Wednesday, 17 February 2016

Basic Science Behind NMIBC and its Treatment

The established “two-pathway” model of bladder cancer suggests epithelial hyperplasia and recruitment of branching vasculature as the pathway for the development of papillary NMIBC.
The healthy urothelium is about 60 μm thick. The increase in the epithelial thickness in malignancy reflects the increase in cell dimensions in basal and intermediate layers.

Tumours originating from basal cells were shown to be associated with the worst outcome. Invasive carcinomas arise clonally from a single cell progeny, initially generating a precursor CIS lesion. Basal cells are likely progenitors of CIS, muscle-invasive lesions and SCC, depending on the genetic background. Cancer stem cells are infamous for their inherent diminished susceptibility to treatment and for being generally difficult
to reach. They were suggested to contribute to therapeutic resistance through repopulation of residual tumours between chemotherapy cycles. Morphologically “normal” or dysplastic urothelium contains alterations found in tumour, pointing to spread of tumour cells or tumour development within the adjacent urothelium. Although some patients develop a true oligoclonal disease, tumours in the same patient are mostly related, showing evidence of subclonal evolution in different lesions. Genetic alterations pertinent to urothelial tumours are frequently found in the adjacent stromal cells. The importance of tumour milieu (surrounding stromal cells, extracellular matrix) in bladder cancer development is further underscored by its role in epithelial-to-mesenchymal transition (EMT). Cell invasivity and drug resistance then appear to increase in parallel with their angiogenetic and metastatic ability, thus contributing to tumourigenesis, tumour progression, and metastasis formation. Stromal cell types shown to contribute to bladder cancer progression include the mesenchymal stem cells and tumour-associated fibroblasts.
The immune system is another important determinant of tumour environment. The tumour-associated macrophages (TAMs) count in invasive cancers is significantly higher than in superficial cancers, and, correlates with TNM classification, tumour grade, vascular invasion, distant metastasis, response to BCG treatment and higher rates of cystectomy. Conversely, tumour infiltration by both Cytotoxic T-cells (CD68+) and T-cells in general (CD3+) promotes survival in patients with urothelial carcinoma.
The nature of immunological response induced by different molecular subtypes of urothelial carcinoma is independent of tumour stage and includes both TILs (Tumour-Infiltrating Lymphocytes) and TAMs. The strongest association with poor survival was observed for a high ratio between CD68+and CD3+. Susceptibility to specific drugs is more likely to be associated with the molecular stratification, rather than with pathologic classification.
To reduce the risk of bladder cancer recurrence and/or progression effectively, a treatment must ideally
a) Have an impact on cancer stem cells, harbouring the innermost tumour locations; b) Exert force on cellular and extracellular components on both sides of the basal membrane, to disrupt or transform the potentially disastrous interplay; and c) Modify the type of immunological response in the tumour vicinity to help offset cancer propagation.
The efficacy of Radiofrequency-Assisted chemotherapy instillation on drug diffusion was demonstrated with
Mitomycin C diffusing 6-fold higher using Synergo® RITE. MMC penetration of the bladder wall and cells can be explained by inter and intracellular drug-mobilising electric (“Foucault”) currents produced by the RF radiation and very efficient deep heat delivery. The same currents are also responsible for the cellular membrane "micro-poring" that enhance drug uptake, owing to ionic transfer. Tumour recurrence is substantially reduced following MMC via Synergo® RITE treatment compared with “conventional” MMC, or BCG instillation, and disease progression is reduced, even in patients presenting with CIS, G3 and patients failing BCG prior to Synergo® RITE treatment. As the available data on conductive heat-assisted MMC instillation indicates, it differs greatly from that of Synergo® RITE and it is apparent that the effect of Synergo® RITE cannot be explained by heat alone. Furthermore, it was demonstrated that liquid at 50-60°C irrigating the human bladder for up to two hours, did not destroy the urothelium (no denaturation of proteins took place) implying that the tissue was not effectively heated. A unique pattern of humoural and cell-mediated immunological response observed in patients treated with MMC via Synergo® RITE could also be a contributing factor in the apparently low recurrence and progression figures reported, even in high-risk patients. Early histological findings following treatment with MMC via Synergo® RITE show stromal behaviour post treatment. Intense vasodilatation and mainly lymphocytic infiltrate in peri-tumoural regions
were the hallmark of treatment with MMC via Synergo® RITE ˗ effects not seen with conventional or heated MMC instillation. Moreover, treatment with MMC via Synergo® RITE shows elevated urinary cytokine levels, with MCP-1 and IL-6 levels being significantly higher as well as increased macrophage-derived chemokine levels.

