Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. / Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU).

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.

Toxicity study in a pig model of intraperitoneal collagenase as an "enzymatic scalpel" directed to break stroma in order to generate a new perspective for peritoneal carcinomatosis approach: an experimental research.

BACKGROUND: This study aimed to measure the toxicity resulting from collagenase administration to the peritoneal cavity in a pig model as a preliminary step to break down the stroma surrounding tumors. METHODS: Eight pigs were treated with 2 different collagenase concentrations previously tested in rats by our group. Time and temperature were controlled using a peritoneal lavage system (PRS System, Combat Medical Ltd.) identical to that used in human surgeries through hyperthermic intraperitoneal chemotherapy (HIPEC); 2 additional pigs were treated with peritoneal lavage only. Samples of blood and peritoneal fluid were collected pre-treatment, immediately after treatment, and 24 h postoperatively. In addition, histological studies and blood collagenase levels were measured. RESULTS: No complications were observed during the surgeries. Intraoperative images evidenced the release of peritoneal tissue during collagenase treatment. After surgery, the animals showed no signs of pain. Diet and mobility were normal at 4 h postoperatively, and there were no significant differences in hematologic or biochemical parameters. Quantification of MMP1 and MMP2 in all samples as measured by absorbance showed no differences in blood collagenase levels between pre-treatment, post-treatment, and 24 h postoperatively. None of the animals treated with collagenase showed peritoneal adhesions during the second surgery. Histologically, peritoneal organs and serous structures did not show any microscopic alterations associated with collagenase treatment in any group. CONCLUSION: Lavage of the peritoneal cavity with doses of up to 100,000 collagen digestion units/animal for 30 min is safe and removes connective tissue from the peritoneal cavity.

Changes in the requirement for early surgery in inflammatory bowel disease in the era of biological agents.

BACKGROUND AND AIM: Biological therapies may be changing the natural history of inflammatory bowel diseases (IBDs), reducing the need for surgical intervention. We aimed to assess whether the availability of anti-TNF agents impacts the need for early surgery in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Retrospective, cohort study of patients diagnosed within a 6-year period before and after the licensing of anti-TNFs (1990-1995 and 2007-2012 for CD; 1995-2000 and 2007-2012 for UC) were identified in the ENEIDA Registry. Surgery-free survival curves were compared between cohorts. RESULTS: A total of 7370 CD patients (2022 in Cohort 1 and 5348 in Cohort 2) and 8069 UC patients (2938 in Cohort 1 and 5131 in Cohort 2) were included. Immunosuppressants were used significantly earlier and more frequently in both CD and UC post-biological cohorts. The cumulative probability of surgery was lower in CD following anti-TNF approval (16% and 11%, 22% and 16%, and 29% and 19%, at 1, 3, and 5 years, respectively P < 0.0001), although not in UC (3% and 2%, 4% and 4%, and 6% and 5% at 1, 3, and 5 years, respectively; P = 0.2). Ileal involvement, older age at diagnosis and active smoking in CD, and extensive disease in UC, were independent risk factors for surgery, whereas high-volume IBD centers (in both CD and UC) and immunosuppressant use (in CD) were protective factors. CONCLUSIONS: Anti-TNF availability was associated with a reduction in early surgery for CD (driven mainly by earlier and more widespread immunosuppressant use) but not in UC.

Mesenchymal stem cells in perianal Crohn's disease.

The use of mesenchymal stem cells has resulted in a breakthrough for the treatment of complex perianal fistulas in Crohn's disease. This novel treatment is associated with a minimally invasive surgical technique that can be well defined. However, our previous experience has taught us that neglecting any of the critical steps in the operation can result in frequent treatment failure. We have put together a comprehensive guide, a stepwise algorithm, for our minimally invasive approach to identify common pitfalls and reduce treatment failures. Using data we have collected over the past 15 years from drug development, execution of clinical trials, and enacting an advanced educational training program, we spelt out each stage of the minimally invasive surgical intervention for stem cell delivery for perianal Crohn's disease. In this article, we provide 21 tips for a correct approach during the five major phases of the surgical procedure. To optimize the efficacy of mesenchymal stem cells for perianal Crohn's disease, a standardized minimally invasive technique including a reliable and reproducible series of key steps should be utilized.

