Donglin Ren

Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial

PURPOSE Total mesorectal excision with fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy is a standard treatment of locally advanced rectal cancer. This study investigated the addition of oxaliplatin with and without preoperative radiotherapy. METHODS In this multicenter, open-label, phase III trial, we randomly assigned (1:1:1) Chinese adults (age 18 to 75 years) with locally advanced stage II/III rectal cancer to three treatments: five 2-week cycles of infusional fluorouracil (leucovorin 400 mg/m(2), fluorouracil 400 mg/m(2), and fluorouracil 2.4 g/m(2) over 48 h) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 through 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m(2) on day 1 of each cycle (modified FOLFOX6 [mFOLFOX6]), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Random assignment was performed by using computer-generated block randomization codes. The primary end point was 3-year disease-free survival. Secondary end points of histopathologic response and toxicity are reported. RESULTS A total of 495 patients were enrolled from June 2010 to February 2015; 475 were evaluable (fluorouracil-radiotherapy, n = 155; mFOLFOX6-radiotherapy, n = 157; mFOLFOX6, n = 163). In the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, the rate of pathologic complete response (pCR) was 14.0%, 27.5%, and 6.6%, and downstaging (ypStage 0 to 1) was achieved by 37.1%, 56.4%, and 35.5% of patients, respectively. Higher toxicity and more postoperative complications were observed in patients who received radiotherapy. CONCLUSION mFOLFOX6-based preoperative chemoradiotherapy results in a higher pCR rate than fluorouracil-based treatment. Perioperative mFOLFOX6 alone had inferior results and a lower pCR rate than chemoradiotherapy but led to a similar downstaging rate as fluorouracil-radiotherapy, with less toxicity and fewer postoperative complications.

Expression of the phosphorylated MEK5 protein is associated with TNM staging of colorectal cancer.

BackgroundActivation of MEK5 in many cancers is associated with carcinogenesis through aberrant cell proliferation. In this study, we determined the level of phosphorylated MEK5 (pMEK5) expression in human colorectal cancer (CRC) tissues and correlated it with clinicopathologic data.MethodspMEK5 expression was examined by immunohistochemistry in a tissue microarray (TMA) containing 335 clinicopathologic characterized CRC cases and 80 cases of nontumor colorectal tissues. pMEK5 expression of 19 cases of primary CRC lesions and paired with normal mucosa was examined by Western blotting. The relationship between pMEK5 expression in CRC and clinicopathologic parameters, and the association of pMEK5 expression with CRC survival were analyzed respectively.ResultspMEK5 expression was significantly higher in CRC tissues (185 out of 335, 55.2%) than in normal tissues (6 out of 80, 7.5%; P < 0.001). Western blotting demonstrated that pMEK5 expression was upregulated in 12 of 19 CRC tissues (62.1%) compared to the corresponding adjacent nontumor colorectal tissues. Overexpression of pMEK5 in CRC tissues was significantly correlated to the depth of invasion (P = 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001) and high preoperative CEA level (P < 0.001). Consistently, the pMEK5 level in CRC tissues was increased following stage progression of the disease (P < 0.001). Analysis of the survival curves showed a significantly worse 5-year disease-free (P = 0.002) and 5-year overall survival rate (P < 0.001) for patients whose tumors overexpressed pMEK5. However, in multivariate analysis, pMEK5 was not an independent prognostic factor for CRC (DFS: P = 0.139; OS: P = 0.071).ConclusionspMEK5 expression is correlated with the staging of CRC and its expression might be helpful to the TNM staging system of CRC.

The tissue-selecting technique: segmental stapled hemorrhoidopexy.

We describe a technique for the management of prolapsing hemorrhoids, with the aim to minimize the risk of anal stricture and rectovaginal fistula and to reduce the impact of the stapling technique on rectal compliance. This modified procedure was successfully applied in China, and preliminary data showed promising outcomes (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A117).

Clinical Significance of 2 Deep Posterior Perianal Spaces to Complex Cryptoglandular Fistulas.

