[Watch and Wait for Rectal Cancer]. / Surveillance bei Watch-and-Wait nach neoadjuvanter Therapie beim Rektumkarzinom.

About one third of all colorectal carcinomas (CRC) are localised in the rectum. As part of a multimodal therapy concept, neoadjuvant therapy achieves downstaging of the tumour in 50-60% of cases and a so-called complete clinical response (cCR), defined as clinically (and radiologically) undetectable residual tumour after completion of neoadjuvant therapy, in 10-30% of cases.In view of the perioperative morbidity and mortality associated with radical rectal resection, including the occurrence of a symptom complex known as low anterior resection syndrome (LARS) and the need for deviation, at least temporarily, the question of the risk-benefit balance of organ resection in the presence of cCR has been raised. In this context, the therapeutic concept of a "watch-and-wait" approach with omission of immediate organ resection and inclusion in a structured surveillance regime, has emerged.For a safe, oncological implementation of this option, it is necessary to develop standards in the definition of a suitable patient clientele and the implementation of the concept. In addition to the initial correct selection of the patient group that is suitable for a primarily non-surgical procedure, the inherent goal is the early and sufficient detection of tumour recurrence (so-called local regrowth) during the "watch-and-wait" phase (surveillance).In this context, in this paper we address the questions of: 1. the optimal timing of initial re-staging, 2. the criteria for assessing the clinical response and selecting the appropriate patient clientele, 3. the rhythm and design of the surveillance protocol.

PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma.

In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

Low-grade mucinous neoplasms (LAMN) of the appendix in Germany between 2011 and 2018: a nationwide analysis based on data provided by the German Center for Cancer Registry Data (ZfKD) at the Robert Koch Institute (RKI).

INTRODUCTION: Low-grade appendiceal mucinous neoplasms (LAMN) are semi-malignant tumors of the appendix which are incidentally found in up to 1% of appendectomy specimen. To this day, no valid descriptive analysis on LAMN is available for the German population. METHODS: Data of LAMN (ICD-10: D37.3) were collected from the population-based cancer registries in Germany, provided by the German Center for Cancer Registry Data (Zentrum für Krebsregisterdaten-ZfKD). Data was anonymized and included gender, age at diagnosis, tumor staging according to the TNM-classification, state of residence, information on the performed therapy, and survival data. RESULTS: A total of 612 cases were reported to the ZfKD between 2011 and 2018. A total of 63.07% were female and 36.93% were male. Great inhomogeneity in reporting cases was seen in the federal states of Germany including the fact that some federal states did not report any cases at all. Age distribution showed a mean age of 62.03 years (SD 16.15) at diagnosis. However, data on tumor stage was only available in 24.86% of cases (n = 152). A total of 49.34% of these patients presented with a T4-stage. Likewise, information regarding performed therapy was available in the minority of patients: 269 patients received surgery, 22 did not and for 312 cases no information was available. Twenty-four patients received chemotherapy, 188 did not, and for 400 cases, no information was available. Overall 5-year survival was estimated at 79.52%. Patients below the age of 55 years at time of diagnosis had a significantly higher 5-year survival rate compared to patients above the age of 55 years (85.77% vs. 73.27%). DISCUSSION: In this study, we observed an incidence of LAMN in 0.13% of all appendectomy specimen in 2018. It seems likely that not all cases were reported to the ZfKD; therefore, case numbers may be considered underestimated. Age and gender distribution goes in line with international studies with females being predominantly affected. Especially regarding tumor stage and therapy in depth information cannot be provided through the ZfKD-database. This data analysis emphasizes the need for further studies and the need for setting up a specialized registry for this unique tumor entity to develop guidelines for the appropriate treatment and follow-up.

RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells.

Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

Surgical Site Infection Following Single-Port Appendectomy: A Systematic Review of the Literature and Meta-Analysis.

