The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial.

PURPOSE: The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection. METHODS: This is an extension of a multicentre RCT (NCT01110798). Kaplan-Meier method and the log-rank test were used to estimate and compare the 3-, 5-, and 10-year OS and DFS, and local and distant recurrence in patients with and without AL. Predictors of OS and DFS were evaluated using the Cox regression analysis as secondary aim. RESULTS: Follow-up was available for 311 patients. Of them, 252 (81.0%) underwent neoadjuvant chemoradiotherapy and 138 (44.3%) adjuvant therapy. AL occurred in 63 (20.3%) patients. At a mean follow-up of 69.5 ± 31.9 months, 23 (7.4%) patients experienced local recurrence and 49 (15.8%) distant recurrence. The 3-, 5-, and 10-year OS and DFS were 89.2%, 85.3%, and 70.2%; and 80.7%, 75.1%, and 63.5% in patients with AL, and 88.9%, 79.8% and 72.3%; and 83.7, 74.2 and 62.8%, respectively in patients without (p = 0.89 and p = 0.84, respectively). At multivariable analysis, AL was not an independent predictor of OS (HR 0.65, 95%CI 0.34-1.28) and DFS (HR 0.70, 95%CI 0.39-1.25), whereas positive circumferential resection margins and pathological stage impaired both. CONCLUSIONS: In the context of modern multimodal rectal cancer treatment, AL does not affect long-term OS, DFS, and local and distant recurrence in patients with mid-low rectal cancer.

Colonic J-Pouch or Straight Colorectal Reconstruction After Low Anterior Resection For Rectal Cancer: Impact on Quality of Life and Bowel Function: A Multicenter Prospective Randomized Study.

