The cell-division cycle of Caulobacter crescentus depends on periodic activation and deactivation of the essential response regulator CtrA. Although CtrA is critical for transcription during some parts of the cell cycle, its activity must be eliminated before chromosome replication because CtrA also blocks the initiation of DNA replication. CtrA activity is down-regulated both by dephosphorylation and by proteolysis, mediated by the ubiquitous ATP-dependent protease ClpXP. Here we demonstrate that proteins needed for rapid CtrA proteolysis in vivo form a phosphorylation-dependent and cyclic diguanylate (cdG)-dependent adaptor complex that accelerates CtrA degradation in vitro by ClpXP. The adaptor complex includes CpdR, a single-domain response regulator; PopA, a cdG-binding protein; and RcdA, a protein whose activity cannot be predicted. When CpdR is unphosphorylated and when PopA is bound to cdG, they work together with RcdA in an all-or-none manner to reduce the Km of CtrA proteolysis 10-fold. We further identified a set of amino acids in the receiver domain of CtrA that modulate its adaptor-mediated degradation in vitro and in vivo. Complex formation between PopA and CtrA depends on these amino acids, which reside on alpha-helix 1 of the CtrA receiver domain, and on cdG binding by PopA. These results reveal that each accessory factor plays an essential biochemical role in the regulated proteolysis of CtrA and demonstrate, to our knowledge, the first example of a multiprotein, cdG-dependent proteolytic adaptor.

Although widespread PSA screening has inevitably led to increased diagnosis of lower risk prostate cancer, the number of patients with nodal involvement at baseline remains high (nearly 40% of high risk patients initially staged cN0). These rates probably do not reflect the true incidence of prostate cancer with lymph node involvement among patients selected for external beam radiotherapy (EBRT), as patients selected for surgery often have more favorable prognostic features. At many institutions, radical treatment directed only at the prostate is considered standard and patients known to have regional disease are often managed palliatively with androgen deprivation therapy (ADT) for presumed systemic disease. New imaging tools such as MR lymphangiography, choline-based PET imaging or combined SPECT/CT now allow surgeons and radiation oncologists to identify and target nodal metastasis and/or lymph nodes with a high risk of occult involvement. Recent advances in the field of surgery including the advent of extended nodal dissection and sentinel node procedures have suggested that cancer-specific survival might be improved for lymph-node positive patients with a low burden of nodal involvement when managed with aggressive interventions. These new imaging tools can provide radiation oncologists with maps to guide delivery of high dose conformal radiation to a target volume while minimizing radiation toxicity to non-target normal tissue. This review highlights advances in imaging and reports how they may help to define a new paradigm to manage node-positive prostate cancer patients with a curative-intent.

Purpose

Evaluate efficacy and toxicity of salvage high-dose-rate brachytherapy (HDRB) for locally recurrent prostate cancer after definitive radiation therapy (RT).

Methods and materials

We retrospectively analyzed 52 consecutively accrued patients undergoing salvage HDRB between 1998 and 2009 for locally recurrent prostate cancer after previous definitive RT. After pathologic confirmation of locally recurrent disease, patients received 36 Gy in 6 fractions. Twenty-four patients received neoadjuvant hormonal therapy before salvage, and no patients received adjuvant hormonal therapy. Determination of biochemical failure after salvage HDRB was based on the Phoenix definition. Overall survival (OS) and bF distributions were calculated using the Kaplan-Meier method. Univariate analyses were performed to identify predictors of biochemical control. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities, based on Common Terminology Criteria for Adverse Events (version 4), were documented.

Results

Median follow-up after salvage HDRB was 59.6 months. The 5-year OS estimate was 92% (95% confidence interval [CI]: 80%-97%) with median survival not yet reached. Five-year biochemical control after salvage was 51% (95% CI: 34%-66%). Median PSA nadir postsalvage was 0.1 (range: 0-7.2) reached at a median of 10.2 months after completing HDRB. As for complications, acute and late grade 3 GU toxicities were observed in only 2% and 2%, respectively. No grade 2 or higher acute GI events and 4% grade 2 GI late events were observed. On univariate analysis, disease-free interval after initial definitive RT (P=.07), percent of positive cores at the time of diagnosis (P=.08), interval from first recurrence to salvage HDRB (P=.09), and pre-HDRB prostate-specific antigen (P=.07) were each of borderline significance in predicting biochemical control after salvage HDRB.

Conclusions

Prostate HDRB is an effective salvage modality with relatively few long-term toxicities. We provide potential predictors of biochemical control for prostate salvage HDRB.