Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.

BACKGROUND: The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. RESULTS: Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets. CONCLUSIONS: Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

The right atrium in idiopathic hypereosinophilic syndrome : Insights from the 3D speckle tracking echocardiographic MAGYAR-Path Study.

BACKGROUND: Idiopathic hypereosinophilic syndrome is characterized by a persistent eosinophil blood count of >1.5 × 109 cells/l and organ damage, independent of the primary and secondary causes of eosinophilia. The purpose of the present study was to assess the three-dimensional speckle tracking echocardiography-derived right atrial volumetric and functional properties between hypereosinophilic syndrome patients and matched controls. METHODS: A total of 11 patients with idiopathic hypereosinophilic syndrome and 22 age- and gender-matched healthy controls were enrolled in the study. Three-dimensional speckle tracking echocardiography was used for calculation of right atrial volumes, volume-based functional properties, and strain parameters. RESULTS: Significantly increased right atrial maximum (68.7 ± 33.1 ml vs. 40.3 ± 12.1 ml, respectively; p = 0.001) and minimum volumes (48.3 ± 31.0 ml vs. 28.3 ± 9.4 ml, respectively; p = 0.009), as well as right atrial volume before atrial contraction (58.6 ± 27.3 ml vs. 34.5 ± 11.8 ml, respectively; p = 0.001), were found in hypereosinophilic syndrome patients compared with controls. Total and passive right atrial stroke volumes proved to be significantly increased in hypereosinophilic syndrome patients. However, global and mean segmental strain parameters did not differ significantly between the groups. CONCLUSION: Increased cyclic right atrial volumes and mild alterations in right atrial functional properties could be demonstrated in idiopathic hypereosinophilic syndrome patients.

Late cardiac effect of anthracycline therapy in physically active breast cancer survivors - a prospective study.

The late-onset cardiotoxic effect of anthracycline is known, however the early detection and prevention of subclinical myocardial damage has not been fully understood yet. Besides medical therapy regular physical activities may also play a role in the prevention and reduction of side effects of chemotherapy. The aim of our present study was to detect the effect of regular physical activities on the diastolic function and on the symptoms of late heart failure in case of anthracycline chemotherapy. The prospective study included 55 female patients (age 31-65 year, average 49.5 years) with breast cancer and no cardiovascular risk factors. Proper cardiologic checkup included physical examination (blood pressure, pulse, etc.), ECG, standard echocardiography parameters (EF, LV dimensions etc.) and specific tissue Doppler (TDI) measurements. Symptoms of heart failure were also recorded. After five years of follow-up, symptoms of heart failure were evaluated again. Patients were assigned into two groups depending on their physical activity: 36 patients did perform regular physical activities (mean age 49.2 years) and 19 patients did not (average age 50.1 years). There was no significant difference between the two groups in basic physiological or standard echocardiography parameters neither at the baseline nor at the later time points. Diastolic dysfunction (decreased E/A) was detected 6 months after the beginning of the treatment (T2 time point) in both groups. In the inactive group this value fell below one however there was no significant difference (1.1±0.25 vs. 0.95±0.22). One year after the beginning of the treatment (T3) a significant difference could be detected between the two groups (1.05±0.28 vs. 0.86±0.25. P=0.038). Consistent change in diastolic function (Ea/Aa) could be detected with the more sensitive TDI (Tissue Doppler Imaging) measurements after treatments in both groups, especially in the septal segment (in the non active group the Ea/Aa decreased markedly but not significantly at T2 - 1.1±0.55 vs. 0.81±0.44, and this difference became significant at T3 and 2 years after treatment (T4), p=0.007 and p=0.065). The filling pressure (E/Ea) rose above 10 (p=0.09) in the non active group at T2; and it kept rising in both groups and became significant at T3 (p=0.012). Five years after the onset of the treatment symptoms of heart failure were less frequently reported in the physically active group than in the inactive one (19.45% vs. 68.42%). The data of our study show that the diastolic dysfunction of the left ventricle related to the anthracycline therapy became evident in the physically active group later and the symptoms of heart failure were less frequent than in the non active group after five years period. Enrollment in sport activities could be a good means for partial prevention in this group of patients. Cardiologic checkup at proper intervals plays a pivotal role in detection of possible cardiotoxicity. This is a strong indication for changes in the lifestyle of the patient and the treatment protocol alike.