BACKGROUND: Patient-reported outcomes associated with different bowel reconstruction techniques following anterior resection for rectal cancer are still a matter of debate. OBJECTIVE: This study aimed to assess quality of life and bowel function in patients who underwent colonic J-pouch or straight colorectal anastomosis reconstruction after low anterior resection. DESIGN: Bowel function and quality of life were assessed within a multicenter randomized trial. Questionnaires were administered before the surgery (baseline) and at 6, 12, and 24 months after surgery. SETTINGS: Patients were enrolled by 19 centers. The enrollment started in October 2009 and was stopped in February 2016. The study was registered at www.clinicaltrials.gov (Identifier: NCT01110798). PATIENTS: Patients who underwent low anterior resection for primary mid-low rectal cancer and who were randomly assigned in a 1:1 ratio to receive either stapled colonic J-pouch or straight colorectal anastomosis were selected. MAIN OUTCOME MEASURES: The primary outcomes measured were quality of life and bowel function. RESULTS: Of the 379 patients who were evaluable, 312 (82.3%) completed the baseline, 259 (68.3%) the 6-month, 242 (63.9%) the 12-month, and 199 (52.5%) the 24-month assessment. Bowel functioning and quality of life did not significantly differ between arms for almost all domains. The total bowel function score, the urgency, and the stool fractionation scores significantly worsened after surgery and remained impaired over time in both arms (p < 0.0032), whereas constipation improved after surgery but recovered to baseline levels from 1 year onward (p < 0.0036). All patients showed a significant and continuous improvement in emotional functioning (p < 0.0013) and future perspective (p < 0.0001) from baseline to the end of the study. LIMITATIONS: Limitations of the study include missing data, which increased over time; the possibility that some treatments have slightly changed since the study was conducted; and investigators not blind to treatment allocation. CONCLUSION: The findings of this study do not support the routine use of colonic J-pouch reconstruction in patients with rectal cancer who undergo a low anterior resection. See Video Abstract at http://links.lww.com/DCR/B328. BOLSA J COLÓNICA O RECONSTRUCCIÓN COLORRECTAL RECTA DESPUÉS DE RESECCIÓN ANTERIOR BAJA PARA CÁNCER RECTAL: IMPACTO EN LA CALIDAD DE VIDA Y LA FUNCIÓN INTESTINAL: UN ESTUDIO ALEATORIZADO PROSPECTIVO MULTICÉNTRICO: Los resultados informados por el paciente asociados con diferentes técnicas de reconstrucción intestinal después de la resección anterior para el cáncer de recto aún son tema de debate.Evaluar la calidad de vida y la función intestinal en pacientes que se sometieron a una bolsa en J colónica o reconstrucción de anastomosis colorrectal recta después de una resección anterior baja.La función intestinal y la calidad de vida se evaluaron en un ensayo aleatorizado multicéntrico. Los cuestionarios se administraron antes de la cirugía (basal) y a los 6, 12 y 24 meses después de la cirugía.Los pacientes fueron incluidos en 19 centros. La inscripción comenzó en Octubre de 2009 y se detuvo en Febrero de 2016. El estudio se registró en www.clinicaltrials.gov (Identificador: NCT01110798).Pacientes que se sometieron a resección anterior baja por cáncer rectal primario medio-bajo y que fueron aleatorizados en una proporción de 1: 1 para recibir bolsa J colónica con grapas o anastomosis colorrectal recta.calidad de vida y función intestinal.De los 379 pacientes que fueron evaluables, 312 (82.3%) completaron la evaluación inicial, 259 (68.3%) a los 6 meses, 242 (63.9%) a los 12 meses y 199 (52.5%) a los 24 meses. . El funcionamiento intestinal y la calidad de vida no difirieron significativamente entre los dos grupos en casi todos los dominios. La puntuación total de la función intestinal, la urgencia y las puntuaciones de fraccionamiento de las heces empeoraron significativamente después de la cirugía y continuaron con el tiempo extra en ambos grupos (p <0.0032), mientras que el estreñimiento mejoró después de la cirugía pero se recuperó a los niveles basales a partir de 1 año en adelante (p <0.0036). Todos los pacientes mostraron una mejora significativa y continua en el funcionamiento emocional (p <0.0013) y la perspectiva futura (<0.0001) desde el inicio hasta el final del estudio.Datos faltantes, que aumentaron con el tiempo; la posibilidad de que algunos tratamientos hayan cambiado ligeramente desde que se realizó el estudio; investigadores no cegados a la asignación del tratamiento.Los hallazgos de este estudio no respaldan el uso rutinario de la reconstrucción de la bolsa J colónica en pacientes con cáncer rectal que se someten a una resección anterior baja. Consulte Video Resumen en http://links.lww.com/DCR/B328. (Traducción-Dr. Yesenia Rojas-Khalil).

The detection of interval colorectal cancers following screening by fecal immunochemical test may predict worse outcomes and prompt ethical concerns: a 6-year population-based cohort study in a full district.

The rates of colorectal cancer (CRC) interval surveyed in screen-detected patients using a fecal immunochemical test (FIT) are not negligible. The aim of this study was to assess the effect of interval cancer on outcomes compared with a population with cancer diagnosed after a positive test result. All patients between 50 and 71 years of age, who were residents of the Mantua district, affected by CRC and operated on from 2005 to 2010 were reviewed. Other than patient-related, disease-related, and treatment-related factors and tumor location, this population was differentiated as either participating or not to screening and then into populations developing interval cancer after a negative FIT result. Mortality was investigated by univariate analysis and by overall survival rates. The mean age of the 975 patients enrolled was 62 years (61.7% males). Most patients (n=575, 59%) were not screen detected, and 400 (41%) were screen detected. Fifty-six (5.7%) patients in the latter group, representing 14% of the participants, developed interval cancer after a negative FIT result. Their cancer was mostly localized in the right colon (41.1%) instead of the left colon and rectum (P=0.02). They also showed higher stages (P=0.001), a moderate degree of differentiation (P=0.001), and overall higher mortality rates than patients with cancer diagnosed after a positive test result (P=0.001). The effect of interval CRC after screening with FIT resulted in worse outcomes compared with the FIT-positive group. With such findings, patients who had negative results for FIT should be informed of the risk of developing cancer within the rounds of screening to independently gain educational skills in the area of health prevention.

Comparing outcomes after treatment of rectal cancer over a long-lasting follow-up between patients who were offered surgery alone and surgery with neoadjuvant therapy.

