International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

Conservative surgery versus colorectal resection for endometriosis with rectal involvement: a systematic review and meta-analysis of surgical and long-term outcomes.

PURPOSE: The optimal surgical approach for removal of colorectal endometrial deposits is unclear. Shaving and discoid excision of colorectal deposits allow organ preservation but risk recurrence with associated functional issues and re-operation. Formal resection risks potential higher complications but may be associated with lower recurrence rates. This meta-analysis compares peri-operative and long-term outcomes between conservative surgery (shaving and disc excision) versus formal colorectal resection. METHODS: The study was registered with PROSPERO. A systematic search was performed on PubMed and EMBASE databases. All comparative studies examining surgical outcomes in patients that underwent conservative surgery versus colorectal resection for rectal endometrial deposits were included. The two main groups (conservative versus resection) were compared in three main blocks of variables including group comparability, operative outcomes and long-term outcomes. RESULTS: Seventeen studies including 2861 patients were analysed with patients subdivided by procedure: colorectal resection (n = 1389), shaving (n = 703) and discoid excision (n = 742). When formal colorectal resection was compared to conservative surgery there was lower risk of recurrence (p = 0.002), comparable functional outcomes (minor LARS, p = 0.30, major LARS, p = 0.54), similar rates of postoperative leaks (p = 0.22), pelvic abscesses (p = 0.18) and rectovaginal fistula (p = 0.92). On subgroup analysis, shaving had the highest recurrence rate (p = 0.0007), however a lower rate of stoma formation (p < 0.00001) and rectal stenosis (p = 0.01). Discoid excision and formal resection were comparable. CONCLUSION: Colorectal resection has a significantly lower recurrence rate compared to shaving. There is no difference in complications or functional outcomes between discoid excision and formal resection and both have similar recurrence rates.

The mesocolic apical fragment in complete mesocolic excision colectomies: Should it be analysed separately? A proof-of-concept study.

AIM: The aim of this work is to describe a protocol and assess the feasibility of harvesting and analysing the mesocolic apical fragment (MAF) for the presence of central lymph node (LN) metastasis and extra lymphatic free tumour cells in a random subgroup extracted from a cohort of complete mesocolic excision colectomies with central vascular ligation. METHOD: Forty-seven patients diagnosed with colorectal cancer were included. A 2/2 cm pyramid of tissue was cut around the central tie and sent for pathological examination. The MAF was sectioned into 16 slices. High-definition images were taken from the slices which were merged into a panoramic three-dimensional image of the MAF. The distribution of LNs in the MAF was quantified. Immunohistochemistry staining for cytokeratin 14 was used to identify isolated tumour cells and micrometastases in the extranodal tissue. RESULTS: No tumoural cells migrating through the apical zone, outside of the LNs, were identified. Margins of resection, mesocolic tissue and LNs were all negative in the subgroup of ultrastaged MAFs. The number of examined central LNs varied between 0 and 24, with positive MAF LNs being identified only in pN2 stages. The rate of positive apical LNs in our cohort was 4.2% (n = 2). CONCLUSIONS: The MAF can be easily extracted from standard specimens, allowing for accurate analysis of lymphatic and extra-nodal tumour cells on the central resection margins, in central LNs and in the apical mesocolic tissue. Future research on larger cohorts is required to establish if analysing the MAF has an impact on patient staging, prognosis and management.

Solid-Phase Synthesized Copolymers for the Assembly of pH-Sensitive Micelles Suitable for Drug Delivery Applications.

Diblock copolymers of polyhistidine are known for their self-assembly into micelles and their pH-dependent disassembly due to the amphiphilic character of the copolymer and the unsaturated imidazole groups that undergo a hydrophobic-to-hydrophilic transition in an acidic pH. This property has been largely utilized for the design of drug delivery systems that target a tumor environment possessing a slightly lower extracellular pH (6.8-7.2). The main purpose of this study was to investigate the possibility of designed poly(ethylene glycol)-polyhistidine sequences synthesized using solid-phase peptide synthesis (SPPS), to self-assemble into micelles, to assess the ability of the corresponding micelles to be loaded with doxorubicin (DOX), and to investigate the drug release profile at pH values similar to a malignant extracellular environment. The designed and assembled free and DOX-loaded micelles were characterized from a physico-chemical point of view, their cytotoxicity was evaluated on a human breast cancer cell line (MDA-MB-231), while the cellular areas where micelles disassembled and released DOX were assessed using immunofluorescence. We concluded that the utilization of SPPS for the synthesis of the polyhistidine diblock copolymers yielded sequences that behaved similarly to the copolymeric sequences synthesized using ring-opening polymerization, while the advantages of SPPS may offer facile tuning of the histidine site or the attachment of a large variety of functional molecules.

Experimental Models for Controlled Burn Injuries in Rats: A Systematic Analysis of Original Methods and Burn Devices.

Despite a wide variety of models found in literature, choosing the right one can be difficult as many of them are lacking precise methodology. This study aims to analyze and compare original burn models in terms of burn device and technique, parameters, and wound depth assessment. A systematic search was performed according to PRISMA guidelines on studies describing original experimental burn models in rats. The adapted PICO formula and ARRIVE checklist were followed for inclusion and assessment of quality of studies. Characteristics of animals, burn technique, burn parameters, and method of histological confirmation of burn depth were recorded. Twenty-seven studies were included in the final analysis. Most studies used direct contact with skin for burn infliction (n = 20). The rat's dorsum was the most common site (n = 18). Ten studies used manually controlled burn devices, while 10 designed automatic burn devices with control over temperature (n = 10), exposure time (n = 5), and pressure (n = 5). Most studies (n = 7) used a single biopsy taken from the center of the wound to confirm burn depth immediately after burn infliction. From the wide variety of burn models in current literature, our study provides an overview of the most relevant experimental burn models in rats aiding researchers to understand what needs to be addressed when designing their burn protocol. Models cannot be compared as burn parameters variate significantly. Assessment of burn depth should be done in a standardized, sequential fashion in future burn studies to increase reproducibility.