BACKGROUND: Confusion exists regarding the clinical significance of the deep posterior intersphincteric space and deep postanal space to complex perianal fistulas. OBJECTIVE: The purpose of this study was to assess the clinical significance of the 2 deep posterior perianal spaces and to describe in detail the courses of posterior complex cryptoglandular fistula extensions. DESIGN: This was a retrospective study. MRI-based characteristics of selected perianal fistulas were independently evaluated by examiners who focused on lesions in these 2 spaces and were blinded to each other’s findings. SETTINGS: This study was conducted in the colorectal surgery and radiology departments of a large university teaching hospital in China. PATIENTS: Included in the study were patients who underwent pelvic MRI for posterior perianal fistula between October 2012 and December 2014. MAIN OUTCOME MEASURES: The occurrence rates of these 2 deep perianal space lesions in posterior cryptoglandular fistulas were determined. RESULTS: A total of 513 primary posterior cryptoglandular fistulas were identified in 508 patients, including 167 deep posterior intersphincteric space lesions (32.6%) and 23 deep postanal space lesions (4.5%). Of those, 173 fistulas (33.7%) were evaluated as complex. The former and latter spaces were involved in 79.2% (137/173) and 13.3% (23/173) of posterior complex fistulas. Compared with deep postanal space lesions, deep posterior intersphincteric space lesions were more common in cases with high transsphincteric or suprasphincteric fistulas (80.1% vs 15.8%), synchronous multiple transsphincteric fistulas (82.4% vs 20.6%), horseshoe-like fistulas (85.5% vs 14.5%), and supralevator fistulas (93.5% vs 16.1%). Similar incidences were also seen in cases with ischioanal-involved horseshoe-like fistulas (75.0% vs 25.0%). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: The deep posterior intersphincteric space is more likely than the deep postanal space to be involved in complex cryptoglandular fistulas and is likely to play a more important role in the management of complex cryptoglandular fistulas.

Tumor Volume Reduction Rate Predicts Pathologic Tumor Response of Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemotherapy alone: Results from a Prospective Trial.

Purpose: To evaluate tumor volume reduction rate (TVRR) measured by three-dimensional region-of-interest (3D-ROI) magnetic resonance (MR) volumetry in predicting pathological tumor response of preoperative chemotherapy alone for locally advanced rectal cancer (LARC). Methods: LARC patients who received neoadjuvant chemotherapy only from a prospective and randomized trial were recruited. Tumor volumes were measured with 3D-ROI MR volumetry. TVRR was determined using the equation TVRR = (VPre-Therapy - VPost-Therapy) / VPre-Therapy ×100%. Correlation between TVRR and clinical or pathological characteristics and predictive value of TVRR for pathological tumor response in terms of Tumor Regression Grade (TRG), T downstage, N downstage and overall downstage were analyzed. Results: 80 eligible cases of LARC were included in our study with TVRR of (51.7±25.1) %. TVRR was higher in well-differentiated tumors compared with poor-differentiated tumors (P=0.040). TVRR was found to be related with TRG (P<0.001), T downstage (P<0.001) and overall downstage (P<0.001). Risk of achieving TRG 2/3 decreased to 57.5% (P=0.002) and odds of achieving overall downstage increase to 179.3% (P<0.001) when TVRR increased by every 10%. A sensitivity of 0.704 and specificity of 0.804 were calculated when ROC curve was constructed to predict TRG using TVRR with a cutoff of 65%. Conclusion: TVRR is correlated with TRG and overall downstage significantly in LARC patients treated with preoperative chemotherapy alone and shows great value in predicting favorable TRG and overall downstage with good sensitivity and specificity. It could be considered as a promising parameter candidate for efficacy evaluation.

Recurrent granular cell tumor of the anal-perianal region: how much anal sphincter can be resected?

