Phase 3 Study of Adjuvant Radiotherapy Versus Wait and See in pT3 Prostate Cancer: Impact of Pathology Review on Analysis

Background

In a randomised trial, radical prostatectomy (RP) followed by adjuvant radiotherapy (aRT) was compared with RP alone in patients with pT3 pN0 prostate cancer with or without positive margin at local pathology (German Cancer Society trial numbers ARO 96-02/AUO AP 09/95).

Objective

A pathology review was performed on 85% of RP specimens of patients to investigate the influence of pathology review on the analysis.

Design, setting, and participants

Patients post-RP (n = 385) were randomised before achieving an undetectable prostate-specific antigen (PSA) level to either wait and see (n = 192) or 60 Gy aRT (n = 193). Of 307 patients with undetectable PSA after RP, 262 had pathology review. These results were included prospectively into the analysis.

Outcome measurements and statistical analysis

Agreement between local and review pathology was measured by the total percentage of agreement and by simple kappa statistics. The prognostic reliability for the different parameters was analysed by Cox regression model. Event-free rates were determined by Kaplan-Meier analysis with a median follow-up of 40 mo for the wait-and-see arm and 38.5 mo for the aRT arm.

Results and limitations

There was fair concordance between pathology review and local pathologists for seminal vesicle invasion (pT3c: 91%; κ = 0.76), surgical margin status (84%; κ = 0.65), and for extraprostatic extension (pT3a/b: 75%; κ = 0.74). Agreement was much less for Gleason score (47%; κ = 0.42), whereby the review pathology resulted in a shift to Gleason score 7. In contrast to the analysis of progression-free survival with local pathology, the multivariate analysis including review pathology revealed PSMs and Gleason score >6 as significant prognostic factors.

Conclusions

Phase 3 studies of postoperative treatment of prostate cancer should be accomplished in the future with a pathology review. In daily practice, a second opinion by a pathologist experienced in urogenital pathology would be desirable, in particular, for high-risk patients after RP.     

HAROW: the first comprehensive prospective observational study comparing treatment options in localized prostate cancer

Purpose

To collect data on primary treatment decision and follow-up in patients with diagnosed, histologically confirmed localized (T1a–T2c/N0/M0) prostate cancer (PCa) for up to 5 years in a prospective observational non-interventional study.

Methods

Patients were non-randomly allocated to one of the five treatment strategies: hormone therapy, active surveillance, radiation, operation, or watchful waiting.

Results

A total of 3169 patients were included by 259 participating sites; 2957 patients had at least one follow-up visit. 54.8 % of tumors at baseline were staged as T1c, 38 % as T2a–T2c, and 7.1 % as T1a or T1b (missing: 0.2 %). 38.9, 32.6 and 26.6 % of patients were classified as low risk, intermediate risk, and high risk according to d’Amico, respectively (missing: 1.8 %). 56.6 % of patients underwent prostatectomy as primary therapy, 16.4 % received radiation, 6.9 % HT, 15.8 and 4.3 % decided for AS or WW. Mean follow-up was 28.4 months. Progression rates were between 8.6 % (RT) and 33.1 % (AS).

Conclusion

Whereas RP remains the main treatment option of localized PCa, active surveillance appears to become an accepted and selectively employed treatment option. Careful selection of patients is documented by the highest proportion of patients with low risk (82.5 %), PSA density <0.2 ng/ml/ml (77.5 %), T1 staging (83.6 %), Gleason score ≤6 (92.5 %), ≤2 positive biopsies (79.4 %), and lowest mean PSA (5.8 ng/ml) in the AS group. The relatively high progression rate in the AS group has to be considered in the context of treatment changes; 71/155 patients had a documented change of treatment and 62 of them with a follow-up period of >3 months.

