MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation.

The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.

Molecular Profiling of Low-Grade Appendiceal Mucinous Neoplasms (LAMN).

Low-grade appendiceal mucinous neoplasia (LAMN) represents a relatively rare tumor of the appendix typically diagnosed incidentally through appendectomy for acute appendicitis. In cases where perforation occurs, mucinous content may disseminate into the abdominal cavity, leading to the development of pseudomyxoma peritonei (PMP). The primary objective of this study was to elucidate the molecular characteristics associated with various stages of LAMN and PMP. DNA was extracted from LAMN, primary PMPs, recurrent PMPs, and adenocarcinomas originating from LAMN. The subsequent analysis involved the examination of mutational hotspot regions within 50 cancer-related genes, covering over 2800 COSMIC mutations, utilizing amplicon-based next-generation sequencing (NGS). Our findings revealed activating somatic mutations within the MAPK-signaling pathway across all tumors examined. Specifically, 98.1% of cases showed mutations in KRAS, while one tumor harbored a BRAF mutation. Additionally, GNAS mutations were identified in 55.8% of tumors, with no significant difference observed between LAMN and PMP. While LAMN rarely displayed additional mutations, 42% of primary PMPs and 60% of recurrent PMPs showed additional mutations. Notably, both adenocarcinomas originating from LAMN showed mutations within TP53. Furthermore, 7.7% (4/52) of cases exhibited a potentially targetable KRAS G12C mutation. In four patients, NGS analysis was performed on both primary PMP and recurrent PMP/adenocarcinoma samples. While mutations in KRAS and GNAS were detected in almost all samples, 50% of recurrent cases displayed an additional SMAD4 mutation, suggesting a notable alteration during disease progression. Our findings indicate two key points: First, mutations within the MAPK pathway, particularly in KRAS, are evident across all tumors, along with a high frequency of GNAS mutations. Second, progression toward PMP or adenocarcinoma is associated with an accumulation of additional mutations within common oncogenic pathways.

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.

OBJECTIVE: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). DESIGN: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice. RESULTS: Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. CONCLUSION: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.

Ten Year Time Trends of Amputation Surgery in Peripheral Arterial Disease in Germany: Before and During the COVID-19 Pandemic.

OBJECTIVE: Peripheral arterial disease (PAD) has been associated with suboptimal treatment, high mortality, and high amputation rates. It is unclear how the COVID-19 (coronavirus disease 2019) pandemic affected this development in a long term context. METHODS: This is a registry based, retrospective, nationwide cohort study including patients hospitalised with PAD as a main or secondary diagnosis and amputation surgery between 2012 - 2021 in Germany. Primary endpoints were population wide major and minor amputation rates, in hospital death, and in hospital mortality rates. Secondary endpoints were same admission revascularisations and in hospital death in the event of complications, i.e., failure to rescue (FTR). Pre-pandemic and pandemic trends, focusing on lockdown periods, were analysed. RESULTS: A total of 365 926 patient records with PAD and amputation surgery were analysed. The median patient age was 75 years and 28.8% were female. Overall population wide amputation and in hospital mortality rates (monthly decrease -0.002/100 000, p < .001, and -0.001/100 000, p< .001, respectively) and in hospital mortality rate (8.0% for 2012 - 2014 vs. 6.5% for 2020 - 2021; p < .001) declined between 2012 and 2020. Concurrently, same admission revascularisations increased (41.0% for 2012 - 2014 vs. 47.0% for 2020 - 2021; p < .001), while FTR decreased in a subset of complications (acute ischaemia, major bleeding, compartment syndrome, and mesenterial ischaemia). In the first pandemic lockdown, there was a temporary trend change to higher major amputations rates (+0.02/100 000; p < .001) and higher in hospital mortality rates (+0.007/100 000; p < .001), which changed to a decrease as of the second lockdown (-0.03/100 000, p = .034, and -0.010/100 000, p < .001, respectively) in an interrupted time series analysis. There was no statistically significant change in observed amputation rates during lockdowns, while observed in hospital mortality rates decreased by 12.0% in the first lockdown (0.22/100 000 vs. 0.25/100 000; p = .005) compared with reference periods of the two previous years. CONCLUSION: Between 2012 and 2021, pre-pandemic trends toward decreasing population wide overall amputation rates, fewer major amputations, more amputation related revascularisation procedures, and lower in hospital mortality were maintained despite a temporary trend to increased major amputations and in hospital mortality during the first COVID-19 related lockdown in Germany.

Surgical options in retrosternal oesophageal reconstruction.