Introduction: Surgical site infections (SSIs) are one of the most common postoperative complications after appendectomy leading to recurrent surgery, prolonged hospital stay, and the use of antibiotics. Numerous studies and meta-analyses have been published on the effect of open versus conventional laparoscopic appendectomy (CLA) reporting faster postoperative recovery and less postoperative pain for CLA. A development from CLA has been the single-port appendectomy (SPA), associated with a better cosmesis but seemingly having a higher risk of wound infections. The aim of this systematic literature review and meta-analysis is to investigate whether reduced port or SPA alters the ratio of SSIs. Methods: Pubmed, Embase, and Cochrane databases were screened for suitable articles. All articles published between January 1, 2002, and March 23, 2022, were included. Articles regarding children below the age of 18 were excluded as well as manuscripts that investigated solemnly open appendectomies. Articles were screened for inclusion criteria by two independent authors. Incidence of SSI was the primary outcome. Duration of operation and length of hospital stay were defined as secondary outcomes. Results: A total of 25 studies were found through a database search describing 5484 patients. A total of 2749 patients received SPA and 2735 received CLA. There was no statistical difference in the rate of SSI (P = 0.98). A total of 22 studies including 4699 patients reported the duration of operation (2223 SPA and 2476 CLA). There was a significantly shorter operation time seen in CLA. The length of hospital stay was reported in 23 studies (4735 patients: 2235 SPA and 2500 CLA). A shorter hospital stay was seen in the SPA group (P < 0.00001). Separately performed analysis of randomized controlled trials could not confirm this effect (P = 0.29). Discussion: SPA is an equally safe procedure considering SSI compared to CLA and does not lead to an increased risk of SSI. A longer operation time for SPA and a minor difference in the length of stay does lead to the use of SPA in selected patients only.

[Complete response after neoadjuvant therapy of rectal cancer: implications for surgery]. / Komplette Response nach neoadjuvanter Therapie beim Rektumkarzinom: Implikationen für die Chirurgie.

For (locally advanced) rectal cancer, a multimodal therapy concept comprising neoadjuvant radiotherapy/chemoradiotherapy, radical surgical resection with partial/complete mesorectal excision and subsequent adjuvant chemotherapy represents the current international standard of care. Further developments in neoadjuvant therapy concepts, such as the principle of total neoadjuvant therapy, lead to an increasing number of patients who show a complete clinical response in restaging after neoadjuvant therapy without clinically detectable residual tumor. In view of the risk associated with radical surgical resection in terms of perioperative morbidity and a potentially non-continence-preserving procedure, the question of the oncological justifiability of an organ-preserving procedure in the case of a complete clinical response under neoadjuvant therapy is increasingly being raised. The therapeutic principle of watch and wait, defined by refraining from immediate radical surgical resection and inclusion in a close-meshed, structured follow-up program, currently appears to be oncologically justifiable based on the current study situation; however, for the initial evaluation of the extent of the clinical response and for the structuring of the close-meshed follow-up program, further optimization and standardization based on broadly designed studies appear necessary in order to be able to provide this concept to a clearly defined patient collective as an oncologically equivalent therapy principle also outside specialized centers.

Organoid Models for Cancer Research-From Bed to Bench Side and Back.

Organoids are a new 3D ex vivo culture system that have been applied in various fields of biomedical research. First isolated from the murine small intestine, they have since been established from a wide range of organs and tissues, both in healthy and diseased states. Organoids genetically, functionally and phenotypically retain the characteristics of their tissue of origin even after multiple passages, making them a valuable tool in studying various physiologic and pathophysiologic processes. The finding that organoids can also be established from tumor tissue or can be engineered to recapitulate tumor tissue has dramatically increased their use in cancer research. In this review, we discuss the potential of organoids to close the gap between preclinical in vitro and in vivo models as well as clinical trials in cancer research focusing on drug investigation and development.

Changes in appendicitis treatment during the COVID-19 pandemic - A systematic review and meta-analysis.

BACKGROUND: During the COVID-19 pandemic in 2020 a decrease of emergency consultations and modification in treatment of numerous medical conditions were observed. Aim of this paper was to evaluate the effect of the COVID-19 pandemic on incidence, treatment strategies, severity, length of hospital stay and time of presentation in adults and children with acute appendicitis. METHODS: A systematic literature search of Pubmed, Embase and Cochrane databases was performed, and eligible studies used to perform a meta-analysis. RESULTS: 46 suitable studies were identified with an overall reduction of appendicitis cases by 20.9% in adults and an increase of 13.4% in children. The rate of open appendectomies increased without statistical significance in both groups (adults: 8.5% vs. 7.1%, P = 0.32; children: 7.1% vs. 5.3%, P = 0.13), whereas the rate of antibiotic treatment increased significantly (P = 0.007; P = 0.03). Higher rates of complicated appendicitis were observed in adults (adults: OR 2.00, P < 0.0001; children: OR 1.64, P = 0.12). Time to first consultation did not change significantly (adults: 52.3 vs. 38.5 h - P = 0.057; children: 51.5 vs. 32.0 h - P = 0.062) and length of stay was also not lengthened during the pandemic (adults: 2.9 vs. 2.7 days, P = 0.057; children: 4.2 vs. 3.7 days, P = 0.062). CONCLUSION: The COVID-19 pandemic of 2020 had major impact on incidence and treatment strategies of acute appendicitis. Results of this meta-analysis might be another hint to support the theory that appendicitis is not a progressive disease and surgeons can safely consider antibiotic therapy for acute uncomplicated appendicitis.