A 48-year-old Chinese woman presented with a 6-month history of a progressively growing perianal mass but no pain, hematochezia, tenesmus, or weight loss. She had a history of hyperlipidemia and of perianal granular cell tumor (GCT) resection 7 years prior. Physical examination showed a 5-cm surgical scar on the skin 3 cm from the anus, a tough perianal mass adhering to the external anal sphincter (EAS) and extending to the left half of the anal circumference under the old scar. The mass was 3 9 4 cm with smooth borders and fixed to the underlying tissues. All blood and biochemical test results were within the normal range with one exception: the CA 19–9 level was 70 U/L. Pelvic magnetic resonance imaging (MRI) revealed a brightly enhancing mass Fig. 1a. Considering the presence of a tumor involving more than half of the EAS and the high risk of fecal incontinence and recurrence, we recommended abdominoperineal excision. However, the patient refused a permanent colostomy and consented only to a sphincter-sparing procedure, accepting the risk of recurrence and of anal incontinence. We therefore performed a local excision with sphincteroplasty. The patient underwent bowel preparation with polyethylene glycol solution the night before surgery. A broad spectrum parenteral antibiotic was administered preoperatively and was continued for 48 h after the operation. The patient was given epidural anesthesia without any local infiltration anesthesia, was placed in the jackknife position, and had a urinary catheter placed. An incision was made using Peng’s multifunctional operational dissectors (PMOD) (Shuyou Surgical Instrument Co., Ltd. Zhejiang, China), beginning at the original incision with arc-shaped extensions under the mass. The incision reaching the perianal skin was carried back along the expected outer edge of the EAS. The mass presented as white and tough and infiltrated almost half of the EAS. The perianal skin, internal anal sphincter (IAS), rectal muscularis propria, and puborectalis muscle were then dissected free along the mass. The excision included more than half of the peripheral part of the EAS. Care was taken to preserve the underlying IAS as much as possible. The free edges of the EAS and IAS were approximated separately. Then, the EAS was brought together in an overlapping fashion using an 3–0 vicryl suture (Ethicon, Somerville, NJ, USA), followed by levatorplasty, which was accomplished with a 2 cm 9 3 cm, 4-ply sheet of bioprosthetic mesh (Surgisis ES, Cook surgical Inc, Bloomington, IN, USA) (Fig. 2). Finally, the perianal skin was sutured. Postoperatively, the patient’s diet consisted of liquids and then a soft diet, supplemented with stool softeners and fiber. The patient was discharged on postoperative day 5, after return of bowel function and was seen as an outpatient every 2 weeks until full wound healing was achieved (Fig. 3). X. Y. Wan B. Hu D. L. Ren (&) Division of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Erheng Road, Guangzhou 510655, Guangdong, People’s Republic of China e-mail: rxyz111@yahoo.com.cn

Reply to invited comment on “Partial stapled hemorrhoidopexy versus circular stapled hemorrhoidopexy for grade III–IV prolapsing hemorrhoids: a two-year prospective controlled study” by I. Khubchandani

We appreciate the opportunity to respond to the letter by Dr. Khubchandani. Based upon the comment from Dr. Khubchandani, we are pleased to find a very thorough colorectal specialist with acute eyesight and cautious support for a novel technique. Circular stapled hemorrhoidopexy (CSH), which has gained wide popularity since 1998 because of its efficacy and the low postoperative pain associated with the technique [1], was adopted by more and more proctologists to treat prolapsing hemorrhoids. According to our estimate, about 20, 000 cases of PPH were treated in China each year. However, potential complications including rectovaginal fistula and anal stenosis cannot be avoided completely, whereas lifethreatening severe complications are increasingly reported [2]. The need to improve the results of this stapled technique led surgeons to develop a modified technique, even a novel technique. The idea of tissue-selecting technique (TST), namely partial stapled hemorrhoidopexy, is aimed at overcoming the weakness and limitations of CSH. Anal stenosis after CSH was often encountered in clinical practice. Some of these cases may be attributed to surgical error such as removal of large areas of anoderm. However, even an experienced surgeon with meticulous technique will also find that a little anal stricture develops in some patients after this circular technique. It will not always be due to surgical error and may be due to the fact that full circumference of the rectal mucosa is affected. TST gets partial circumference anastomosis to avoid anal stenosis and spares the rectal wall adjacent to the vagina to avoid rectovaginal fistula completely by using our specially designed anoscope in female patients. Further clarifications of the ‘‘mucosal bridge’’ in our article are required. Actually, after the stapler in TST is fired and gently withdrawn, a minimal mucosal bridge with some staples connecting the two edges of the mucosectomies (Fig. 1), like in the case of STARR, was found and dissected using electrocautery. Due to the protection by the spatula of the tri-window anoscope, a mucosal bridge, consisting of normal rectal mucosa, was spared (Fig. 2). Because of the preservation of partial of rectal wall between mucosectomies, a better rectal compliance was maintained and this resulted in less damage to anorectal function. CSH has the same safety and efficacy as conventional hemorrhoidectomy, and this could account for the widespread adoption of CSH. Nevertheless, few studies have been performed investigating the potential influence on the anorectal function and the mechanism of postoperative outcomes including pain, fecal urgency, and anal stenosis after CSH. Our preliminary study on TST has demonstrated that this modified technique is associated with good anorectal function including fewer episodes of urgency and no anal incontinence or anal stenosis [3]. Nevertheless, randomized controlled trials that compare the TST and CSH procedures are required to confirm the results of this preliminary trial. Damage to the healthy tissue should be lessened on the condition that therapeutic efficacy is guaranteed. TST is designed to treat prolapsing hemorrhoids with minimal damage to the normal tissue. This is the fundamental idea of TST. Any new approach, first introduced into clinical This reply refers to the comment available at doi:10.1007/s10151-012-0866-x.