BACKGROUND: To assess outcomes of patients operated on for rectal cancer (RC) by analysing the trends of disease free survival curves (DFSc) after a very long-term follow-up. METHODS: All patients treated with curative intent for RC from 1986 to 2005 were retrospectively analyzed. Other than demographics, disease characteristics and treatment-related factors were considered. The DFSc were compared between patients who had neoadjuvant therapy (NAT) and those who had surgery alone. RESULTS: Median age of 319 patients included in the study was 66.3 years (range 23-89) and 140 (57.6%) of them were males. Moreover, NAT was given in 24 (11.8%) patients, and adjuvant therapy in 40 (19.7%) patients. Median follow-up was of 150 months (60-240). In patients who had NAT the mean age was higher (P=0.05), RC were located lower (P=0.009) and higher positive lymph-nodes were found (P=0.003), whereas the number of both local (P=0.4) and distant recurrences (P=0.7) was not significantly lower, compared to the other group. Comparing trends of DFSc a more progressive decrease was shown in patients treated with surgery alone. Even if the differences of DSFc between groups at the end of follow-up were not significant (95% CI: 0.609-2.963, P=0.46), patients who had NAT displayed better survival up to 180 months. CONCLUSIONS: Overall, these results showed comparable outcomes between both groups over such a long lasting follow-up. This time frame might be used more extensively for increasing our knowledge of RC biological behaviour as well.

The impact of colorectal screening program on the detection of right-sided colorectal cancer. A 5-year cohort study in the Mantua District.

BACKGROUND: High rates of advanced colorectal cancer (CRC) are still diagnosed in the right side of the colon. This study aimed to investigate whether screening programs increase CRC detection and whether tumor location is associated with survival outcome. METHODS: Patients affected by CRC, aged from 50 to 69 years and operated on from 2005 to 2009 were reviewed. Other than patient-, disease-, and treatment-related factors, detection mode and tumor location were recorded. Overall (OS) and disease-free survival (DFS) were investigated, using univariate and multivariate analyses. RESULTS: Mean age of 386 patients included was 62.0 years, 59 % were males. CRC was detected by screening in 17 % of cases, and diagnosis was made from symptoms in 67 % and emergency surgery for 16 %. Screen-detected CRCs were located in the left colon (59 %), then in rectum (25 %) and in proximal colon (16 %) (p = 0.02). Most of CRC patients urgently operated on had cancer located in proximal colon (45 %), then in the left colon (36 %) and in rectum (18 %) (p = 0.001). Right-sided CRC demonstrated higher pTNM stage (p = 0.001), adequate harvest count nodes (p = 0.0001), metastatic nodes (p = 0.02), and poor differentiation grading (p = 0.0001). With multivariate analysis, poor differentiation grade was independently associated with both worse OS (HR 3.6, p = 0.05) and worse DFS (HR 8.1, p = 0.0001), while distant recurrence was associated with worse OS (HR 20.1, p = 0.0001). CONCLUSION: Low rates of right-sided CRC are diagnosed following screening program. Proximal CRC demonstrates aggressive behavior without impact on outcome. These findings prompt concern about population awareness for CRC screening.

Neuromodulation for fecal incontinence: an effective surgical intervention.

Fecal incontinence is a disabling symptom with medical and social implications, including fear, embarrassment, isolation and even depression. Most patients live in seclusion and have to plan their life around the symptom, with secondary impairment of their quality of life. Conservative management and biofeedback therapy are reported to benefit a good percentage of those affected. However, surgery must be considered in the non-responder population. Recently, sacral nerve electrostimulation, lately named neuromodulation, has been reported to benefit patients with fecal incontinence in randomized controlled trials more than placebo stimulation and conservative management, by some unknown mechanism. Neuromodulation is a minimally invasive procedure with a low rate of adverse events and apparently favorable cost-efficacy profile. This review is intended to expand knowledge about this effective intervention among the non-surgically skilled community who deals with this disabled group of patients.

