Digestive and breast cancer patients managed during the first wave of COVID-19 pandemic: Short and middle term outcomes.

BACKGROUND: The first wave of coronavirus disease 2019 (COVID-19) pandemic in Spain lasted from middle March to the end of June 2020. Spanish population was subjected to lockdown periods and scheduled surgeries were discontinued or reduced during variable periods. In our centre, we managed patients previously and newly diagnosed with cancer. We established a strategy based on limiting perioperative social contacts, preoperative screening (symptoms and reverse transcription-polymerase chain reaction) and creating separated in-hospital COVID-19-free pathways for non-infected patients. We also adopted some practice modifications (surgery in different facilities, changes in staff and guidelines, using continuously changing personal protective equipment…), that supposed new inconveniences. AIM: To analyse cancer patients with a decision for surgery managed during the first wave, focalizing on outcomes and pandemic-related modifications. METHODS: We prospectively included adults with a confirmed diagnosis of colorectal, oesophago-gastric, liver-pancreatic or breast cancer with a decision for surgery, regardless of whether they ultimately underwent surgery. We analysed short-term outcomes [30-d postoperative morbimortality and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection] and outcomes after 3 years (adjuvant therapies, oncological events, death, SARS-CoV-2 infection and vaccination). We also investigated modifications to usual practice. RESULTS: From 96 included patients, seven didn't receive treatment that period and four never (3 due to COVID-19). Operated patients: 28 colon and 21 rectal cancers; laparoscopy 53.6%/90.0%, mortality 3.57%/0%, major complications 7.04%/25.00%, anastomotic leaks 0%/5.00%, 3-years disease-free survival (DFS) 82.14%/52.4% and overall survival (OS) 78.57%/76.2%. Six liver metastases and six pancreatic cancers: no mortality, one major complication, three grade A/B liver failures, one bile leak; 3-year DFS 0%/33.3% and OS 50.0%/33.3% (liver metastases/pancreatic carcinoma). 5 gastric and 2 oesophageal tumours: mortality 0%/50%, major complications 0%/100%, anastomotic leaks 0%/100%, 3-year DFS and OS 66.67% (gastric carcinoma) and 0% (oesophagus). Twenty breast cancer without deaths/major complications; 3-year OS 100% and DFS 85%. Nobody contracted SARS-CoV-2 postoperatively. COVID-19 pandemic-related changes: 78.2% treated in alternative buildings, 43.8% waited more than 4 weeks, two additional colostomies and fewer laparoscopies. CONCLUSION: Some patients lost curative-intent surgery due to COVID-19 pandemic. Despite practice modifications and 43.8% delays higher than 4 weeks, surgery was resumed with minimal changes without impacting outcomes. Clean pathways are essential to continue surgery safely.

Stem cell therapy applied for digestive anastomosis: Current state and future perspectives.

BACKGROUND: Digestive tract resections are usually followed by an anastomosis. Anastomotic leakage, normally due to failed healing, is the most feared complication in digestive surgery because it is associated with high morbidity and mortality. Despite technical and technological advances and focused research, its rates have remained almost unchanged the last decades. In the last two decades, stem cells (SCs) have been shown to enhance healing in animal and human studies; hence, SCs have emerged since 2008 as an alternative to improve anastomoses outcomes. AIM: To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks. METHODS: PubMed, Science Direct, Scopus and Cochrane searches were performed using the key words "anastomosis", "colorectal/colonic anastomoses", "anastomotic leak", "stem cells", "progenitor cells", "cellular therapy" and "cell therapy" in order to identify relevant articles published in English and Spanish during the years of 2000 to 2021. Studies employing SCs, performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally included. Reference lists from the selected articles were reviewed to identify additional pertinent articles.Given the great variability in the study designs, anastomotic models, interventions (SCs, doses and vehicles) and outcome measures, performing a reliable meta-analysis was considered impossible, so we present the studies, their results and limitations. RESULTS: Eighteen preclinical studies and three review papers were identified; no clinical studies have been published and there are no registered clinical trials. Experimental studies, mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis, have been demonstrated SCs as safe and have shown some encouraging morphological, functional and even clinical results. Mesenchymal SCs are mostly employed, and delivery routes are mainly local injections and cell sheets followed by biosutures (sutures coated by SCs) or purely topical. As potential weaknesses, animal models need to be improved to make them more comparable and equivalent to clinical practice, and the SC isolation processes need to be standardised. There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed to establish the indications, the administration system, potential adjuvants, the final efficacy and to confirm safety and exclude definitively oncological concerns. CONCLUSION: The future role of SC therapy to induce healing processes in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.

