Risk of Lymphoma and Leukemia in Thyroid Cancer Patients: A Retrospective Cohort Study in Germany.

Thyroid cancer is the ninth most common cancer worldwide. While differentiated thyroid cancer (DTC) has a high survival rate, concerns arise regarding optimal treatment strategies and potential long-term risks, including second primary malignancies (SPMs), associated with therapies such as radioiodine (RAI). The aim of the present study was to investigate the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia in Germany. This retrospective cohort study used the IQVIA TM Disease Analyzer database and included adults with a first documented diagnosis of thyroid cancer between January 2005 and December 2021 as well as propensity score matched individuals without thyroid cancer in 1284 general practices. Univariate Cox regression models were performed to examine the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia. A total of 4232 thyroid cancer patients (mean age: 54.2 years; 73.6% female) and 21 160 controls (mean age: 54.2 years; 72.6% female) were available for analyses. Thyroid cancer was significantly associated with a higher lymphoma incidence (HR: 3.35, 95% CI: 2.04-5.52), especially in men (HR: 5.37) and those aged 61-70 years. Leukemia incidence was not significantly associated with thyroid cancer (HR: 1.79, 95% CI: 0.91-3.53), although associations were notable in younger age groups. Thyroid cancer is positively associated with a risk of subsequent lymphoma, highlighting the need for vigilant surveillance and tailored treatment strategies. While the association with leukemia is less pronounced, close surveillance remains critical, especially in younger patients.

Is there a link between appendicitis and the risk of diverticular disease?: a large German cohort study.

PURPOSE: Appendicitis, characterized by inflammation of the vermiform appendix, is a common abdominal emergency necessitating appendectomy. Recent evidence suggests a potential link between appendicitis and subsequent diverticular disease, yet population-based studies investigating this association are limited. METHODS: Utilizing the Disease Analyzer database encompassing data from over 1000 primary care practices in Germany, we conducted a retrospective cohort study. We included 25,379 adults diagnosed with appendicitis and an equal number of matched controls without appendicitis. The incidence of diverticular disease over a 10-year follow-up period was compared between the two cohorts. Cox regression analysis was performed to assess the association between appendicitis and diverticular disease, adjusting for potential confounders. RESULTS: Our findings revealed a significant association between appendicitis and subsequent diverticular disease (HR: 1.76; 95% CI: 1.57-1.97), with an increased risk observed across all age groups. Notably, this association was stronger in men (HR: 2.00; 95% CI: 1.68-2.37) than in women (HR: 1.58; 95% CI: 1.36-1.84). The cumulative 10-year incidence of diverticular disease was higher in patients with appendicitis (6.5%) compared to those without (3.6%). Additionally, we observed a clear age-dependent increase in the incidence of diverticular disease. CONCLUSION: This large-scale population-based study provides valuable insights into the interaction between appendicitis and diverticular disease. The study underscores the need for further research elucidating the underlying mechanisms linking appendicitis to diverticular disease. Probiotics emerge as a potential therapeutic avenue warranting exploration in the management of both conditions. These findings have important implications for clinical practice, highlighting the importance of considering appendicitis as a potential risk factor for diverticular disease, particularly in men. Further investigation is warranted to validate these findings and explore potential therapeutic interventions targeting the shared pathophysiological pathways underlying both conditions.

Trends and outcomes in colorectal cancer surgery: a multicenter cross-sectional study of minimally invasive versus open techniques in Germany.