[Spinal deformity in Parkinson's disease: a treatment proposal]. / Wirbelsäulendeformitäten bei Parkinson: Ein Behandlungsvorschlag.

Spinal deformities in Parkinson's disease are difficult to treat but with good indications, spinal surgery is a better treatment option taking into account all factors that accompany Parkinson's disease. Despite greater operational time and cost expenditure with a long rehabilitation period, long stretch segmental fusion is preferable to short stretch segment fusion due to the lower revision rate. An adequate postoperative rehabilitation and good patient care is essential for success. This case illustrates successful treatment of a patient with Parkinson's disease and camptocormia by long stretch segmental fusion.

Early results in the treatment of proximal humeral fractures with a polyaxial locking plate.

OBJECTIVES: We report early results using a second generation locking plate, non-contact bridging plate (NCB PH((R)), Zimmer Inc. Warsaw, IN, USA), for the treatment of proximal humeral fractures. The NCB PH combines conventional plating technique with polyaxial screw placement and angular stability. DESIGN: Prospective case series. SETTING: A single level-1 trauma center. PATIENTS: A total of 50 patients with proximal humeral fractures were treated from May 2004 to December 2005. INTERVENTION: Surgery was performed in open technique in all cases. MAIN OUTCOME MEASURES: Implant-related complications, clinical parameters (duration of surgery, range of motion, Constant-Murley Score, subjective patient satisfaction, complications) and radiographic evaluation [union, implant loosening, implant-related complications and avascular necrosis (AVN) of the humeral head] at 6, 12 and 24 weeks. RESULTS: All fractures available to follow-up (48 of 50) went to union within the follow-up period of 6 months. One patient was lost to follow-up, one patient died of a cause unrelated to the trauma, four patients developed AVN with cutout, one patient had implant loosening, three patients experienced cutout and one patient had an axillary nerve lesion (onset unknown). The average age- and gender-related Constant Score (n = 35) was 76. CONCLUSIONS: The NCB PH combines conventional plating technique with polyaxial screw placement and angular stability. Although the complication rate was 19%, with a reoperation rate of 12%, the early results show that the NCB PH is a safe implant for the treatment of proximal humeral fractures.

Treatment of periprosthetic femur fractures with the non-contact bridging plate: a new angular stable implant.

OBJECTIVES: We report the application of a new fixed angle plate (NCB DF, Zimmer inc. USA, Warsaw, IN) in the treatment of periprosthetic femur fractures. The NCB DF combines conventional plating technique with polyaxial screw placement and angular stability. DESIGN: Prospective cohort study. SETTING: A single level-1 trauma center. PATIENTS: From May 2003 to December 2005, a total of 24 patients with periprosthetic femur fractures were treated. The NCB DF femur plate was used in all cases. The average follow-up period was 12 months (3-31 months). Twelve patients had a periprosthetic fracture after total knee replacement (TKA) and 12 patients after total hip replacement (THA). The mean period from primary joint replacement to periprosthetic fracture was 8.2 years for the THA group and 7.2 years for the TKA group. INTERVENTION: A combined conventional/locking surgical technique was performed in all the cases. MAIN OUTCOME MEASURES: Union, non-union, mal-union, duration of surgery, range of motion, postoperative mobility, subjective patient satisfaction and complications. RESULTS: The union rate was 90%, the mal-union rate 5% and the re-operation rate 15%. Postoperative mobility reached the preoperative level in all but for two patients. Three complications occurred relating to the implant or the procedure: one fatigue failure of the plate (non-union), one screw breakage, and one wound infection. CONCLUSIONS: The NCB DF combines conventional plating technique with polyaxial screw placement and angular stability. This combination technique shows promising results regarding union and mal-union rates in periprosthetic fractures in elderly and osteoporotic patients.

["... The better to see you with"--phothodynamic diagnostic in superficial bladder cancer]. / "... damit ich Dich besser sehen kann"--Photodynamische Diagnostik beim oberflächlichen Blasenkarzinom.

Fluorescence cystoscopy of the urinary bladder allows to better identify tumors and altered bladder mucosa (e.g. Carcinoma in situ). Instillation of 5-aminolevulinic acid or hexyl aminolevulinate approx. two hours before transurethral resection leads to metabolism of these compounds in the Häm-biosynthesis and to accumulation of protoporphyrin IX (PPIX). PPIX is an excellent fluorochrom, which lights up red when illuminated by blue light. During transurethral resection all tumors and all suspicious mucosal areas can be completely resected. As a consequence recurrence rate drops and patients need less re-operations and hospitalizations.