Effectiveness and safety of local adalimumab injection in patients with fistulizing perianal Crohn's disease: a pilot study.

BACKGROUND: Various blockers of tumor necrosis factor-α are available for treatment of Crohn's disease. Randomized controlled trials have demonstrated the effects of systemic therapy with adalimumab, a fully humanized monoclonal antibody against tumor necrosis factor-α. OBJECTIVE: The aim of this study was to investigate the effectiveness and safety of local injection of adalimumab along the fistula in the treatment of perianal Crohn's disease. DESIGN AND SETTING: This was a prospective, uncontrolled, open-label observational study performed at a university tertiary care center. PATIENTS: A total of 12 outpatients (9 women, 3 men) treated for fistulizing perianal Crohn's disease between 2009 and 2010 were enrolled. The mean age was 43.5 (range, 27-59) years. The fistula was classified as anovaginal in 3 patients, transsphincteric in 7 patients (low in 2, high in 5), and complex (multiple tracts) in 2 patients. Pikarsky's Perianal Crohn's Disease Activity Index was used to evaluate severity of the perianal disease. INTERVENTION: Adalimumab was injected locally along the fistula tract and around the internal orifice every 2 weeks. MAIN OUTCOME MEASURES: The primary end point of the study was the proportion of patients in whom complete or improved healing of fistulas was observed at follow-up, with improvement based on the number of daily changes of sanitary pads. RESULTS: The median number of injections per patient was 7 (range, 4-16). The mean length of follow-up was 17.5 (range, 5-30) months; 75% of patients (9 of 12) reached complete cessation of fistula drainage, and 3 patients (25%), all with transsphincteric fistula, showed improvement. Comparison of overall follow-up scores on the Perianal Crohn's Disease Activity Index with baseline showed significant improvement (p = 0.002). No adverse side effects were noted. LIMITATIONS: The study was limited by its small sample size and by the absence of a control group. CONCLUSIONS: This pilot study suggests that a high local concentration of adalimumab favors prompt and definitive healing of the fistulous tract in patients with perianal Crohn's disease. Future randomized trials with well-defined selection criteria are needed to determine the relative risks and benefits of available anti-TNF-α blockers (chimeric vs fully humanized) and the optimal mode of administration (systemic use vs local injection) in the treatment of fistulizing perianal Crohn's disease.

An assessment of enteric nervous system and estroprogestinic receptors in obstructed defecation associated with rectal intussusception.

BACKGROUND: The pathophysiological basis of obstructed defecation (OD) is still incompletely understood. In particular, few or no data are available concerning the enteric nervous system (ENS) in this condition. We investigated ENS abnormalities in patients with OD, undergoing surgery, together with the presence of estrogen (α and ß) and progesterone receptors, and compare the results with those obtained in controls. METHODS: Full-thickness rectal samples were obtained from 17 patients undergoing stapled transanal rectal resection for OD associated with rectal intussusception. Samples were analyzed by immunohistochemistry for enteric neurons, enteric glial cells, interstitial cells of Cajal (ICC), and for estrogen and progesterone receptors. Data were compared with those obtained in 10 controls. KEY RESULTS: No differences between patients and controls were found for enteric neurons, whereas (compared with controls) OD patients displayed a significant decrease of enteric glial cells in both the submucous (P = 0.0006) and the myenteric (P < 0.0001) plexus. ICC were significantly increased in patients in the submucosal surface (P < 0.0001) and the myenteric area (P < 0.0001). Concerning estroprogestinic receptors, both were present on ICC in patients and controls. Estrogen receptors α and progesterone receptors were absent on enteric neurons and enteric glial cells in patients and controls, whereas estrogen receptors ß were present in all controls and in 69% of patients' enteric neurons (P = 0.18) and in 12% of patients' glial cells (P = 0.0001). CONCLUSIONS & INFERENCES: Patients with OD associated to rectal intussusception display abnormalities of the ENS and of estrogen receptors ß.

Chronic proctalgia and chronic pelvic pain syndromes: new etiologic insights and treatment options.