A Modification of the Stapled TransAnal Rectal Resection (STARR) Procedure for Rectal Prolapse

Purpose. This study was designed to assess the safety, efficacy, and postoperative outcomes of the modified Stapled TransAnal Rectal Resection (modified STARR) in patients presenting with cases of limited external rectal prolapse. Methods. A prospective cohort of patients with mild rectal prolapse undergoing rectal resection with the Tissue-Selecting Technique Stapled TransAnal Rectal Resection Plus (TSTStarr Plus) stapler between February 2014 and September 2016 was reviewed retrospectively. Results. Twenty-five eligible patients underwent rectal resection with the TSTStarr Plus stapler. The median vertical height of the resected specimen was 5.0 cm (range = 3.1-10 cm) with all cases being confirmed histologically as full-thickness resections. Over a follow-up of 33.6 ± 9.4 months, only 1 case (4%) was encountered with recurrence. The mean postoperative Wexner score was significantly improved when compared with the preoperative scores (preoperative: median = 3, range = 0-20, vs postoperative: median = 2, range = 0-20, respectively; P = .010). The median preoperative Symptom Severity Score and Obstructed Defecation Score were both decreased compared with the postoperative scores (P = .001). Conclusions. Modified STARR in management of mild rectal prolapse appear to be a safe and effective technique. The initial results would encourage a more formal prospective assessment of this technique as part of a randomized trial for the management of mild rectal prolapse.

Stapled Transperineal Fistula Repair of Rectovaginal Fistula: A Preliminary Experience

Purpose. This study is designed to assess the safety, efficacy, and postoperative outcomes of stapled transperineal repair in management of rectovaginal fistula (RVF). Methods. A prospective database of patients with RVF undergoing stapled transperineal repair between May 2015 and December 2017 was established and studied retrospectively. Results. Seven consecutive RVF patients underwent stapled transperineal repair. The mean operative time was 119 ± 42 minutes. The estimated blood loss during operation was 24 ± 14 mL. Concomitant levatorplasty was performed with 4 patients and sphincteroplasty with 2 patients. Over a median follow-up of 6 months (range 3-33 months), no case was encountered with recurrence. The mean postoperative Wexner score was significantly improved when compared with the preoperative scores (mean preoperative vs postoperative Wexner scores 3 [range 3-4] vs 1 [range 1-2], respectively; P = .01). Conclusions. Stapled transperineal repair of RVF appears safe and effective. The initial results are encouraging, suggesting the need for a more formal prospective assessment of this technique as part of a randomized trial for the management of low- and mid-vaginal fistulas.

Prognostic and predictive value of interstitial cells of Cajal populations following stapled transanal rectal resection (STARR) in patients with obstructed defecation syndrome

Abstract Objective The present study was designed to evaluate the functional outcome of stapled transanal rectal resection (STARR) and to examine the relationship between the population density of the interstitial cells of Cajal (ICC) and the efficacy of the STARR operation in the management of obstructed defecation syndrome (ODS) patients. Methods Full-thickness rectal samples were obtained from 50 ODS patients who underwent STARR. Samples were analysed using ICC immunohistochemistry. Clinical and functional parameters obtained with defecography and anorectal manometry were compared with 20 controls. Results ICCs were significantly decreased in patients in the submucosal (SM), intramuscular (IM) and myenteric (MY) regions when compared with the control group (P < 0.05). The mean pre-operative Cleveland Constipation Score (CCS) was 24.2 ± 4.1, whilst the CCS at 1, 2, 3, 4 and 5 years post-operatively decreased significantly (P < 0.05). At 3 post-operative years, 58.3% (28/48) of the patients reported a favorable outcome (CCS ≤ 10). On univariate analysis, the functional results were worse in those with pre-operative digitation (P = 0.017), a decreased ICC-MY cell population (P = 0.067), a higher resting anal canal pressure (P = 0.039) and a higher rectal sensory threshold (P = 0.073). Multivariate analysis showed the decreased ICC-MY cell population was an independent predictor for low unfavorable functional outcome (odds ratio = 0.097, 95% confidence interval: 0.012–0.766). Conclusions STARR achieved acceptable results at the cost of a slight deterioration over a more prolonged follow-up. Patients with a decreased ICC number in the rectal specimen showed an unfavorable functional outcome where pre-operative histological assessment of a full-thickness rectal sample might predict for the functional outcome following STARR.