorectal cancer treated with mFOLFOX6 (n = 37) or oral fluorouracil and leucovorin (n = 66) after curative surgery. SV was measured three times; pre-operatively, after chemotherapy, and 1 year after chemotherapy. RESULTS: SV was higher after mFOLFOX6 (median 135.89 mL) than pre-operatively (105.75 mL) (P < 0.001); SV at 1-year after finishing mFOLFOX6 (114.16 mL) returned to the same level as before surgery (P = 0.0015). SV increased in 28 patients (75.7%) treated with mFOLFOX6 (95%CI, 61.8-89.5), but had not recovered in 12 of these cases (42.9%) 1 year after finishing treatment (95%CI, 17.3-47.5). In contrast, oral fluorouracil and leucovorin did not change SV. CONCLUSIONS: SV increased after adjuvant mFOLFOX6, and had not recovered in almost half of cases 1-year after finishing chemotherapy. This increase may indicate continuous SOS, which can adversely affect treatment after recurrence.

[Obstructive Colon Cancer with Triple-Vessel Coronary Artery Disease - A Case Report].

The patient was a 70-year-old woman who was diagnosed with obstructive transverse colon cancer suspected of invading the abdominal wall by abdominal CT imaging. Since the preoperative electrocardiogram showed an ischemic change, echocardiography and coronary angiography were performed. We diagnosed chronic heart failure and angina pectoris because echocardiography showed low cardiac function(left ventricular ejection fraction; LVEF 37%)and coronary angiography indicated triple-vessel disease. We firstly performed coronary artery bypass graft surgery following self-expanding metallic stent placement as a bridge to surgery(BTS), because we judged this patient as a perioperative high-risk case. After improvement of cardiac function(LVEF 49%), expanded right hemicolectomy with partial resection of abdominal wall could be performed without perioperative complications. Colonic stenting as a BTS allowed us to treat comorbidities properly, and perform a radical surgery safely for such a high-risk patient.

Utility of KRAS mutation detection using circulating cell-free DNA from patients with colorectal cancer.

In this study, we evaluated the clinical utility of detecting KRAS mutations in circulating cell-free (ccf)DNA of metastatic colorectal cancer patients. We prospectively recruited 94 metastatic colorectal cancer patients. Circulating cell-free DNA was extracted from plasma samples and analyzed for the presence of seven KRAS point mutations. Using the Invader Plus assay with peptide nucleic acid clamping method and digital PCR, KRAS mutations were detected in the ccfDNA in 35 of 39 patients previously determined to have primary tumors containing KRAS mutations using the Luminex method, and in 5 of 55 patients with tumors containing wild-type KRAS. Curative resection was undertaken in 7 of 34 patients with primary and ccfDNA KRAS mutations, resulting in the disappearance of the mutation from the cell-free DNA in five of seven patients. Three of these patients had tumor recurrence and KRAS mutations in their ccfDNA reappeared. Epidermal growth factor receptor blockade was administered to 24 of the KRAS tumor wild-type patients. Of the 24 patients with wild-type KRAS in their primary tumors, three patients had KRAS mutations in their ccfDNA and did not respond to treatment with epidermal growth factor receptor (EGFR) blockade. We also detected a new KRAS mutation in five patients during chemotherapy with EGFR blockade, before disease progression was detectable with imaging. The detection of KRAS mutations in ccfDNA is an attractive approach for predicting both treatment response and acquired resistance to EGFR blockade, and for detecting disease recurrence.

A case of repeated small bowel perforations in a short period in a patient with cholesterol crystal embolism.

We report a case of jejunal perforation related to cholesterol crystal embolism (CCE) in a woman in her seventies. The jejunum was partially resected;histological examination of the resected tissue revealed that the perforation was caused by CCE. On postoperative day 12, computed tomography (CT) showed free air in the abdomen. We then performed a second operation to alleviate the anastomotic leakage. Subsequently, 26 days after the second surgery, CT again showed free air in the abdomen. A third operation was performed, and multiple perforations of the jejunum were detected. She died of multiple organ failure 43 days after the first surgery. The prognosis of CCE with gastrointestinal perforation is reported to beextremely poor, and there is a high rate of anastomotic leakage. Partial resection of the intestine and ileostomy might be useful for removing the intestinal perforations caused by a CCE. Steroid administration should be continued, however, because discontinuation may worsen the problem.

[Skeletal Mass Depletion Is a Negative Prognostic Factor in Gastrointestinal Cancer Patients in the Terminal Stage].

BACKGROUND: Skeletal mass depletion has been reported to be a prognostic factor for cancer patients. However, special and expensive devices are required to measure skeletal mass, and this is a major reason why skeletal mass is not used extensively for prognostic marker in clinical settings. We developed a new method to measure skeletal mass for use as a prognostic marker using CT images without special and expensive devices. In this study, we evaluated the usefulness of skeletal mass as measured by this new method as a prognostic marker for gastrointestinal cancer patients. METHOD: Patients who died from gastrointestinal cancer between March 2010 and October 2013 were included. We measured the right-sided maximum psoas muscle cross sectional area (MPCA) by using CT images before surgery and after the patients developed a terminal condition. The maximum psoas muscle cross sectional area ratio (MPCA-R) was defined as follows: MPCA-R=MPCA before surgery/MPCA after developing a terminal condition. We evaluated the correlation between MPCA-R and survival. RESULT: Fifty-nine patients were included. The median survival was 44 days, and MPCA-R was significantly correlated with survival (p=0.001). On receiver operating characteristic (ROC) analysis, the area under the curve (AUC) to predict 30-day and 90-day survival was 0.710 and 0.748, respectively. CONCLUSION: MPCA-R is a new and novel prognostic marker for gastrointestinal cancer patients in terminal condition.