Laparoscopic bariatric surgery in a patient with idiopathic intracranial hypertension and lumboperitoneal shunt: Anesthetic implications.

Idiopathic intracranial hypertension (IIH) typically affects obese young women. Treatment is mainly medical, but some cases require surgery; ventriculoperitoneal (VPS) or lumboperitoneal shunts (LPS) being the most common procedures. Although bariatric surgery is not the first-line surgical treatment, it can be useful in refractory cases and allows treating the major underlying risk factor and its comorbidities. Laparoscopic bariatric surgery is the gold standard; however, literature in patients with shunts is scarce. In the present study, we report the case of a morbidly obese female with IIH treated with an LPS and with refractory headache, scheduled for laparoscopic Roux-en-Y gastric bypass. LPS position was checked before surgery (abdominal X-ray) and during pneumoperitoneum was clamped. Anesthetic management was guided to minimize increases in intracranial pressure (ICP). Surgery and anesthesia were uneventful. Three months later, headaches disappeared and analgesics were discontinued. In conclusion, laparoscopic bariatric surgery may be an option for IIH. It is safe in patients with LPS, although concerns should be taken into account (avoid any damage to the shunt, limit digestive tract contents spillage, and strict vigilance for early detection of intracranial hypertension signs). Although valve system could prevent pressure complications, the catheter can be clamped to avoid retrograde insufflation of CO2 or digestive tract content.

Stem cell therapy for faecal incontinence: Current state and future perspectives.

Faecal continence is a complex function involving different organs and systems. Faecal incontinence is a common disorder with different pathogeneses, disabling consequences and high repercussions for quality of life. Current management modalities are not ideal, and the development of new treatments is needed. Since 2008, stem cell therapies have been validated, 36 publications have appeared (29 in preclinical models and seven in clinical settings), and six registered clinical trials are currently ongoing. Some publications have combined stem cells with bioengineering technologies. The aim of this review is to identify and summarise the existing published knowledge of stem cell utilization as a treatment for faecal incontinence. A narrative or descriptive review is presented. Preclinical studies have demonstrated that cellular therapy, mainly in the form of local injections of muscle-derived (muscle derived stem cells or myoblasts derived from them) or mesenchymal (bone-marrow- or adipose-derived) stem cells, is safe. Cellular therapy has also been shown to stimulate the repair of both acute and subacute anal sphincter injuries, and some encouraging functional results have been obtained. Stem cells combined with normal cells on bioengineered scaffolds have achieved the successful creation and implantation of intrinsically-innervated anal sphincter constructs. The clinical evidence, based on adipose-derived stem cells and myoblasts, is extremely limited yet has yielded some promising results, and appears to be safe. Further investigation in both animal models and clinical settings is necessary to drawing conclusions. Nevertheless, if the preliminary results are confirmed, stem cell therapy for faecal incontinence may well become a clinical reality in the near future.

Rat model of anal sphincter injury and two approaches for stem cell administration.

