Management, treatment and prognostic significance of lateral lymph node metastases in rectal cancer-a regional cohort study.

PURPOSE: Lateral lymph node metastases in rectal cancer remain a clinical challenge. Different treatment regimens have been suggested. This retrospective regional cohort study examines outcome after combined oncological and surgical treatment of MRI-positive lateral lymph nodes (LLN). METHODS: Data from the Swedish Colorectal Cancer Registry (SCRCR) and patient records were used for retrospective analysis of resected high-risk rectal cancers between 2009 and 2014. The aim was to compare tumour characteristics, neoadjuvant therapy, recurrence and outcome after lateral lymph node dissection. RESULTS: One thousand and one hundred nineteen cases were identified and after exclusion 344 patients with cT3-T4 ≤ 10 cm from the anal verge were analysed. Thirty (8.7%) patients with MRI-positive LLN were identified. Synchronous distant metastases were associated with MRI-positive LLN (p-value 0.019). Long-course chemoradiotherapy was clinical practice in cases of MRI-positive LLN. No differences in local (p-value 0.154) or distant (p-value 0.343) recurrence rates between MRI-positive LLN patients and MRI-negative patients were detected. Only four patients underwent lateral lymph node dissection (LLND). There was no significant difference in overall survival during follow-up between the MRI-negative (CI at 95%; 99-109 months) and MRI-positive group (CI at 95%; 69-108 months; p-value 0.14). CONCLUSION: Lateral lymph node metastases present a challenging clinical situation. The present study shows that combination of neoadjuvant therapy and selective LLND is an applicable strategy in cases of MRI-positive LLN.

Split-thickness skin graft as a treatment for voluminous vaginal fluid discharge after surgery due to vesico-intestino-vaginal fistulation: A case report and review of the literature.

•Repeated pelvic surgery in irradiated tissue increases the risk for vaginal rupture.•We present a rare case with heavy secretion from the ruptured vagina.•Split skin grafting was used as an unusual treatment for this complication.

Postoperative non-steroidal anti-inflammatory drug use and oncological outcomes of rectal cancer.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to suppress the inflammatory response after surgery and are often used for pain control. This study aimed to investigate NSAID use after radical surgical resection for rectal cancer and long-term oncological outcomes. METHODS: A cohort of patients who underwent anterior resection for rectal cancer between 2007 and 2013 in 15 hospitals in Sweden was investigated retrospectively. Data were obtained from the Swedish Colorectal Cancer Registry and medical records; follow-up was undertaken until July 2019. Patients who received NSAID treatment for at least 2 days after surgery were compared with controls who did not, and the primary outcome was recurrence-free survival. Cox regression modelling with confounder adjustment, propensity score matching, and an instrumental variables approach were used; missing data were handled by multiple imputation. RESULTS: The cohort included 1341 patients, 362 (27.0 per cent) of whom received NSAIDs after operation. In analyses using conventional regression and propensity score matching, there was no significant association between postoperative NSAID use and recurrence-free survival (adjusted hazard ratio (HR) 1.02, 0.79 to 1.33). The instrumental variables approach, including individual hospital as the instrumental variable and clinicopathological variables as co-variables, suggested a potential improvement in the NSAID group (HR 0.61, 0.38 to 0.99). CONCLUSION: conventional modelling did not demonstrate an association between postoperative NSAID use and recurrence-free survival in patients with rectal cancer, although an instrumental variables approach suggested a potential benefit.

Impact of rectal perforation on recurrence during rectal cancer surgery in a national population registry.

