Excisional biopsy of perforated gastric ulcer: mandatory or potentially harmful?

PURPOSE: This study aimed to evaluate the morbidity associated with excisional biopsy in patients with spontaneous gastric perforation. METHODS: A retrospective, single-center, observational study was performed. All consecutive patients with spontaneous gastric perforation who underwent surgical therapy were included. Outcomes were assessed concerning the performance of excisional biopsy. RESULTS: A total of 135 adult patients were enrolled. Of these, 110 (81.5%) patients underwent excisional biopsy, while 17 (12.6%) did not. The remaining eight (5.9%) patients who underwent gastric resection were excluded from the analysis. Patients undergoing excisional biopsy developed significantly higher rates of postoperative complications (p = 0.007) and experienced more severe complications according to the Clavien-Dindo classification, particularly type III and above (p = 0.017). However, no significant differences were observed regarding in-hospital mortality, reoperation, suture dehiscence, or length of hospital stay. CONCLUSION: Excisional biopsy for gastric perforation has been shown to be associated with increased morbidity. Surgical closure followed by early endoscopic biopsy may be a superior approach for gastric perforation management to rule out malignancy.

DIALAPP: a prospective validation of a new diagnostic algorithm for acute appendicitis.

PURPOSE: The management of patients with suspected appendicitis remains a challenge in daily clinical practice, and the optimal management algorithm is still being debated. Negative appendectomy rates (NAR) continue to range between 10 and 15%. This prospective study evaluated the accuracy of a diagnostic pathway in acute appendicitis using clinical risk stratification (Alvarado score), routine ultrasonography, gynecology consult for females, and selected CT after clinical reassessment. METHODS: Patients presenting with suspected appendicitis between November 2015 and September 2017 from age 18 years and above were included. Decision-making followed a clear management pathway. Patients were followed up for 6 months after discharge. The hypothesis was that the algorithm can reduce the NAR to a value of under 10%. RESULTS: A total of 183 patients were included. In 65 of 69 appendectomies, acute appendicitis was confirmed by histopathology, corresponding to a NAR of 5.8%. Notably, all 4 NAR appendectomies had other pathologies of the appendix. The perforation rate was 24.6%. Only 36 patients (19.7%) received a CT scan. The follow-up rate after 30 days achieved 69%, including no patients with missed appendicitis. The sensitivity and specificity of the diagnostic pathway was 100% and 96.6%, respectively. The potential saving in costs can be as much as 19.8 million €/100,000 cases presenting with the suspicion of appendicitis. CONCLUSION: The risk-stratified diagnostic algorithm yields a high diagnostic accuracy for patients with suspicion of appendicitis. Its implementation can safely reduce the NAR, simultaneously minimizing the use of CT scans and optimizing healthcare-related costs in the treatment of acute appendicitis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02627781 (December 2015).

Appendicitis during the COVID-19 lockdown: results of a multicenter analysis in Germany.

PURPOSE: The COVID-19 pandemic has transformed medical care worldwide. General surgery has been affected in elective procedures, yet the implications for emergency surgery are unclear. The current study analyzes the effect of the COVID-19 lockdown in spring 2020 on appendicitis treatment in Germany. METHODS: Hospitals that provided emergency surgical care during the COVID-19 lockdown were invited to participate. All patients diagnosed with appendicitis during the lockdown period (10 weeks) and, as a comparison group, patients from the same period in 2019 were analyzed. Clinical and laboratory parameters, intraoperative and pathological findings, and postoperative outcomes were analyzed. RESULTS: A total of 1915 appendectomies from 41 surgical departments in Germany were included. Compared to 2019 the number of appendectomies decreased by 13.5% (1.027 to 888, p=0.003) during the first 2020 COVID-19 lockdown. The delay between the onset of symptoms and medical consultation was substantially longer in the COVID-19 risk group and for the elderly. The rate of complicated appendicitis increased (58.2 to 64.4%), while the absolute number of complicated appendicitis decreased from 597 to 569, (p=0.012). The rate of negative appendectomies decreased significantly (6.7 to 4.6%; p=0.012). Overall postoperative morbidity and mortality, however, did not change. CONCLUSION: The COVID-19 lockdown had significant effects on abdominal emergency surgery in Germany. These seem to result from a stricter selection and a longer waiting time between the onset of symptoms and medical consultation for risk patients. However, the standard of emergency surgical care in Germany was maintained.

Bad bacteria in acute appendicitis: rare but relevant.

