Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study.

BACKGROUND AIMS: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS: We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS: Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS: Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.

Cecum to pelvis technique: a simple and autologous solution to prevent postoperative complications in pelvic surgery.

BACKGROUND: Empty Pelvis Syndrome, subsequent to the removal of pelvic organs, results in the descent of the small bowel into an inflamed pelvic cavity, leading to the formation of adhesions and subsequent small bowel obstruction. However, no effective measures have been previously described. OBJECTIVE: Describe a simple and autologous solution to prevent "Empty Pelvis Syndrome," small bowel obstruction, and adhesions by utilizing the cecum to occlude the pelvis. DESIGN: Mobilization of the right colon to lower the cecum into the pelvic cavity to occlude the superior pelvic ring to some degree and changing the direction of the terminal ileum. SETTINGS: Hospital Universitario Fundación Jiménez Díaz, Department of General Surgery, Colorectal Service. PATIENTS: Eight anonymized patients were included in this study, each with varying colorectal pathologies. Patients were above 18 years old. MAIN OUTCOME MEASURES: Percent of blockage of the superior pelvic ring produced by the descended cecum recorded in percentage; the amount of small intestine descended past the superior pelvic ring recorded in cm. RESULTS: The mobilization of the cecum achieved partial occlusion of the superior pelvic ring. The descent of the small bowel beyond this landmark ranged from 0 to 4.9 cm. LIMITATIONS: Given the small number of patients included in this study, these results cannot be generalized to the whole of the population. A bladder emptying protocol prior to CT scans was not implemented, resulting in variations in measurements among patients. CONCLUSION: The cecum-to-pelvis technique is a simple method that can serve as an autologous solution to EPS (enteropelvic fistula) and help reduce postoperative complications such as SBO (small bowel obstruction) and adhesions. It is not essential to completely occlude the superior pelvic ring to achieve successful outcomes.

Study of the Effect of Wild-Type and Transiently Expressing CXCR4 and IL-10 Mesenchymal Stromal Cells in a Mouse Model of Peritonitis.

Sepsis due to peritonitis is a process associated with an inflammatory state. Mesenchymal stromal cells (MSCs) modulate the immune system due to the paracrine factors released and may be a therapeutic alternative. Three treatment groups were developed in a murine model of peritonitis to verify the effect of human adipose mesenchymal stem cell (hASCs). Additionally, a temporary modification was carried out on them to improve their arrival in inflamed tissues (CXCR4), as well as their anti-inflammatory activity (IL-10). The capacity to reduce systemic inflammation was studied using a local application (peritoneal injection) as a treatment route. Comparisons involving the therapeutic effect of wild-type ASCs and ASCs transiently expressing CXCR4 and IL-10 were carried out with the aim of generating an improved anti-inflammatory response for sepsis in addition to standard antibiotic treatment. However, under the experimental conditions used in these studies, no differences were found between both groups with ASCs. The peritoneal administration of hASCs or genetically modified hASCs constitutes an efficient and safe therapy in our model of mouse peritonitis.

Evolution of perioperative quality of life in patients under enhanced recovery after surgery care in colorectal cancer.

BACKGROUND: the Enhanced Recovery After Surgery (ERAS) protocols aim to improve postoperative outcomes by obtaining a functional rehabilitation after surgery. The purpose of this study was to evaluate the impact of ERAS on the quality of life (QOL) of patients undergoing colorectal cancer surgeries. METHODS: a cohort observational study was designed of patients with colorectal cancer undergoing elective surgeries during a one-year period. Patients were included when the ERAS protocol was fully achieved for all the interventions, including the expected hospital discharge day. Patient reported outcomes (PROs) were evaluated by the EORTC QLQ-C30 and the QLQ-CR29 questionnaires on three different occasions: baseline before surgery and on postoperative days 7 and 30. RESULTS: the study included 40 patients who completed QOL evaluations with a mean age of 70 ± 11 years. There were no statistical differences between preoperative and postoperative QOL scores. By subgroups of QOL items, a significant decrease was observed in physical activity and role functioning when comparing preoperative vs postoperative status, whereas the cognitive, social and emotional functioning scales were similar or improved over time. CONCLUSIONS: in our experience, surgery under ERAS protocols did not have an impact on decreasing global QOL in patients undergoing elective colorectal cancer surgery. The use of ERAS protocols in colorectal surgery achieves a positive influence, not only by decreasing surgical-related complications but also in terms of functional recovery, by decreasing the negative effects of surgery on patient QOL.

Cell therapy with autologous mesenchymal stromal cells in post-traumatic syringomyelia.