BACKGROUND: Incidental perforation in rectal cancer surgery is considered a risk factor for poorer oncological outcome. Most studies emanate from the era before total mesorectal excision when staging, neoadjuvant treatment and surgical technique were suboptimal. This study assessed the impact of incidental perforation on oncological outcome in a cohort of patients with optimized management. METHODS: Data from the Swedish Colorectal Cancer Registry for patients undergoing R0 abdominal surgery for TNM stage I-III rectal cancer between 2007 and 2012, with 5-year follow-up, were analysed. Multivariable analysis was performed. RESULTS: In total, 6176 patients were analysed (208 with and 5968 without perforation). The local recurrence rate was increased after perforation (7·2 per cent (15 of 208) versus 3·2 per cent (188 of 5968); P = 0·001), but there were no differences in rates of distant metastasis (16·3 per cent (34 of 208) versus 19·8 per cent (1183 of 5968); P = 0·215) and overall recurrence (20·7 per cent (43 of 208) versus 21·0 per cent (1256 of 5968); P = 0·897). The 5-year overall survival rate was lower after perforation (66·4 versus 75·5 per cent; P = 0·002), but the 5-year relative survival rate was no different (79·9 versus 88·2 per cent; P = 0·083). In multivariable analysis, perforation was a risk factor for local recurrence (hazard ratio 2·10, 95 per cent c.i. 1·19 to 3·72; P = 0·011), but not for the other outcomes. CONCLUSION: Incidental perforation remains a significant risk factor for LR, even with optimized management of rectal cancer. This must be considered when discussing adjuvant treatment and follow-up.

ANTECEDENTES: La perforación incidental durante la cirugía de cáncer de recto se considera un factor de riesgo de un peor resultado oncológico. La mayoría de los estudios proceden de la era previa a la exéresis total del mesorrecto cuando la estadificación, el tratamiento neoadyuvante y la técnica quirúrgica eran subóptimos. En este estudio se evalúa el impacto de la perforación incidental en el resultado oncológico en una cohorte de pacientes con un tratamiento óptimo. MÉTODOS: Se analizaron los datos del Registro Sueco de Cáncer Colorrectal para pacientes sometidos a cirugía abdominal R0 en estadios TNM I-III entre 2007-2012 con un seguimiento de 5 años. Se realizó un análisis multivariable. RESULTADOS: En total, se analizaron 6.176 pacientes (208 con perforación, 5.968 sin perforación). La tasa de recidiva local (local recurrence, LR) aumentó después de la perforación (7,2% (15/208) versus 3,2% (188/5.968); P = 0,001)), pero no se detectaron diferencias con respecto a las tasas de metástasis a distancia (16,3% (34/208) versus 19,8% (1.183/5.968); P = 0,215)) ni de recidiva global (20,7% (43/208) versus 21,0% (1.256/5.968); P = 0,897)). La tasa de supervivencia global a los 5 años fue menor después de la perforación (66,4% versus 75,5%; P = 0,002), pero la tasa de supervivencia relativa a los 5 años fue similar (79,9% versus 88,2%; P = 0,083). En el análisis multivariable, la perforación fue un factor de riesgo para la LR (cociente de riesgos instantáneos, hazard ratio, HR 2,10 (i.c. del 95% 1,19-3,72); P = 0,011], pero no fue un factor de riesgo para los otros resultados. CONCLUSIÓN: La perforación incidental sigue siendo un factor de riesgo significativo para la LR incluso con el tratamiento optimizado del cáncer de recto, lo que debe tenerse en cuenta al discutir la indicación de tratamiento adyuvante y el tipo de seguimiento.

Risk of local recurrence of rectal cancer and circumferential resection margin: population-based cohort study.

BACKGROUND: A circumferential resection margin (CRM) of 1·0 mm or less after rectal cancer surgery is thought to increase the risk of local recurrence (LR). This retrospective population-based study examined how CRM distance affects the LR risk. METHODS: Data from the Swedish Colorectal Cancer Registry were used in a retrospective analysis of rectal cancers resected between 2005 and 2013. The primary endpoint was LR. RESULTS: A total of 12 146 patients were identified, of whom 8392 were included in the analysis; 739 patients had a CRM of 1·0 mm or less and 7653 had a CRM larger than 1·0 mm. The mean follow-up time was 51 months. There were 66 LRs (8·9 per cent) in the group with a CRM of 1·0 mm or less, and 256 (3·3 per cent) among patients with a CRM larger than 1·0 mm. The LR rate was 17·0 per cent (27 of 159), 6·7 per cent (39 of 580), 1·9 per cent (2 of 103) and 3·4 per cent (254 of 7550) when the CRM was 0, 0·1-1·0, 1·1-1·9 and at least 2·0 mm respectively. The risk of LR among patients with a CRM of 0 mm was higher than that in all other subgroups with a larger CRM (P < 0·050). There was no difference in LR between the subgroups with CRM 1·1-1·9 mm and at least 2·0 mm. LR was diagnosed earlier when the CRM was 1·0 mm or less. CONCLUSION: LR risk is related to exact CRM, with the highest risk in patients with a CRM of 0 mm. Close monitoring of patients with no measurable clear margin may allow early detection of LR.

