Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer.

BACKGROUND: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

[Collected data on freehand technique instrumentation and literature comparison on fluoroscopic and CT-assisted navigation]. / Erhobene Daten zur Instrumentierung in Freihandtechnik und Literaturvergleich zu fluoroskopisch- und CT-gestützter Navigation.

BACKGROUND: A proven and frequently used surgical procedure in patients with idiopathic scoliosis (IS) is posterior transpedicular corrective spondylodesis using the freehand technique. Novel procedures with fluoroscopically and computed tomography (CT)-assisted navigation are presumed to be less risky and more accurate. OBJECTIVE: Is the freehand technique for IS safe with respect to screw-associated complications and intraoperative radiation exposure? MATERIAL AND METHODS: Prospectively collected data (2017-2018) from 39 consecutive patients (average age 18.7 years) with thoracic single curvature IS (61.7°â€¯± 13.9°) from a specialized scoliosis center were evaluated for the following parameters (mean ± standard deviation): total radiation product, fluoroscopy time, fused segments, operative time, blood loss and screw-associated complications. A comparison with data from the literature on intraoperative radiation exposure using navigation procedures was carried out. RESULTS: The total radiation product per patient was 71.7 ± 44.0 cGy*cm2, fluoroscopy time 17.4 ± 8.6 s. (7.8 segments), operative time 183.5 ± 54.2 min and blood loss 379.5 ± 183 ml. There were no screw-associated complications in the entire collective. Correction of the main curvature was 75.7%. Comparison of the data with index data from the literature showed a 1.25-12.5-fold higher radiation exposure for patients with fluoroscopically assisted navigation and 9.25-12.3-fold higher radiation exposure with CT-assisted procedures compared to the present results. CONCLUSION: The results of this study showed that with appropriate experience freehand positioning of pedicle screws is associated with comparable accuracy and less radiation exposure for patients than navigation procedures. With respect to the young age of patients, a radiation-induced long-term risk for malignant diseases should be taken into consideration.

A rare case of perivascular epithelioid cell tumor (PEComa) of the pancreas diagnosed by endoscopic ultrasound.

A 49-year-old woman consulted her general practitioner (GP) regarding epigastric pain that she had experienced for 2 months. Physical examination and laboratory results were unremarkable. An abdominal ultrasound indicated a solid pancreatic tumor, which was confirmed on subsequent CT and MRI. Endoscopic ultrasound (EUS) showed a well-defined heterogeneous, predominantly hypoechoic mass in the pancreatic body, so a neuroendocrine tumor (NET) was suspected. However, EUS-guided fine-needle aspiration (EUS-FNA) was performed and based on (immuno-)histochemical findings, the extremely rare diagnosis of a perivascular epithelioid cell tumor (PEComa) of the pancreas was made. Due to the malignant potential of pancreatic PEComas, laparoscopic left-sided pancreatectomy was performed. We present a case diagnosed by preoperative EUS-FNA highlighting the clinical and endosonographic features which help to distinguish it from its most important differential diagnosis, neuroendocrine tumors (NETs) of the pancreas.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

The effect of incidental dural lesions on outcome after decompression surgery for lumbar spinal stenosis: results of a multi-center study with 800 patients.

PURPOSE: Incidental durotomy is one of the most common complications in lumbar spine surgery. There are conflicting reports whether a dural lesion is associated with an inferior outcome after lumbar decompression. This study analyzed the effect of incidental durotomy in this specific group of patients (Dura+) and compared the results with the remaining cohort without dural laceration (Dura-). METHODS: This prospective multi-center study included 800 patients with lumbar spinal stenosis who underwent exclusive decompression surgery. All procedures were performed as part of a multi-center investigation at three highly specialized spine clinics. Outcome measures (ODI, EQ5D, VASback pain and VASleg pain) were obtained preoperatively as well as 3 and 12 months after surgery. The effect of an incidental durotomy on the clinical outcomes was analyzed statistically between the two cohorts. RESULTS: An intraoperative dura lesion was recorded in 6.5 % (n = 52/800) of all cases. Both cohorts (Dura+ and Dura-) did not reveal any differences regarding patient demographics, risk factors, or co-morbidities at baseline. The length of the hospital stay was significantly longer for the Dura+ cohort (8.0 vs. 6.4 days; p < 0.01). After 12 months, the Dura- cohort demonstrated a significantly greater improvement in VASback pain in comparison to the Dura+ cohort (Δ21.4 vs. Δ7.2 points; p < 0.05). The differences for the remaining outcome measures were not statistically significant (p > 0.05). CONCLUSIONS: The results of this study reveal that an incidental durotomy was associated with a significant increase in the patient's length of stay, and risk for re-intervention for the treatment of persisting CSF leakage. In contrast to previous reports which have investigated the effects of incidental durotomies on the clinical outcome after lumbar decompression surgery, our data further suggest a possible inferior outcome in terms of low back pain improvement in the Dura+ cohort, which became clinically apparent at the 12-month follow-up period. Future studies should investigate whether a more pronounced decompression required for adequate exposure and repair of a dural laceration may, ultimately, result in increased segmental instability and in clinically undesirable low back pain.

