Oncological impact of neoadjuvant hormonal therapy on permanent iodine‐125 seed brachytherapy in patients with low‐ and intermediate‐risk prostate cancer

Objectives

To determine whether neoadjuvant hormonal therapy improves oncological outcomes of patients with localized prostate cancer treated with permanent brachytherapy.

Methods

Between January 2004 and November 2014, 564 patients underwent transperineal ultrasonography‐guided permanent iodine‐125 seed brachytherapy. We retrospectively analyzed low‐ or intermediate‐risk prostate cancer based on the National Comprehensive Cancer Network guidelines. The clinical variables were evaluated for influence on biochemical recurrence‐free survival, progression‐free survival, cancer‐specific survival and overall survival.

Results

A total of 484 patients with low‐risk (259 patients) or intermediate‐risk disease (225 patients) were evaluated. Of these, 188 received neoadjuvant hormonal therapy. With a median follow up of 71 months, the 5‐year actuarial biochemical recurrence‐free survival rates of patients who did and did not receive neoadjuvant hormonal therapy were 92.9% and 93.6%, respectively (P = 0.2843). When patients were stratified by risk group, neoadjuvant hormonal therapy did not improve biochemical recurrence‐free survival outcomes in low‐ (P = 0.8949) or intermediate‐risk (P = 0.1989) patients. The duration or type of hormonal therapy was not significant in predicting biochemical recurrence. In a multivariate analysis, Gleason score, pretreatment prostate‐specific antigen, clinical T stage, and prostate dosimetry, primary Gleason score and positive core rate were significant predictive factors of biochemical recurrence‐free survival, whereas neoadjuvant hormonal therapy was insignificant. Furthermore, neoadjuvant hormonal therapy did not significantly influence progression‐free survival, cancer‐specific survival or overall survival.

Conclusions

In patients with low‐ or intermediate‐risk disease treated with permanent prostate brachytherapy, neoadjuvant hormonal therapy does not improve oncological outcomes. Its use should be restricted to patients who require prostate volume reduction.     

Carbon‐ion radiation therapy for prostate cancer

In 1994, carbon‐ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy‐Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phase I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon‐ion radiotherapy for both early‐ and advance‐stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon‐ion radiotherapy, a phase II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5 weeks) obtained from the phase I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phase II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon‐ion radiotherapy for prostate cancer was approved as “Highly Advanced Medical Technology” from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon‐ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon‐ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.     

Therapeutic options in the management of intermediate‐risk nonmuscle‐invasive bladder cancer

Non‐muscle‐invasive bladder cancers form a heterogeneous group of tumours with varying recurrence and progression rates. Recently low‐, intermediate‐ and high‐risk categories, based on tumour stage and grade, have been used to predict prognosis and guide treatment. Whilst the therapeutic options for the low‐ and high‐risk groups are well defined, the optimal treatment for patients in the intermediate‐risk group is unknown. We review current treatment options, recent advances and future developments in the treatment of patients with intermediate‐risk non‐muscle‐invasive bladder cancer.     

Alendronate decreases the fracture risk in patients with prostate cancer on androgen‐deprivation therapy and with severe osteopenia or osteoporosis

OBJECTIVE

To evaluate changes in bone mass and fracture risk in patients with prostate cancer on androgen‐deprivation therapy (ADT) and with a basal T‐score of >?2.0, who were treated with an oral bisphosphonate, as such patients treated with ADT are at increased risk of bone loss and bone fracture.

PATIENTS AND METHODS

We selected 61 patients with prostate cancer treated with ADT; 31 were treated with oral alendronate 70 mg once‐weekly and a control group of 30 were not. At baseline and 12 months we measured bone mineral density (BMD) of the lumbar spine, femoral neck and total hip by dual‐energy X‐ray absorptiometry. All patients had severe osteopenia or osteoporosis at baseline. The risk of femoral neck fracture was calculated at baseline and 12 months (Z‐score 2.7).

RESULTS

Patients treated with alendronate had a significant increase in BMD at the lumbar spine and femoral neck after 1 year of follow‐up, with mean (sd ) values of 1.06 (0.26) vs 1.01 (0.21) g/cm² at baseline (P < 0.001), and 0.75 (0.07) vs 0.73 (0.07) g/cm² (P = 0.03), respectively, while the control group had a significant loss of BMD at the total hip of 0.79 (0.14) vs 0.81 (0.13) g/cm² (P = 0.03). BMD was significantly improved at the three locations in patients treated with alendronate compared with the control group, with differences at the lumbar spine, femoral neck and total hip of 0.05 (0.07) vs 0.01 (0.10) (P = 0.001), 0.01 (0.04) vs ?0.002 (0.03) (P = 0.04) and 0.01 (0.04) vs ?0.01 (0.02) g/cm², respectively (P = 0.001). Patients treated with alendronate had a significant decrease in the fracture risk at the femoral neck, by ?0.54 (1.29) (P = 0.04) after 1 year of follow‐up.