AIM: To establish a rat model of anal sphincter injury and test different systems to provide stem cells to injured area. METHODS: Adipose-derived stem cells (ASCs) were isolated from BDIX rats and were transfected with green fluorescent protein (GFP) for cell tracking. Biosutures (sutures covered with ASCs) were prepared with 1.5 x 106 GFP-ASCs, and solutions of 106 GFP-ASCs in normal saline were prepared for injection. Anorectal normal anatomy was studied on Wistar and BDIX female rats. Then, we designed an anal sphincter injury model consisting of a 1-cm extra-mucosal miotomy beginning at the anal verge in the anterior middle line. The sphincter lesion was confirmed with conventional histology (hematoxylin and eosin) and immunofluorescence with 4', 6-diamidino-2-phenylindole (commonly known as DAPI), GFP and α-actin. Functional effect was assessed with basal anal manometry, prior to and after injury. After sphincter damage, 36 BDIX rats were randomized to three groups for: (1) Cell injection without repair; (2) biosuture repair; and (3) conventional suture repair and cell injection. Functional and safety studies were conducted on all the animals. Rats were sacrificed after 1, 4 or 7 d. Then, histological and immunofluorescence studies were performed on the surgical area. RESULTS: With the described protocol, biosutures had been covered with at least 820000-860000 ASCs, with 100% viability. Our studies demonstrated that some ASCs remained adhered after suture passage through the muscle. Morphological assessment showed that the rat anal anatomy is comparable with human anatomy; two sphincters are present, but the external sphincter is poorly developed. Anal sphincter pressure data showed spontaneous, consistent, rhythmic anal contractions, taking the form of "plateaus" with multiple twitches (peaks) in each pressure wave. These basal contractions were very heterogeneous; their frequency was 0.91-4.17 per min (mean 1.6980, SD 0.57698), their mean duration was 26.67 s and mean number of peaks was 12.53. Our morphological assessment revealed that with the aforementioned surgical procedure, both sphincters were completely sectioned. In manometry, the described activity disappeared and was replaced by a gentle oscillation of basal line, without a recognizable pattern. Surprisingly, these findings appeared irrespective of injury repair or not. ASCs survived in this potentially septic area for 7 d, at least. We were able to identify them in 84% of animals, mainly in the muscular section area or in the tissue between the muscular endings. ASCs formed a kind of "conglomerate" in rats treated with injections, while in the biosuture group, they wrapped the suture. ASCs were also able to migrate to the damaged zone. No relevant adverse events or mortality could be related to the stem cells in our study. We also did not find unexpected tissue growths. CONCLUSION: The proposed procedure produces a consistent sphincter lesion. Biosutures and injections are suitable for cell delivery. ASCs survive and are completely safe in this clinical setting.

Treatment of Crohn's-Related Rectovaginal Fistula With Allogeneic Expanded-Adipose Derived Stem Cells: A Phase I-IIa Clinical Trial.

: The aim of this clinical trial was to determine the safety and feasibility of expanded allogeneic adipose-derived stem cells to treat Crohn's-related rectovaginal fistula (CRRVF). We designed a phase I-II clinical trial (https://ClinicalTrials.gov, NCT00999115) to treat 10 patients with CRRVF. Patients receiving biological therapy during follow-up were excluded. Curettage was performed, and a vaginal or rectal flap was added if the surgeon considered it necessary. The therapeutic protocol included intralesional injection of 20 million stem cells in the vaginal walls (submucosal area) and fistula tract. Healing was evaluated 12 weeks later. If the fistula had not healed, a second dose of 40 million stem cells was administered. Patient follow-up was 52 weeks from last cell injection. Healing was defined as re-epithelialization of both vaginal and rectal sides and absence of vaginal drainage. Cytokines and immunological blood tests were monitored. Serious adverse events or rejection issues were not observed. Five patients were excluded because biologic drugs were required to treat a Crohn's disease flare-up during follow-up. Cytokine profiles and immunotoxicity assays showed no statistically significant alterations. Sixty percent of the nonexcluded patients achieved a complete healing. Expanded allogeneic adipose-derived stem-cell injection is a safe and feasible therapy for treating CRRVF, and the healing success rate seems promising (60%). The results of this trial encourage further exploration into this therapy. SIGNIFICANCE: This may be the first publication in which allogeneic stem cells to treat rectovaginal fistula in Crohn´s disease seem to be a feasible and safe treatment. Additional studies are necessary to confirm the efficacy profile of the allogeneic stem cells strategy in a controlled design.

Coloduodenal fistula in a patient with Crohn’s disease / Fístula coloduodenal en un paciente con enfermedad de Crohn

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Sutures enriched with adipose-derived stem cells decrease the local acute inflammation after tracheal anastomosis in a murine model.