Bisphosphonate-related osteonecrosis. Application of adipose-derived stem cells in an experimental murine model.

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw is a pathological condition without effective established treatment and preventive strategies. The aim of this study was to analyse the effect of adipose-derived stem cells (ASC) in an experimental murine model of osteonecrosis. MATERIAL AND METHODS: 38 Wistar rats were injected intraperitoneally with zoledronic acid. After treatment, upper jaw molars were extracted. The animals were randomly assigned to one of two groups. In the control group, saline solution was applied over the alveolar sockets after the tooth extractions. In the treatment group, ASCs were applied instead of saline solution. The control and treatment groups were subdivided based on the time of euthanasia. A clinical and histological analysis was performed. RESULTS: The presence of osteonecrosis in alveolar bone was observed in a similar distribution in both groups. In the ASC-treated group, new bone formation was greater than in controls. CONCLUSION: In this study, application of ASCs showed greater new bone formation in an osteonecrosis-like murine model. Previous inhibited post-extraction bone remodelling could be reactivated, and these findings appeared to be secondary to implantation of ASCs.

Incomplete type of intestinal metaplasia has the highest risk to progress to gastric cancer: results of the Spanish follow-up multicenter study.

BACKGROUND AND AIM: In high or moderate risk populations, periodic surveillance of patients at risk of progression from gastric precursor lesions (PL) to gastric cancer (GC) is the most effective strategy for reducing the burden of GC. Incomplete type of intestinal metaplasia (IIM) may be considered as the best candidate, but it is still controversial and more research is needed. To further assess the progression of subtypes of IM as predictors of GC occurrence. METHODS: A follow-up study was carried-out including 649 patients, diagnosed with PL between 1995-2004 in 9 participating hospitals from Spain, and who repeated the biopsy during 2011-2013. Medical information and habits were collected through a questionnaire. Based on morphology, IM was sub-classified as complete (small intestinal type, CIM) and incomplete (colonic type, IIM). Analyses were done using Cox (HR) models. RESULTS: At baseline, 24% of patients had atrophic gastritis, 38% CIM, 34% IIM, and 4% dysplasia. Mean follow-up was 12 years. 24 patients (3.7%) developed a gastric adenocarcinoma during follow-up. The incidence rate of GC was 2.76 and 5.76 per 1,000 person-years for those with CIM and IIM, respectively. The HR of progression to CG was 2.75 (95% CI 1.06-6.26) for those with IIM compared with those with CIM at baseline, after adjusting for sex, age, smoking, family history of GC and use of NSAIDs. CONCLUSIONS: IIM is the PL with highest risk to progress to GC. Sub-typing of IM is a valid procedure for the identification of high risk patients that require more intensive surveillance.

Potential of mesenchymal stem cell in stabilization of abdominal aortic aneurysm sac.

BACKGROUND: In their origin, abdominal aortic aneurysms (AAAs) are related to an inflammatory reaction within the aortic wall, which can lead to weakness and degeneration of this structure. One of the most widely accepted treatment modalities for AAAs is the placement of stent grafts. Nevertheless, in some patients blood re-enters the aneurysm sac, creating so-called leaks, which constitute a renewed risk of rupture and death.This study explores the possibility of filling aneurysm sacs treated by endovascular aneurysm repair with adipose tissue-derived mesenchymal stem cells (ASCs) in a porcine model. METHODS: We developed a porcine model using 22 animals by creating an artificial AAA made with a Dacron patch. AAAs were then treated with a coated stent that isolated the aneurysm sac, after which we introduced allogeneic ASC into the sac. Animals were followed-up for up to 3 mo. The experiment consisted of the aforementioned surgical procedure performed first, followed by computed tomography and echo-Doppler imaging during the follow-up, and finally, after sacrificing the animals, histologic analysis of tissue samples from the site of cell implantation by a blinded observer and the detection of implanted cells by immunofluorescence detection of the Y chromosome. RESULTS: Our findings demonstrate the survival of ASCs over the 3 mo after implantation and histologic changes associated with this treatment. Treated animals had less acute and chronic inflammation throughout the study period, and we observed increasing fibrosis of the aneurysm sac, no accumulation of calcium, and a regeneration of elastic fibers in the artery. CONCLUSIONS: The combination of endovascular aneurysm repair and cell therapy on AAAs has promising results for the stabilization of the sac, resulting in the generation of living tissue that can secure the stent graft and even showing some signs of wall regeneration. The therapeutic value of such cell-based therapy will require further investigation.