Dysmotility by mechanical bowel preparation using polyethylene glycol.

BACKGROUND: The effects of mechanical bowel preparation (MBP) on morbidity (e.g., anastomotic leakage and surgical site infection) have been evaluated. Its effect on early recovery after surgery has drawn renewed attention, and its use is discouraged in the postsurgical management of enhanced recovery. However, most surgeons in Japan prefer polyethylene glycol (PEG) for MBP. We investigated the effect of MBP with PEG on postoperative intestinal motility. MATERIALS AND METHODS: We prospectively evaluated a consecutive series of 258 colon cancer patients who underwent colonic resection and primary anastomosis. We orally administered 2000 mL of PEG in the PEG group and did not administer PEG to patients in the no-PEG group. Postoperative gastrointestinal motility was assessed with radiopaque markers. All patients ingested radiopaque markers 2 h before surgery. Postoperative intestinal motility was radiologically assessed by counting the number of residual markers. Abdominal radiography was conducted on postoperative days 1, 3, and 5 to count residual markers in the large and small intestines. RESULTS: The total number of residual markers in the no-PEG group was less than that in the PEG group on day 5 (P < 0.01) but not on days 1 and 3. On all 3 d, the numbers of residual markers in the small intestine were significantly less in the no-PEG group than in the PEG group (P < 0.001). There were no differences in postoperative complications between the no-PEG and PEG groups. CONCLUSIONS: PEG can negatively affect postoperative intestinal motility, and MBP using PEG is unnecessary in elective colon cancer surgery.

[A case of multiple primary small intestinal adenocarcinomas].

A 62-year-old woman, with a past history of long-term non-steroidal anti-inflammatory drug use and gastric ulcer, was hospitalized for intestinal obstruction in April 2012. Two stenoses were identified in the ileum in association with small intestinal ulcers, and she underwent partial resection of the small intestine. Histologically, the two lesions were poorly differentiated adenocarcinomas; metastatic small intestinal cancer was suspected, but whole body examination revealed no other lesions. The final diagnosis was multiple primary small intestinal malignancies, necessitating additional resection of the small intestine in July. We report this case to raise awareness among physicians of the possibility of primary small intestinal cancer in patients with multiple small intestinal stenoses.

A case report of anal fistula-associated mucinous adenocarcinoma developing 3 years after treatment of perianal abscess.

BACKGROUND: A long-standing (over 10 years) anal fistula is considered a fundamental cause of fistula-associated mucinous adenocarcinoma (FAMC). Perianal abscesses and anal fistulas are two sequential phases of the same anorectal infectious process. We experienced a case of FAMC which developed 3 years after the treatment of a perianal abscess. CASE PRESENTATION: A 68-year-old woman was admitted to our hospital because of progressive anal pain and a palpable tumor. She had a history of undergoing a drainage operation for a perianal abscess 3 years previously. A 15 × 15-mm tumor at the former drainage site was identified; transanal ultrasonography showed an intersphincteric fistula connecting to the tumor. A biopsy taken from the tumor demonstrated mucinous adenocarcinoma; the tumor was diagnosed as FAMC. Laparoscopic abdominoperineal resection was performed. Histopathology showed highly dysplastic cells lining the lumen of the anal fistula and poorly differentiated mucinous adenocarcinoma proliferating in the dermis and epidermis in the distal aspect of the fistula. CONCLUSIONS: FAMC can develop within fewer than 3 years after the development of a perianal abscess and anal fistula.

[Reduction in oxaliplatin-related neurotoxicity by the administration of Keishikajutsubuto(TJ-18)and powdered processed aconite root].

Oxaliplatin (L-OHP)is an important chemotherapeutic drug for the treatment of colorectal cancer. Peripheral neuropathy was observed in 90% of patients who received L-OHP.Neuropathy often results in the discontinuation of treatment or a decrease the quality of life(QOL). The most effective method for reducing neuropathy is the discontinuation of L-OHP. To reduce neuropathy, we administered Keishikajutsubutou(TJ-18)with powdered processed aconite root(TJ-3023), and we report the effect of these compounds. The subjects comprised 11 patients with metastatic colorectal cancer. L-OHP(85mg/m2)was administered as part of the FOLFOX6(10 patients)or FOLFOX7(1 patient)regimen. All patients had experienced neuropathy. We administered TJ-18(7.5 g)and T-3023(1 g). After 2 weeks, the TJ-3023 dose was increased to 2 g for nonresponders. The response was evaluated according to the Neurotoxicity Criteria of DEBIOPHARM. Reduction in neuropathy was observed in 5 cases(45.5% ). Among 6 patients whose feet and hands felt warm, reduction in neuropathy was observed in 5(83.3% ).