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.

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.

Risk of colorectal cancer following CT-verified acute diverticulitis: a nationwide population-based cohort study.

AIM: Routine colonoscopy to exclude colorectal cancer (CRC) after CT-verified acute diverticulitis is controversial. This study aimed to compare the incidence of CRC in patients with acute diverticulitis with that in the general population. METHOD: Patients with an emergency admission for diverticular disease to any Norwegian hospital between 1 January 2008 and 31 December 2010 were included through identification in the Norwegian Patient Registry using International Classification of Diseases (ICD-10) codes K57.1-9. To estimate the age-specific distribution of CT-verified acute uncomplicated diverticulitis (AUD) and acute complicated diverticulitis (ACD) in this nationwide study population, numbers from the largest Norwegian emergency hospital were used. Patients diagnosed with CRC within 1 year following their admission for acute diverticulitis were detected through cross-matching with the Cancer Registry of Norway. Based on both Norwegian age-specific incidence of CRC and estimated age-specific distribution of CT-verified diverticulitis, standard morbidity ratios (SMRs) were calculated. RESULTS: A total of 7473 patients with emergency admissions for diverticular disease were identified (estimated CT-verified AUD n = 3523, ACD n = 1206); of these 155 patients were diagnosed with CRC within 1 year. Eighty had a CT-verified diverticulitis at index admission [41 AUD (51.3%); 39 ACD (49.7%)]. Compared with the general population, the SMR was 6.6 following CT-verified AUD and 16.3 following ACD, respectively. CONCLUSION: In the first year after CT-verified acute diverticulitis, especially after ACD, the risk of CRC is higher than in the general population. This probably represents misdiagnosis of CRC as acute diverticulitis. Follow-up colonoscopy should be recommended to all patients admitted with acute diverticulitis.

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.

Meta-analysis of prophylactic mesh to prevent parastomal hernia.

BACKGROUND: Rates of parastomal hernia following stoma formation remain high. Previous systematic reviews suggested that prophylactic mesh reduces the rate of parastomal hernia; however, a larger trial has recently called this into question. The aim was to determine whether mesh placed at the time of primary stoma creation prevents parastomal hernia. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase and CINAHL were searched using medical subject headings for parastomal hernia, mesh and prevention. Reference lists of identified studies, clinicaltrials.gov and the WHO International Clinical Trials Registry were also searched. All randomized clinical trials were included. Two authors extracted data from each study independently using a purpose-designed sheet. Risk of bias was assessed by a tool based on that developed by Cochrane. RESULTS: Ten randomized trials were identified among 150 studies screened. In total 649 patients were included in the analysis (324 received mesh). Overall the rates of parastomal hernia were 53 of 324 (16·4 per cent) in the mesh group and 119 of 325 (36·6 per cent) in the non-mesh group (odds ratio 0·24, 95 per cent c.i. 0·12 to 0·50; P < 0·001). Mesh reduced the rate of parastomal hernia repair by 65 (95 per cent c.i. 28 to 85) per cent (P = 0·02). There were no differences in rates of parastomal infection, stomal stenosis or necrosis. Mesh type and position, and study quality did not have an independent effect on this relationship. CONCLUSION: Mesh placed prophylactically at the time of stoma creation reduced the rate of parastomal hernia, without an increase in mesh-related complications.

One-year results of the SCANDIV randomized clinical trial of laparoscopic lavage versus primary resection for acute perforated diverticulitis.