Use of platelet-rich plasma in the healing of chronic ulcers of the lower extremity.

INTRODUCTION AND OBJECTIVES: Platelet-rich plasma (PRP) is used as an adjuvant in the treatment of chronic ulcers of the lower extremity and has shown particularly promising results in the case of neuropathic ulcers. There has been less research, however, into its use in venous and hypertensive ulcers. Our aim was to assess the safety and feasibility of using PRP in the treatment of chronic ulcers of the lower extremity and to evaluate its potential benefits in directed healing. MATERIAL AND METHODS: We prospectively selected 11 patients with nonischemic ulcers of the lower extremity that had been present for at least 6 weeks. PRP was injected subcutaneously into the perilesional tissue and applied topically in 4 sessions held at 1-week intervals. We assessed quality of life (SF-12 questionnaire), pain (visual analog scale), and the circumference of the ulcer before and after treatment. RESULTS: There was a predominance of women (8/11, 73%), and venous ulcers (7/11, 64%) were more common than hypertensive ulcers (4/11, 36%). The median age of the patients was 79 years and the median time since onset of the ulcer was 17 months (range, 6-108 months). We observed a significant reduction in pain (P<.05) and a significant improvement in the physical and mental components of the SF-12 (P<.05). The mean reduction in ulcer size was 60%, and complete healing was achieved in 5 cases. No adverse effects were observed. CONCLUSION: The local application of PRP is a valuable and practical procedure that promotes the healing of chronic ulcers of the lower extremity; it can improve patient quality of life and is particularly effective in local pain relief.

Undetectable circulating tumor DNA confirms the inability of pseudomyxoma peritonei to systemic dissemination.

The study of circulating tumor DNA (ctDNA) plays a pivotal role in advancing precision oncology, providing valuable information for individualized patient care and contributing to the ongoing effort to improve cancer diagnosis, treatment, and management. However, its applicability in pseudomyxoma peritonei (PMP) remains unexplored. In this multicenter retrospective study involving 21 PMP patients, we investigated ctDNA presence in peripheral blood using three distinct methodologies. Despite mucinous tumor tissues exhibiting KRAS and GNAS mutations, ctDNA for these mutations was undetectable in blood samples. In this pilot study, circulating tumor DNA was not detected in blood when the tumor harbored mutations of known significance. In the future, a study with a larger sample size is needed to confirm these findings and to determine whether ctDNA could identify patients at risk for early recurrence and/or systemic metastases.

Therapeutic effect of adipose-derived mesenchymal stem cells in a porcine model of abdominal sepsis.