ANTECEDENTES: Se cree que un margen de resección circunferencial (circumferential resection margin, CRM) de ≤1,0 mm tras la cirugía de cáncer de recto aumenta el riesgo de recidiva local (local recurrence, LR). Este estudio retrospectivo de base poblacional evaluó cómo la distancia del CRM afectaba al riesgo de LR. MÉTODOS: Se utilizaron los datos del Registro Sueco de Cáncer Colorrectal (SCRCR) para el análisis retrospectivo de los cánceres de recto resecados entre 2005 y 2013. El objetivo primario fue la LR. RESULTADOS: Se identificaron 12.146 pacientes, con 8.666 pacientes analizados después de las exclusiones. Un total de 739 pacientes tenían CRM de ≤ 1,0 mm y 7.653 pacientes CRM de > 1,0 mm. El tiempo medio de seguimiento fue de 51 meses. Hubo 66 (8,9%) casos de LR en grupo de CRM de ≤ 1,0 mm y 256 (3,3%) casos de LR en el grupo de CRM de > 1,0 mm. La tasa de LR fue del 17% (n = 27/159), 6,7% (n = 39/580), 1,9% (n = 2/103) y 3,4% (n = 254/7550) cuando el CRM fue de 0,0 mm, 0,1-1,0 mm, 1,1-1,9 mm y CRM ≥ de 2 mm, respectivamente. El riesgo de LR en CRM de 0,0 mm fue mayor en comparación con todos los otros grupos con CRM mayores (P < 0,05). No se observó diferencia en LR entre CRM de 1,1-1,9 mm y ≥ 2 mm. La LR se diagnosticó más precozmente cuando el CRM era de ≤ 1,0 mm. CONCLUSIÓN: El riesgo de LR está relacionado con el CRM exacto, con un riesgo más alto en pacientes con CRM de 0,0 mm. La monitorización estrecha de pacientes sin un margen claro medible puede permitir la detección temprana de LR.

High risk of permanent stoma after anastomotic leakage in anterior resection for rectal cancer.

AIM: This study investigates how often bowel continuity was restored after anastomotic leakage in anterior resection for rectal cancer and assesses the clinical factors associated with permanent stoma. METHOD: The Swedish Colorectal Cancer Registry was used to identify cases of anastomotic leakage registered in southern Sweden between January 2001 and December 2011. Patient characteristics, surgical details and clinical information about the anastomotic leakages were retrieved from medical records. RESULTS: Of the 1442 patients operated on with anterior resection in 11 hospitals, 144 (10%) were diagnosed with anastomotic leakage after anterior resection for rectal cancer. After a median follow-up of 87 months (range 21-165), the overall rate of permanent stoma among patients with anastomotic leakage was 65%. Age ≥ 70 years (P = 0.02) and re-laparotomy (P < 0.001) were independently related to permanent stoma. Compared with nondefunctioned patients with anastomotic leakage, defunctioned patients with anastomotic leakage at the index procedure less often required re-laparotomy at some point during the entire clinical course (P < 0.001), but nondefunctioned and defunctioned patients with anastomotic leakage both had permanent stoma to the same extent (67% and 62%, respectively). CONCLUSION: Anastomotic leakage is highly associated with permanent stoma after anterior resection, especially in patients aged ≥ 70 years. In this cohort of patients with anastomotic leakage, 65% had permanent stoma at long-term follow-up. A defunctioning stoma ameliorates the clinical course but does not affect the end result of bowel continuity in established anastomotic leakage after anterior resection.