Medical Enterprises Group.
For more information and the full list of references, enter:

Monday, 30 June 2014

BAUS Annual Meeting in Liverpool 2014

BAUS Liverpool 2014

The Synergo booth at the recent BAUS meeting in Liverpool was well-attended by both British and overseas urologists. Over the past few years I have seen growing interest and also familiarity with the Synergo technology. The group from St. George’s, London, presented a 7-year study of 100 HR-NMIBC patients, treated with Synergo, showing a five-year survival comparable to that after cystectomy but with a lower morbidity.

A lively interest was also shown in our upcoming multicentric study in which a number of British Urology Departments will be taking part.

I would like to thank the organisers and BAUS members for making our participation such a memorable one.

Dr. Zvi Bar
Head of Clinical Department
Medical Enterprises Group

Dr. Zvi Bar, Head of Clinical Affairs, has been with MEL for two years. His main responsibilities are in the area of clinical training, seminars and research and development. Zvi joined MEL after a 35 year long career in Anesthesiology during which he held various posts including Head of Dept. of Anesthesiology and Chairman of The Committee ‎for Quality Assurance of The Ramat Marpe Hospital Group, as well as ‎Examiner in Anesthesiology for The Israel Medical Council‎.

Sunday, 25 May 2014

Erlangen Urology meeting 2014

The last urology meeting in Erlangen was well organized and the Synergo® RITE was well located! Few words in German for those who came to share experience and also just to express their interest. Below is Ms. Reich and her booth neighbour dressed in traditional Bavarian costume.

Es ist uns eine Freude, unsere neuen erfahrenen klinischen Fachleute im Team von Synergo® willkommen zu heißen, die uns bei der Ausdehnung unserer Aktivitäten mit urologischen Kliniken in Deutschland und Österreich helfen werden. Unser Ziel besteht darin, urologischen Kliniken eine Verbesserung von Ausbildung, Service und Unterstützung zu bieten. Wir erweitern unsere Aktivitäten mit der Synergo® Technologie, die überall auf der Welt zunehmend routinemäßig für die Behandlung von Patienten mit Blasenkrebs im mittleren Stadium oder mit hohem Risiko eingesetzt wird.

Frau Naama Reich, unsere medizinische Kontaktperson,  
40. Gemeinsamen Tagung der Bayerischen Urologenvereinigung sowie der Österreichischen Gesellschaft für Urologie und Andrologie zu treffen. Erlangen (Germany) 2014

Synergo® RITE (durch Radiofrequenz induzierter Thermo-Chemotherapie-Effekt) gegen nicht muskel-invasiven Blasenkrebs. 

Tuesday, 29 April 2014

Synergo at the EAU Annual Meeting 2014

EAU Annual Meeting, April 2014
Medical Enterprises thanks the urology colleagues, teams and organizers for the successful EAU congress in Stockholm this month. The congress was very successful and fruitful. Also many thanks for the new visitors who expressed their interest in the Synergo system.
2 poster sessions were presented at the EAU meeting this year by Mr. Issa and Mr. Nair from the UK. 