CONCLUSIONS

Treatment with once‐weekly 70 mg alendronate significantly improved the BMD at the lumbar spine and femoral neck in patients with prostate cancer with severe osteopenia or osteoporosis and on ADT, and significantly decreased the risk of femoral neck fracture.     

Viral load,CMV‐specific T‐cell immune response and cytomegalovirus disease in solid organ transplant recipients at higher risk for cytomegalovirus infection during preemptive therapy

Despite advances in prevention, cytomegalovirus (CMV) recurrence is an important challenge in high‐risk organ recipients. The present study prospectively evaluates the impact of CMV‐specific T‐cell immune response and secondary prophylaxis on the risk of recurrence in a cohort of CMV high‐risk organ recipients and whether it is possible to determine a safe standardized viral load value below which CMV disease is unlikely. Thirty‐nine recipients were included. Thirty‐six had primary infections, and 88.9% recurred. Rate and duration of recurrent CMV infection was similar in patients with and without secondary prophylaxis: 57.9% vs. 53.6%, P = 0.770 and 16 vs. 15 days, P = 0.786, respectively. The only factor independently associated with no episodes of CMV recurrence was the acquisition of CMV‐specific T‐cell immune response (OR: 0.151, 95% CI: 0.028–0.815; P = 0.028). Cytomegalovirus diseases (N = 5) occurred in patients with CMV viral load above 1500 IU/ml who did not follow the planned monitorization schedule. Our observations suggest that episodes of recurrent CMV infection are common after preemptive therapy despite secondary prophylaxis and that CMV‐specific T‐cell immune response is associated with a decreased risk of recurrent infections. Preemptive therapy may be safe in patients at high risk for CMV infection with strict close monitoring of the CMV viral load.     

Rationale and timeliness for IL‐1β‐targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantation

Wanderer AA. Rationale and timeliness for IL‐1β‐targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantation.
Clin Transplant 2010: 24: 307–311. © 2010 John Wiley & Sons A/S. Abstract: Ischemia‐reperfusion injury (IRI) involving allograft transplantation and procured organs may in part be induced by stimulation of a newly described innate pro‐inflammatory immune system (i.e., NALP‐3‐inflammasome), which can cause secretion of IL‐1β and subsequent neutrophilic inflammation. Ischemia and/or hypoxia/anoxia can induce anaerobic metabolism with metabolic acidosis and subsequent development of danger signals known to stimulate IL‐1β secretion from the NALP‐3 inflammasome. Observations from IRI studies and hereditary auto‐inflammatory syndromes with NALP‐3 inflammasome mutations suggest that IL‐1β secretion can induce robust neutrophilic inflammation that is responsive to IL‐1β targeted therapy. Based on these observations and data from transplantation studies, it may be timely to consider commercially available IL‐1β targeted biologic therapy to improve allograft tolerance and viability of procured organs.     

5‐Aminolevulinic acid‐mediated photodynamic therapy for bladder cancer

Photodynamic therapy using 5‐aminolevulinic acid is a treatment method in which the fluorescent substance of protoporphyrin IX excessively accumulated specifically in cancer cells is excited by visible red or green light irradiation, and reactive oxygen is produced and injures cancer cells. Photodynamic therapy using 5‐aminolevulinic acid less markedly influences the surrounding normal cells and tissue as a result of no accumulation of protoporphyrin IX, being a low‐invasive, less harmful treatment localized to cancer. Furthermore, photodynamic therapy using 5‐aminolevulinic acid is painless, requiring no anesthesia because localized lesions are treated at a low‐energy level, and repeatedly applicable, unlike radiotherapy, and so is expected to be a new low‐invasive treatment based on a concept completely different from existing treatments. In fact, photodynamic therapy using 5‐aminolevulinic acid for bladder cancer was clinically demonstrated mainly for treatment‐resistant bladder carcinoma in situ, and favorable outcomes have been obtained. Photodynamic therapy using 5‐aminolevulinic acid are photodynamic technologies based on the common biological characteristic of cancers, and are expected as novel therapeutic strategies for many types of cancer.     

Virus‐specific T‐cell therapy in solid organ transplantation

This article reviews the current state of T‐cell therapy as therapeutic option for virus‐associated diseases against the background of the most common viral complications and their standard treatment regimens after SOT. The available data of clinical T‐cell trials in SOT are summarized. References to the hematopoietic stem cell transplantation are made if applicable data in SOT are not available and their content was considered likewise valid for cell therapy in SOT. Moreover, aspects of different manufacturing approaches including beneficial product characteristics and the importance of GMP compliance are addressed.     