BACKGROUND: The objective of this study was to assess the trend from open to modern minimally invasive (laparoscopic and robot-assisted) surgical techniques for colorectal cancer (CRC) in Germany, with a particular focus on hospital mortality, postoperative complications, and length of hospital stay. METHODS: A multicenter cross-sectional study was conducted using data from 36 German hospitals, encompassing 1,250,029 cases from January 2019 to December 2023. The study included all hospitalized patients aged ≥ 18 with CRC who underwent surgery. Surgical cases were categorized as open or minimally invasive. Outcomes assessed included in-hospital mortality, morbidity, and hospital length of stay. Statistical analyses involved multivariable logistic and linear regression models adjusted for main diagnosis, metastasis presence, age, sex, and comorbidities. RESULTS: The study included 4525 CRC cases: 2767 underwent open surgery and 1758 underwent minimally invasive surgery (173 robotic). In-hospital mortality was significantly higher in open surgery (6.1% vs. 1.7%). Open surgery was also significantly associated with higher rates of acute post-hemorrhagic anemia (OR: 2.38; 95% CI: 1.87-3.02), respiratory failure (OR: 1.71; 95% CI: 1.34-2.18), and intraoperative and postprocedural complications (OR: 3.64; 95% CI: 2.83-4.70). Average hospital stay was longer for open surgery (19.5 days vs. 11.0 days). CONCLUSION: Despite the advantages of minimally invasive surgery, including reduced mortality, morbidity, and shorter hospital stays, open surgery remains the predominant approach for CRC in Germany. These findings underscore the need for increased adoption of minimally invasive techniques and highlight the potential benefits of shifting toward minimally invasive methods to enhance the overall quality of CRC care.

A Revised Version of the TNM Classification Leads to Optimized Predictive Performance in Patients with Adrenocortical Carcinoma.

The prognostic stratification of the current AJCC/UICC TNM classification for adrenocortical carcinoma (ACC) has been validated in only a few studies. In this study, it was hypothesized that redefining the T category cut-off would result in a significant improvement in estimated stage-related survival. In 935 patients with ACC from the SEER database, optimal cut-off values based on tumor size were first determined to redefine T1 and T2 categories. Cox proportional hazards regression analysis and receiver operating characteristics (ROC) were then used to determine the prognostic value of the revised version. A new cut-off value of 9.5 cm tumor size was established to differentiate between T1 and T2 tumors, leading to a revised TNM classification. As a result, a more homogeneous distribution of patients with ACC across all stages was observed. Notably, the predictive value of the newly proposed TNM classification in the ROC analysis exceeded that of the 7th and 8th editions of the AJCC/UICC classification system. Finally, the prognostic superiority of the revised TNM classification was confirmed in a multivariate Cox proportional hazards regression model. In conclusion, the present study demonstrates that updating the current staging system with revised T1 and T2 categories significantly improves the prediction of cancer-specific survival (CSS) in patients with ACC.

The Role of Alternative Lymph Node Classification Systems in Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN): Superiority of a LODDS Scheme Over N Category in Pancreatic NEN (pNEN).

Lymph node (LN) involvement in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) has been reported to have prognostic and therapeutic implications. Numerous novel LN classifications exist; however, no comparison of their prognostic performance for GEP-NEN has been done yet. Using a nationwide cohort from the German Neuroendocrine Tumor (NET) Registry, the prognostic and discriminatory power of different LN ratio (LNR) and log odds of metastatic LN (LODDS) classifications were investigated using multivariate Cox regression and C-statistics in 671 patients with resected GEP-NEN. An increase in positive LN (pLN), LNR, and LODDS was associated with advanced tumor stages, distant metastases, and hormonal functionality. However, none of the alternative LN classifications studied showed discriminatory superiority in predicting prognosis over the currently used N category. Interestingly, in a subgroup analysis, one LODDS classification was identified that might be most appropriate for patients with pancreatic NEN (pNEN). On this basis, a nomogram was constructed to estimate the prognosis of pNEN patients after surgery. In conclusion, a more accurate classification of LN status may allow a more precise prediction of overall survival and provide the basis for individualized strategies for postoperative treatment and surveillance especially for patients with pNEN.

Drug landscape in patients receiving general outpatient palliative care in Germany: results from a retrospective analysis of 10,464 patients.