A case of cutaneous Rhodotorula infection mimicking cryptococcosis.

Rhodotorula is a ubiquitous environmental and commensal yeast, and an emerging opportunistic pathogen, particularly in immunocompromised individuals. Clinical infections with Rhodotorula have been increasingly recognized over the past 30 years; however, infections in solid-organ transplant recipients are uncommon, and cutaneous manifestations have rarely been reported. We describe a 59-year-old male renal transplant recipient, who developed cutaneous infection with Rhodotorula upon failure of his graft and commencement of haemodialysis.

Obesity-related immune responses and their impact on surgical outcomes.

The obesity epidemic represents a critical disease burden with broad clinical consequences. At the same time, obesity has been linked to inferior surgical outcomes and considered a contraindication for some elective surgical procedures. A growing body of mechanistic evidence has accumulated linking obesity to changes of metabolism and immune responses. This concept provides an integrated inflammatory network based on the perception of obesity as a state of chronic low-grade inflammation. With a more detailed understanding of this dynamic network and mechanistic insights, novel treatment and management strategies may be developed with the goal to optimize surgical outcomes in obese patients.

Bilateral parotid gland metastases from carcinoma of the breast that presented 25 years after initial treatment.

We report a case of a 76-year-old woman with metastases to both parotid glands almost 25 years after mastectomy and chemotherapy for primary carcinoma of the breast. Immunohistochemical staining is invaluable in establishing the origin of metastatic deposits, in this case, expression of oestrogen receptors in a previously resected adenocarcinoma of the breast. The information can be used to target treatment accurately in selected cases of advanced malignancy.

[Thromboprophylaxis and platelet aggregation inhibitors in spinal surgery: perioperative management]. / Thromboseprophylaxe und Aggregationshemmer in der Wirbelsäulenchirurgie: perioperative Management.

BACKGROUND: The perioperative use of anticoagulants (AC) and platelet aggregation inhibitors (PAI) in the field of spinal surgery suggests an increased rate of epidural bleeding. However, evidence is lacking and these medications are most often indispensable in the prevention of thromboembolic complications. Comprehensive recommendations for the correct use of AC and PAI are lacking. OBJECTIVE: The aim of this study was an analysis of the current situation with regards to the use of AC and PAI in spinal surgery and development of new recommendations. MATERIAL AND METHODS: Two independent surveys on the perioperative use of AC and PAI were obtained from centers for spinal surgery in Germany. The study obtained information on the perioperative use of AC and PAI, risk assessment of thromboembolic and hemorrhagic events as well as on the type and extent of the substance groups used. RESULTS: Almost the entire patient collective (98%) received perioperative low molecular weight heparin. In 64% the medical prophylaxis was started before surgery and in 36% after surgery. The period of prophylaxis was determined arbitrarily. Approximately 40% of interviewees employed paravertebral infiltration and 19% injected into the epidural space in patients on PAI medication. Open spinal canal surgery was performed in 30% of PAI medicated patients and closed spinal canal surgery was executed in 40%. The risk assessment of PAI differed significantly between aspirin and receptor blocker medication as well as dual administration of PAI. DISCUSSION: The use of AC and PAI in spinal surgery in Germany is very heterogeneous and large deviations from the guidelines frequently occurred. Therefore, there is a strong need for further studies to accurately assess the perioperative use of AC and PAI and to formulate precise recommendations.

[The impact of sleep endoscopy for obstructive sleep-disordered breathing in children and adolescents]. / Bedeutung der Schlafendoskopie bei obstruktiv-schlafbezogener Atmungsstörung im Kindes- und Jugendalter.