[Benign space-occupying cysts in the testis. An overview]. / Benigne zystische Raumforderungen des Hodens. Eine Ubersicht.

Testicular cysts are increasingly diagnosed in the course of scrotal ultrasound examination. Among other things this is due to the general availability of modern high-resolution ultrasound devices. Benign and malignant diseases with testicular cyst formation need to be differentiated by differential diagnosis and by their aetiology. Benign diseases with cystic space-occupying lesions of the testicle are tubular ectasia of the rete testis, cystic dysplasia, epidermoid cysts, simple intraparenchymatous testicular cysts and cysts of the tunica albuginea. Testicular dermoid cyst was long misleadingly regarded as potentially malignant, but is now classified as benign. On diagnosis of a benign lesion of the testis an organ-conserving surgical therapy or an observational watch-and-wait strategy can be recommended in most cases.

Cardiotoxicity of anthracycline in young breast cancer female patients: the possibility of detection of early cardiotoxicity by TDI.

Tissue Doppler imaging (TDI) was investigated for its applicability for detecting cardiac function and early cardiotoxicity in breast cancer patients treated with anthracyclines. A total of 40 women (age range 18 to 65 years) were enrolled, who had not received anthracyclines previously and had normal systolic and diastolic cardiac function. All healthy patients in the control group were of the same age. Each patient underwent not only standard echocardiographic measurements (ventricular dimensions and wall thickness, ejection fraction, E-wave deceleration time (DT), E/A ratio), but also specific imagings (E-septum separation, pulmonary venous flow), and in addition the myocardial velocity of many segments of mitral anulus obtained with pulsed wave tissue Doppler imaging were performed during the one year of observation period. Based on the results we found that systolic left ventricular function did not change significantly - neither in the study nor in the control group. Diastolic left ventricular function was impaired in 39 patients (97.5%), and 30 (75%) of these showed clear changes by means of both the traditional E/A ratio and TDI. Diastolic dysfunction in 9 patients (22.5%), however, could be detected only with TDI. The analysis of myocardial velocity in different segments showed that diastolic dysfunction does not develop in a homogeneous way but in a different way in segments. Diastolic function was intact in the control group during the study. The detectable myocardial damage occurred in the study group of young female patients without risk factors as a result of one year anthracycline therapy was so severe that the possible outcome might be serious congestive heart failure or death. Our results confirmed our assumptions that TDI is a more precise and useful examination method than traditional ones (E/A ratio or deceleration time) to demonstrate isolated diastolic dysfunction as a result of chemotherapy. Relevant extra information might be given by TDI compared to parameters describing diastolic functions depending on several changing values. TDI may become a regularly and more widely used noninvasive method to detect subclinical cardiotoxicity emerging after chemotherapy.

[Photoselective vaporization of the prostate: experience with prostate adenomas >80 cm3]. / Photoselektive Vaporisation der Prostata: Erfahrungen mit Prostataadenomen >80 cm3.

BACKGROUND: We report about our experiences with photoselective vaporization of the prostate (PVP) in patients with symptomatic benign prostatic hyperplasia (BPH) and total prostate volume larger than 80 cm(3). PATIENTS AND METHODS: The study included 201 patients with BPH: 51 (25.4%) patients had a prostate volume larger than 80 cm(3) and 150 (74.6%) patients had a volume smaller than 80 cm(3) in the preoperative transrectal ultrasound. RESULTS: The mean operation time for patients with large prostates was 79 min. Neither TUR syndrome nor severe bleeding was observed. In patients with large adenomas peak urinary flow increased by 135, 136, and 132% after 6, 12, and 24 months, respectively. The overall complication rate was comparable in both groups. CONCLUSION: PVP is characterized by excellent perioperative safety and significant improvement of voiding parameters. PVP is feasible in patients with large prostates.

Retroperitoneoscopic pyeloplasty for ureteropelvic junction obstruction (UPJO): solving the technical difficulties.

