Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance—protocol for a systematic review

Background: Testicular cancer is primarily treated with the surgical removal of the affected testis. About 50 % of testicular cancer patients present with a stage I seminoma. If no chemo- or radiotherapy as adjuvant treatment is initiated after orchiectomy, 15–20 % of these patients will develop metastases. Although adjuvant treatment is effective in reducing the relapse risk, there is rising concern about overtreatment of these patients. Prognostic factors at primary diagnosis might have the potential to identify patients at higher risk of tumor relapse, allowing to guide individual therapy and to avoid overtreatment. Therefore, we aim to synthesize the available evidence on tumor or patient characteristics as possible prognostic factors for cancer recurrence in patients with clinical stage I seminoma. Methods/design: We will conduct a broad systematic review to analyze what prognostic factors predict cancer recurrence in patients with a first time diagnosis of clinical stage I seminoma, who received no adjuvant chemo- or radiotherapy after orchiectomy. The literature search will comprise MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), and the conference proceedings of the American Society of Clinical Oncology (ASCO), American Urologic Association (AUA), and European Urologic Association (EAU) Annual Meetings. Prospective and retrospective longitudinal studies reporting on prognostic factors for cancer recurrence will be considered. We will consider the wealth of any candidate clinical or pathological prognostic factor reported in the literature. Our outcome of interest will be tumor recurrence at a minimum of 2 years follow-up. Study screening, data extraction, and quality assessment will be done by two reviewers independently. Hazard ratios will be used to measure the relationship between the potential prognostic factor and tumor recurrence. Meta-analyses will be conducted with sufficiently homogeneous studies and separately with respect to study design, by using the random-effects generic inverse variance model. Discussion: Limitations and strengths will be discussed in our review, and the results will be put into context with other studies in this field. Our results will help to guide evidence-based decision-making on patients with clinical stage I seminoma, allowing a better adjustment of therapies with regard to the individual patient’s risk. Our findings will furthermore help to formulate recommendations for future research. Systematic review registration: PROSPERO CRD4201400943

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

Introduction: Lower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or β3-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues. Methods: Female and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 µM) and EHT1864 (100 µM) on detrusor contractions were studied in an organ bath. Results: Electric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC50 values, but unchanged Emax values. EHT1864 reduced carbachol-induced contractions, resulting in reduced Emax values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864. Conclusions: NSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A2-induced detrusor contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is noncholinergic. In vivo, both compounds may improve OAB-related LUTS

Oncological outcome of patients treated by radical vaginal trachelectomy with early-stage cervical carcinoma