BACKGROUND: According to § 27 and § 87 1b of the German Social Code, Book V, general outpatient palliative care (GOPC) aims to promote, maintain, and improve the quality of life and self-determination of seriously ill people. It should enable them to live in dignity until death in their preferred environment. Instead of a curative approach GOPC treatment focuses on the multiprofessional objective of alleviating symptoms and suffering on a case-by-case basis using medication or other measures, as well as the management of an individual treatment plan. The aim of this study was therefore to investigate to what extent medication differs from 12 months prior GOPC treatment within 12 months following GOPC treatment. METHODS: A retrospective database cross sectional study based on the IQVIA Disease Analyzer (DA) was performed, including adult patients with cancer diagnosis and at least one documentation of palliative support between January 1st, 2018 and December 31st, 2021, in 805 general practices (GP). RESULTS: The results of this study show, that in the context of general general outpatient palliative care, there is a significant increase in the prescription of opioids (18.3% vs. 37.7%), sedatives (7.8% vs. 16.2%) and antiemetics (5.3% vs. 9.7%), as well as a significant reduction in other medications such as statins (21.4% vs. 11.5%), proton pump inhibitors (PPI) (41.2% vs. 35.3%), or antihypertensives (57.5% vs. 46.6%). CONCLUSIONS: Our results support the role of GOPC as an important element in improving pharmacological symptom control and deprescription to improve quality of life of patients at the end of their life.

A single center comparative retrospective study of in situ split plus portal vein ligation versus conventional two-stage hepatectomy for cholangiocellular carcinoma.

INTRODUCTION: Cholangiocellular carcinoma (CCA) has a poor prognosis and the goldstandard even in locally advanced cases remains radical surgical resection. This approach however is limited by the future liver remnant volume (FLRV) after extensive parenchymal dissection leading to post-operative liver failure and high mortality rates. The aim of this study was to compare the outcome of in situ liver transection with portal vein ligation (ISLT) procedure and conventional two-stage hepatectomy with portal vein embolization (PVE/TSH) in patients with CCA. METHODS: All patients with CCA and insufficient FLR considered for either ISLT or PVE/TSH were analyzed for outcomes including post-operative morbidity, mortality, and overall survival rates (OS). RESULTS: Sixteen patients received ISLT and eight patients underwent PVE/TSH. The completion rate of the second stage in the PVE/TSH group was 62% and 100% in the ISLT group (p = 0.027). The overall 90-day morbidity rates including severe complications (Clavien-Dindo ≥3b) were comparable (PVE/TSH 40% vs. ISLT 69%, p = 0.262). The median OS (PVE/TSH 7 months vs. ISLT 3 months) and the 90-day mortality rates (PVE/TSH 0% vs. ISLT 50%) did not significantly differ between the two groups (p > 0.05). In multivariate analysis, biliary resection and reconstruction was the only risk factor independently associated with 90-day post-operative morbidity [HR = 20.0; 95%CI (1.68-238.63); p = 0.018]. CONCLUSION: Our results demonstrate comparable outcomes in both groups in a rather prognostically unfavorable disease. The completion rate in the ISLT group was significantly higher than in the PVE/TSH cohort. This work encourages specialized hepato-biliary-pancreatic centers in applying the ISLT procedure in selected cases with CCA.

Long-term effects of retrograde approach on the knee after motorized femoral limb lengthening.

BACKGROUND AND PURPOSE: The retrograde femoral approach is an established technique for implantation of nails for leg lengthening and correction and in cases of distal femoral fractures. The purpose of this study was to determine the 10-year outcome of this technique by analyzing the clinical long-term effects and radiological status of the knee after leg lengthening via a retrograde femoral approach. PATIENTS AND METHODS: This retrospective single-center study included 13 patients (median age at surgery 17 [range 15-20] years) who underwent unilateral, retrograde, femoral lengthening with a motorized nail. Outcome measurements were graded variables of the SF-36, ISKD score, and Lysholm score. MRI of both knees was performed in all patients. MRI was evaluated for the presence of degenerative changes and compared with the healthy contralateral knee. Cartilage condition was graded according to the International Cartilage Repair Society (ICRS) scoring system. RESULTS: All patients were pain-free and had a full range of motion 10 (range 10.0-12.2) years after surgery. All postoperative knees showed fibrosis of Hoffa's fat pad and moderate to severe cartilage defects (ICRS Grade 2-4) of the trochlear groove (nail entry site). 6 out of 13 operated knees exhibited retropatellar cartilage defects. CONCLUSION: Our study showed that patients were pain-free, but cartilage defects at the entry point and arthrofibrosis at Hoffa's fat pad were observed without causing clinical impairment.