BACKGROUND: The term sepsis refers to a complex and heterogeneous syndrome. Although great progress has been made in improving the diagnosis and treatment of this condition, it continues to have a huge impact on morbidity and mortality worldwide. Mesenchymal stem cells are a population of multipotent cells that have immunomodulatory properties, anti-apoptotic effects, and antimicrobial activity. We studied these capacities in a porcine model of peritoneal sepsis. METHODS: We infused human adipose-derived mesenchymal stem cells (ADSCs) into a porcine model of peritoneal sepsis. Twenty piglets were treated with antibiotics alone (control group) or antibiotics plus peritoneal infusion of ADSCs at a concentration of 2 × 106 cells/kg or 4 × 106 cells/kg (low- and high-dose experimental groups, respectively). The animals were evaluated at different time points to determine their clinical status, biochemical and hematologic parameters, presence of inflammatory cytokines and chemokines in blood and peritoneal fluid, and finally by histologic analysis of the organs of the peritoneal cavity. RESULTS: One day after sepsis induction, all animals presented peritonitis with bacterial infection as well as elevated C-reactive protein, haptoglobin, IL-1Ra, IL-6, and IL-1b. Xenogeneic ADSC infusion did not elicit an immune response, and peritoneal administration of the treatment was safe and feasible. One day after infusion, the two experimental groups showed a superior physical condition (e.g., mobility, feeding) and a significant increase of IL-10 and TGF-ß in blood and a decrease of IL-1Ra, IL-1b, and IL-6. After 7 days, all animals treated with ADSCs had better results concerning blood biomarkers, and histopathological analysis revealed a lower degree of inflammatory cell infiltration of the organs of the peritoneal cavity. CONCLUSIONS: Intraperitoneal administration of ADSCs as an adjuvant therapy for sepsis improves the outcome and diminishes the effects of peritonitis and associated organ damage by regulating the immune system and reducing intra-abdominal adhesions in a clinically relevant porcine model of abdominal sepsis.

Seroprevalence of ANTI-SARS-CoV-2 antibodies in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) treated with biologic and/or immunosuppressant drugs are at increased risk for opportunistic infections. Seroprevalence studies can confirm the diagnosis of SARS-CoV-2 infections as well as the associated risk factors. This is a descriptive study which primary endpoints were to highlight the prevalence of SARS-CoV-2 antibodies in a cohort of IBD patients in March 2021, and to analyze seroconversion in patients with known COVID-19 infection and its relationship with IBD treatments. Patients filled in a questionnaire about symptoms of COVID-19 infection and clinical information about their IBD. All included patients were tested for SARS-CoV-2 antibodies. 392 patients were included. Among patients with clinical infection, 69 patients (17,65%) were IgG-positive, 286 (73,15%) IgG-negative and 36 (9,21%) indeterminate. In relation to seroconversion among patients under biologic treatment, 13 patients of the 23 with a previous positive CRP developed antibodies (56.5%). However, when the influence of immunosuppressive treatment on the probability of developing antibodies was analyzed, no significant differences were seen between those patients with or without treatment (77.8% vs. 77.1%, p = 0.96). In our cohort of IBD patients, after one year of pandemic, there were 18.64% IgG positive patients, a higher prevalence than the general population (15.7%).

Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation.

BACKGROUND: Autologous adipose-derived stem cells may represent a novel approach for the management of complex fistula-in-ano. After successful phase I and II clinical trials, a phase III trial was performed to investigate the safety and efficacy. DESIGN: In this multicenter, randomized, single-blind, add-on clinical trial, 200 adult patients from 19 centers were randomly assigned to receive 20 million stem cells (group A, 64 patients), 20 million adipose-derived stem cells plus fibrin glue (group B, 60 patients), or fibrin glue (group C, 59 patients) after closure of the internal opening. Fistula healing was defined as reepithelization of the external opening and absence of collection >2 cm by MRI. If the fistula had not healed at 12 weeks, a second dose (40 million stem cells in groups A and B) was administered. Patients were evaluated at 24 to 26 weeks (primary end point) and at 1 year (long-term follow-up). RESULTS: All results are according to the "blinded evaluator" assessment. After 24 to 26 weeks, the healing rate was 39.1%, 43.3%, 37.3% in groups A, B, and C (p = 0.79). At 1 year, the healing rates were 57.1%, 52.4%, and 37.3 % (p = 0.13). On analysis of the subpopulation treated at the technique's pioneer center, healing rates were 54.55%, 83.33%, and 18.18%, at 24 to 26 weeks (p < 0.001). No SAEs were reported. CONCLUSIONS: In treatment of complex fistula-in-ano, a dose of 20 or 60 million adipose-derived stem cells alone or in combination with fibrin glue was considered a safe treatment, achieving healing rates of approximately 40% at 6 months and of more than 50% at 1-year follow-up. It was equivalent to fibrin glue alone. No statistically significant differences were found when the 3 groups where compared. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, identifier NCT00475410; Sponsor, Cellerix SA.