OBJECTIVE: Studies on the surgical treatment of OSAS in adults have shown an improved outcome after targeted therapy by drug-induced sleep endoscopy (DISE). So far, only a few studies have focused on this method in children. The aim of this study is to evaluate the impact of DISE for children with obstructive sleep-disordered breathing and to determine the influence of DISE on treatment recommendations. SUBJECTS AND METHODS: The medical records of children (n=25) who underwent polysomnography and DISE between 05/2012 and 12/2013 were retrospectively reviewed. The subjects were divided into an UARS (upper airway resistance syndrome)/mild OSAS group (AHI<5; n=10) and a moderate/severe OSAS group (AHI≥5; n=15). RESULTS: The oropharynx was the most common site of obstruction. Prevalence of complete obstruction at the oropharynx was significantly higher in moderate or severe OSAS (p=0.02). The obstruction pattern of the velopharynx was significantly associated with the size of the adenoids (p=0.02), but tonsil and adenoid size were not related to the severity of OSAS. 71% of children with grade IV tonsils showed complete obstruction of the oropharynx. After DISE, the initial management plan changed in 5 patients (20%). CONCLUSION: DISE is a promising technique to identify sites of obstruction in children with OSAS and to guide treatment decisions. Further studies are needed to predict persistent OSAS based on this tool.

[What are the reasons for patient preference? A comparison between oral and subcutaneous administration]. / Was sind die Gründe der Patientenpräferenz? Vergleich von oraler und subkutaner Darreichungsform.

BACKGROUND: Today there are different subcutaneous and three oral applicable medications for prevention of venous thromboembolism after knee and hip replacement. It is a general opinion that patients will prefer oral administration. However, until today there has been no study that analysed patient preferences and motives for deciding on the kind of administration. These data would be of interest since the consideration of patient preferences could improve adherence. The present study analysed patient preferences regarding oral or subcutaneous administration of medication after elective hip or knee replacement surgery. The results will have implications for clinical practice and for decision-making concerning the kind of administration. MATERIAL AND METHODS: This prospective, multi-centric, observational study was conducted in six emergency hospitals and six rehabilitation hospitals. 178 current hip and knee replacement patients undergoing thromboprophylaxis and at least one further oral medication were interviewed. Subjective assessment data of patients were collected on study-specific questionnaires (epidemiological data, amount and background of general oral medication, details on subcutaneous thromboprophylaxis, preference of administration, causes for preference). RESULTS: 71.91 % of the interviewed patients preferred the daily intake of a tablet, whereas only 14.61 % favoured the daily subcutaneous injection. Main causes for the preference of oral administration were easier (86.6 % of nominations) and less complex (73.1 % of nominations) handling. 70.9 % reported that one more oral application would be unproblematic. Painlessness of oral administration was relevant for 65.7 %. Causes for preferring subcutaneous administration were "safety" (55.3 % of nominations) and an assumption of a generally better effectivity of subcutaneous (47.4 % of nominations) administration. Subjective discomfort induced by subcutaneus administration increased with the time interval since surgery. Less than 5 % of patients prefer subcutaneous administration due to the high volume of their existing oral medication. CONCLUSION: Patient approval of oral administration is governed by practical and comfort issues. In general, patients on existing oral medications are uncritical concerning a temporary additional oral medication. The clear discomfort measured in association with subcutaneous administration supports the idea that the oral route will have advantages for patient adherence. In particular this is of relevance with increasing time interval since surgery. Patients who have a very high volume of oral medications will probably profit from subcutaneous administration. The main reasons that patients gave for the preference of subcutaneous administration are based on incorrect knowledge. Therefore it is necessary to improve patient education concerning the existing alternatives for thromboprophylaxis.

[Transforaminal lumbar interbody fusion for the treatment of degenerative spondylolisthesis]. / Transforaminale lumbale interkorporelle Fusion zur Versorgung der degenerativen Spondylolisthese.