This systematic review addresses the pathophysiology, diagnostic evaluation, and treatment of several chronic pain syndromes affecting the pelvic organs: chronic proctalgia, coccygodynia, pudendal neuralgia, and chronic pelvic pain. Chronic or recurrent pain in the anal canal, rectum, or other pelvic organs occurs in 7% to 24% of the population and is associated with impaired quality of life and high health care costs. However, these pain syndromes are poorly understood, with little research evidence available to guide their diagnosis and treatment. This situation appears to be changing: a recently published large randomized, controlled trial by our group comparing biofeedback, electrogalvanic stimulation, and massage for the treatment of chronic proctalgia has shown success rates of 85% for biofeedback when patients are selected based on physical examination evidence of tenderness in response to traction on the levator ani muscle--a physical sign suggestive of striated muscle tension. Excessive tension (spasm) in the striated muscles of the pelvic floor appears to be common to most of the pelvic pain syndromes. This suggests the possibility that similar approaches to diagnostic assessment and treatment may improve outcomes in other pelvic pain disorders.

Defunctioning stoma in high ASA grade, aged patients, with bowel occlusion due to advanced cancer: is it still worthwhile?

PURPOSE: The aim of this study was to assess the role of defunctioning stoma (DS) in elderly high-risk patients with bowel obstruction from advanced colorectal cancer, by exploring consistent variables of outcome, because every other procedure was unfeasible. MATERIALS AND METHODS: A 6-year survey in a single surgery unit (between 1999 and 2004) was retrospectively evaluated, allowing to collect a cohort of 75 patients, aged over 65, who overall presented such critical condition. Pre-operatively, American Society of Anaesthesiologist grade classification was used. Post-operative course was monitored by focusing on gauging symptom relief. So, a validated assessment scale was employed to evaluate physical distress symptoms, graduated on a Likert scale and compared at baseline and day 7, on days 7 and 30, post-operatively. Length of hospital stay (LHS), morbidity, in-hospital (within 30 days) and overall mortality (within 6 months) were also assessed. Paired t test was used as statistical analysis to ascertain improvement of symptoms. RESULTS: All symptoms improved significantly (range, p < 0.05 to p < 0.01) within the surveyed time, with exception of vomiting on day 30 (p = 0.14). Average LHS was 22.8 (standard deviation, +/-3.856) days. Overall morbidity was detected in 68 (91%) patients. In-hospital and overall mortality rates accounted for 27 (35.8%) patients and for 48 (100%) patients, respectively. CONCLUSIONS: The role of DS was effective to improve symptom relief but was poor in terms of morbidity and mortality control. So, ethical concerns have to be addressed, and medical treatment or stenting for left-side obstructions only should be considered as alternative procedures.

Colonic neuropathological aspects in patients with intractable constipation due to obstructed defecation.

One of the most frequent subtypes of constipation is represented by obstructed defecation, and it has recently been reported that these patients may have colonic motor abnormalities in addition to alterations of the anorectal area. However, it is unknown whether these patients display abnormalities of the enteric nervous system, as reported in other groups of constipated subjects. For this reason, we evaluated the neuropathologic aspects of the enteric nervous system in a homogeneous group of patients with obstructed defecation. Colonic specimens from 11 patients (nine women, age range 39-66 years) undergoing surgery for symptoms refractory to any therapeutic measure, including biofeedback training, were obtained and examined by means of conventional histological methods and immunohistochemistry (NSE, S100, c-Kit, formamide-mAb, Bcl-2, CD34, alfa-actin). Analysis of the specimens showed that the enteric neurons were significantly decreased only in the submucosal plexus of patients (P<0.0001 vs controls), whereas the enteric glial cells of constipated patients were reduced in both the myenteric (P=0.018 vs controls) and the submucosal plexus (P=0.004 vs controls). No difference between patients and controls were found concerning c-Kit and CD34 expression, and the number of apoptotic neurons. These findings support the concept that at least a subgroup of patients with obstructed defecation and severe, intractable symptoms display abnormalities of the enteric nervous system, mostly related to the enteric glial cells. These findings might explain some of the pathophysiological abnormalities, and help to better understand this condition.

Treatment of perianal fistulas in Crohn's disease by local injection of antibody to TNF-alpha accounts for a favourable clinical response in selected cases: a pilot study.

OBJECTIVE: Intravenously administered infliximab, a monoclonal antibody directed against tumor necrosis factor-alpha, has been proven to be efficacious in the treatment of fistulas in patients with Crohn's disease. It has recently been suggested that local injections of infliximab might be beneficial as well. The aim of this study was to assess whether infliximab could play an effective role in the local treatment of perianal fistulas in Crohn's disease. MATERIAL AND METHODS: Local infliximab injections were administered to 11 patients suffering from Crohn's disease complicated by perianal disease. Eligible subjects included Crohn's disease patients with single or multiple draining fistulas, regardless of status of luminal disease at baseline. Patients, however, were excluded from the study if they had perianal or rectal complications, such as abscesses or proctitis or if they had previously been treated with infliximab. Twenty-milligram doses of infliximab were injected along the fistula tract and around both orifices at baseline and then every 4 weeks for up to 16 weeks or until complete cessation of drainage. No further doses were administered to patients who did not respond after three injections. Efficacy was measured in terms of response (a reduction in fistula drainage of 50% or more) and remission (complete cessation of fistula drainage for at least 4 weeks). Time to loss of response and health-related quality of life were also evaluated. RESULTS: Overall, 8/11 patients (72.7%) responded to the therapy and 4/11 (36.4%) reached remission, whereas 3/11 patients (27.2%) showed no response. Response or remission was very much dependent on the location of the fistulas, and time to loss of response was generally longer for patients who reached remission compared to patients in response. Changes in health-related quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), also reflected response or remission, with more marked improvements associated with remission. After a mean 10.5 months' follow-up (range 7-18 months), 6/11 patients (54.5%) are in response and 4/11 patients (36.4%) are in remission. No adverse events have been observed in this cohort of patients. CONCLUSIONS: Local injections of infliximab along the fistula tract seem to be an effective and safe treatment of perianal fistulas in Crohn's disease. However, further controlled clinical investigations are warranted.

The rational principles of neo-adjuvant therapy for rectal cancer.

BACKGROUND: Aim of the study is to analyze rational principles which at present govern the neoadjuvant therapy for rectal cancer and justify his application. First step is definition of targets: cellular replication block, volumetric reduction of rectal cancer, mesorectum and lateral nodes (Down staging), reduction of side-effects on close organs, radiation on more limited tissue volumes, major series of sphincter saving procedures, minor risk of microscopic tumour deposits. Second step regards standards which Protocols strive in order to: patients selection, therapeutic index, restaging before surgery, total mesorectal excision (TME). Further step accounts for evidence of drawbacks, related to Neoadjuvant approach, both Radiotherapy alone (RT) or Radiochemotherapy (CH-RT). METHODS: Indications for neoadjuvant therapy, basing a difference between the absolute and relative one, are explained. Given that granting role to such therapy still now remain partially unclear, we have outlined the following topics: A) survey of main protocols is managed, taking care on dose/response ratio, focusing on enhanced supply for fixed tumours, checking on a list of several drugs (oxaliplatinum, capecitabin, raltitrexed, CPT-11, eniluracil), which are medicated with RT and furthermore on a list of substitute RT methods (HART, IORT, Endocavitary). B) following whole treatments, according such a different approaches, analysis of obtained outcomes in the literature are carried out. C) Personal experience, basing on a previous series where Down-staging has been sought, comparing indicatively clinical and diagnostic data before neoadjuvant therapy and before surgery. D) List of open issues, not solved at present, is shown CONCLUSIONS: Neoadjuvant therapy may be considered a rational approach for treatment of curative rectal cancer; indeed, preliminary results seem to introduce a real advantage compared to adjuvant therapy, even if is mandatory to associate proper surgical procedure, as TME, to warrant low local recurrences. Targets, related to such therapy, may be noticed ideal even though outcomes don't come up always to statements. So, continuous efforts to ameliorate rates of free-disease series, as well mortality rates and toxical effects are advised.