BACKGROUND: Recent randomized trials demonstrated that laparoscopic lavage compared with resection for Hinchey III perforated diverticulitis was associated with similar mortality, less stoma formation but a higher rate of early reintervention. The aim of this study was to compare 1-year outcomes in patients who participated in the randomized Scandinavian Diverticulitis (SCANDIV) trial. METHODS: Between February 2010 and June 2014, patients from 21 hospitals in Norway and Sweden presenting with suspected perforated diverticulitis were enrolled in a multicentre RCT comparing laparoscopic lavage and sigmoid resection. All patients with perforated diverticulitis confirmed during surgery were included in a modified intention-to-treat analysis of 1-year results. RESULTS: Of 199 enrolled patients, 101 were assigned randomly to laparoscopic lavage and 98 to colonic resection. Perforated diverticulitis was confirmed at the time of surgery in 89 and 83 patients respectively. Within 1 year after surgery, neither severe complications (34 versus 27 per cent; P = 0·323) nor disease-related mortality (12 versus 11 per cent) differed significantly between the lavage and surgery groups. Among the 144 patients with purulent peritonitis, the rate of severe complications (27 per cent (20 of 74) versus 21 per cent (15 of 70) respectively; P = 0·445) and disease-related mortality (8 versus 9 per cent) were similar. Laparoscopic lavage was associated with more deep surgical-site infections (32 versus 13 per cent; P = 0·006) but fewer superficial surgical-site infections (1 versus 17 per cent; P = 0·001). More patients in the lavage group underwent unplanned reoperations (27 versus 10 per cent; P = 0·010). Including stoma reversals, a similar proportion of patients required a secondary operation (28 versus 29 per cent). The stoma rate at 1 year was lower in the lavage group (14 versus 42 per cent in the resection group; P < 0·001); however, the Cleveland Global Quality of Life score did not differ between groups. CONCLUSION: The advantages of laparoscopic lavage should be weighed against the risk of secondary intervention (if sepsis is unresolved). Assessment to exclude malignancy (although uncommon) is advised. Registration number: NCT01047462 ( http://www.clinicaltrials.gov).

Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.

Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2-av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy.

Cohort study of mesenteric panniculitis and its relationship to malignancy.

BACKGROUND: Mesenteric panniculitis (MP) is a rare condition that historically has been associated with the presence of malignancy. Paraneoplastic phenomena in general regress with cure and in most cases with treatment of the cancer. This study was undertaken to determine whether MP regressed with cancer treatment and cure. METHODS: This was a retrospective review of a database of all patients with MP confirmed on CT between 2003 and August 2015 at Christchurch Hospital. Patients were categorized as having malignant or non-malignant disease, and follow-up scans were assessed for remission of MP. Patients with malignancy were further categorized as having malignancy cured or not cured. RESULTS: A total of 308 patients were identified with possible MP; 135 were excluded as radiological appearances were not typical of MP (43 patients) or there was no follow-up CT (92). Of 173 patients (131 men) included, 75 (43·4 per cent) were diagnosed with malignancy. Follow-up imaging showed that 33 patients (19·1 per cent) had remission of MP, whereas 140 (80·9 per cent) had no remission. There was no difference in the rates of MP remission in the malignancy versus no malignancy groups (P = 1·000), or between groups in which malignancy was cured or not cured (P = 0·572). Nor was there any difference in the rates of MP remission in malignancy cured versus no malignancy groups (P = 0·524). CONCLUSION: MP does not behave like a paraneoplastic phenomenon. The association with malignancy is most likely an epiphenomenon of the many CT images acquired for staging of cancer.

No benefit of extended mesenteric resection with central vascular ligation in right-sided colon cancer.

AIM: The optimal extent of mesenteric resection in colon cancer surgery is not known. We have previously shown an increased mortality associated with wider mesenteric resection in right hemicolectomy. This study compares the short- and long-term outcome in three variations of right hemicolectomy based on the position of the vascular ligature in the mesentery. METHOD: In all, 2084 cases of cancer in the caecum or ascending colon were identified in the Swedish Colorectal Cancer Registry and categorized according to the position of the vascular ligature: central ligation of ileocolic vessels (ICVs) ± right colic vessels (n = 390), central ligation of ICVs + right branch of middle colic vessels (MCVs) (n = 1360) and central ligation of ICVs + central ligation of MCVs (n = 334). RESULTS: Neither 3-year overall survival, 3-year disease-free survival nor local recurrence rate differed between the groups (P = 0.604; P = 0.247; P = 0.237). There was still no difference after multivariate analysis adjusted for age, sex, American Society of Anesthesiologists classification, TNM stage and adjuvant therapy. An increased peri-operative mortality, however, was observed in extended mesenteric resections, increasing from 0.8% in non-extended to 3.6% in more extended resection, P = 0.025. CONCLUSION: The study showed no survival benefit by more extended mesenteric resection, indicating that there is no need to extend the mesenteric resection to involve the MCVs in cancer of the caecum or ascending colon. On the contrary, increased peri-operative mortality by more extensive mesenteric resection was noted suggesting that a more conservative approach may be favourable.

Recent advances in the design and development of soft drugs.