INTRODUCTION: Degenerative spondylolisthesis (DS) is a common cause of lumbal and lumbosacral pain as well as radicular pain. Retention and fusion is a good treatment option. Some patients have a symptomatic adjacent degenerative disc disease (DDD) in addition to DS. In these cases the adjacent segments should be fused as well. There are different techniques of fusion available, such as posterior with instrumentation or additional anterior support. This study evaluated results of transforaminal lumbar interbody fusion (TLIF) in patients with monosegmental DS and adjacent DDD. MATERIAL AND METHODS: A total of 28 patients with monosegmental DS and adjacent DDD were included into the study (all patients with bisegmental posterior instrumentation and fusion, 14 patients 1 level TLIF, 14 patients 2 level TLIF). Before surgery and 12 months after surgery the following measurements were made: pain (visual analog scale VAS), Oswestry disability index (ODI) and plain radiographs with radiometric analysis. In a sub-analysis patients with 1 and 2 level TLIF were compared. RESULTS: Pain reduction (average VAS from 8.7-3.1) and ODI (63% to 28%) showed significant improvements. Radiometric analysis showed a significant disc height reconstruction and a significant reduction of spondylolisthesis (TLIF level with spondylolisthesis). Bisegmental anterior support showed a significantly better relordosation compared to monosegmental anterior support. The complication rate was 21.4% including hemorrhages, dura leakage, wound infection and adjacent segment degeneration. There were no fatal complications. DISCUSSION: The TLIF procedure is a safe and effective treatment for monosegmental DS with adjacent symptomatic DDD. Clinical results (pain, function) show no difference between both kinds of fusion (dorsal fusion and instrumentation versus dorsal fusion with instrumentation and TLIF) for the adjacent DDD. However, additional anterior support is more effective for relordosation of the segment. This could have impact on the mid-term and long-term outcome or in cases of adjacent segment fusion.

Liver transplantation to treat suspected hepatocellular carcinoma in iron-free foci in congenital hemochromatosis: case report.

Hepatocellular carcinoma (HCC) commonly develops in cirrhotic or noncirrhotic livers affected by congenital hemochromatosis. In patients with congenital hemochromatosis and HCC, liver transplantation is a therapeutic option with a 5-year posttransplantation survival rate as high as 80%. Herein is reported congenital hemochromatosis in a 37-year-old man. During a routine checkup, 2 liver nodules were detected. Signal characteristics at magnetic resonance imaging indicated the presence of iron-free foci (IFF). The serum α-fetoprotein concentration was within the range of normal, and repeated liver biopsy did not show histomorphologic signs of malignancy but confirmed the presence of IFF in surrounding siderosis. The patient was listed for liver transplantation with match MELD (Model of End-Stage Liver Disease including exceptions) because of suspected HCC. After 173 days on the waiting list, liver transplantation was performed successfully. Histologic examination of the explanted liver confirmed 2 HCC lesions with a diameter of 0.9 cm in the exact projection as the IFF detected at magnetic resonance imaging. At 20 months of rapamycin-based immunosuppression therapy, there were no signs of HCC recurrence. This is, to our knowledge, the first report of liver transplantation performed to treat suspected HCC based on the finding of IFF in congenital hemochromatosis, with histopathologic confirmation of the diagnosis of HCC after transplantation. According to this case and the current literature, IFF in patients with congenital hemochromatosis should be considered preneoplastic lesions vulnerable to possible development of HCC.

Vertical emission profiles for Europe based on plume rise calculations.

The vertical allocation of emissions has a major impact on results of Chemistry Transport Models. However, in Europe it is still common to use fixed vertical profiles based on rough estimates to determine the emission height of point sources. This publication introduces a set of new vertical profiles for the use in chemistry transport modeling that were created from hourly gridded emissions calculated by the SMOKE for Europe emission model. SMOKE uses plume rise calculations to determine effective emission heights. Out of more than 40,000 different vertical emission profiles 73 have been chosen by means of hierarchical cluster analysis. These profiles show large differences to those currently used in many emission models. Emissions from combustion processes are released in much lower altitudes while those from production processes are allocated to higher altitudes. The profiles have a high temporal and spatial variability which is not represented by currently used profiles.

[Oral prevention of thromboembolism with rivaroxaban and dabigatran: are the newly approved drugs innovations in orthopaedic and trauma surgery? ]. / Orale Thromboembolieprophylaxe mit Rivaroxaban und Dabigatran: Sind die Neuzulassungen Innovationen für die operative Orthopädie und Unfallchirurgie?