Laparoscopic appendectomy versus antibiotic treatment for acute appendicitis-a systematic review.

BACKGROUND: Over the last years, laparoscopic appendectomy has progressively replaced open appendectomy and become the current gold standard treatment for suspected, uncomplicated appendicitis. At the same time, though, it is an ongoing discussion that antibiotic therapy can be an equivalent treatment for patients with uncomplicated appendicitis. The aim of this systematic review was to determine the safety and efficacy of antibiotic therapy and compare it to the laparoscopic appendectomy for acute, uncomplicated appendicitis. METHODS: The PubMed database, Embase database, and Cochrane library were scanned for studies comparing laparoscopic appendectomy with antibiotic treatment. Two independent reviewers performed the study selection and data extraction. The primary endpoint was defined as successful treatment of appendicitis. Secondary endpoints were pain intensity, duration of hospitalization, absence from work, and incidence of complications. RESULTS: No studies were found that exclusively compared laparoscopic appendectomy with antibiotic treatment for acute, uncomplicated appendicitis. CONCLUSIONS: To date, there are no studies comparing antibiotic treatment to laparoscopic appendectomy for patients with acute uncomplicated appendicitis, thus emphasizing the lack of evidence and need for further investigation.

Brain Metastases from Colorectal Cancer: A Systematic Review of the Literature and Meta-Analysis to Establish a Guideline for Daily Treatment.

Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words "brain", "metastas*", "tumor", "colorectal", "cancer", and "malignancy". In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1% and 11.5%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment.

Impact of the COVID-19 pandemic on appendicitis treatment in Germany-a population-based analysis.

PURPOSE: Acute appendicitis is one of the most common reasons for emergency medical consultation. While simple appendicitis can be treated with antibiotics or surgery, complex appendicitis including gangrene, abscess, and perforation requires appendectomy. During the COVID-19 pandemic in early 2020, an overall drop in emergency room consultations was observed. We therefore aimed to investigate the incidence and treatment strategies of acute appendicitis during that period. METHODS: Data of insurance holders with the ICD code for "acute appendicitis" or OPS procedure of appendectomy of a major health insurance company in Germany were analyzed retrospectively. Groups were built, containing of the means of March-June of 2017, 2018, and 2019, defined as "pre-COVID group" with the "COVID group," defined as data from March to June of 2020. Data was analyzed by age, sex, comorbidities, length of hospital stay, diagnoses, and treatment. Data of the COVID group was analyzed for simultaneous COVID-19 infection. RESULTS: During the COVID-19 pandemic of early 2020, an overall reduction by 12.9% of patients presenting with acute appendicitis was noticeable. These results were mainly due to decreased rates of uncomplicated appendicitis, while complicated appendicitis was scarcely affected. Especially in the group of females < 40 years, a drastic reduction was visible. Rates of extended surgery did not change. Likewise, the complication rate like appendix stump leakage or need for re-operation did not differ. In March 2020, 4.8% of acute appendicitis patients had concomitant COVID-19 infection. CONCLUSION: In line with the overall drop of emergency room visits during the COVID-19 pandemic of spring 2020 in Germany, a significantly lowered number of patients with uncomplicated appendicitis were noticeable, whereas complicated appendicitis did not differ. Also, treatment and complication rate of acute appendicitis did not change. These findings might be a hint that acute appendicitis is not a progressing disease but caused by different entities for uncomplicated and complicated appendicitis and therefore another clue that uncomplicated appendicitis can be treated with antibiotics or observation. Nevertheless provided data does not cover outpatient treatment; therefore, no statement observation or antibiotics in outpatients can be made.

Systematic review and meta-analysis on volume-outcome relationship of abdominal surgical procedures in Germany.

BACKGROUND: In the past, for a number of abdominal surgical interventions a correlation between treatment volume of a hospital and the patient's outcome was shown in national and international studies. METHODS: Based on a systematic literature search we analyzed the absolute and risk-adjusted in-house lethality as well as the rate of complications and the failure to rescue after abdominal surgery in Germany. The hospitals were grouped in quintiles according to the volume of treatment. RESULTS: 11 studies including more than 2 million patients were identified and surgeries for the treatment of 9 disease conditions were studied. The meta-analysis shows a significantly lower absolute and risk-adjusted in-house mortality for surgery in hospitals with high treatment volumes compared to low volume hospitals. In the context of subgroup analysis, this effect is demonstrated especially for complex surgical procedures. The failure to rescue in patients suffering from sepsis is significantly lower in high volume centers compared to low volume centers. CONCLUSION: This systematic review and meta-analysis shows on more than 2 million patients that there is a volume-outcome relationship for the surgical treatment of abdominal diseases in Germany across various organ systems, which is particularly true for complex interventions.