A New Nomogram-Based Prediction Model for Postoperative Outcome after Sigmoid Resection for Diverticular Disease.

Background and Objectives: Sigmoid resection still bears a considerable risk of complications. The primary aim was to evaluate and incorporate influencing factors of adverse perioperative outcomes following sigmoid resection into a nomogram-based prediction model. Materials and Methods: Patients from a prospectively maintained database (2004-2022) who underwent either elective or emergency sigmoidectomy for diverticular disease were enrolled. A multivariate logistic regression model was constructed to identify patient-specific, disease-related, or surgical factors and preoperative laboratory results that may predict postoperative outcome. Results: Overall morbidity and mortality rates were 41.3% and 3.55%, respectively, in 282 included patients. Logistic regression analysis revealed preoperative hemoglobin levels (p = 0.042), ASA classification (p = 0.040), type of surgical access (p = 0.014), and operative time (p = 0.049) as significant predictors of an eventful postoperative course and enabled the establishment of a dynamic nomogram. Postoperative length of hospital stay was influenced by low preoperative hemoglobin (p = 0.018), ASA class 4 (p = 0.002), immunosuppression (p = 0.010), emergency intervention (p = 0.024), and operative time (p = 0.010). Conclusions: A nomogram-based scoring tool will help stratify risk and reduce preventable complications.

Methylation and copy number profiling: emerging tools to differentiate osteoblastoma from malignant mimics?

Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOS/FOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.

Prognostic Performance of Alternative Lymph Node Classification Systems for Patients with Medullary Thyroid Cancer: A Single Center Cohort Study.

BACKGROUND: Lymph node ratio (LNR) and the log odds of positive lymph nodes (LODDS) have been proposed as alternative lymph node (LN) classification schemes. Various cut-off values have been defined for each system, with the question of the most appropriate for patients with medullary thyroid cancer (MTC) still remaining open. We aimed to retrospectively compare the predictive impact of different LN classification systems and to define the most appropriate set of cut-off values regarding accurate evaluation of overall survival (OS) in patients with MTC. METHODS: 182 patients with MTC who were operated on between 1985 and 2018 were extracted from our medical database. Cox proportional hazards regression models and C-statistics were performed to assess the discriminative power of 28 LNR and 28 LODDS classifications and compare them with the N category according to the 8th edition of the AJCC/UICC TNM classification in terms of discriminative power. Regression models were adjusted for age, sex, T category, focality, and genetic predisposition. RESULTS: High LNR and LODDS are associated with advanced T categories, distant metastasis, sporadic disease, and male gender. In addition, among 56 alternative LN classifications, only one LNR and one LODDS classification were independently associated with OS, regardless of the presence of metastatic disease. The C-statistic demonstrated comparable results for all classification systems showing no clear superiority over the N category. CONCLUSION: Two distinct alternative LN classification systems demonstrated a better prognostic performance in MTC patients than the N category. However, larger scale studies are needed to further verify our findings.

The early evolutionary landscape of osteosarcoma provides clues for targeted treatment strategies.

Osteosarcomas are aggressive primary tumors of bone that are typically detected in locally advanced stages; however, which genetic mutations drive the cancer before its clinical detection remain unknown. To identify these events, we performed longitudinal genome-sequencing analysis of 12 patients with metastatic or refractory osteosarcoma. Phylogenetic and molecular clock analyses were carried out next to identify actionable mutations, and these were validated by integrating data from additional 153 osteosarcomas and pre-existing functional evidence from mouse PDX models. We found that the earliest and thus clinically most promising mutations affect the cell cycle G1 transition, which is guarded by cyclins D3, E1, and cyclin-dependent kinases 2, 4, and 6. Cell cycle G1 alterations originate no more than a year before the primary tumor is clinically detected and occur in >90% and 50% of patients of the discovery and validation cohorts, respectively. In comparison, other cancer driver mutations could be acquired at any evolutionary stage and often do not become pervasive. Consequently, our data support that the repertoire of actionable mutations present in every osteosarcoma cell is largely limited to cell cycle G1 mutations. Since they occur in mutually exclusive combinations favoring either CDK2 or CDK4/6 pathway activation, we propose a new genomically-based algorithm to direct patients to correct clinical trial options. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Surgical management in immunosuppressed patients with sigmoid diverticulitis, still a challenge: a single-center observational study.

PURPOSE: The question of whether immunosuppressed (IS) patients should be offered elective sigmoidectomy following a single episode of diverticulitis is controversial. We intended to examine the perioperative outcome of IS and immunocompetent (IC) patients after sigmoid resection. METHODS: A single institutional cohort study was conducted, including all surgically treated patients with sigmoid diverticulitis between 2004 and 2021. IS and IC patients were further subdivided into emergency and elective cases. Morbidity and mortality in both groups and factors influencing surgical outcome were examined using uni- and multivariate regression analyses. RESULTS: A total of 281 patients were included in the final analysis. Emergency surgery was performed on 98 patients while 183 patients underwent elective sigmoid resection. Emergency sigmoidectomy demonstrates significantly higher morbidity and mortality rates in IS patients as compared to IC patients (81.81% vs. 42.1%; p = 0.001, respectively 27.27% vs. 3.94%; p = 0.004), while major morbidity and mortality was similar in both groups in the elective setting (IS: 23.52% vs. IC: 13.85%; p = 0.488, respectively IS: 5.88% vs. IC: 0%; p = 1). On multivariate regression analysis for major postoperative morbidity, ASA score [OR 1.837; (95% CI 1.166-2.894); p = 0.009] and emergency surgery under immunosuppression [OR 3.065; (95% CI 1.128-8.326); p = 0.028] were significant. In-hospital mortality was significantly related to age [OR 1.139; (95% CI 1.012-1.282); p = 0.031], preoperative CRP count [OR 1.137; (95% CI 1.028-1.259); p = 0.013], and immunosuppression [OR 35.246; (95% CI 1.923-646.176), p = 0.016] on multivariate analysis. CONCLUSIONS: Elective surgery for sigmoid diverticulitis in immunocompromised patients demonstrates higher efficacy and safety when compared to sigmoid resection in the emergency setting.

The optimal timing of elective surgery in sigmoid diverticular disease: a meta-analysis.

PURPOSE: The aim of this meta-analysis was to investigate the optimal time point of elective sigmoidectomy regarding the intraoperative and postoperative course in diverticular disease. METHODS: A comprehensive literature research was conducted for studies comparing the operative outcome of early elective (EE) versus delayed elective (DE) minimally invasive sigmoidectomy in patients with acute or recurrent diverticular disease. Subsequently, data from eligible studies were extracted, qualitatively assessed, and entered into a meta-analysis. By using random effect models, the pooled hazard ratio of outcomes of interest was calculated. RESULTS: Eleven observational studies with a total of 2096 patients were included (EE group n = 828, DE group n = 1268). Early elective sigmoidectomy was associated with a significantly higher conversion rate as the primary outcome in comparison to the delayed elective group (OR 2.48, 95% CI 1.5427-4.0019, p = 0.0002). Of the secondary outcomes analyzed only operative time (SMD 0.14, 95% CI 0.0020-0.2701, p = 0.0466) and time of first postoperative bowel movement (SMD 0.57, 95% CI 0.1202-1.0233, p = 0.0131) were significant in favor of the delayed elective approach. CONCLUSIONS: Delayed elective sigmoid resection demonstrates benefit in terms of reduced conversion rates and shortened operative time as opposed to an early approach. Conversely, operative morbidities seem to be unaffected by the timing of surgery. However, a final and robust conclusion based on the included observational cohort studies must be cautiously made. We therefore highly advocate larger randomized controlled trials with homogenous study protocols.