OBJECTIVES: Local inflammatory reaction and tension are the main causes of postoperative complications after tracheal surgery. Adipose-derived stem cells (ASCs) are known to have immunomodulatory activity. The exact mechanism of this activity is not known, although it is possible that they modulate the function of different cells involved in the immune response. Little is known of their impact on acute inflammation, especially in the problematic tracheal area. We aimed to study the effect of ASCs applied locally in an animal model of tracheal resection and anastomosis. METHODS: ASCs from the subcutaneous fat of BDIX rats were infected for expression of the enhanced green fluorescent protein (eGFP) and were cultured with Polyglactin 910 sutures to obtain biosutures (ASC-coated sutures). After tracheal resection, 90 BDIX rats (syngeneic, autologous model) underwent anastomosis with biosutures (1.5 10(6) cells/biosuture [Group 1] or 0.5 10(6) cells/biosuture [Group 2]) or conventional sutures (Group 3). The animals were killed after 1, 4, 10, 30 or 60 days and histological and immunofluorescence studies were performed on the anastomotic areas. Inflammatory cell densities were graded semiquantitatively by the pathologist in a blinded fashion. RESULTS: In the early period (1 and 4 days), the biosuture groups presented an atypical pattern of acute inflammation, characterized by the almost complete absence of neutrophils, and the presence of abundant lymphocytes and plasma cells, compared with the control group (P < 0.05). Moreover, abundant macrophages/monocytes were immunolocated around blood vessels near the biosutures and between biosuture threads 1 day after anastomosis, whereas the presence of macrophages/monocytes in animals treated with conventional sutures was discrete (P < 0.05). No differences were observed in the later period. No side effects in the biosuture groups were found. CONCLUSIONS: Biosutures are a comfortable way of stem cell delivery to the surgical field without modification of the operative protocol. ASCs suppress the local acute inflammatory reaction (increased macrophage migration and decreased neutrophil infiltration) in the tracheal anastomosis and cause an early switch from acute to chronic inflammation.

Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas.

PURPOSE: In patients with perianal fistulas, administration of adult stem cells (ASCs) derived from liposuction samples has proved a promising technique in a preceding phase II trial. We aimed to extend follow-up of these patients with this retrospective study. METHOD: Patients who had received at least one dose of treatment (ASCs plus fibrin glue or fibrin glue alone) were included. Adverse events notified since the end of the phase II study were recorded. Clinical and magnetic resonance imaging (MRI) criteria were used to determine whether recurrence of the healed fistula had occurred. RESULTS: Data were available for 21 out of 24 patients treated with ASCs plus fibrin glue and 13 out of 25 patients treated with fibrin glue in the phase II study. Follow-up lasted a mean of 38.0 and 42.6 months, respectively. Two adverse events unrelated to the original treatment were reported, one in each group. There were no reports of anal incontinence associated with the procedure. Of the 12 patients treated with ASCs plus fibrin glue who were included in the retrospective follow-up in the complete closure group, only 7 remained free of recurrence. MRI was done in 31 patients. No relationship was detected between MRI results and the clinical fistula status, independent of the treatment received. CONCLUSIONS: Long-term follow-up reaffirmed the very good safety profile of the treatment. Nevertheless, a low proportion of the stem cell-treated patients with closure after the procedure remained free of recurrence after more than 3 years of follow-up.

Abdomen agudo en una paciente con cáncer de mama tratada con quimioterapia / Acute abdomen in a chemotherapy treated breast cancer patient

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Treatment of enterocutaneous fistula in Crohn's Disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion.

BACKGROUND: Expanded adipose-derived stem cells (ASC) have been shown to be effective in treating Crohn's patients with enterocutaneous fistulas. It is possible that unexpanded cells corresponding to the stromal vascular fraction (SVF) may also be effective. MATERIALS AND METHODS: A subpopulation of patients from a previous proof-of-concept phase I study with enterocutaneous fistulas received autologous expanded ASCs. The same selection criteria for inclusion were applied to patients who underwent SVF implantation to treat enterocutaneous fistulas. After tract curettage, cell suspensions (either SVF cells from lipoaspirate or expanded ASCs) were injected into the tract walls, and the fistulous tract was sealed with fibrin adhesive (with or without cells). RESULTS: In the series that received ASCs, four fistulas could be evaluated, and cure was achieved in three out of four cases. In the series that received SVF cells, four fistulas were evaluated, with cure achieved in one out of four cases. CONCLUSIONS: Although a comparison of case series cannot be considered firm evidence, a therapeutic protocol that uses expansion prior to implantation does seem to be more effective than one that uses SVF cells directly from a lipoaspirate sample.