BACKGROUND AIMS: Recently, clinical studies show that cell therapy with mesenchymal stromal cells (MSCs) improves the sequelae chronically established in paraplegic patients, being necessary to know which of them can obtain better benefit. METHODS: We present here a phase 2 clinical trial that includes six paraplegic patients with post-traumatic syringomyelia who received 300 million MSCs inside the syrinx and who were followed up for 6 months. Clinical scales, urodynamic, neurophysiological, magnetic resonance (MR) and studies of ano-rectal manometry were performed to assess possible improvements. RESULTS: In all the cases, MR at the end of the study showed a clear reduction of the syrinx, and, at this time, signs of improvement in the urodynamic studies were found. Moreover, four patients improved in ano-rectal manometry. Four patients improved in neurophysiological studies, with signs of improvement in evoked potentials in three patients. In the American Spinal Injury Association (ASIA) assessment, only two patients improved in sensitivity, but clinical improvement in neurogenic bowel dysfunction was observed in four patients and three patients described improvement in bladder dysfunction. Spasms reduced in two of the five patients who had them previous to cell therapy, and spasticity was improved in the other two patients. Three patients had neuropathic pain before treatment, and it was reduced or disappeared completely during the study. Only two adverse events ocurred, without relation to the cell therapy. CONCLUSIONS: Cell therapy can be considered as a new alternative to the treatment of post-traumatic syringomyelia, achieving reduction of syrinx and clinical improvements in individual patients.

Short-term outcomes and benefits of ERAS program in elderly patients undergoing colorectal surgery: a case-matched study compared to conventional care.

PURPOSE: The aim of the study was to evaluate the benefits of implementing Enhanced Recovery After Surgery (ERAS) protocols in elderly patients undergoing elective colorectal surgery. METHODS: A retrospective non-randomized cohort study was conducted from September 2012 to December 2016. We included patients ≥ 70 years undergoing elective colorectal surgery. Outcome measures, compliance with interventions, and postoperative complications of patients treated under ERAS were case-matched (based on gender, age, type of surgery, and the presence/absence of a temporal stoma) to a retrospective group of patients ≥ 70 years treated under conventional care. RESULTS: A total of 312 patients (156 ERAS vs. 156 non-ERAS) were included in the study. The ERAS group had a significant reduction of grade III/IV Dindo-Clavien's postoperative complications when compared with conventional care. ERAS had a positive effect in reducing anastomotic leakage (14.7% non-ERAS vs. 9%) and postoperative mortality (11.5% non-ERAS vs. 1.9% ERAS; p = 0.001). A reduction of 2 days in length of hospital stay was achieved after implementing ERAS (8 (6.75) vs. 6 (5.25); p < 0.0001), while readmission rates remained unaffected. The average of global compliance (GC) with all ERAS interventions was 42%. GC was significantly lower in patients with permanent/temporary stomas and in patients in whom an open approach was performed. CONCLUSION: In our experience, ERAS should be implemented without reservations in elderly patients expecting the same goals and benefits as with other age groups. Barriers in achieving a high compliance rate are common and will require a great effort in patient's education, an intensive perioperative care, and sometimes a change in the surgeons' practice.

Enhanced recovery care after colorectal surgery in elderly patients. Compliance and outcomes of a multicenter study from the Spanish working group on ERAS.

PURPOSE: ERAS (enhanced recovery after surgery) programs have proven to reduce morbidity and hospital stay in colorectal surgery. However, the feasibility of these programs in elderly patients has been questioned. The aim of this study is to assess the implementation and outcomes of an ERAS program for colorectal cancer in elderly patients. METHODS: This is a multicenter observational study of a cohort of elderly patients undergoing colorectal surgery within an ERAS program. A total of 188 consecutive patients over 70 years who underwent elective colorectal surgery within an ERAS program at three institutions during a 2-year period were included. The compliance with the ERAS protocol interventions was measure. Complications were evaluated according to Clavien-Dindo classification. Data on length of stay and readmission rates were analyzed. RESULTS: Early intake and early mobilization were the most successfully carried out interventions. There was a global compliance rate of 56 % of patients for whom compliance was achieved with all measured interventions. The median hospital length of stay was 6 days. Almost 60 % of patients had no complications, 24 % had minor complications while 13 % had major complications; of them, 8 % patients were reoperated. The readmission rate was 6.4 %. CONCLUSIONS: ERAS after colorectal surgery in elderly patients presents as safe and feasible based on good reported outcomes of compliance rates, complications, readmissions, and needs for reoperation.

KRAS G12V Mutation Detection by Droplet Digital PCR in Circulating Cell-Free DNA of Colorectal Cancer Patients.

KRAS mutations are responsible for resistance to anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer patients. These mutations sometimes appear once treatment has started. Detection of KRAS mutations in circulating cell-free DNA in plasma ("liquid biopsy") by droplet digital PCR (ddPCR) has emerged as a very sensitive and promising alternative to serial biopsies for disease monitoring. In this study, KRAS G12V mutation was analyzed by ddPCR in plasma DNA from 10 colorectal cancer patients and compared to six healthy donors. The percentage of KRAS G12V mutation relative to wild-type sequences in tumor-derived DNA was also determined. KRAS G12V mutation circulating in plasma was detected in 9 of 10 colorectal cancer patients whose tumors were also mutated. Colorectal cancer patients had 35.62 copies of mutated KRAS/mL plasma, whereas in healthy controls only residual copies were found (0.62 copies/mL, p = 0.0066). Interestingly, patients with metastatic disease showed a significantly higher number of mutant copies than M0 patients (126.25 versus 9.37 copies/mL, p = 0.0286). Wild-type KRAS was also significantly elevated in colorectal cancer patients compared to healthy controls (7718.8 versus 481.25 copies/mL, p = 0.0002). In conclusion, KRAS G12V mutation is detectable in plasma of colorectal cancer patients by ddPCR and could be used as a non-invasive biomarker.

Prevalence of abnormal anal cytology and high-grade squamous intraepithelial lesions among a cohort of HIV-infected men who have sex with men.

BACKGROUND: The incidence of anal cancer among HIV-infected patients is higher than that in other populations. Anal high-grade squamous intraepithelial lesions are considered precursors to invasive squamous-cell carcinomas and are strongly associated to high-risk human papillomavirus infection. OBJECTIVE: The aim of this study is to determine the prevalence of anal high-grade squamous intraepithelial lesions through screening based on cytology and high-resolution anoscopy with biopsy in a cohort of HIV-infected men who have sex with men. DESIGN: This investigation is an observational cross-sectional cohort study. SETTING: The study was conducted in the HIV unit of a tertiary hospital in Spain. PATIENTS: Three hundred HIV-infected men who have sex with men participated. Physical examination led to a diagnosis of perianal squamous-cell carcinoma and high-grade squamous intraepithelial lesions in 2 patients who were then excluded. INTERVENTIONS: Anal liquid cytology was performed. Patients with cytological abnormalities underwent high-resolution anoscopy and biopsy. MAIN OUTCOME MEASURE: The primary outcome measured was biopsy-proven high-grade squamous intraepithelial lesions. RESULTS: The median age was 41 ± 10.5 years. The mean and nadir CD4 cell counts were 651 ± 205 cells/mm(3) (interquartile range, 438-800) and 273 ± 205 cells/mm(3) (interquartile range, 131-362). High-risk human papillomavirus was detected in 80.9% of patients, and human papillomavirus 16 was detected in 35.9% of patients. The mean number of human papillomavirus genotypes was 4.6 ± 2.9 (CI, 2-6). Anal cytology was abnormal in 40.9% of patients (n = 122/298; interquartile range, 35.4%-46.6%). High-resolution anoscopy and biopsies were performed in 119 patients. The results of histological analyses were as follows: normal, 7.7% (n = 23); condyloma, 4.3% (n = 13); anal intraepithelial neoplasia 1, 5.7% (n = 17); anal intraepithelial neoplasia 2, 14% (n = 42); and anal intraepithelial neoplasia 3, 8% (n = 24). The overall prevalence of high-grade squamous intraepithelial lesions among patients with abnormal cytology was 54% (95% CI, 45.1%-62.8%). A diagnosis of high-grade squamous intraepithelial lesions was associated with human papillomavirus 16 and human papillomavirus 51 infection, and with detection of a higher number of human papillomavirus genotypes. LIMITATIONS: High-resolution anoscopy was only performed in patients with abnormal cytology. CONCLUSIONS: The prevalence of high-risk human papillomavirus infection and high-grade squamous intraepithelial lesions is high in our cohort. Physical examination enabled straightforward diagnosis of perianal high-grade squamous intraepithelial lesions and squamous-cell carcinoma in 2 patients.

Under the Hood: Understanding the Features of Mucin in Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant growth characterized by the production of mucin and the potential for peritoneal relapse. This study aimed to investigate the immunohistochemical and biological characteristics of mucin in patients with cellular and acellular PMP. We prospectively analyzed mucin specimens obtained from our patient cohort and described the composition and type of mucin present in each sample. A metagenomic analysis of the samples was performed to investigate the bacterial composition of the PMP microbiome. Secreted mucins 2 and 5AC and membrane-associated mucin-1 were the primary components of mucin in both cellular and acellular tumor specimens. The metagenomic study revealed a predominance of the phylum Proteobacteria and the genus Pseudomonas. Notably, Pseudomonas plecoglossicida, a species not previously reported in the human microbiome, was found to be the most abundant organism in the mucin of pseudomyxoma peritonei. Our findings suggest that the presence of MUC-2 and mucin colonization by Pseudomonas are characteristic features of both cellular and acellular disease. These results may have significant implications for the diagnosis and treatment of this rare entity.

Understanding CAR T cell therapy and its role in ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

Ovarian cancer is the seventh most common cancer worldwide in women and the most lethal gynecologic malignancy due to the lack of accurate screening tools for early detection and late symptom onset. The absence of early-onset symptoms often delays diagnosis until the disease has progressed to advanced stages, frequently when there is peritoneal involvement. Although ovarian cancer is a heterogeneous malignancy with different histopathologic types, treatment for advanced tumors is usually based on chemotherapy and cytoreduction surgery. CAR T cells have shown promise for the treatment of hematological malignancies, though their role in treating solid tumors remains unclear. Outcomes are less favorable owing to the low capacity of CAR T cells to migrate to the tumor site, the influence of the protective tumor microenvironment, and the heterogeneity of surface antigens on tumor cells. Despite these results, CAR T cells have been proposed as a treatment approach for peritoneal carcinomatosis from colorectal and gastric origin. Local intraperitoneal administration of CAR T cells has been found to be superior to systemic administration, as this route is associated with increased tumor reduction, a more durable effect, protection against local relapse and distant metastases, and fewer systemic adverse effects. In this article we review the application of CAR T cells for the treatment of ovarian cancer and peritoneal carcinomatosis from ovarian cancer.

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.

The Role of Shared Decision-Making in Personalised Medicine: Opening the Debate.

Surgeons and cancer patients are starting to open the debate on how personalised medicine could use shared decision-making (SDM) to balance the personal and clinical components and thus improve the quality and value of care. Personalised precision medicine (PPM) has traditionally focused on the use of genomic information when prescribing treatments, which are usually pharmaceutical. However, the knowledge base is considerably scarcer in terms of how clinicians can individualise the information they provide patients about the consequences of different treatments, and in doing so involve them in the decision-making process. To achieve this, the ethical implications of SDM must be addressed from both sides. This paper explores the medical characteristics, the SDM implications in severe and fragile patients, potential risks, and observed benefits within this healthcare approach through four clinical cases. Findings shed light on current needs for clinician and patient training and tools related to SDM in PPM, and also remarks on the way in which this shift in healthcare settings is taking place to include the human component together with the biological and technological advances when designing care processes in colorectal cancer.

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.

Analysis of Septin 9 Gene Hypermethylation as Follow-Up Biomarker of Colorectal Cancer Patients after Curative Surgery.

BACKGROUND: The Septin 9 test analyzes the methylation status of the SEPT9 gene, which appears to be hypermethylated in patients with colorectal cancer (CRC). This has been validated as a colorectal cancer screening test. Due to the high sensitivity and specificity found, the justification was to use it as a biomarker tool for monitoring minimal residual disease after radical surgery and recurrence. METHODS: A prospective study was carried out at the Fundación Jiménez Díaz University Hospital extracting peripheral blood from 28 patients and 4 healthy donors. Free circulating DNA was obtained and subsequently a PCR reaction to quantify the number of methylated genes. Samples were obtained preoperatively and postoperatively at five to seven days, one and three months after surgery. RESULTS: A total of 32 preoperative samples were analyzed. The sensitivity of the test to detect CRC was 55.6% and specificity was 100%. There were 22 postsurgical samples obtained at 5-7 days after surgery, the sensitivity to detect tumor recurrences was 100% and specificity was 75%. There were 21 samples analyzed 1 month after surgery exhibiting a sensitivity and specificity of 100% and 94.7%, respectively. At 3 months, 31 postsurgical samples were analyzed and the sensitivity and specificity were 66.7% and 80%. CONCLUSIONS: Detection of methylation of Septin 9 gene in circulating plasma DNA, obtained from a peripheral blood sample, may be a useful, non-invasive and effective method for detecting minimal residual disease and could therefore predict CRC tumor recurrences. The optimal time in our series to obtain the best prediction results based on Septin 9 methylation levels was one month after surgery. Despite these considerable findings, a study with more patients is necessary to obtain more robust conclusions.