Die Erkrankung an einem Zervixkarzinom hat sich aufgrund der verbesserten Vorsorge- und Screeningprogramme hin zu immer mehr diagnostizierten Frühstadien entwickelt. Die Frauen, welche von solch einem Zervixkarzinom betroffen sind, werden immer jünger, bekommen jedoch aus demographischer Sicht später Kinder als es noch im letzten Jahrhundert der Fall war. Mit dieser Aussicht auf die weitere Entwicklung ist es nahe liegend, dass eine neue Möglichkeit und Lösung für diesen Konflikt gefunden werden musste, indem zwar radikal, aber die Gebärmutter erhaltend, operiert und den Frauen damit die Chance auf eigene Kinder ermöglicht bleibt. So entwickelte sich in den letzten zwei Jahrzehnten die radikale Trachelektomie als Operationsmethode zur Fertilitätserhaltung. Doch neue Methoden müssen zuerst auf ihre Tauglichkeit und Sicherheit überprüft werden, wozu diese Studie beitragen soll. Von der Deutschen Gesellschaft der gynäkologischen Onkologen wurde Mitte der 1990er Jahre eine prospektive klinische Studie zur onkologischen Sicherheit für gerade diese Frauen initiiert. 2006 wurden bereits von Hertel et al. (Hertel, Kohler et al. 2006) die vorläufigen Ergebnisse von damals 100 Patientinnen veröffentlicht. Meine Studie baut auf diese Ergebnisse auf und führt sie weiter. In dem Zeitraum von 1995 bis 2010 wurden 225 Frauen in die Evaluation eingeschlossen, mittels radikaler vaginaler Trachelektomie und laparoskopischer Lymphadenektomie operiert, und prospektiv beobachtet. 212 Frauen wurden gemäß den Kriterien des Studienprotokolls in die Auswertung miteinbezogen. Aus onkologischer Sichtweise sind die Daten bezüglich Rezidivfreiheit und Gesamtüberleben die entscheidenden. Die Kohorte zeigt ein mittleres Beobachtungsintervall von 37 Monaten auf. Im Betrachtungszeitraum traten 8 Fälle von Rezidiven auf, wobei 4 von diesen Frauen an ihrem Rezidiv verstarben. Es konnte jedoch kein signifikanter Zusammenhang zwischen dem histologischen Typ des Tumors und dem Auftreten eines Rezidivs nachgewiesen werden. Der gemeinsa- me Befall der lympho- und angiovaskulären Räume hat sich im Laufe der Zeit als Risikofaktor herausgestellt, weshalb im weiteren Verlauf keine Patientinnen mehr mit einem kombinierten Befall eingeschlossen worden sind. Die 5-Jahres-rezidivfreie Überlebensrate liegt bei 94,4% und die Rezidivrate nach 5 Jahren bei 5,7%. Die Gesamtüberlebensrate beläuft sich auf 97,4%. Es stellen sich keine schwerwiegenden Komplikationen dar, welche die Tauglichkeit und Sicherheit der Operation untermauern. Milde Komplikationen wurden perioperativ bei 2,8% der Patientinnen beobachtet. Kurzzeitige postoperative Komplikationen traten bei 7,5% der Frauen auf, von denen sich 5 (2,3%) noch einer weiteren Operation im stationären Verlauf unterziehen mussten. Im Laufe der nachstationären Beobachtung sind keine schwerwiegenden Langzeitprobleme aufgetreten. Ich habe jedoch auch ein Augenmerk auf diejenigen Beschwerden gelegt, welche die Patientinnen nicht immer auf Anhieb an- und zugeben, sondern erst bei konkreter Nachfrage mitteilen. Darunter waren milde Lymphödeme der Beine bei 24,1% sowie Sensibilitätsstörungen des Nervus obturatorius oder genitofemoralis bei 21,7% der Frauen aufgetreten. Weitere leichtere Beschwerden wie Störungen der Blasenfunktion, eine postoperativ aufgetretene Zervikalkanalstenose, zeitweiliger diffuser Unterbauchschmerz und Dyspareunie wurden nur auf direkte Nachfrage von einigen Patientinnen angegeben (aufgezählt in absteigender Reihenfolge der Häufigkeit). Änderungen in Dauer und Qualität der Menstruation im Gegensatz zur präoperativen Gewohnheit wurden von 17% der Patientinnen berichtet, jedoch gab es keinen Fall von schwerer Hypermenorrhoe oder permanenter Blutung. Somit konnte mithilfe dieser Studie gezeigt werden, dass die radikale vaginale Trachelektomie zusammen mit der laparoskopischen Lymphadenektomie eine onkologisch sichere Operations- und Therapiemethode für Frauen ist, welche an einem Frühstadium des Zervixkarzinoms erkrankt sind und bei denen Kinderwunsch besteht. Die Überlebensraten und Rezidivraten entsprechen denen der radikalen Hysterektomie, welche gemäß den Leitlinien noch der Standardtherapie in diesem Stadium entspricht.Despite good public health infrastructure and screening programs cervical cancer is still the seventh most common cancer in countries with higher resources. Due to the fact that the mean age of primiparous women has been continuously increasing during the last years, fertility sparing surgery of cervical cancer is an important issue since more and more emphasis is placed on the quality of life of cancer survivors. Fertility preservation is a very crucial component of quality of life in young women and there is a great psychosocial impact of cancer-related infertility in women treated for gynecologic malignancies who often suffer from depression and sexual dysfunction. Radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy with more than 1000 procedures is currently the standard of fertility preserving surgery with the greatest experience all over the world. Oncologic results of RVT with laparoscopic pelvic lymphadenectomy are comparable to radical hysterectomy in tumors less than 2 cm in size with recurrence rates about 5%. Our study is a prospective evaluation of the oncologic safety of RVT. We report the oncologic results of 212 consecutive patients treated by radical vaginal trachelectomy combined with pelvic lymphadenectomy. In this according to protocol cohort, we found a recurrence rate of 5.7% (95%-confidence interval (CI) 1.3-10.1%). Four patients out of 9 with recurrence were diagnosed with adenocarcinoma and there was no significant difference in the recurrence-free survival of patients with adenocarcinoma and squamous cell carcinoma. This is also be confirmed by others. RVT is a surgically safe procedure with a low complication rate. In our study, we observed intraoperative complications in 2.8% of patients, postoperative short-term complications occurred in 7.5% of patients, and 5 of these 16 patients needed subsequent laparoscopic surgery. These data are comparable with the literature where complications rates vary between 2.1% and 25%. In our study, we analysed the complications during follow up very accurately. We noticed that women asked in a general way about their wellbeing deny problems, but when asked concretely about frequent symptoms such as mild leg oedema they admit intermittent complaints. The percentage of patients having complaints such as intermittently appearing lymphoedema (51 patients (24.1%)) or irritation of the obturator or genitofemoral nerves (46 patients (21.7%)) might appear relatively high, but we believe that these symptoms might be rather underestimated in other studies because many patients do not consider mild problems being important enough to be mentioned to their doctor. As far as we know, our series of patients who received trachelectomy for early stage cervical cancer is the largest with the longest follow up until now. In this series, recurrence free and overall survival rates comparable to radical hysterectomy could again be shown for more than 200 patients. We are convinced that RVT is a feasible and oncologic safe method for fertility-sparing surgery in young women with early stage cervical cancer. The collection of oncologic and fertility data of different surgical fertility-sparing procedures and their comparison is therefore crucial for the decision for best treatment of future patients