BACKGROUND: Retrosternal oesophageal reconstructions with collar anastomoses can become necessary when the stomach is either unavailable for oesophageal replacement, or orthotopic reconstruction is deemed impractical. Our aim was to analyse our results regarding technical approaches and outcomes. MATERIALS AND METHODS: All patients undergoing primary and secondary oesophageal retrosternal reconstructions with collar anastomoses at our centre (2019-2023) were retrospectively analysed and individual surgical reconstruction options were presented. RESULTS: Overall, twelve patients received primary (n = 5; 42.7%) or secondary (n = 7; 58.3%) reconstructions; ten with colonic interposition and two with gastric pull-up. Male/female ratio was 4:8; median age 66 years (30-87). Charlson-Comorbidity-Score (CCS) was 5 (1-7); 8/12 patients (67%) had ASA-classification score ≥ 3. We observed no conduit necrosis, but one patient (8.3%) with a leakage of the oesophago-colonostomy which was successfully treated by endoscopic vacuum therapy. Four patients (33.3%) acquired nosocomial pneumonia. Additional drainages for pleural fluid collections were necessary in three patients (25%). Overall comprehensive-complication-index (CCI) was 26.2 (0-44.9). Length-of-stay (LOS) was 22 days median (15-40). There was no 90-days mortality. Overall, CCI during the follow-up (FU) period at median 26 months (16-50) was 33.7 (0-100). 10 out of 12 patients were on sufficient oral nutrition at 12 months FU. CONCLUSION: Primary and secondary oesophageal retrosternal reconstructions encompass diverse entities and typically requires tailored decision-making. These procedures, though rare, are feasible with acceptable complication rates and positive functional outcomes when performed in experienced hands.

Proficiency in bariatric surgery may shorten the learning curve for minimally-invasive D2 gastrectomy.

INTRODUCTION: Evidence from Asian studies suggests that minimally-invasive gastrectomy achieves equivalent oncological but improved perioperative outcomes compared to open surgery. Oncological gastric resections are less frequent in European countries. Index procedures may play a role for the learning curve of minimally-invasive gastrectomy. The aim of our study was to evaluate if skills acquired in bariatric surgery allow a safe and oncologically adequate implementation of minimally-invasive gastrectomy in a cohort of european patients. METHODS: In this single-center retrospective study, all patients who received primary bariatric surgery between January 2015 and December 2018 and minimally-invasive surgery for gastric cancer treated from June 2019 to January 2023 were evaluated. Primary endpoints were operation time, lymph node yield and lymph node fractions. Secondary endpoints included postoperative complications and oncological outcomes. RESULTS: Learning curves for two surgeons with 350 bariatric procedures and 44 minimally-invasive gastrectomies were analyzed. For bariatric surgery, the mean operation time decreased from initially 82 ± 27 to 45 ± 21 min and 118 ± 28 to 81 ± 36 min for sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), while the complication rate remained within the international benchmark. For laparoscopic gastrectomy (n = 30), operation times decreased but then remained stable over time. Operation times for the robotic platform were longer (302 ± 60 vs. 390 ± 48 min; p < 0.001) with the learning curve remaining incomplete after 14 procedures. R0 status was achieved in 95.5% of patients; the mean number of lymph nodes retrieved was 37 ± 14 with no differences between the groups. Complete mesogastric excision was more frequently achieved during the later laparoscopic cases whereas it occurred earlier for the robotic group (p = 0.004). Perioperative morbidity was comparable to the European benchmark. Textbook outcome was achieved in 54.4% of the cases. CONCLUSION: In summary, we could demonstrate a successful skill transfer from bariatric surgery to minimally-invasive laparoscopic oncological gastric surgery enabling safe and oncologically adequate minimally-invasive D2 gastrectomy in a central European patient collective.

[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.

Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids.

Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.

Nationwide volume-outcome relationship concerning in-hospital mortality and failure-to-rescue in surgery of sigmoid diverticulitis.

PURPOSE: A correlation between the hospital volume and outcome is described for multiple entities of oncological surgery. To date, this has not been analyzed for the surgical treatment of sigmoid diverticulitis. The aim of this study was to explore the impact of the annual caseload per hospital of colon resection on the postoperative incidence of complications, failure to rescue, and mortality in patients with diverticulitis. METHODS: Patients receiving colorectal resection independent from the diagnosis from 2012 to 2017 were selected from a German nationwide administrative dataset. The hospitals were grouped into five equal caseload quintiles (Q1-Q5 in ascending caseload order). The outcome analysis was focused on patients receiving surgery for sigmoid diverticulitis. RESULTS: In total, 662,706 left-sided colon resections were recorded between 2012 and 2017. Of these, 156,462 resections were performed due to sigmoid diverticulitis and were included in the analysis. The overall in-house mortality rate was 3.5%, ranging from 3.8% in Q1 (mean of 9.5 procedures per year) to 3.1% in Q5 (mean 62.8 procedures per year; p < 0.001). Q5 hospitals revealed a risk-adjusted odds ratio of 0.85 (95% CI 0.78-0.94; p < 0.001) for in-hospital mortality compared to Q1 during multivariable logistic regression analysis. High-volume centers showed overall lower complication rates, whereas the failure-to-rescue did not differ significantly. CONCLUSION: Surgical treatment of sigmoid diverticulitis in high-volume colorectal centers shows lower postoperative mortality rates and fewer postoperative complications.