[Evidence in minimally invasive oncological surgery of the colon and rectum]. / Evidenz in der minimal-invasiven onkologischen Chirurgie des Kolons und des Rektums.

An essential component of the treatment of colorectal cancer is a resection of the tumor-bearing segment of the bowels. After the development of minimally invasive procedures the feasibility and safety in oncological, colorectal surgery was questioned. The broad study situation for colon cancer over the last years showed predominantly consistent benefits during the perioperative phase and non-inferiority concerning long-term oncological outcomes. The implementation of laparoscopic rectal resection was more hesitant due to the complexity of the procedure and insufficient study data; however, overall the short-term benefits seem to be maintained and laparoscopic rectal resection is thought to be noninferior to open resection in the long run even though findings on the quality of the resected specimen are heterogeneous. Accordingly, most guidelines now include a recommendation of laparoscopic resection for colorectal cancer. The limitation with respect to an achievable oncological equivalency of resection takes account of the complexity and the requirements of the intervention only in the setting of rational selection of patients and sufficient experience of the surgeon.

Mortality and Complications Following Visceral Surgery: A Nationwide Analysis Based on the Diagnostic Categories Used in German Hospital Invoicing Data.

BACKGROUND: The in-hospital mortality after visceral surgery in Germany is unknown. METHODS: In this retrospective, descriptive analysis, nationwide hospital billing data based on diagnosis-related groups (DRG) over the period 2009-2015 were studied to determine the in-hospital mortality, complications and their management, and deaths after documented severe complications (failure to rescue, FTR) after visceral surgery in Germany. Organ-system subgroups were defined and subdivided into frequent operations (inguinal hernia repair, appendectomy, thyroid operations, cholecystec- tomy), colorectal operations, and complex operations (surgery of the esophagus, pancreas, liver, and stomach). RESULTS: 3 287 199 patients from 1392 hospitals were included in the analysis. The in-hospital mortality after visceral surgery was 1.9%. The lowest mortality was after the frequently performed operations (0.04-0.4%), the highest after complex surgery of the esophagus (8.6%) and stomach (11.7%). Severe complications were most commonly seen after complex surgery of the pan- creas (27.7%), liver (24.3%), esophagus (37.8%), and stomach (36.7%). 90.6% of deaths occurred after colorectal or complex operations, which together accounted for 23% of all operations. The FTR rate was 8.4% after appendectomy and cholecystec- tomy (95% confidence interval [8.34; 8.46]) and 20.3% after esophageal surgery ([19.8; 20.8]). CONCLUSION: In Germany, in-hospital mortality after visceral surgery is not uncommon, with a frequency of nearly 2%. Improved complication management after complex operations appears necessary. A limitation of this study is the identification of compli- cations from anonymized billing data.

Perioperative management of anticoagulant therapy.

About 10% of patients taking a chronic, oral anticoagulant therapy require an invasive procedure that can be associated with an increased risk for peri-interventional or perioperative bleeding. Depending on the risk for thromboembolism and the risk for bleeding, the physician has to decide whether the anticoagulant therapy should be interrupted or continued. Patient characteristics such as age, renal function and drug interactions must be considered. The perioperative handling of the oral anticoagulant therapy differs according to the periprocedural bleeding risk. Patients requiring a procedure with a minor risk for bleeding do not need to pause their anticoagulant therapy. For procedures with an increased risk for perioperative bleeding, the anticoagulant therapy should be adequately paused. For patients on a coumarin derivative with a high risk for a thromboembolic event, a perioperative bridging therapy with a low molecular weight heparin is recommended. Due to an increased risk for perioperative bleeding in patients on a bridging therapy, it is not recommended in patients with a low risk for thromboembolism. For patients taking a non-vitamin K oral anticoagulant, a bridging therapy is not recommended due to the fast onset and offset of the medication.

LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins that drive the malignant phenotype of CML. Recently, the LIM and SH3 domain protein 1 (LASP1) was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in CML patients. However, the underlying mechanisms why LASP1 expression correlates with dismal outcome remained unresolved. Here, we identified LASP1 as a novel and overexpressed direct substrate of BCR-ABL in CML. We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients, which is abolished by tyrosine kinase inhibitor therapy. Further studies revealed that LASP1 phosphorylation results in an association with CRKL - another specific BCR-ABL substrate and bona fide biomarker for BCR-ABL activity. pLASP1-Y171 binds to non-phosphorylated CRKL at its SH2 domain. Accordingly, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of LASP1 in CML disrupts normal regulation of CRKL and LASP1, which likely has implications on downstream BCR-ABL signaling. Collectively, our results suggest that LASP1 phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of LASP1 function in CML.