Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guérin: results of a retrospective multicenter study of 2451 patients

BACKGROUND The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. OBJECTIVE To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. DESIGN, SETTING, AND PARTICIPANTS Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). RESULTS AND LIMITATIONS With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise. CONCLUSIONS T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. PATIENT SUMMARY Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

Monitoring asthma in children.

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence.

“Unconformity-Bounded” Stratigraphic Units in the South Polar Layered Deposits (Promethei Lingula, Mars)

We conducted a stratigraphic analysis of the South Polar Layered Deposits (SPLDs) in Promethei Lingula (PL, Mars) based on the identification of regional unconformities at visible and radar wavelengths. According to the terrestrial classification, this approach constrains the stratigraphy of the region and remedies the ambiguous interpretation of stratigraphy through marker layers, bypassing the problem related to the morphologic and radiometric appearance of the layers. Thus, the approach does not exclude diverse classifications, but complements them, whereas other discriminant elements are doubtful or difficult/impossible to be defined. Using this approach, we defined two stratigraphic units (or synthems: PL1 and PL2) in PL, which are morphologically different and divided by a regional unconformity (AuR1). This stratigraphic architecture implies that the geological history of PL has been conditioned by periodic changes in climate, which in turn are related to orbital variations of Mars.

P. Gespräche über Staat und Kirche

Boberach: In Form der Diskussion eines politischen Klubs werden außer dem Verhältnis von Kirche und Staat auch die notwendige Reform des Deutschen Bundes und die Vorzüge der konstitutionellen Monarchie vor anderen Staatsformen behandelt. - Welsch (Projektbearbeiter): Geschrieben (unter dem Pseudonym J. Steverlys) am Jahreswechsel 1847/1848 von dem Marburger Juraprofessor a.D. und späteren Abgeordneten der Frankfurter Nationalversammlung Jordan

Jordan und Dingelstedt : Zeitstimmen aus Hessen ; 1840 - 1848

Boberach: Nachdruck des Jordan gewidmeten "Osterworts" aus dem "Stuttgarter Morgenblatt" vom 30. Mai 1840 mit Jordans Äußerung dazu in "Wanderungen aus meinem Gefängnisse" (Frankfurt 1847, S. 326 - 330) und Widmung Dingelstedts vom 21. März 1848

Murine coronavirus ubiquitin-like domain is important for papain-like protease stability and viral pathogenesis

Ubiquitin-like domains (Ubls) now are recognized as common elements adjacent to viral and cellular proteases; however, their function is unclear. Structural studies of the papain-like protease (PLP) domains of coronaviruses (CoVs) revealed an adjacent Ubl domain in severe acute respiratory syndrome CoV, Middle East respiratory syndrome CoV, and the murine CoV, mouse hepatitis virus (MHV). Here, we tested the effect of altering the Ubl adjacent to PLP2 of MHV on enzyme activity, viral replication, and pathogenesis. Using deletion and substitution approaches, we identified sites within the Ubl domain, residues 785 to 787 of nonstructural protein 3, which negatively affect protease activity, and valine residues 785 and 787, which negatively affect deubiquitinating activity. Using reverse genetics, we engineered Ubl mutant viruses and found that AM2 (V787S) and AM3 (V785S) viruses replicate efficiently at 37°C but generate smaller plaques than wild-type (WT) virus, and AM2 is defective for replication at higher temperatures. To evaluate the effect of the mutation on protease activity, we purified WT and Ubl mutant PLP2 and found that the proteases exhibit similar specific activities at 25°C. However, the thermal stability of the Ubl mutant PLP2 was significantly reduced at 30°C, thereby reducing the total enzymatic activity. To determine if the destabilizing mutation affects viral pathogenesis, we infected C57BL/6 mice with WT or AM2 virus and found that the mutant virus is highly attenuated, yet it replicates sufficiently to elicit protective immunity. These studies revealed that modulating the Ubl domain adjacent to the PLP reduces protease stability and viral pathogenesis, revealing a novel approach to coronavirus attenuation. IMPORTANCE Introducing mutations into a protein or virus can have either direct or indirect effects on function. We asked if changes in the Ubl domain, a conserved domain adjacent to the coronavirus papain-like protease, altered the viral protease activity or affected viral replication or pathogenesis. Our studies using purified wild-type and Ubl mutant proteases revealed that mutations in the viral Ubl domain destabilize and inactivate the adjacent viral protease. Furthermore, we show that a CoV encoding the mutant Ubl domain is unable to replicate at high temperature or cause lethal disease in mice. Our results identify the coronavirus Ubl domain as a novel modulator of viral protease stability and reveal manipulating the Ubl domain as a new approach for attenuating coronavirus replication and pathogenesis.

Cesare Lombroso

Sylvester

The Right to Die Debate: The Demonization of Dr. Kevorkian and the Creation of a Moral Panic Surrounding Physician-Assisted Suicide in the United States

The Right to Die Debate is a recent but highly controversial moral matter. In particular, physician-assisted suicide (PAS) is an issue that has been evaded by the medical community for years. As of 1990, most states had never encountered the issue before and therefore did not have any laws in place to prohibit PAS (Strate et. al, 2005). Dr. Jack Kevorkian, a retired pathologist from Royal Oak Michigan was the first to publicly address PAS. He brought the issue into the limelight through a bizarre and crude series of assisted deaths that had a lasting impact on not only the Right to Die Debate as whole, but on public policy and both federal and state governmental agendas. This study focuses on the way in which the media, in particular the New York Times (NYT) has portrayed Dr. Jack Kevorkian as incompetent, morally culpable and in an overall negative light in the past twenty years. Applying Stanley Cohen’s 1972 theory of moral panic, a content analysis of NYT media publications between 1990 and 1999 supports Cohen’s theory and reveals that the media has created a moral panic surrounding Kevorkian. This has in turn led to public policy that prevents both terminally ill individuals and their doctors from having a desirable choice; that of voluntary euthanasia and PAS.

Volume 11, Number 3: September/October 2005

Page 2 – The University and its Libraries celebrate 125 years of growth and service to the citizens of Connecticut. • UConn joins the Center for Research Libraries, the nation’s oldest and most significant library consortium. Page 3 - A profile of Stanley Israelite recounts his civic contributions and his role as a creator of the Dodd Research Center. Page 4 - The Thomas J. Dodd Research Center celebrates its 10th anniversary with a series of special events. • The Pharmacy Library occupies new quarters in UConn’s new Pharmacy/Biology Building. Page 5 - The 2005 Connecticut Children’s Book Fair features a great lineup of authors and illustrators. Page 6 - Staff News • The Wharton Data Research Service is now available for financial research. Page 7 - Donors to the University Libraries, January 1 – June 30, 2005

Soliman der Zweyte, oder die drey Sultaninnen : Ein Singspiel in zwey Aufzügen ; für die k. k. Hoftheater

nach dem Französischen des Herrn Favart bearbeitet von Franz Xaver Huber. Die Musik ist von Hrn. Franz Xav. Süßmayer, Kapellmeister in wirklichen Diensten der k. k. Theatral-Hof-Direktion