     

Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens

The development of MHC/peptide multimers has facilitated the visualization and purification of antigen-specific T cells. However, the persistence of multimers leads to prolonged T cell receptor signaling and subsequently to altered T-cell function. We have recently developed a new type of MHC/peptide multimers, which can be dissociated from the T cell. Herein, we have generated and tested for the first time reversible HLA/peptide multimers, termed Streptamers, for the isolation of human T cells. The Streptamer technique demonstrates the specificity and sensitivity of conventional HLA/peptide tetramers with regards to the sorting of human T lymphocytes. This is shown for T cells directed against immunogenic peptides derived from viral and tumor-associated antigens. We show that antigen-specific cytotoxic T cells remain functionally active following Streptamer dissociation, whereas lytic function and proliferation of the T cells is impaired in the presence of conventional tetramers. These novel HLA/peptide Streptamer reagents allow the isolation of antigen-specific T cells with preserved function and, therefore, facilitate the development of adoptive T cell transfer regimens for the treatment of patients with cancer or infectious diseases.     

Load-bearing capacity of all-ceramic posterior four-unit fixed partial dentures with different zirconia frameworks

The aim of this in vitro study was to compare the load-bearing capacity of posterior four-unit fixed partial dentures (FPDs) produced with two different yttria-stabilized polycrystalline tetragonal zirconia (Y-TZP) ceramics, one being a presintered material, the other a fully sintered, hot isostatically pressed material. Additionally, as a novel approach, the influence of preliminary mechanical damage upon the fracture force of an FPD has been investigated. A total of 20 frameworks each were milled from presintered zirconia and from fully sintered zirconia. Prior to veneering, 10 frameworks of each material were 'damaged' by a defined saw cut similar to an accidental flaw generated during shape cutting. Before fracture testing, all FPDs were subjected to thermal and mechanical cycling. Additionally, scanning electron microscopy was used to investigate fracture surfaces. Statistical analysis showed that FPDs milled from fully sintered zirconia had a significantly higher fracture resistance compared with specimens made from presintered material, whereas preliminary damage did not have a significant effect. After aging, FPDs made from both materials were capable of withstanding occlusal forces reported in the literature. Therefore, both types of Y-TZP may be suitable for posterior four-unit all-ceramic FPDs, although further prolonged aging experiments and prospective clinical trials are required to prove their fitness for clinical use.     

Temsirolimus in Daily Use: Results of a Prospective Multicentre Noninterventional Study of Patients with Metastatic Kidney Cancer

Background

Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis.

Objective

The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC.

Design, setting, and participants

Metastatic RCC patients treated with 25 mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures.

Outcome measurements and statistical analysis

All data were centrally analysed by an independent clinical research organisation.

Results and limitations

This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79–100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0–23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2–5.6) and 11.6 mo (95% CI, 9.3–13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review.

Conclusions

TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.     

Precocious synapses in 13.5-week fetal holoprosencephalic cortex and cyclopean retina

Background: Genetic programming of cerebral development involves tissue morphogenesis and also timing of developmental processes. Precocious synaptogenesis in the neocortical plate was previously demonstrated in 5 of 6 fetuses of 20–31 weeks gestation. Materials and methods: Neuropathological examination was performed of a 13-week-5-day fetus with trisomy-13, alobar holoprosencephaly, hydrocephalus, cyclopia and absence of ears. Immunocytochemical demonstration of the synaptic vesicle protein synaptophysin was performed in the brain and retina, along with other neuronal markers. Results: Synaptophysin reactivity in the cortical plate was patchy and precocious. Radial glial fibres, demonstrated by vimentin, were oriented parallel to the cortical plate rather than perpendicular, probably because of hydrocephalus. A corpus striatum was not identified, but the poorly formed thalamus exhibited synaptophysin reactivity around many neurones. The cyclopean eye had ocular features of maturational delay including persistent hyaloid artery; ganglion cells were reduced in number, but retinal synaptophysin reactivity was paradoxically precocious. Conclusions: Holoprosencephaly exhibits abnormal patchy synapse distribution in the neocortex and retina; synaptogenesis was precocious, as we previously described in older fetuses. Too soon an onset of synapse formation may promote early epileptic circuitry, leading to severe infantile epilepsies postnatally. The visual system is the last of the special sensory systems to mature, yet in this case showed too early synapse formation. In HPE, cyclopia and in trisomy 13, total absence of external ears has not been reported; it results from faulty craniofacial induction by neural crest.     