Sleep Impairment and Psychological Distress among Patients with Inflammatory Bowel Disease-beyond the Obvious.

BACKGROUND: A healthy sleep-wake cycle is fundamental for regulating immune function. Sleepiness and fatigue are often manifestations of chronic inflammatory disorders, such as inflammatory bowel disease (IBD), potentially influencing the course of the disease. Our aim was to characterize sleep impairment in patients with IBD and to identify potential associated factors. METHODS: We conducted a single-center prospective case control study including IBD patients and healthy controls. We evaluated clinical and biochemical parameters, sleep impairment through Pittsburgh Sleep Quality Index (PSQI) and anxiety and depression through Hospital Anxiety and Depression Scale (HADS) questionnaires. RESULTS: In total, 110 patients with IBD and 66 healthy controls were included. Patients with IBD had a significantly altered sleep quality compared to the control group (p < 0.001), with sleep impairment also occurring for patients in remission (median PSQI = 7), but without significant differences between ulcerative colitis and Crohn's disease. However, PSQI was correlated with disease activity scores only for ulcerative colitis and not for Crohn's disease. Among patients with increased PSQI, only 30.19% used sleep medication. Sleep impairment was significantly correlated with altered psychological status (p < 0.01) and the presence of extraintestinal manifestations (p = 0.0172). CONCLUSIONS: Sleep impairment is frequent among patients with IBD, is associated with psychological distress and several disease-related parameters and should be routinely evaluated, at least in several IBD patient subgroups, to improve disease management.

Design and Testing of an Experimental Steam-Induced Burn Model in Rats.

BACKGROUND: Most of the current models for experimental burns pose difficulties in ensuring consistency and standardization. AIM OF STUDY: We aimed to develop an automated, reproducible technique for experimental burns using steam-based heat transfer. METHODS: The system developed for steam exposure was based on a novel, integrated, computer-controlled design. Three groups of rats were exposed to steam for 1, 3, and 7 seconds. The lesions were evaluated after 20 minutes, 48 hours, and 72 hours after burn induction. RESULTS: One-second steam application produced a superficial second-degree burn; three-second application induced deep second-degree burn; and seven-second application led to a third-degree burn. CONCLUSION: The high level of automation of our integrated, computer-controlled system makes the difference between our system and other models, by ensuring the control of the duration of exposure, temperature, and pressure and eliminating as many potential human generated errors as possible. The automated system can accurately reproduce specific types of burns, according to histological assessment. This model could generate the reproducible data needed in the study of burn pathology and in order to assess new treatments.

EGIST of the greater omentum - case study and review of literature.

The development of immunohistochemical methods has outlined a particular group of tumors, with very specific features and treatment, originating in the Cajal cells of the muscularis propria or related stem cell-like precursors present in the wall of the digestive tract called gastrointestinal stromal tumors (GISTs). A sub-segment with similar features may develop outside the digestive tract, namely extra-gastrointestinal stromal tumors (EGISTs). From the small category of EGISTs, we report on a case of a primary epithelioid EGIST of the greater omentum, which is seldom reported in literature. The tumor was diagnosed in a man with non-specific symptoms who presented for abdominal enlargement. The tumor was characterized and there was a preoperative suspicion of a non-digestive tumor located in the greater omentum. The tumor was surgically removed showing no contact with adjacent organs. Immunohistochemical examination was consistent with a primary EGIST of the greater omentum. Treatment with Imatinib mesylate was started and at two-year follow-up, the patient is disease free. The case raises problems regarding pathogenesis, immunohistochemical features, behavior, evolution and prognosis of omental EGIST, for which no significant or conflicting data are available in the literature.

Laparoscopic-assisted percutaneous endoscopic transgastrostomy jejunostomy.

BACKGROUND AND OBJECTIVES: New therapeutic protocols for patients with end-stage Parkinson disease include a carbidopa/levodopa combination using continuous, modulated enteral administration via a portable pump. The typical approach involves a percutaneous endoscopic transgastrostomy jejunostomy (PEG-J), which requires a combination of procedures designed to ensure that no organ is interposed between the abdominal wall and the gastric surface. Lack of transillumination in maximal endoscopic light settings is a major contraindication for PEG-J, and we decided to use a different approach to establish enteric access for long-term medication delivery via pump, using a minimally invasive procedure. METHODS: In all patients, we performed a laparoscopic-assisted percutaneous transgastrostomy jejunostomy (LAPEG-J) after an unsuccessful endoscopic transillumination. RESULTS: Five patients with end-stage Parkinson disease were referred to our department after successful therapeutic testing with administration of levodopa/carbidopa via naso-jejunal tube. All patients failed the endoscopic transillumination during the endoscopic procedure and were considered for LAPEG-J. In all patients, the LAPEG-J procedure was uneventful. The most common reason identified for failed transillumination was a high position of the stomach, followed by interposition of the liver or colon between the stomach and anterior abdominal wall. There were no complications regarding the LAPEG-J procedure, and all patients were discharged during the second postprocedural day. CONCLUSIONS: LAPEG-J provides a simple and safe option for placing a jejunostomy after an unsuccessful PEG-J attempt.