Two‐step stem cell therapy improves bone regeneration compared to concentrated bone marrow therapy

Adult stem cells are a promising tool to positively influence bone regeneration. Concentrated bone marrow therapy entails isolating osteoprogenitor cells during surgery with, however, only low cells yield. Two step stem cell therapy requires an additional harvesting procedure but generates high numbers of progenitor cells that facilitate osteogenic pre‐differentiation. To further improve bone regeneration, stem cell therapy can be combined with growth factors from platelet rich plasma (PRP) or its lysate (PL) to potentially fostering vascularization. The aim of this study was to investigate the effects of bone marrow concentrate (BMC), osteogenic pre‐differentiation of mesenchymal stromal cells (MSCs), and PL on bone regeneration and vascularization. Bone marrow from four different healthy human donors was used for either generation of BMC or for isolation of MSCs. Seventy‐two mice were randomized to six groups (Control, PL, BMC, BMC + PL, pre‐differentiated MSCs, pre‐differentiated MSCs + PL). The influence of PL, BMC, and pre‐differentiated MSCs was investigated systematically in a 2 mm femoral bone defect model. After a 6‐week follow‐up, the pre‐differentiated MSCs + PL group showed the highest bone volume, highest grade of histological defect healing and highest number of bridged defects with measurable biomechanical stiffness. Using expanded and osteogenically pre‐differentiated MSCs for treatment of a critical‐size bone defect was favorable with regards to bone regeneration compared to treatment with cells from BMC. The addition of PL alone had no significant influence; therefore the role of PL for bone regeneration remains unclear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1318–1328, 2019.     

A new concept for non‐invasive renal tumour ablation using real‐time MRI‐guided radiation therapy

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? The increasing use of imaging techniques resulted in an enormous increase of incidentally diagnosed renal cell carcinomas (RCC). At the moment surgery is the only established curative approach for the treatment of RCC. The smaller size of these incidental RCC tumours demands far less invasive treatment techniques, preferably without piercing the tumour. This study presents the latest developments in the field of radiation therapy, which provides treatment alternatives for tumour sites currently not treated with radiation therapy. Real‐time magnetic resonance imaging guided radiation therapy might become a valuable non‐invasive alternative to treat renal cell carcinoma. OBJECTIVE To present a new concept for non‐invasive renal tumour ablation using real‐time magnetic resonance imaging (MRI)‐guided radiation therapy. All currently available treatment techniques for localized renal cell carcinoma (RCC) have to be performed in a laparoscopic or percutaneous way. MATERIALS AND METHODS A technical prototype MRI‐accelerator which performs real‐time 1.5 T MRI imaging during the irradiation has been constructed. We performed a technical feasibility study on real‐time MRI‐guided arc therapy using repeated breath‐holds for renal tumour ablation by (i) investigating renal mobility during breath‐holding, (ii) performing dose calculation and (iii) measuring the radiation delivery time on a phantom. The renal mobility during free breathing and end‐expiration breath‐holding during 15 s was investigated for three patients with renal tumour appearance. Conventional MRI screening data of four patients was used for arc therapy dose calculation. Tumour and normal tissues were delineated and a tumour margin of 3 mm was applied. The radiation delivery time of a 25‐Gy arc therapy plan was measured on a phantom. RESULTS Renal mobility during free breathing varied from 10 to 25 mm, whereas breath‐holding resulted in nearly non‐moving kidneys (0 to 2 mm) for all patients. Arc therapy dose calculation resulted in an adequate tumour coverage. The radiation delivery time of the arc therapy plan was about 10 min. This means that 20 to 40 repeated breath‐holds of 15 to 30 s will be needed for a single session treatment. A higher maximum dose rate would reduce the number of breath‐holds needed and improve patient comfort. A phase I study will be started to proof the clinical feasibility. CONCLUSION Real‐time MRI‐guided radiation therapy using an MRI‐accelerator might become a valuable non‐invasive alternative to the current RCC treatment options.     

Limb salvage procedure in immunocompromised patients with therapy‐resistant leg ulcers—The value of ultra‐radical debridement and instillation negative‐pressure wound therapy

The purpose of this study was to analyse the outcome of our established triple treatment strategy in therapy‐resistant deep‐thickness chronic lower leg ulcers. This limb salvage approach consists of ultra‐radical surgical debridement, negative‐pressure wound therapy (NPWT) with or without instillation, and split‐thickness skin grafting. Between March 2003 and December 2019, a total of 16 patients and 24 severe cases of lower leg ulcers were eligible for inclusion in this highly selective population. A total of seven patients received immunosuppressive medication. Complete wound closure was achieved in 25% and almost 90% of included lower leg ulcer cases after 3 and 24 months of our triple treatment strategy, respectively. The overall limb salvage rate was 100%. Bacterial colonisation of these wounds was significantly reduced after multiple surgical debridements and NPWT. Fasciotomy and radical removal of devitalised tissue such as deep fascia, tendons, and muscles combined with NPWT showed promising results in terms of the overall graft take rate. This treatment strategy was considered as last resort for limb salvage in such a critically ill and immunocompromised patient population. Surgeons should be aware of its efficacy and consider the triple treatment strategy especially if no other limb salvage option remains.