This paper summarizes recent developments in the field of soft drug development as collected and reviewed for the 9th Retrometabolism-Based Drug Design and Targeting Conference. Soft drugs are still often confused with prodrugs because they both require metabolic transformations; however, they are conceptual opposites: whereas, prodrugs are pharmacologically inactive and are converted by a predictable mechanism to the active drug, soft drugs are active therapeutic agents as such and are designed to undergo a predictable and controllable metabolic deactivation after exerting their desired therapeutic effect. Several rationally designed soft drug examples including clinically approved ones (e.g., clevidipine, esmolol, landiolol, loteprednol etabonate, and remifentanil) as well as others that have reached clinical investigations within different therapeutic areas (e.g., budiodarone, naronapride, remimazolam, tecarfarine) are briefly summarized. Anesthesiology, which requires a high degree of pharmacologic control during the surgical procedure to maintain the anesthetic state together with a quick return to responsiveness at the end of this procedure, is a particularly well-suited area for soft drug development. Several new initiatives (e.g., MOC-etomidate, AZD3043) are focused in this area; they are also briefly reviewed. Finally, just as there are many 'accidental' prodrugs, there are 'accidental' soft drugs too: i.e., therapeutics that were not intentionally designed to be soft drugs, but turned out to be essentially soft drugs. Some examples, such as articaine or methylphenidate, are briefly reviewed.

Exploratory computational assessment of possible binding modes for small molecule inhibitors of the CD40-CD154 co-stimulatory interaction.

Protein-protein interactions (PPI) tend to involve extensive, flat, and featureless interfaces that are difficult to disrupt by small molecule binding. However, recently, PPIs are being recognized as increasingly valuable 'druggable' targets. We have identified several small molecule inhibitors of the immunologically relevant CD40-CD154 co-stimulatory interaction that bind to the homotrimeric CD154, a member of the tumor necrosis factor superfamily (TNFSF). Recently, on the basis of the co-crystal structure of CD154 with another small molecule (BIO8898), it has been suggested that these PPIs could be particularly susceptible to small molecule blockade due to a subunit fracture mechanism resulting in a distortion of the trimeric structure. To investigate whether this mechanism can occur with our organic dye-related inhibitors, we performed exploratory computational docking experiments. Possible druggable pockets that can serve as binding sites for small molecule inhibitors were identified with the FFT map algorithm both along the CD154-CD40 binding interface (competitive, orthosteric model) and in the interior core of the CD154 trimer corresponding to the BIO8898 binding site (allosteric model). Docking experiments (using Glide) were performed at these sites using the PDB ID: 3QD6 (CD40-CD154) and 3LKJ (BIO8898-CD154) co-crystal structures, respectively. The docking algorithm was able to better discriminate binders from non-binders at the deeper allosteric site than at the competitive site. Accordingly, an allosteric inhibitory mechanism that involves intercalation between monomeric subunits seems feasible for our small molecules making the constitutively trimeric CD154 a likely druggable target.

Feasibility of localized immunosuppression: 3. Preliminary evaluation of organosilicone constructs designed for sustained drug release in a cell transplant environment using dexamethasone.

As part of our ongoing effort to develop biohybrid devices for pancreatic islet transplantation, we are interested in establishing the feasibility of a localized immune-suppressive approach to avoid or minimize the undesirable side effects of existing systemic treatments. Since biohybrid devices can also incorporate biocompatible scaffold constructs to provide a support environment for the transplanted cells that enhances their engraftment and long-term function, we are particularly interested in an approach that would use the same three-dimensional construct, or part of the same construct, to also provide sustained release of therapeutic agents to modulate the inflammatory and immune responses locally. Within this framework, here, we report preliminary results obtained during the investigation of the suitability of organosilicone constructs for providing sustained localized drug release using small, matrix-type polydimethylsiloxane (PDMS) disks and dexamethasone as a model hydrophobic drug. Following a short burst, long-term steady sustained release was observed under in vitro conditions at levels of 0.1-0.5 microg/day/disk with a profile in excellent agreement with that predicted by the Higuchi equation. To verify that therapeutic levels can be achieved, suppression of LPS-induced activation has been shown in THP-1 cells with disks that have been pre-soaked for up to 28 days. These preliminary results prove the feasibility of this approach where an integral part of the biomaterial construct used to enhance cell engraftment and long-term function also serves to provide sustained local drug release.

Standard protocol for assessment of colon cancer improves the quality of pathology.