PURPOSE: Bacterial infections are a factor for morbidity in patients with acute appendicitis (AA). The spreading of multidrug-resistant (MDR) bacteria is a significant problem in surgery, and the most relevant MDR pathogens are summarized as Enterobacteriaceae, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococci (ESKAPE) bacteria. Data regarding the species and distribution of bacteria in AA are available, but information about the resistances and their relevance is deficient. METHODS: In this retrospective study, we analyzed microbiological swabs of patients with AA. The outcome parameters of patients after laparoscopic appendectomy were analyzed against microbiological results, including antibiotic resistance testing. Positive swabs were compared with bacteria cultivated after alternative abdominal emergency surgery (AES). RESULTS: In total, 584 patients with AA were included and had a mean age of 35.5 years. In 216 patients (36.9%), a swab was taken, and in 128 (59.3%) swabs, bacteria could be cultivated. The most frequent organisms were Escherichia coli, Bacteroides species, and Pseudomonas. In 9.4% of the positive AA swabs, MDR germs were cultivated, and all of them were ESKAPE pathogens. Patients with MDR bacteria in AA suffered more infectious complications (p = 0.006) and needed longer hospitalizations (p < 0.009). In AES, aside from appendicitis, a different spectrum containing more MDR bacteria was cultivated (5.9 vs. 20.9%; p < 0.0001). CONCLUSIONS: Although they occur less frequently in appendectomy compared to emergency surgeries for other abdominal diseases, MDR bacteria are traceable in this common disease and contribute to additional morbidity.

Selective AKT Inhibition by MK-2206 Represses Colorectal Cancer-Initiating Stem Cells.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences. METHODS: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo. RESULTS: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206. CONCLUSION: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.

Education in thyroid surgery: a matched-pair analysis comparing residents and board-certified surgeons.

PURPOSE: Resident participation in operative procedures is mandatory in educational residency programs but remains controversial, especially in the context of patient safety. This study compared the surgical quality and outcomes of thyroidectomies performed by surgical residents (RESs) and board-certified surgeons (BCSs). METHODS: This retrospective matched-pair study included patients undergoing thyroidectomies for multinodular goiter, Grave's disease and early-stage thyroid cancer that were performed by a RES with BCS supervision between 2006 and 2014. The intraoperative and postoperative course, complication rates and handling of the recurrent laryngeal nerve (RLN) and parathyroid glands were analyzed. RESULTS: In total, 112 thyroidectomies that were performed by a RES fulfilled the inclusion criteria and were matched 1:1 with BCS patients. We included 88 hemithyroidectomies, 80 subtotal thyroidectomies and 56 total thyroidectomies. No significant differences in the handling of the RLN or parathyroid glands, the rates of postoperative RLN palsies or the rates of hypocalcaemia were found. No intraoperative complications led to the replacement of the RES as the surgeon-in-charge. Three RES and two BCS patients experienced postoperative haemorrhages (p = 0.205), and three surgical site infections (p = 1.000) occurred in each group. The mean operative time and the length of stay did not differ significantly between the two groups. CONCLUSIONS: Major aspects of patient safety in thyroid surgery are not affected by resident participation. Thyroidectomies performed by RES are not significantly longer and reveal no differences in length of stay or complication rates. The economic burden of resident involvement is modest.

The clinical relevance of the Fong and the Nordlinger scores in the era of effective neoadjuvant chemotherapy for colorectal liver metastasis.

PURPOSE: The clinical risk scores (CRSs) of Fong and Nordlinger are used to predict the outcome of patients with colorectal liver metastases (CRLMs). This study investigated whether CRSs could predict the overall survival of patients with CRLM treated with or without neoadjuvant chemotherapy prior to resection. METHODS: Patients with CRLM undergoing liver resection were analyzed retrospectively. The primary outcome measure was overall survival with vs. without neoadjuvant chemotherapy. RESULTS: Between August 2002 and October 2011, 300 patients underwent liver resection for CRLMs at a large university hospital in Germany. Group A comprised 117 patients who received neoadjuvant chemotherapy and group B comprised 71 patients who did not. The Fong score predicted overall survival for patients who did not receive chemotherapy (p = 0.02), but not for those treated with chemotherapy (p = 0.69). The Nordlinger score was not predictive for either of the groups (p = 0.71 vs. p = 0.08 for groups A and B, respectively). Subgroup analysis of the Nordlinger score identified better overall survival in the high-risk group treated with chemotherapy (p = 0.05). Multivariate analysis identified a resection margin of <1 cm [OR 0.622 (95% CI: 0.17-2.31); p = 0.044], age >60 years [OR 0.535 (95% CI: 0.16-1.77); p = 0.022] and number of metastases >4 [OR 0.189 (95% CI: 0.06-0.61); p = 0.018] as independent prognostic factors for overall survival. CONCLUSION: Thus, CRSs were not reliable prognostic tools for patients treated with neoadjuvant chemotherapy before liver resection in this analysis.

Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway.

Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells. TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling. TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

[Digital applications in prehabilitation before major visceral surgery procedures]. / Digitale Applikationen in der Prähabilitation vor großen viszeralchirurgischen Operationen.

BACKGROUND: Prehabilitation is of becoming of growing interest in the medical specialist societies, especially before major surgical procedures in older and frail patients. The body of evidence in steadily growing. OBJECTIVES: Are there good digital solutions for a remote prehabilitation program at home? METHODS: Narrative review of the evidence and current study activities in analogous and digital prehabilitation. RESULTS: Prehabilitation is becoming increasingly more important in the optimal preparation of patients before major surgical procedures. With the help of tailored programs patients can be improved and the risk of complications can be significantly lowered. With an optimal selection, this is not associated with a deterioration of the prognosis for patients with cancer during the intervention lasting for 3-6 weeks. There is still a lack of results and good evidence from well-designed trials for digital solutions. CONCLUSION: Prehabilitation can be safely implemented in the preparation of patients before major surgical procedures. Digital solutions are currently being developed and tested and could possibly increase the acceptance in the currently intensifying resource shortages.

Transglutaminase 2 is associated with adverse colorectal cancer survival and represents a therapeutic target.

Molecular markers for predicting prognosis of colorectal cancer (CRC) patients are urgently needed for effective disease management. We reported previously that the multifunctional enzyme Transglutaminase 2 (TGM2) is essential for CRC cell survival by inactivation of the tumor suppressor p53. Based on these data, we determined the clinical relevance of TGM2 expression and explored its potential as prognostic marker and therapeutic target in CRC. We profiled TGM2 protein expression in tumor samples of 279 clinically characterized CRC patients using immunohistochemical staining. TGM2 expression was upregulated in matched tumor samples in comparison to normal tissue. A strong TGM2 expression was associated with advanced tumor stages and predicted worse prognosis regarding progression-free and overall-survival, even at early stages. Inhibition of TGM2 in CRC cell lines by the inhibitors LDN27219 and Tyrphostin resulted in a strong reduction of cancer cell proliferation and tumorsphere formation in vitro by induction of p53-mediated apoptosis. Primary patient-derived tumorsphere formation was significantly reduced by inhibition of TGM2. Treatment of mice with TGM2 inhibitors exhibited a significant deceleration of tumor progression. Our data indicate that high TGM2 expression in CRC is associated with worse prognosis and may serve as a therapeutic target in CRC patients with strong TGM2 expression.

A toolbox for a structured risk-based prehabilitation program in major surgical oncology.

Prehabilitation is a multimodal concept to improve functional capability prior to surgery, so that the patients' resilience is strengthened to withstand any peri- and postoperative comorbidity. It covers physical activities, nutrition, and psychosocial wellbeing. The literature is heterogeneous in outcomes and definitions. In this scoping review, class 1 and 2 evidence was included to identify seven main aspects of prehabilitation for the treatment pathway: (i) risk assessment, (ii) FITT (frequency, interventions, time, type of exercise) principles of prehabilitation exercise, (iii) outcome measures, (iv) nutrition, (v) patient blood management, (vi) mental wellbeing, and (vii) economic potential. Recommendations include the risk of tumor progression due to delay of surgery. Patients undergoing prehabilitation should perceive risk assessment by structured, quantifiable, and validated tools like Risk Analysis Index, Charlson Comorbidity Index (CCI), American Society of Anesthesiology Score, or Eastern Co-operative Oncology Group scoring. Assessments should be repeated to quantify its effects. The most common types of exercise include breathing exercises and moderate- to high-intensity interval protocols. The program should have a duration of 3-6 weeks with 3-4 exercises per week that take 30-60 min. The 6-Minute Walking Testing is a valid and resource-saving tool to assess changes in aerobic capacity. Long-term assessment should include standardized outcome measurements (overall survival, 90-day survival, Dindo-Clavien/CCI®) to monitor the potential of up to 50% less morbidity. Finally, individual cost-revenue assessment can help assess health economics, confirming the hypothetic saving of $8 for treatment for $1 spent for prehabilitation. These recommendations should serve as a toolbox to generate hypotheses, discussion, and systematic approaches to develop clinical prehabilitation standards.