OBJECTIVES: To evaluate our current practice in retroperitoneoscopic pyeloplasty in patients with ureteropelvic junction obstruction (UPJO). Special interest was paid to technical difficulties associated with the retroperitoneoscopic approach. METHODS: Our retroperitoneoscopic approach for pyeloplasty is explained step for step including the most technically challenging part: the ureteropelvic anastomosis. RESULTS: Within 49 months a total of 47 retroperitoneoscopic pyeloplasties we performed at our institution. Before pyeloplasty an endopyelotomy had failed in five patients (11%). We did not necessarily perform a ventral transposition of the anastomosis in cases with a crossing vessel. Two (4%) conversions to open surgery were required because of scarring after previous endopyelotomy and massive obesity resulting in a limited working space. There were no intraoperative complications. A recurrence of UPJO was observed in 2% (n = 1). CONCLUSION: Functional results after retroperitoneoscopic pyeloplasty are excellent and comparable to those of open surgery. However, special knowledge of retroperitoneoscopy is necessary to provide the patient with a safe and effective minimally invasive alternative to open pyeloplasty.

Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1alpha determined by microarray analysis.

The human ovarian surface epithelium (HOSE) is a common site of gynaecological disease including endometriosis and ovarian cancer, probably due to serial injury-repair events associated with successive ovulations. To comprehend the importance of steroid signalling in the regulation of the HOSE, we used a custom microarray to catalogue the expression of over 250 genes involved in the synthesis and reception of steroid hormones, sterols and retinoids. The array included a subset of non-steroidogenic genes commonly involved in pro-/anti-inflammatory signalling. HOSE cells donated by five patients undergoing surgery for non-malignant gynaecological conditions were cultured for 48 h in the presence and absence of 500 pg/ml interleukin-1alpha (IL-1alpha). Total RNA was reverse-transcribed into biotin-labelled cDNA, which was hybridised to the array and visualised by gold-particle resonance light scattering and charge-coupled device (CCD) camera detection. Results for selected genes were verified by quantitative reverse-transcription PCR. In five out of five cases, untreated HOSE cells expressed genes encoding enzymes required for de novo biosynthesis of cholesterol from acetate and subsequent formation of C21-pregnane and C19-androstane steroids. Consistent with the inability of HOSE cells to synthesise glucocorticoids, oestrogens or 5alpha-reduced androgens de novo, CYP21, CYP19 and 5alpha-reductase were not detected. The only steroidogenic gene significantly up-regulated by IL-1alpha was 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Other cytokine-induced genes were IL-6, IL-8, nuclear factor kappaB (NFkappaB) inhibitor alpha, metallothionein-IIA and lysyl oxidase: inflammation-associated genes that respond to glucocorticoids. The only steroidogenic gene significantly suppressed by IL-1alpha was 3betaHSD1. Other genes suppressed by IL-1alpha were aldehyde dehydrogenase (ALDH) 1, ALDH 10, gonadotrophin hormone-releasing hormone receptor, peroxisome proliferation-activated receptor-binding protein (PPAR-bp) and nuclear receptor subfamily 2 group F member 2. These results define a steroidogenic phenotype of cultured HOSE cells and provide a limited expression profile for genes with associated signalling functions. IL-1alpha co-ordinately induces 11betaHSD1 and a panel of glucocorticoid-regulated, inflammation-associated genes in HOSE cells, providing further evidence that cortisol generated by 11betaHSD1 could participate in the local resolution of inflammation associated with ovulation.

[Manually-assisted laparoscopic donor nephrectomy]. / Handassistierte laparoskopische Spendernephrektomie.

The number of patients suffering from terminal renal failure awaiting kidney transplantation has continued to increase. Since the number of available cadaver donor kidneys has largely remained unchanged, a special publicity campaign achieved that almost one-half of the kidneys transplanted in Basle come from live donors. We performed a laparoscopic live donor nephrectomy in 14 patients between March 1998 and August 1999. Despite good experience regarding transplant function and patient satisfaction, the hand-assisted technique was introduced in 1999 because of the long average operating time of 230 min (200-270) and warm ischemia time of 7.5 min (4-9). In the 33 operations performed up to now, the average operating time and warm ischemia time could be significantly reduced to 185 min (135-240) and 2.4 min (1.5-4), respectively. Most recently, the technique of retroperitoneoscopic live donor nephrectomy was successfully employed in 4 patients and could possibly represent the method of choice for the future.

Outcome after extended follow-up in a prospective study of operable breast cancer: key factors and a prognostic index.

In 1990, 215 patients with operable breast cancer were entered into a prospective study of the prognostic significance of five biochemical markers and 15 other factors (pathological/chronological/patient). After a median follow-up of 6.6 years, there were 77 recurrences and 77 deaths (59 breast cancer-related). By univariate analysis, patient outcome related significantly to 13 factors. By multivariate analysis, the most important of nine independent factors were: number of nodes involved, steroid receptors (for oestrogen or progestogen), age, clinical or pathological tumour size and grade. Receptors and grade exerted their influence only in the first 3 years. Progestogen receptors (immunohistochemical) and oestrogen receptors (biochemical) were of similar prognostic significance. The two receptors were correlated (r=+0.50, P=0.001) and displaced each other from the analytical model but some evidence for the additivity of their prognostic values was seen when their levels were discordant.

[HER-2 and TOP 2A gene amplifications in urinary bladder carcinoma]. / HER-2 und TOP 2A Genamplifikationen beim Harnblasenkarzinom.

The HER-2/neu gene is frequently amplified in bladder cancer. Topoisomerase 2 Alpha (TOP2A) which is located nearby the HER-2/neu gene is an important molecular target for several anti cancer drugs. The frequency of TOP2A amplification in urinary bladder cancer is unknown. It was the aim of this study to determine the frequency of HER-2 and TOP2A amplification in urinary bladder cancer and to evaluate the association of these amplifications with tumor phenotype. For this purpose a tissue microarray containing 768 pTa, 425 pT1 and 571 pT2-4 carcinomas was analyzed by fluorescence in situ hybridization (FISH). Amplifications of both genes were significantly associated with advanced tumor stage and high grade. HER-2 amplification was found in 1.6% of pTa, 7.2% of pT1 and 13.8% of pT2-4 carcinomas (p < 0.0001). HER-2 amplification was present in only 1.1% of grade 1 and 0.8% of grade 2 tumors but in 14.2% of grade 3 tumors (p < 0.0001). TOP2A amplification was present in 0.7% pTa, 1.8% pT1 and 3.4% pT2-4 carcinomas (p < 0.0001). TOP2A was found in none of the grade 1, in 0.2% of grade 2 and 3.8% of grade 3 tumors (p < 0.0001). 1% of all analyzed tumors had simultaneously high level amplification of TOP2A and HER-2. Amplification of both genes were significantly associated with tumor specific survival if all tumors were analyzed together. Given the high frequency of HER-2 amplification in urinary bladder cancer, some of these tumors may respond favorable to Herceptin therapy. The TOP2A amplification status may influence response to anthracyclin treatment.

Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade.

The number of genes suggested to play a role in cancer biology is rapidly increasing. To be able to test a large number of molecular parameters in sufficiently large series of primary tumours, a tissue microarray (TMA) approach has been developed where samples from up to 1000 tumours can be simultaneously analysed on one glass slide. Because of the small size of the individual arrayed tissue samples (diameter 0.6 mm), the question arises of whether these specimens are representative of their donor tumours. To investigate how representative are the results obtained on TMAs, a set of 2317 bladder tumours that had been previously analysed for histological grade and Ki67 labelling index (LI) was used to construct four replica TMAs from different areas of each tumour. Clinical follow-up information was available from 1092 patients. The histological grade and the Ki67 LI were determined for every arrayed tumour sample (4x2317 analyses each). Despite discrepancies in individual cases, the grade and Ki67 information obtained on minute arrayed samples were highly similar to the data obtained on large sections (p<0.0001). Most importantly, every individual association between grade or Ki67 LI and tumour stage or prognosis (recurrence, progression, tumour-specific survival) that was observed in large section analysis could be fully reproduced on all four replica TMAs. These results show that intra-tumour heterogeneity does not significantly affect the ability to detect clinico-pathological correlations on TMAs, probably because of the large number of tumours that can be included in TMA studies. TMAs are a powerful tool for rapid identification of the biological or clinical significance of molecular alterations in bladder cancer and other tumour types.

[Impending paradoxical embolism]. / Fenyegetó paradox embolia esete.

The case history of a 49-year-old female patient is reported, who was operated on because of varicose vein in the left lower extremity. A few days after the operation serious signs of cerebrovascular insult appeared. The clinical picture and the result of an urgent transoesophageal echocardiography are described; a serpentine thrombus was found to be trapped in the patent foramen ovale. During continuous intravenous heparin treatment, the patient gradually recovered, but a residual neurological deficit could be detected on discharge from the hospital. Six days after the admission, repeated transoesophageal echocardiographic examination showed no signs of intracardiac thrombus. The clinical feature of the illness, the predisposing factors, the diagnostic and therapeutic possibilities are discussed.