AIM: Tumour stage is the most important prognostic factor in colon cancer. The aim of this study was to examine the impact on the quality of pathology of the use of a standardized pathological and anatomical (PAD) protocol. METHOD: A standardized PAD protocol for colorectal cancer was developed and all patients subjected to colon resection due to adenocarcinomas between 2004 and 2006 were analysed regarding lymph node status, circumferential resection margin (CRM), and intravascular and perineural growth. Moreover, usage of the PAD protocol and whether a pathologist or biomedicine analytical technician (BMA) performed the lymph node dissection was noted, and also whether the surgical procedure was elective or acute. RESULTS: During the study period 302 colon resections were carried out. The standard protocol was employed in 68% of the cases, varying from 0% to 100% between pathologists. The median number of investigated lymph nodes was 16 ± 11. When the lymph node dissection was performed by a BMA, significantly more lymph nodes were examined; 22 ± 15 and 14 ± 9, respectively (P < 0.01). There was a positive correlation between application of the standard protocol and the number of analysed lymph nodes (< 0.05). Comments on CRM, perineural growth and intravascular growth were also significantly more frequent when the protocol was used. Emergency surgery did not influence the handling of the specimens. CONCLUSION: Minor changes in procedure in terms of a standard protocol for pathology and specimen dissection by BMAs, leading to an increased quality of the PAD-report, may also improve the long-term outcome for patients.

Organoid microphysiological system preserves pancreatic islet function within 3D matrix.

Three-dimensional (3D) multicellular organoids recapitulate the native complexities of human tissue better than traditional cellular monolayers. As organoids are insufficiently supported using standard static culture, microphysiological systems (MPSs) provide a key enabling technology to maintain organoid physiology in vitro. Here, a polydimethylsiloxane-free MPS that enables continuous dynamic culture and serial in situ multiparametric assessments was leveraged to culture organoids, specifically human and rodent pancreatic islets, within a 3D alginate hydrogel. Computational modeling predicted reduced hypoxic stress and improved insulin secretion compared to static culture. Experimental validation via serial, high-content, and noninvasive assessments quantitatively confirmed that the MPS platform retained organoid viability and functionality for at least 10 days, in stark contrast to the acute decline observed overnight under static conditions. Our findings demonstrate the importance of a dynamic in vitro microenvironment for the preservation of primary organoid function and the utility of this MPS for in situ multiparametric assessment.

Recent advances in retrometabolic drug design (RMDD) and development.

As a general review for the 7th Retrometabolism-Based Drug Design and Targeting Conference, recent developments within this field are briefly reviewed with various illustrative examples from different therapeutic areas. Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs and of chemical delivery systems (CDS). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure-activity and structure-metabolism relationships; however, they achieve it by different means: whereas soft drugs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps.

Pharmacokinetics and delta1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats.

Detailed pharmacokinetic (PK) studies in rats were performed (i)to compare the PK of prednisolone (PRN) and loteprednol etabonate (LE, a soft corticosteroid) as well as their common inactive metabolite delta1-cortienic acid (delta1-CA), (ii) to investigate the excretion of delta1-CA after PRN and LE administration, and (iii) to investigate the effect of delta1-unsaturation on the excretion of delta1-CA versus CA. Following a 10 mg x kg(-1) intravenous bolus dose, the total clearance (CL(tot)) of PRN (27.0 +/- 1.4 mL x min(-1) kg(-1)) was significantly lower than that of LE (67.4 +/- 11.6 mL x min(-1) kg(-1)) or delta1-CA (53.8 +/- 1.4 mL x min(-1) kg(-1)) indicating that the metabolism/elimination of PRN in the liver (primarily, conjugation) may be less efficient than that of LE (primarily, hydrolysis) or delta1-CA (unchanged). The volume of distribution (Vd(ss)) of PRN (823 +/- 78 mL x kg(-1)) was significantly lower than that of LE (3078 +/- 79 mL x kg(-1)) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that delta1-CA is indeed a metabolite of PRN. After intravenous injection of 10 mg x kg(-1), less than 1% of the administered PRN was excreted as delta1-CA by 4 h (0.38 +/- 0.10% in bile and 0.18 +/- 0.04% in urine), significantly less than for LE (17.01 +/- 2.09% in bile and 2.53 +/- 1.17% in urine) indicating that extent of this metabolic transformation can indeed be affected by molecular design. At doses of 100 mg/kg, the proportion of delta1-CA excreted after PRN administration (0.12 +/- 0.03% in bile and 0.19 +/- 0.03% in urine) was similar to that of CA excreted after hydrocortisone administration (0.11 +/- 0.03% in bile and 0.22 +/- 0.04% in urine) indicating that the presence of the delta1 double bond (delta1-unsaturation) does not affect significantly this metabolic conversion.