Diverticulitis patient care during the Covid-19 pandemic in Germany-a retrospective nationwide population-based cohort study.

PURPOSE: Coronavirus disease 2019 (COVID-19) impacted health care systems around the world. Despite a decrease in emergency admissions, an increased number of complicated forms of diverticulitis was reported. It was the aim of this study to analyze the pandemic impact on diverticulitis management in Germany. METHODS: This is a retrospective population-wide analysis of hospital billing data (2012-2021) of diverticulitis in Germany. Patients were identified based on diagnosis (ICD10) and procedural codes to stratify by conservative and operative management. Primary outcome of interest was admission rates, secondary outcomes were rates of surgical vs conservative treatment and fraction of complicated clinical courses during the pandemic. RESULTS: Of a total of 991,579 cases, 66,424 (6.7%) were admitted during pandemic lockdowns. Conservative treatment was the most common overall (66.9%) and higher during lockdowns (70.7%). Overall admissions and population adjusted rates of surgically treated patients decreased, the latter by 12.7% and 11.3%, corrected to estimated rates, in the two lockdowns. Surgery after emergency presentation decreased by 7.1% (p=0.053) and 11.1% (p=0.002) in the two lockdowns with a higher rate of ostomy and/or revision (+5.6%, p=0.219, and +10.2%, p=0.030). In-hospital mortality was increased in lockdown periods (1.64% vs 1.49%). In detail, mortality was identical in case of conservative treatment during lockdown periods (0.5%) but was higher in surgically treated patients (4.4% vs 3.6%). CONCLUSION: During lockdowns, there was an overall decrease of admissions for diverticulitis, especially non-emergency admissions in Germany, and treatment was more likely to be conservative. In case of surgery, however, there was increased risk of a complicated course (ostomy, re-surgery), possibly due to patient selection.

Risk-adjusted perioperative bridging anticoagulation reduces bleeding complications without increasing thromboembolic events in general and visceral surgery.

BACKGROUND: Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events. METHODS: We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality. RESULTS: A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed. CONCLUSION: It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low.

Does Concurrent Cholestasis Alter the Prognostic Value of Preoperatively Elevated CA19-9 Serum Levels in Patients with Pancreatic Head Adenocarcinoma?

BACKGROUND: Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified. METHODS: Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values. RESULTS: Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment. CONCLUSIONS: In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.

Population-Based Analysis of Sex-Dependent Risk Factors for Mortality in Thoracic Surgery for Lung Cancer.

OBJECTIVE: Sex is an important predictor for lung cancer survival and a favorable prognostic indicator for women compared to men. Specific surgery-related sex differences of patients with lung cancer remain unclear. The aim of this study is to analyze sex-specific differences after lung cancer resections to identify factors for an unfavorable prognosis. METHODS: This is a retrospective analysis of a German nationwide discharge register of every adult inpatient undergoing pulmonary resection for lung cancer from 2014 until 2017. DRG data and OPS procedures were analyzed with the help of the Federal Statistical Office using remote controlled data. A multivariable regression model was established in a stepwise process to evaluate the effect of sex on inpatient mortality. RESULTS: A total of 38,806 patients underwent surgical resection for lung cancer between January 2014 and December 2017 in Germany. Women were significantly younger at admission than men (mean 64.7 years [SD 10.1] vs. 66.6 years [SD 9.5]; p < 0.0001). They had fewer unreferred admissions (risk ratio 0.83 [0.77, 0.90], p < 0.0001) and were significantly less likely to have recorded comorbidities. Raw in-hospital mortality was 1.8% for women and 4.1% for men. In the multivariable analysis of in-hospital mortality, the likelihood of death for women compared to men was 21% reduced (OR 0.79 [CI: 0.66, 0.93, p = 0.005]). The risk of postoperative complications such as ventilation >48 h, ARDS, tracheotomy, or pneumonia was significantly lower for women. CONCLUSIONS: Women undergoing lung cancer surgery were younger and had less comorbidities than men in Germany. Female sex was associated with lower mortality and less postoperative complications.

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.

Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing's syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing's syndrome.

PURPOSE: In selected cases of severe Cushing's syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing's syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing's syndrome regarding postoperative outcomes. METHODS: We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008-2021. Patients with adrenal Cushing's syndrome due to adenoma were compared with patients with ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival. RESULTS: Of 83 patients with adrenalectomy for hypercortisolism (65.1% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing's syndrome in 60 patients (72.2%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing's disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0% vs. 33%; p < 0.001) and delayed recovery (median: 10.2% vs. 79.2%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2% vs. 25.0% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0% vs. 8.3%; p = 0.081). CONCLUSION: While unilateral adrenalectomy for adrenal Cushing's syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing's syndrome or Cushing's disease is a more complicated intervention with a mortality of nearly 10%.