Late leakage after anterior resection: a defunctioning stoma alters the clinical course of anastomotic leakage.

AIM: Anastomotic leakage (AL) is common after anterior resection (AR). Long term clinical outcomes of AL including late presenting leakage (LL) are not well studied. This study was undertaken to assess clinical features of LL with respect to incidence, association with predisposing factors and need for re-intervention. METHODS: The Swedish Colorectal Cancer Registry (SCRCR) was explored for AL cases after AR for rectal cancer in patients operated in the south of Sweden from 1 January 2001 to 31 December 2011. Demographic data, surgical technical details, number of postoperative days (POD) until diagnosis of AL, presenting symptoms, methods of diagnosis and treatment were retrieved from medical records. LL was defined according to different cut-offs as leakages occurring after hospital discharge (LLAHD), after 30 POD (LL ≥ POD 30) and after 90 POD (LL ≥ POD 90). RESULTS: In total, 1442 patients were operated on with AR of whom 144 cases of AL (10%) were identified. Median time from operation to follow-up was 87 months (range 21-162). LLAHD, LL ≥ POD 30 and LL ≥ POD 90 were present in 51%, 24% and 9% respectively. All categories of LL were associated with a defunctioning stoma. Relaparotomy was significantly less often employed in LLAHD, but not in other categories of LL. CONCLUSION: LL constitutes a substantial portion of all AL after AR for rectal cancer. The large proportion of LLAHD calls for awareness in the outpatient setting.

Nonsteroidal anti-inflammatory drugs and the risk of anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in colorectal surgery due to their opioid-sparing effect. However, several studies have indicated an increased risk of anastomotic leakage following NSAID treatment, although conflicting results exist. The primary goal of this study was to further examine whether postoperative NSAIDs are independently associated with anastomotic leakage after anterior resection for rectal cancer. METHODS: Patients who underwent anterior resection for rectal cancer during 2007-2013 in 15 different hospitals in three healthcare regions in Sweden were included in the study. Registry data and information from patient records were retrieved. The association between NSAID treatment (for at least two days in the first postoperative week) and symptomatic anastomotic leakage (within 90 days) was evaluated with multiple logistic regression, with adjustment for pertinent confounding factors. RESULTS: Some 1495 patients were included in the study. Of these, 27% received postoperative NSAIDs for at least two days in the first postoperative week. Symptomatic anastomotic leakage occurred in 11% and 14% in the NSAID and non-NSAID group, respectively. With adjustment for confounders, the odds ratio for leakage among patients who received NSAIDs compared with those who did not was 0.88 (95% CI 0.65-1.20). No differences were seen between non-selective and COX-2-selective NSAIDs. CONCLUSION: Postoperative NSAID treatment does not seem to increase the risk of symptomatic anastomotic leakage after anterior resection for rectal cancer. NSAID use appears to be safe, but a well-powered randomized clinical trial is warranted.

Gender aspects of survival after surgical treatment for rectal cancer.

AIM: Longer survival in women than men after rectal cancer surgery has been reported. Our hypothesis was that after correction for their longer life expectancy a survival benefit for women would still remain. METHOD: We studied 2792 patients diagnosed with rectal cancer in the southern part of Sweden between 1996 and 2006. The following parameters were included in a prespecified multivariable Cox regression analysis: age at diagnosis, gender, preoperative radiotherapy, stage, year and type of surgery. In addition to overall survival, relative survival was calculated using the Hakulinen approach utilizing an age-, gender- and calendar year-matched Swedish control cohort. RESULTS: Female patients were significantly older, received neoadjuvant treatment less often and were more often operated on by local excision. Overall survival was significantly longer in women. In the multivariable analysis of relative survival, controlling for neoadjuvant treatment, Dukes stage and year and type of surgery, no significant effect of gender [hazard ratio (HR) 1.10 for men, P = 0.114] was found, whereas an improved relative survival with increased age (HR 0.96 per year, P < 0.001) was seen. In contrast, using the same multivariable model with no correction for underlying mortality in the population, male gender (HR 1.38, P < 0.001) and greater age (HR 1.05 per year, P < 0.001) increased the risk of death. CONCLUSION: The results show that after correction for the underlying longer survival in women and some known confounders, survival after surgical treatment for rectal cancer appears to be gender neutral.