Purinergic smooth muscle contractions in the human prostate: estimation of relevance and characterization of different agonists

Non-adrenergic prostate smooth muscle contractions may account for the limited effectiveness of α1-adrenoceptor antagonists, which are the first-line option for medical treatment of voiding symptoms suggestive of benign prostatic hyperplasia. In non-human prostates, purinergic agonists induce contractions reaching similar magnitudes as α1-adrenergic contractions. However, evidence for the human prostate is highly limited, and pointed to much weaker purinergic contractions. Here, we examined contractions of different purinergic agonists in human prostate tissues. Tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, and expression of purinergic receptors was studied by RT-PCR. Electric field stimulation (EFS)-induced contractions amounted to 104% of KCl-induced contractions (95% CI: 84-124%). From all tested agonists, only ATP induced concentration-dependent contractions, reaching an average maximum of 18% (12-24%) of KCl. Maximum tensions following application of other agonists averaged to 7.1% of KCl for α,β-methylene-ATP (1.8-12.4%), 3.9% for β,γ-methylene-ATP (2.0-5.4%), 3.1% for 2-methylthio-ATP (- 0.1-6.3%), and 5.1% for ATPγS (1.0-9.2%). Responses were not affected by the P2X antagonist NF023 or the P2Y antagonist PPADS. mRNA expression of P2X1-4 correlated with expression of a marker for catecholaminergic nerves, although neither ATP, NF023, nor PPADS changed EFS-induced contractions. Correlation between expression of receptors and the smooth muscle marker calponin was not observed. Our findings point to a low relevance of purinergic contractions in the human prostate, compared to other contractile stimuli in the human prostate and compared to purinergic contractions in non-human prostates. Purinergic contractions in the human prostate are not sensitive to NF023 or PPADS

Propensity Score-Matched Analysis of Single Fraction Robotic Radiosurgery Versus Open Partial Nephrectomy in Renal Cell Carcinoma: Oncological Outcomes

Introduction High-dose local stereotactic robotic radiosurgery (RRS) is a non-invasive alternative to surgery in renal masses and selected patients. We have, so far, limited its use to the elderly and patients at high risk from surgery. In this study, we matched patients with renal tumors who were treated with single fraction RRS to patients who underwent open partial nephrectomy (OPN). Methods Between January 2009 and December 2017, we included 571 consecutive patients undergoing OPN and 99 patients who underwent RRS in this retrospective analysis. Patients had to have a follow-up of at least six months and we were able to match 35 with a propensity score. Matching criteria were Eastern Cooperative Oncology Group (ECOG) status, age, clinical tumor, nodes, and metastases (TNM), and tumor diameter. Tumor response, renal function, survival, and adverse events were evaluated every three months until progression or death. Results Median age was 65 years for RRS (range 58-75) and 71 (range 56-76) for OPN (p=0.131). Median diameter of renal tumors was 2.8 cm (range 2.4-3.9) for RRS and 3.5 cm (2.8-4.5) for OPN, p=0.104. Median follow-up was 28.1 months (range 6.0-78.3 months). Local tumor control nine months after RRS and OPN was 98% (95% CI: 89-99%). Renal function remained stable with a median creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) at baseline of 76.8mlmin/1.73m(2) (range 25.3-126.3) and 70.3ml/min/1.73m(2)(range 18.6-127.3) at follow-up (p=0.89). Median overall survival was not reached. No difference in overall survival (OS) was seen in RRS compared to OPN (p=0.459). Conclusions Single fraction RRS is an alternative to OPN in patients unfit for surgery. Oncological and functional results are comparable to those of OPN. Further studies are needed to determine long-term results and limits of RRS in this setting and in younger patients