23Na-magnetic resonance imaging of the human lumbar vertebral discs: in vivo measurements at 3.0 T in healthy volunteers and patients with low back pain

Background context¹H magnetic resonance imaging (MRI) of the spine can rule out common causes of low back pain (LBP), such as disc protrusions or nerve root compression; however, no significant causal relation exists between morphology and the extent of symptoms. Functional MRI techniques, such as ²³Na, may provide additional information, allowing indirect assessment of vertebral glycosaminoglycan concentrations, decreases in which are associated with early degenerative changes.PurposeTo evaluate ²³Na-MRI of asymptomatic healthy volunteers and symptomatic patients with LPB and correlate the results to the Pfirrmann classification of MRI disc morphology.Study designRetrospective cohort study at an academic medical center.Patient sampleTwo groups were studied: (1) 55 healthy volunteers (31 men, 24 women; mean age 28.8 years) and (2) 12 patients (6 men, 6 women; mean age: 35.3 years) with a recent history of LBP.MethodsLumbar spines of the aforementioned groups were examined on a 3.0 T MRI scanner with morphological ¹H and ²³Na imaging. Intervertebral disc (IVD) ²³Na at each level was normalized (²³Na_norm). Distribution and differences between mean ²³Na_norm corresponding to each Pfirrmann classification were evaluated in the two study groups (analysis of variance). Linear correlations between ²³Na_norm, body mass index (BMI), and age were assessed (Pearson correlation coefficient). Gender-dependent differences were evaluated (paired t test).Outcome measuresPhysiological measure: IVD ²³Na_norm as determined by ²³Na-MRI.ResultsA normal distribution of ²³Na_norm was confirmed for both groups (p=.072 and p=.073, respectively). The mean Pfirrmann score statistically significantly differed between them (p<.0001). ²³Na_norm was statistically significantly reduced in degenerated IVDs (Pfirrmann scores 4+5) (p<.0001). No statistically significant differences were seen for the mean ²³Na_norm of IVDs with the same Pfirrmann score in healthy volunteers and patients (.469<p<.967). Age (0.007<R²<0.202) and BMI (0.074<R²<0.288) showed either weak or no correlation to ²³Na_norm. Mean ²³Na_norm was significantly (p=.0002) greater in women relative to men.ConclusionsThe results underline the feasibility and robustness of ²³Na-MRI of human IVDs and affirm, in a large cohort, decreases in ²³Na IVD content seen with disc degeneration.     

Cardiac alternans and intracellular calcium cycling

Cardiac alternans refers to a condition in which there is a periodic beat‐to‐beat oscillation in electrical activity and the strength of cardiac muscle contraction at a constant heart rate. Clinically, cardiac alternans occurs in settings that are typical for cardiac arrhythmias and has been causally linked to these conditions. At the cellular level, alternans is defined as beat‐to‐beat alternations in contraction amplitude (mechanical alternans), action potential duration (APD; electrical or APD alternans) and Ca²⁺ transient amplitude (Ca²⁺ alternans). The cause of alternans is multifactorial; however, alternans always originate from disturbances of the bidirectional coupling between membrane voltage (V_m) and intracellular calcium ([Ca²⁺]_i). Bidirectional coupling refers to the fact that, in cardiac cells, V_m depolarization and the generation of action potentials cause the elevation of [Ca²⁺]_i that is required for contraction (a process referred to as excitation–contraction coupling); conversely, changes of [Ca²⁺]_i control V_m because important membrane currents are Ca²⁺ dependent. Evidence is mounting that alternans is ultimately caused by disturbances of cellular Ca²⁺ signalling. Herein we review how two key factors of cardiac cellular Ca²⁺ cycling, namely the release of Ca²⁺ from internal stores and the capability of clearing the cytosol from Ca²⁺ after each beat, determine the conditions under which alternans occurs. The contributions from key Ca²⁺‐handling proteins (i.e. surface membrane channels, ion pumps and transporters and internal Ca²⁺ release channels) are discussed.