Combined lack of estrogen receptors alpha and beta affects vascular iNOS protein expression.

Endothelial and vascular smooth muscle cells express both estrogen receptor (ER) alpha and beta. Recent findings indicate that vascular ER beta and ER alpha may substitute for one another. Here, we investigate vascular morphology, contractility and protein expression in intact aorta from adult (4 months old) female mice lacking both ER alpha and ER beta (DERKO). The body weights were 17% higher ( P<0.01) in DERKO than in wild-type mice. Vascular morphology, investigated in paraffin sections from aorta stained with hematoxylin-eosin or van Gieson, was identical in DERKO and wild-type mice. Endothelial cells were clearly visible in aorta of both DERKO and wild-type animals. Morphometric analysis of media thickness and wall to lumen ratio using a computerized image analyzing system demonstrated no differences between the two groups of mice. The vascular expression of endothelial nitric oxide synthase (eNOS, NOS III) and inducible nitric oxide synthase (iNOS, NOS II) was investigated using Western blotting. Aorta from both DERKO and wild-type mice expressed iNOS protein, but the iNOS expression was 3 times lower ( P<0.05) in DERKO compared to wild-type mice. No difference in eNOS protein level between the two groups of animals was observed. Force responses to noradrenaline, determined either in the absence or in the presence of the nitric oxide synthase inhibitor l-NAME and the cyclo-oxygenase inhibitor indomethacin, were unaffected by the lack of functional ER alpha/ER beta. In summary, combined lack of functional ER alpha and ER beta lowers the vascular expression of iNOS but has no effects on morphology, eNOS expression, and noradrenaline sensitivity in the intact aorta.

Immunocytochemical demonstration of oestrogen receptor beta in blood vessels of the female rat.

The role of oestrogen receptor (ER) beta in vascular function remains unclear. With the use of a specific ERbeta antibody we have now, using immunocytochemistry, visualized ERbeta in different parts of the vascular tree. In about 70% of medial smooth muscle cells of female rat aorta, tail artery and uterine artery, nuclear immunoreactivity to ERbeta was observed. In these vessels endothelial cells also expressed ERbeta. Vascular expression of the ERalpha subtype was lower than that of ERbeta. In aorta and tail artery, no immunoreactivity towards ERalpha was observed, while in uterine vessels occasional medial smooth muscle and endothelial cells expressed this ER subtype. ERbeta and alpha expression in uterine vessels was independent of the stage of the oestrous cycle, suggesting that variations in uterine blood flow occurring during the cycle are independent of ER density. The regional distribution of ERalpha, as determined by immunocytochemistry, was supported by measurements of ERalpha levels by enzyme immunoassay. In the uterine artery, the level of ERalpha was several times higher (P<0.001) than that of aorta and tail artery (10.1+/-1.7 fmol/mg protein in the uterine artery vs 3.3+/-1.0 and 0.5+/-0.5 fmol/mg protein in aorta and tail artery respectively). Thus, a prominent nuclear expression of ERbeta was observed in the vascular wall of several parts of the vascular tree, while ERalpha predominantly was expressed in uterine vessels, suggesting that ERbeta and alpha may have different roles in vascular function.

Acute and long-term effects of 17 beta-oestradiol on agonist-stimulated force in rat tail artery.