Transforming a public university hospital and its area of influence into a comprehensive resource in response to the COVID-19 pandemic.

INTRODUCTION AND OBJECTIVES: The outbreak of COVID-19 has overwhelmed healthcare systems all over the world. The aim of this article is to describe the process of transforming the Vall d'Hebron University Hospital, the second largest hospital in Spain, into a COVID-19 centre coordinating response to the pandemic in its reference area. MATERIALS AND METHODS: The study draws on the experience of the authors in transforming the hospital into a comprehensive resource in response to the COVID-19 pandemic. The strategy is based on four central strategies: early planning, coordination of all healthcare agents in its reference area, definition of clear leadership roles, and the organisation of care based on multidisciplinary teams with minimal recruitment of new staff. RESULTS: The transformation strategy enabled the hospital to cope with the surge in patients without exceeding its capacity. During the response phases, which amounted to a period of 57 days, 3106 patients consulted the ER and 2054 were admitted, 346 of whom were treated at the ICU. To accommodate the number of adult COVID-19 patients, adult ICU availability was progressive increased by 371%, and ordinary beds increased by 240. A total of 671 staff members went on sick leave after testing positive for COVID-19. CONCLUSION: The transformation experience of the hospital provides insight into how effectively adapt the structures and functioning of large hospitals. The relevance of territorial coordination during the pandemic is stressed as an effective strategy that contributed coping the pandemic.

Risk of Immunomediated Adverse Events and Loss of Response to Infliximab in Elderly Patients with Inflammatory Bowel Disease: A Cohort Study of the ENEIDA Registry.

BACKGROUND AND AIMS: Immunomediated adverse events [IAEs] are the most frequently reported infliximab [IFX]-related adverse events. Combination therapy may reduce their incidence, although this strategy is not recommended in elderly patients. We aimed to compare the rates of IFX-related IAEs and loss of response [LOR] in elderly and younger patients. METHODS: Adult patients in the ENEIDA registry who had received a first course of IFX therapy were identified and grouped into two cohorts regarding age at the beginning of treatment [over 60 years and between 18 and 50 years]. The rates of IAEs and LOR were compared. RESULTS: In total, 939 patients [12%] who started IFX over 60 years of age and 6844 [88%] below 50 years of age were included. Elderly patients presented a higher proportion of AEs related to IFX [23.2% vs 19%; p = 0.002], infections [7.1% vs 4.3%; p < 0.001] and neoplasms [2.2% vs 0.5%; p < 0.001]. In contrast, the rates of IAEs [14.8% vs 14.8%; p = 0.999], infusion reactions [8.1% vs 8.1%; p = 0.989], late hypersensitivity [1.3% vs 1.2%; p = 0.895], paradoxical psoriasis [1% vs 1.5%; p = 0.187] and drug-induced lupus erythematosus [0.6% vs 0.7%; p = 0.947] were similar in elderly and younger patients. LOR rates were also similar between the two groups [20.5% vs 19.3%; p = 0.438]. In the logistic regression analysis, IFX monotherapy, extraintestinal manifestations and female gender were the only risk factors for IAEs, whereas IFX monotherapy, extraintestinal manifestations and Crohn's disease were risk factors for LOR. CONCLUSIONS: Elderly patients with inflammatory bowel disease have a similar risk of developing IFX-related IAEs and LOR to that of younger patients.

Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis?

BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.

A brief and rapid procedure to measure the intensity of depressive symptoms in Primary Care.