Today the indication for thrombosis prophylaxis is a relevant and daily concern in orthopaedic surgery. Recently there are some changes concerning the German guidelines, which are approved by 27 German medical societies. For the first time the guidelines give distinct recommendations for the different indications, the kind of thrombosis prophylaxis and its duration. Some of the recommendations will lead to changes of both processes in outpatient and inpatient management. In parallel 2 new oral anticoagulants have been approved for the prevention of thromboembolic events after elective knee and hip replacement. Dabigatran is an oral thrombin inhibitor. Compared to enoxaparin it has a comparable profile of side effects and efficacy. Rivaroxaban is an oral Xa inhibitor which shows a significantly better efficacy compared to enoxaparin and no difference in side effects. The significant reduction of symptomatic thromboembolisms after elective knee and hip replacement was shown for rivaroxaban compared to enoxaparin in a pooled analysis of phase III data. This review discusses the main topics of the new German guideline and impact of the new oral anticoagulants on in- and outpatient treatment procedures.

[Operative and follow-up treatment of rotator cuff tears--the current situation]. / Operative Therapie und Nachbehandlung der Rotatorenmanschettenruptur--Aktueller Stand.

AIM: The aim of this study was to evaluate the current situation of rotator cuff repair and follow-up treatment in German hospitals. METHODS: An evaluated survey, enquiring about the year 2006, was sent to all 777 German orthopaedic and/or trauma surgery departments. The hospitals were chosen using the official index of hospitals from the German Federal Statistical Office. RESULTS: 44 % of the surveys were sent back, whereby 40 % were of use. Within the 309 departments, 26 % of the total number of 59,957 shoulder operations were rotator cuff repairs. Mini-open was the operation method in 49 %, open in 29 % and arthroscopic in 22 % of cases. Regarding the operational methods, there were differences between the departments and level of care. The arthroscopic technique was used sometimes in 48 % of the departments, whereas 52 % never used it. Specialised shoulder departments employed the total arthroscopic procedure more often. A set follow-up treatment occurred in 79 % of departments. CONCLUSION: Rotator cuff repair is mainly carried out using the mini-open method, which is nowadays regarded as gold standard.

[Anterior scoliosis surgery. State of the art and a comparison with posterior techniques]. / Ventrale Skolioseoperationen. Stand der Technik und Vergleich mit dorsalen Verfahren.

For more than 2 decades ventral derotation spondylodesis (Zielke VDS) as a major improvement over Dwyer instrumentation (DI) was the gold standard of instrumented curve correction and stabilization from the anterior approach. As the first available system it enables a true three-dimensional curve correction. A disadvantage is the low internal stabilization capability with a need for long-term external stabilization by means of cast and brace treatment postoperatively. Meanwhile with the development of modern single and dual solid rod systems these disadvantages can be avoided completely. Video-assisted (thoracoscopic) anterior scoliosis surgery accounts for less than 2% of anteriorly treated scoliosis cases, mainly due to a long operating time and significant learning curve.From the posterior approach the Cotrel-Dubousset instrumentation (CDI) as a polysegmentally attached posterior hook threaded dual rod system used to be state of the art for a long time, since it eliminated the disadvantages of Harrington instrumentation (HI) in terms of only one-dimensional correction and low stabilization capabilities. However even with CDI effective derotation was impossible. In posterior scoliosis surgery there is a strong trend away from hook systems towards transpedicular segmentally fixed dual rod systems not only in the lumbar spine but also in the thoracic area. Advantages of these newer techniques are shorter fusion, improved correction, and less loss of correction over time.Advantages of modern anterior instrumentation systems in comparison to posterior transpedicular instrumented dual rod systems are less blood loss, better derotation, slightly shorter fusion levels, and a better influence on sagittal plane control or improvement especially for hypokyphotic thoracic scoliosis cases. Our data also document a superior spontaneous correction of the lumbar curve after selective anterior instrumented correction (Lenke 1B+C), although other studies could not find significant differences. In our experience the neurological risk of anterior instrumented correction is also lower than that of posterior scoliosis surgery, although the morbidity and mortality data of the Scoliosis Research Society could not prove that anymore in recent years. A negative effect of anterior transthoracic scoliosis surgery in comparison to posterior surgery is a more negative effect on lung function, which improves slower after surgery and does not quite reach the levels of posterior surgery at follow-up. But new data on posterior segmental transpedicular correction and fusion also prove a lordosating effect with negative effect on lung function.