The effects of 17 beta-oestradiol on the force responses to KCI and noradrenaline were investigated in rings of the rat tail artery. Incubation with 10 microM 17 beta-oestradiol for 100-295 min reduced the force amplitude after 5 min in high-K+ (140 mM) to 10% of the control value. The inhibitory effect of the steroid was unaffected by the NO-synthase inhibitor L-NAME. Rings activated by an intermediate degree of depolarization (60 mM K+) were less affected by the steroid (58% of control force). The sustained force response to 1 microM noradrenaline was reduced in the presence of 17 beta-oestradiol to 60% of control value. Lower concentrations of 17 beta-oestradiol (0.1 and 1 microM) were without acute effects on force development. However, longterm effects of 17 beta-oestradiol on vessel reactivity were found at these low concentrations. Rings were cultured for 3-7 days in the absence or in the presence of the steroid before they were stimulated with agonists. Cultured rings developed an increased sensitivity to noradrenaline compared with freshly prepared ones. Cocaine (30 microns) shifted the noradrenaline concentration-response curve to the left in freshly prepared rings while it had no effect in cultured ones, indicating that the increased sensitivity to noradrenaline in cultured rings depends on loss of noradrenaline uptake. Rings cultured for 7 days in the presence of 0.1 microM 17 beta-oestradiol developed a more pronounced supersensitivity to noradrenaline (EC50 for noradrenaline was 0.13 +/- 0.03 microM in steroid exposed rings vs. 0.38 +/- 0.09 microM in control rings). Thus, prolonged treatment with 17 beta-oestradiol results in a potentiation of noradrenaline evoked force, in contrast to the acute effect of the steroid.

Metabolic correlates to pacemaker activity in the smooth muscle of guinea-pig mesotubarium.

Oxygen consumption (FO2) and lactate production (Flac) were measured during spontaneous activity in the guinea-pig mesotubarium. During spontaneous contractions FO2 increased to maximally 0.270 +/- 0.025 mumol min-1g-1 (n = 23), followed by a rapid fall immediately upon relaxation. In the relaxed period (5-15 min) between spontaneous contractions FO2 continued to slowly decrease by about 25% towards a final value of 0.150 +/- 0.01 mumol min-1g-1. Flac showed no consistent variation during the relaxed period. Ouabain (10(-6)M) produced a contracture, which was abolished by the Ca2(+)-antagonist felodipine (10(-6)M). In the presence of felodipine, addition of ouabain caused depolarization and a decrease of oxygen consumption by 21% and of lactate production by 31%. Exchange of glucose in the physiological Krebs solution for beta-hydroxybutyrate did not influence spontaneous activity, while subsequent addition of cyanide (2 mM) abolished contractions and caused a hyperpolarization of 15 mV. Blockade of ATP-dependent K+ channels by addition of glibenclamide (10(-7)M) to the relaxed muscle in this situation caused spontaneous contractile activity to reappear. In glucose-containing Krebs solution glibenclamide had no effect on the spontaneous contractile and electrical activity and contractions persisted after addition of cyanide. The relaxing and hyperpolarizing effect of pinacidil could be counteracted by addition of glibenclamide. The results suggest that a decrease in electrogenic Na+/K(+)-pump activity in the course of the relaxed period between contractions could contribute to the pacemaker behaviour. ATP-dependent K+ channels, while having little influence on the spontaneous contractile activity under normal metabolic conditions, could be activated during blockade of aerobic and anaerobic metabolism, leading to inhibition of pacemaker activity.

Rate of oxidative and glycolytic metabolism in the guinea-pig oviduct in relation to contractility and hormonal cycle.

The rates of oxygen consumption and lactate production in the guinea-pig oviduct were measured together with registration of contractile activity during three phases of the hormonal cycle. In pro-oestrus (high oestrogen, low progesterone levels) and oestrus (time of ovulation, high oestrogen and progesterone) the rate of O2 consumption was higher than in dioestrus (low oestrogen, high progesterone). The frequency of spontaneous contractions was higher in oestrus than in the other phases. No significant differences in the proportion of the cross-sectional area occupied by smooth muscle were found between oviducts in di- and pro-oestrus. Stimulation by phenylephrine caused decreased frequency and increased amplitude of contractions in dioestrus but not in pro-oestrus, suggesting hormonal modulation of adrenergic mechanisms. The rate of relaxation of high-K+ contractures was higher in pro- than dioestrus. Lactate production and contents of ATP, ADP and phosphocreatine showed no significant variation with hormonal state. The increased rate of oxidative metabolism under oestrogenic dominance could in part reflect changes in ionic transport mechanisms, such as intracellular Ca2+ handling.