INTRODUCTION: Depression occupies a substantial part of medical visit attendance. However, medical practitioners have very little time so that a brief, quick and reliable procedure to evaluate the intensity of symptoms and their changes could be useful. Our objective has been to analyze the reliability of a self-applied Visual Analogue Scale (VAS) to measure symptom intensity in depressed patients within this context. MATERIAL AND METHODS: One hundred depressed outpatients (ICD-10) stated their clinical situation on a VAS. The psychiatrist evaluated them using a Global Clinical Impression (GGI) and Hamilton Depression Rating Scale (HDRS-17). RESULTS AND CONCLUSIONS: The patient's VAS showed high correlation with the HDRS-17 and with the GCI used by the psychiatrist (r = 0.63 and r=0.58; p=0.000). This suggests that the use of a VAS in Primary Care could be useful and reliable for these purposes within the medical contexts of those having little time availability. Key-words: Depression, primary care, medical patients, assessment, evaluation.

Characteristics of prolonged noninvasive ventilation in emergency departments and impact upon effectiveness. Analysis of the VNICat registry.

OBJECTIVE: To analyze the characteristics and variables associated with prolonged noninvasive ventilation performed completely in Emergency Departments (NIV-ED) and its influence upon effectiveness. DESIGN: A prospective, multicenter, observational multipurpose cohort study was carried out. SETTING: VNICAT Registry. SUBJECTS: Patients in which NIV-ED was performed in 11 Catalan hospitals in the months of February or March 2015. INTERVENTION: No. VARIABLES: The study variable was NIV-ED, which as a function of time was defined as prolonged or not prolonged. The efficacy variable was the success of the technique in terms of patient improvement. RESULTS: A total of 125 patients were included, with a median NIV-ED duration of 12 h, which was the cut-off point for the comparator groups. In 60 cases (48%) NIV-ED was not prolonged (<12 h), while in 65 cases (52%) ventilation was prolonged (≥12 h). Non-prolonged NIV-ED was associated to the indication of acute heart failure and prolonged ventilation to the presence of diabetes. There were no differences between non-prolonged and prolonged NIV-ED in terms of efficacy, and the success rate in terms of improvement was 68.3% and 76.9%, respectively, with an adjusted odds ratio of 1.49 (95%CI 0.61-3.60). CONCLUSIONS: Prolonged NIV-ED is a frequent situation, but few variables associated to it have been studied. The presence of prolonged ventilation did not influence the success rate of NIV.

Intraperitoneal collagenase as a novel therapeutic approach in an experimental model of colorectal peritoneal carcinomatosis.

The usefulness of local collagenase in therapeutic approaches to solid tumors has been tested recently. In this study, we evaluate the safety and efficacy of intraperitoneal collagenase associated or not to mitomycin for treatment of colorectal peritoneal metastases in an experimental rat model. Using a fixed-dose procedure, we found that a dose of collagenase of 37 IU/mL administered for 15 min with a hyperthermia pump at 37.5 °C, both in isolation or associated to sequential treatment with intraperitoneal mitomycin, led to a macroscopic decrease in tumor volume as evaluated by the modified peritoneal cancer index (mPCI). Concerning the safety of the procedure, the animals showed no physiological or behavioral disorders during 8 weeks of follow-up. Local treatment for peritoneal metastases of colorectal origin with intraperitoneal collagenase has proved safe and effective in an experimental murine model. Therefore, the stroma-first approach by enzymatic breakdown of collagen from the tumor's extracellular matrix provides a new therapeutic target for colorectal peritoneal metastases.

Multidisciplinary Management of the Adverse Effects of Apremilast. / Manejo de los efectos adversos de apremilast desde un abordaje multidisciplinar.

We present a series of general and specific recommendations based on pathophysiologic considerations for managing the most common adverse effects of apremilast that lead to treatment discontinuation: diarrhea, nausea, and headache. The recommendations are based on a review of the literature and the experience of a multidisciplinary team of 14 experts including dermatologists, rheumatologists, neurologists, gastroenterologists, pharmacists, and nurses. We propose a series of simple algorithms that include clinical actions and suggestions for pharmacologic treatment. The adverse effects of apremilast can be managed from a multidisciplinary approach. The purpose of optimizing management is to bring clinical benefits to patients.

Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant.

D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n=758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies.