Allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulas in Crohn's disease: A case series.

AIM: Even with optimal medical and surgical therapy, perianal fistulas in patients with Crohn's disease (CD) have low closure rates. As a new therapeutic option, administration of local mesenchymal stem cells (MSCs) has proved to be an innovative option after failure of treatment with immunosuppressive or immunomodulatory agents. The aim of this work is to share our first experience with MSC administration and demonstrate its efficacy, safety and feasibility outside a clinical trial. METHOD: A total of 11 CD patients with complex perianal fistulas with nonactive or mildly active luminal disease were treated with local injection of 120 million allogeneic adipose-derived stem cells at a tertiary hospital between February 2019 and June 2020. RESULTS: The mean age of the 11 patients was 38.3 years, 72.7% were men and 27.2% were smokers. The mean duration of fistula manifestation was 7.8 years and, except for one patient (therapy with tacrolimus), all other patients had been treated with an antitumour necrosis factor agent without fistula healing in the last 6 months. After a mean follow-up time of 41.5 weeks, 72.7% (8/11) of patients had complete closure of their fistula and three patients failed MSC treatment. Complete fistula healing could be observed 4-6 weeks postoperatively in half of the patients, while 36.5% (4/11) of patients developed a perianal abscess which had to be drained. One patient experienced cytomegalovirus viraemia 2 weeks after MSC administration and one patient developed a testicular carcinoma 16 weeks after treatment. CONCLUSION: This case series demonstrates that the efficacy and safety of darvadstrocel in the ADMIRE trial can be replicated outside a clinical trial. This new modality in the treatment of complex perianal fistulas appears to be a promising therapeutic option for a challenging patient population.

The growing discrepancy between resident training in colonic surgery and the rising number of general surgery graduates.

PURPOSE: The decrease in resident operative experience due to working-hour directives and sub-specialization within general surgery is the subject of growing debate. This study aims to examine how the numbers of colectomies used for resident training have evolved since the introduction of working-hour directives and to place these results within the context of the number of new general surgeons. METHODS: Based on the nationwide database of the Swiss association for quality management in surgery, all segmental colectomies performed at 86 centers were analyzed according to the presence or absence of residents and compared to national numbers of surgical graduates. RESULTS: Of 19,485 segmental colectomies between 2006 and 2015, 36% were used for training purposes. Residents performed 4%, junior staff surgeons 31%, senior staff surgeons 55%, and private surgeons 10%. The percentage performed by residents decreased significantly, while the annual number of graduates increased from 36 to 79. Multivariate analysis identified statutory (non-private) health insurance (OR 7.6, CI 4.6-12.5), right colon resection (OR 3.5, CI 2.5-4.7), tertiary referral center (OR 1.9, CI 1.5-2.6), emergency surgery (OR 1.7, CI 1.3-2.3), and earlier date of surgery (OR 1.1, CI 1.0-1.1) as predictors for resident involvement. CONCLUSIONS: Only a low and declining percentage of colectomies is used for resident training, despite growing numbers of trainees. These data imply that opportunities to obtain technical proficiency have diminished since the implementation of working-hour directives, indicating the need to better utilize suitable teaching opportunities, to ensure that technical proficiency remains high.

Insurance status does not affect short-term outcomes after oncological colorectal surgery in Europe, but influences the use of minimally invasive techniques: a propensity score-matched analysis.

BACKGROUND AND PURPOSE: Controversy exists whether surgical treatment is influenced by insurance status. American studies suggest higher morbidity and decreased survival in uninsured patients with colorectal cancer (CRC). It remains elusive, however, whether these findings apply to European countries with mandatory, government-driven insurance systems. We aimed to analyze whether operative techniques, quality of surgery, and complication rates differ among patients covered by statutory (SI) versus private (PI) healthcare insurance. METHODS: Based on a prospective national surgical quality database, patients undergoing elective resection for CRC during 2007-2015 were identified. A propensity score match of eligible patients with SI and PI yielded 765 patients per group. RESULTS: Hierarchical status of the operating surgeon differed substantially (p = 0.001): junior surgeons operated on > 50% of patients with SI, whereas over 80% of patients with PI were operated by senior surgeons. Minimally invasive techniques were used more frequently in patients with PI (p = 0.001) and patients with SI undergoing colonic resection showed an increased conversion rate (OR 2.44). Median duration of surgery (p = 0.001) and blood loss (p = 0.002) were higher in patients with SI; however, length of hospital stay was equal. Neither the rate of positive resection margins nor the number of resected lymph nodes differed among groups. Complications and mortality occurred with similar frequencies for patients undergoing colon (p = 0.140) and rectal (p = 0.335) resection. CONCLUSION: The use of minimally invasive techniques was favored in patients with PI; however, the quality of oncological resection was not affected by insurance status and only minor differences in perioperative complications observed.

Molecular investigation of lymph nodes in colon cancer patients using one-step nucleic acid amplification (OSNA): a new road to better staging?

BACKGROUND: A new diagnostic system, called one-step nucleic acid amplification (OSNA), has recently been designed to detect cytokeratin 19 mRNA as a surrogate for lymph node metastases. The objective of this prospective investigation was to compare the performance of OSNA with both standard hematoxylin and eosin (H&E) analysis and intensive histopathology in the detection of colon cancer lymph node metastases. METHODS: In total, 313 lymph nodes from 22 consecutive patients with stage I, II, and III colon cancer were assessed. Half of each lymph node was analyzed initially by H&E followed by an intensive histologic workup (5 levels of H&E and immunohistochemistry analyses, the gold standard for the assessment of sensitivity/specificity of OSNA), and the other half was analyzed using OSNA. RESULTS: OSNA was more sensitive in detecting small lymph node tumor infiltrates compared with H&E (11 results were OSNA positive/H&E negative). Compared with intensive histopathology, OSNA had 94.5% sensitivity, 97.6% specificity, and a concordance rate of 97.1%. OSNA resulted in an upstaging of 2 of 13 patients (15.3%) with lymph node-negative colon cancer after standard H&E examination. CONCLUSIONS: OSNA appeared to be a powerful and promising molecular tool for the detection of lymph node metastases in patients with colon cancer. OSNA had similar performance in the detection of lymph node metastases compared with intensive histopathologic investigations and appeared to be superior to standard histology with H&E. Most important, the authors concluded that OSNA may lead to a potential upstaging of >15% of patients with colon cancer.

MMP9 expression in intestinal fistula from patients with fistulizing CD and from human xenograft mouse model.

Fistula treatment represents a major unmet medical need in the therapy of Crohn's disease (CD). Current medical therapies, such as anti-TNF antibody treatments, are often insufficient and do not achieve permanent fistula closure. Previously published data point toward a critical role for metalloproteinase-9 (MMP-9)/gelatinase B in fistula pathogenesis. The aim of this project was to investigate in detail MMP-9 expression in different fistula types and to confirm that MMP-9 is a potential target for fistula therapy in CD patients.Immunohistochemistry for total and active MMP-9, Cytokeratin 8 (CK-8) and co-staining of active MMP-9/CK-8 was performed in specimen derived from perianal fistulas, entero-enteric fistulas and fistulas from patients not responding to anti-TNF therapy. In addition, fistulas from the xenograft mouse model (anti-TNF treated or untreated) were analyzed.Total and active MMP-9 protein was detectable in cells lining the tracts of perianal and entero-enteric fistulas. Of note, total and active MMP-9 was also expressed in fistulas of CD patients non-responding to anti-TNF treatment. Interestingly, we detected considerable co-staining of active MMP-9 and CK-8 in particular in cells lining the fistula tract and in transitional cells around the fistulas. Furthermore, total and active MMP-9 are detectable in both anti-TNF treated and untreated xenograft fistulas.Taken together, our data suggest that MMP-9 is involved in fistula pathogenesis in CD patients, in fistulas of different origins and particularly in patients non-responding to anti-TNF therapy. Our xenograft fistula model is suitable for in vivo studies investigating a possible therapeutic role for MMP-9 targeting as fistula therapy.

Outcome of open inguinal hernia repair using sutureless self-gripping mesh - a retrospective single cohort study.

BACKGROUND: Neurological disturbances after open inguinal hernia repair affect approximately one in ten patients. Sutureless, self-gripping meshes were developed with the aim of reducing postoperative neurological disturbances or neuralgia. This study assessed short- and long-term outcomes after open inguinal hernia repair using a self-gripping light-weight mesh in a peripheral teaching hospital. METHODS: Patients with uni- or bilateral inguinal hernia were included in this study. Open inguinal hernia repair was performed according to the Lichtenstein technique with a self-gripping, lightweight macroporous mesh. Postoperative follow-up was at 6 weeks after surgery and any long-term complications or recurrences were recorded up to 5 years postoperatively. RESULTS: The median follow up time for all patients was 5–6 years and the median operation time was 40.0 minutes (inter quartile range 25.0–55.8). Of the 162 included patients, the mean numeric rating scale for pain (0 = no pain, 10 = excruciating pain) before hospital discharge was 2.7 (standard deviation [SD] 2.6) and 1.1 (SD 1.1) at 6 weeks postoperatively. The overall incidence of neurological disturbances at 6 weeks postoperatively was 11% when surgery was performed by the chief of surgery and 40% when it was performed by a senior consultant, 49% by chief-residents and 47% by supervised residents (p = 0.005). Patients with neurological disturbances were younger than asymptomatic patients (age 50, SD 15 vs 62, SD 17, p <0.001). The 1-, 3- and 5-year recurrence rates were 1%, 2% and 3%, respectively. CONCLUSIONS: This study shows that open inguinal hernia repair using a self-gripping mesh is feasible, with a short operation time and low hernia recurrence rates in a peripheral teaching hospital. However, significant differences in neurological disturbances dependent on the surgeons experience were identified. Especially younger patients should be operated on by an experienced surgeon to reduce neurological disturbances and neuralgia.

Colorectal cancer of the young displays distinct features of aggressive tumor biology: A single-center cohort study.

BACKGROUND: In recent years, a decrease in incidence and mortality of colorectal cancer (CRC) has been observed in developed nations, presumably through public disease awareness and increased screening efforts. However, a rising incidence of CRC in young patients below the age of 50 years has been reported in several studies. AIM: To study tumor biology in CRC patients below 50 years of age. METHODS: All patients with CRC were prospectively enrolled in our single-center oncologic database from January 2013 to December 2018 and were grouped and analyzed according to age (≥ 50 and < 50 years). Clinical as well as histopathological features were analyzed and compared. The study was approved by the local Ethics Committee. Fisher's exact test or t-test was used to test for differences between the groups, as appropriate. All statistical analysis was performed with IBM SPSS software Version 25 (SPSS Inc, Armonk, NY, United States) and with R-Studio using R Version 3.4.1 (RStudio, Boston, MA, United States). RESULTS: Seventeen percent of the 411 patients were younger than 50 years. Young patients were more often diagnosed with locally advanced T4-tumors and lymph node metastases (36.6% and 62% vs 17.7% and 42%; P < 0.01). In addition, a higher frequency of poorly differentiated (G3) tumors (40% vs 22.4% P < 0.05) was observed. More than every second patient below 40 years of age (51.8%) had distant metastases at diagnosis with a significant higher rate ring of signet cell differentiation compared to patients ≥ 50 years (14.8%, P < 0.05). Mutational status (KRAS, NRAS, BRAF, MSI) as well as selected behavioral risk factors showed no significant differences. CONCLUSION: Distinct histopathologic features of increased biologic aggressiveness are found in patients with CRC of young-onset. Those patients present more frequently with more advanced tumor stages compared to older patients. Features of aggressive tumor biology underscore the need for earlier uptake of routine screening measures.

Perianal fistulodesis - A pilot study of a novel minimally invasive surgical and medical approach for closure of perianal fistulae.

BACKGROUND: Perianal fistulae strongly impact on quality of life of affected patients. AIM: To challenge and novel minimally invasive treatment options are needed. METHODS: Patients with Crohn's disease (CD) in remission and patients without inflammatory bowel disease (non-IBD patients) were treated with fistulodesis, a method including curettage of fistula tract, flushing with acetylcysteine and doxycycline, Z-suture of the inner fistula opening, fibrin glue instillation, and Z-suture of the outer fistula opening followed by post-operative antibiotic prophylaxis with ciprofloxacin and metronidazole for two weeks. Patients with a maximum of 2 fistula openings and no clinical or endosonographic signs of a complicated fistula were included. The primary end point was fistula healing, defined as macroscopic and clinical fistula closure and lack of patient reported fistula symptoms at 24 wk. RESULTS: Fistulodesis was performed in 17 non-IBD and 3 CD patients, with a total of 22 fistulae. After 24 wk, all fistulae were healed in 4 non-IBD and 2 CD patients (overall 30%) and fistula remained closed until the end of follow-up at 10-25 mo. In a secondary per-fistula analysis, 7 out of 22 fistulae (32%) were closed. Perianal disease activity index (PDAI) improved in patients with fistula healing. Low PDAI was associated with favorable outcome (P = 0.0013). No serious adverse events were observed. CONCLUSION: Fistulodesis is feasible and safe for perianal fistula closure. Overall success rates is at 30% comparable to other similar techniques. A trend for better outcomes in patients with low PDAI needs to be confirmed.