Early elective versus elective sigmoid resection in diverticular disease: not only timing matters-a single institutional retrospective review of 133 patients.

PURPOSE: The optimal timing of elective surgery in patients with the colonic diverticular disease remains controversial. We aimed to analyze the timing of sigmoidectomy in patients with diverticular disease and its influence on postoperative course with respect to the classification of diverticular disease (CDD). METHODS: Patients who underwent elective laparoscopic sigmoidectomy were retrospectively enrolled and subdivided into two groups based on the time interval between the last attack and surgery: group A, early elective (≤ 6 weeks), and group B, elective (> 6 weeks). Multivariate regression models were used to identify factors which predict conversion to laparotomy, postoperative course, and length of hospital stay. RESULTS: A total of 133 patients (group A (n = 88), group B (n = 45)) were included. Basic demographic data did not differ between groups except for a higher rate of diabetes in group B (p = 0.009). The conversion rate was significantly higher in group A in comparison to group B (group A vs. group B: n = 23 (26.1%) vs. n = 3 (6.7%), p = 0.007). Logistic regression analysis revealed the timing of surgery and CDD stage as significant predictors for intraoperative conversion. Moreover, the postoperative course was influenced by high age as well as intraoperative conversion and length of hospital stay by conversion, preoperative CRP levels, and elective surgery. CONCLUSIONS: Both, timing of surgery and the disease stage, influence the conversion rates in laparoscopic sigmoidectomy for diverticular disease. Accordingly, patients with complicated acute or chronic sigmoid diverticulitis should be operated in the inflammation-free interval.

Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy versus Chest Tube Drainage for Treatment of Secondary Spontaneous Pneumothorax-A Retrospective Single-Center Analysis.

Background and objective: Current guidelines recommend chest tube (CT) drainage as the initial treatment of secondary spontaneous pneumothorax (SSP). Surgery should be considered in cases of persistent air leak or recurrent disease. Video-assisted thoracoscopic surgery (VATS) is nowadays an established surgical treatment for complicated spontaneous pneumothorax. However, reports on VATS-bullectomy with partial pleurectomy (VBPP) for treatment of secondary spontaneous pneumothorax (SSP) are limited. The primary aim of this study was to evaluate and compare the clinical outcomes of patients with secondary pneumothorax treated either by VBPP or CT drainage in our institution. Secondly, we assessed underlying clinical parameters to identify potential risk factors for SSP recurrence. Materials and Methods: Eighty-two patients were included in this study. Long-term recurrence rates and potential risk factors for SSP recurrence were analyzed. Results: Thirty-six patients (43.9%) underwent VBPP, whereas 46 (56.1%) patients subsequently underwent CT treatment. During a median follow-up period of 76.5 months, VBPP patients experienced a significantly low recurrence rate compared to CT patients (VBPP vs. CT: 16.7% vs. 41.3%; p = 0.016). However, VBPP was associated with a higher complication rate and significantly longer length of hospital stay (LOS). Male sex (male vs. female: p = 0.021) and CT treatment (VBPP vs. CT: p < 0.001) were identified as potential risk factors for SSP recurrence. Conclusions: VBPP is a suitable surgical treatment for SSP. However, prolonged LOS and possible complications should be discussed prior to VBPP.

Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response.

Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.

Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms.