Suppurative thyroiditis caused by ingested fish bone in the thyroid gland: a case report on its diagnostics and surgical therapy.

BACKGROUND: Accidental ingestion of fish bone is a common cause of otolaryngological emergency. Migration of the ingested bone into the thyroid gland, however, occurs very rarely. The associated clinical presentation, symptoms and duration of discomfort are also highly variable between patients and can be diagnostically challenging. CASE PRESENTATION: Here, we report the case of a 71-year-old female patient presenting with an ingested fish bone that migrated into the right thyroid lobe as a rare cause of suppurative thyroiditis with the clinical features of sepsis. We outline the diagnostic approach, peri- and intraoperative management as well as complications. It is proposed that besides endoscopy, imaging methods such as ultrasound or computed tomography may be necessary to verify the diagnosis and location of an ingested fish bone. Prompt surgical removal of the foreign body and resection of the infectious focus is recommended to minimize the risk of local inflammation, recurrent nerve lesions and septic complications arising from the spread of infection. CONCLUSION: Fish bone migration into the thyroid gland is an extremely rare event, the successful detection and surgical management of which can be achieved through a careful interdisciplinary approach.

The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis, and seminoma development.

Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations.

Location-specific cell identity rather than exposure to GI microbiota defines many innate immune signalling cascades in the gut epithelium.

OBJECTIVE: The epithelial layer of the GI tract is equipped with innate immune receptors to sense invading pathogens. Dysregulation in innate immune signalling pathways is associated with severe inflammatory diseases, but the responsiveness of GI epithelial cells to bacterial stimulation remains unclear. DESIGN: We generated 42 lines of human and murine organoids from gastric and intestinal segments of both adult and fetal tissues. Genome-wide RNA-seq of the organoids provides an expression atlas of the GI epithelium. The innate immune response in epithelial cells was assessed using several functional assays in organoids and two-dimensional monolayers of cells from organoids. RESULTS: Results demonstrate extensive spatial organisation of innate immune signalling components along the cephalocaudal axis. A large part of this organisation is determined before birth and independent of exposure to commensal gut microbiota. Spatially restricted expression of Toll-like receptor 4 (Tlr4) in stomach and colon, but not in small intestine, is matched by nuclear factor kappa B (NF-κB) responses to lipopolysaccharide (LPS) exposure. Gastric epithelial organoids can sense LPS from the basal as well as from the apical side. CONCLUSION: We conclude that the epithelial innate immune barrier follows a specific pattern per GI segment. The majority of the expression patterns and the function of TLR4 is encoded in the tissue-resident stem cells and determined primarily during development.

Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria.

BACKGROUND: International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. METHODS: Patients' tumours were retrospectively defined borderline resectable according to ICC. The study cohort was grouped into either BR-A or BR-B and compared with patients considered primarily resectable (R). Differences in postoperative complications, pathological reports, overall (OS), and disease-free survival were assessed. RESULTS: A total of 345 patients underwent resection for PDAC. By applying ICC in routine preoperative assessment, 30 patients were classified as stage BR-A and 62 patients as stage BR-B. In total, 253 patients were considered R. The cohort did not contain BR-C patients. No differences in postoperative complications were detected. Median OS was significantly shorter in BR-A (15 months) and BR-B (12 months) compared with R (20 months) patients (BR-A vs. R: p = 0.09 and BR-B vs. R: p < 0.001). CA19-9, as the determining factor of BR-B patients, turned out to be an independent prognostic risk factor for OS. CONCLUSIONS: Preoperative staging defining surgical resectability in PDAC according to ICC is crucial for patient survival. Patients with PDAC BR-B should be considered for multimodal neoadjuvant therapy even if considered anatomically resectable.

Prognostic impact of additive chemotherapy after curative resection of metachronous colorectal liver metastasis: a single-centre retrospective study.

BACKGROUND: A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. METHODS: In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. RESULTS: Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023), but not 5-year survival (58% vs 42%, p = 0.24). Multivariate analysis identified additive chemotherapy (p = 0.016, HR 0.44, 95% CI 0.23-0.86), more than five CRLM (p = 0.026, HR 2.46, 95% CI 1.16-10.32) and disease recurrence (0.009, HR 2.70, 95% CI 1.29-5.65) as independent risk factors for OS. CONCLUSION: Additive chemotherapy significantly prolonged OS and 10-year survival in patients after curative resection of metachronous CRLM. Randomized clinical trials are needed in the future to identify optimal chemotherapy regimens for those patients.