Significantly high expression of platelet-derived growth factor (PDGF) in benign nodules of the thyroid: relevance in the development of goitre recurrence?

PURPOSE: Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation and influences the development of tumors. The role of PDGF in benign thyroid diseases is presently not well-determined. The purpose is to evaluate PDGF isoforms and receptors in primary culture of thyrocytes isolated from human thyroid tissue. METHODS: Forty patients with uninodular (n = 11), multinodular (n = 15) and recurrent goitre (n = 14) were investigated. Nodular and corresponding paranodular thyroid tissues were characterized. RNA and protein were extracted from primary thyrocyte monoculture. RT-PCR, western blot and ELISA were performed to evaluate PDGF isoforms AA, BB, CC, DD and PDGF receptors α and ß. RESULTS: Significantly higher mRNA expression of PDGF-AA, -BB, -CC and PDGFR molecules α and ß was measured by RT-PCR in thyrocytes from uninodular and recurrent nodular tissue compared with corresponding paranodular tissue. Elevated PDGF protein and PDGFR-α and -ß were confirmed by western blot. Likewise, higher secretion of PDGF-AA and -BB was detected in the supernatant of thyrocyte culture from all nodular tissue compared with paranodular tissue. Interestingly, comparison of nodular and corresponding paranodular tissues in multinodular goitre did not show significant difference of expression levels of PDGF isoforms or receptors. CONCLUSION: These findings suggest that the overexpression of PDGF isoforms and receptors may play a crucial role in the development of thyroid nodules and recurrent goitre.

Carbonic-anhydrase IX expression is increased in thyroid cancer tissue and represents a potential therapeutic target to eradicate thyroid tumor-initiating cells.

The expression of Carbonic-anhydrase IX (CAIX) in thyroid cancer (TC) subtypes was determined and its role in cancer cell growth and tumor-initiating cells (TICs) investigated. Immunohistochemistry in 114 TC patients revealed that CAIX expression was increased in tumor specimens of papillary, follicular and anaplastic TCs compared to normal thyroid tissue. Clinicopathological data indicated that lymph node metastases were more frequent in patients with high CAIX expression. The Cancer Genome Atlas database analysis demonstrated that a strong CAIX-mRNA expression was associated with advanced tumor stages and poor survival in TCs. In TC cell lines, CAIX expression was elevated in tumorspheres compared to monolayer cultures and was associated with an increased expression of stemness markers. Genetic knockdown or pharmacological inhibition of CAIX suppressed cell proliferation and the TIC ability to form tumorspheres by an induction of apoptosis and cell-cycle arrest. These findings suggest CAIX as a potential prognostic marker and a therapeutic target for thyroid cancer.

Transglutaminase 2 promotes tumorigenicity of colon cancer cells by inactivation of the tumor suppressor p53.

Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein-protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.

Characteristics and management of penetrating abdominal injuries in a German level I trauma center.

PURPOSE: Penetrating abdominal injuries caused by stabbing or firearms are rare in Germany, thus there is lack of descriptive studies. The management of hemodynamically stable patients is still under dispute. The aim of this study is to review and improve our management of penetrating abdominal injuries. METHODS: We retrospectively reviewed a 10-year period from the Trauma Registry of our level I trauma center. The data of all patients regarding demographics, clinical and outcome parameters were examined. Further, charts were reviewed for FAST and CT results and correlated with intraoperative findings. RESULTS: A total of 115 patients with penetrating abdominal trauma (87.8% men) were analyzed. In 69 patients, the injuries were caused by interpersonal violence and included 88 stab and 4 firearm wounds. 8 patients (6.9%) were in a state of shock at presentation. 52 patients (44.8%) suffered additional extraabdominal injuries. 38 patients were managed non-operatively, while almost two-thirds of all patients underwent surgical treatment. Hereof, 20 laparoscopies and 3 laparotomies were nontherapeutic. There were two missed injuries, but no patient experienced morbidity or mortality related to delay in treatment. 106 (92.2%) FAST and 91 (79.3%) CT scans were performed. Sensitivity and specificity of FAST were 59.4 and 94.2%, while those of CT were 93.2 and 85.1%, respectively. CONCLUSION: In hemodynamically stable patients presenting with penetrating abdominal trauma, CT is indicated and the majority of injuries can be managed conservatively. If surgical treatment is required, diagnostic laparoscopy for stable patients is feasible to avoid nontherapeutic laparotomy.