BACKGROUND: Oncolytic virotherapy is an upcoming treatment option for many tumor entities. But so far, a first oncolytic virus only was approved for advanced stages of malignant melanomas. Neuroendocrine tumors (NETs) constitute a heterogenous group of tumors arising from the neuroendocrine system at diverse anatomic sites. Due to often slow growth rates and (in most cases) endocrine non-functionality, NETs are often detected only in a progressed metastatic situation, where therapy options are still severely limited. So far, immunotherapies and especially immunovirotherapies are not established as novel treatment modalities for NETs. METHODS: In this immunovirotherapy study, pancreatic NET (BON-1, QGP-1), lung NET (H727, UMC-11), as well as neuroendocrine carcinoma (NEC) cell lines (HROC-57, NEC-DUE1) were employed. The well characterized genetically engineered vaccinia virus GLV-1 h68, which has already been investigated in various clinical trials, was chosen as virotherapeutical treatment modality. RESULTS: Profound oncolytic efficiencies were found for NET/NEC tumor cells. Besides, NET/NEC tumor cell bound expression of GLV-1 h68-encoded marker genes was observed also. Furthermore, a highly efficient production of viral progenies was detected by sequential virus quantifications. Moreover, the mTOR inhibitor everolimus, licensed for treatment of metastatic NETs, was not found to interfere with GLV-1 h68 replication, making a combinatorial treatment of both feasible. CONCLUSIONS: In summary, the oncolytic vaccinia virus GLV-1 h68 was found to exhibit promising antitumoral activities, replication capacities and a potential for future combinatorial approaches in cell lines originating from neuroendocrine neoplasms. Based on these preliminary findings, virotherapeutic effects now have to be further evaluated in animal models for treatment of Neuroendocrine neoplasms (NENs).

Activating mutations in the MAP-kinase pathway define non-ossifying fibroma of bone.

Non-ossifying fibroma (NOF), which occasionally results in pathologic fracture, is considered the most common benign and self-limiting lesion of the growing skeleton. By DNA sequencing we have identified hotspot KRAS, FGFR1 and NF1 mutations in 48 of 59 patients (81.4%) with NOF, at allele frequencies ranging from 0.04 to 0.61. Our findings define NOF as a genetically driven neoplasm caused in most cases by activated MAP-kinase signalling. Interestingly, this driving force either diminishes over time or at least is not sufficient to prevent autonomous regression and resolution. Beyond its contribution to a better understanding of the molecular pathogenesis of NOF, this study adds another benign lesion to the spectrum of KRAS- and MAP-kinase signalling-driven tumours. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Loop ileostomy versus loop colostomy as temporary deviation after anterior resection for rectal cancer.

PURPOSE: Construction of a temporary stoma is a common adjunct to low anterior resection for rectal cancer and can be accomplished either with loop ileostomy (LI) or loop colostomy (LC) with the question of the most appropriate one still remaining controversial. The aim of this study is to compare stoma-related morbidity between the two groups. METHODS: A retrospective review was conducted including 148 consecutive patients (LI: 55/LC: 93) who underwent anterior resection for rectal cancer between January 2004 and December 2018 in our department. Time interval between low anterior resection and stoma reversal was similar for both groups. Comparison between the two groups was made regarding stoma-related morbidity after stoma construction and after stoma reversal, respectively. RESULTS: A total number of 17 patients suffered from complications after the construction of a protective LI compared with 25 patients after the construction of a LC (LI vs LC: 17/55 (30.1%) vs 25/93 (26.9%); p = 0.59). The most common morbidity noted in both groups before stoma closure was parastomal hernia, with the difference being statistically not significant (LI vs LC: 11/55 (20%) vs 21/93 (22.6%); p = 0.84). However, patients with LI suffered from significantly more peristomal skin irritations compared with the patients with LC (LI vs LC: 5/55 (9.1%) vs 1/93 (1.1%); p = 0.027). Overall morbidity rate after stoma closure was found to be comparable in both groups (LI vs LC: 7/37 (18.9%) vs 6/64 (9.4%); p = 0.16). The most common complication after stoma reversal was wound infection (LI vs LC: 5/37 (13.5%) vs 5/64 (7.8%); p = 0.49). CONCLUSION: With the exception of a higher rate of skin irritation after LI construction, all other postoperative outcomes were found to be comparable in both study groups. Further randomized clinical trials are required to verify these findings. The study was registered in the German Registry for Clinical Trials (DRKS00020766, date of registration: 11.02.2020).