Synergo at the EAU 2014

Synergo at the EAU 2014

Challenging the gold standard: A comparison of long-term disease specific outcomes for high-risk non-muscle invasive bladder cancer treated with mitomycin hyperthermia and radical cystectomy:
A prospective single-centre review of 96 patients receiving Synergo MMC-HT and matched against 47 cases undergoing RC for High-Risk Non-Muscle Invasive Bladder Cancer. Charlson co-morbidity Index (CCI), and peri- and post-procedure complications were recorded in each group. Post operative pathology, recurrence and progression rates together with five-year overall and disease specific survival were evaluated.
The mean CCI score for patients receiving MMC-HT was significantly higher than RC group (6.1 vs 4.3). Significant complication rates classified as a Clavian-Dindo score of greater than 2, was significantly higher in the RC cohort (21 percent) compared to patients receiving MMC-HT (0 percent).
There were no deaths associated with MMC-HT treatment compared to a ninety-day mortality of four percent in those receiving RC.
Median follow-up was 36 months (3 to 88 months) for both cohorts. Disease specific survival at five years was observed at 85.2 and 74.6 percent in the MMC-HT and the RC cohorts respectively, whilst overall survival figures were 61.9 versus 68.4 percent.
Conclusions: "MMC-HT is both feasible and safe if offered to well selected patients. It provides durable long-term outcomes compared to RC for HR-NMIBC.....there is a clear advantage in complication rates favouring MMC-HT over RC without a significant difference in disease specific or overall survival."

The efficacy and safety of mitomycin-C hyperthermia in the treatment of high risk (HR) non-muscle invasive bladder cancer (NMIBC) in a single regional centre.
A report on seven year experience of MMC-HT, and aim to establish whether it is efficacious in this high risk cohort of patients.
100 patients with HR NMIBC were treated with MMC-HT (3 patients did not complete induction regimen due to side effects,  1 patient developed clinical metastases during the first two weeks of induction course).  96 patients completed induction treatment and had cystoscopy and biopsy at 3 months.  Of these 96 patients, 84 had failed BCG or were intolerant to it.  Patients were given an induction regimen with weekly treatments for 6-8 weeks with MMC-H on an outpatient basis with the Synergo® system SB-TS 101.
Median follow up was 34 months (3 to 88 months). 72% of patients (69/96) had complete response at 3 months, 10% had partial response (10/96) and 18% (17/96) had recurrence. Twenty patients had radical cystectomy.  Eighteen patients had organ confined disease and two patients had T3 disease at histology.  Only one patient developed recurrence of disease after cystectomy. No patients suffered a Clavien-Dindo Complication above 2.
Conclusions: "MMC-HT has comparable five year survival to radical cystectomy in the treatment of high risk superficial bladder cancer after BCG failure. It is well tolerated and can be delivered effectively by a regional centre. In those patients who are medically fit, cystectomy is still a potentially curative option for those patients who fail MMC-HT." 

Wednesday, 12 March 2014

What is RITE (Radiofrequency-Induced Thermo-chemotherapy Effect) for bladder cancer?

Hyperthermia is being used in many medical fields.
Synergo® uses a unique combination of local microwave energy hyperthermia (heating) with simultaneous instillation of cooled chemotherapeutic drug. The target of hyperthermia is to reach effective temperature inside the tissue to enable higher drug penetration and accelerate drug-DNA reactions.
Tissue heating should be adjusted per patient and dynamically maintained during treatment while the tissue temperature is constantly measured and closely followed.
Conduction is governed by the Boltzmann equation: Heat conduction is proportional to a constant K which cannot be changed: (for example: Kfat=0.2, Kmuscle=0.38, Ksilver=420)
Since the bladder wall acts as a good thermal insulator, heat penetration from heated liquid is not efficient (conduction/convection heating). On the other hand, during microwave heating the energy is absorbed directly deep in the tissue to enable efficient homogeneous heating, real-time measurement and follow-up on the tissue temperature and dynamic adjustment of the transmitted energy for each per patient over time (e.g. when blood flow in tissue is increased due to heating).
Warm liquid does not allow any simple adjustments in order to tailor heating per patient over time (e.g. different patients have different blood circulation, different tissues, dynamic changes that occur over time such as vasodilation etc.)
Moving from hot liquid to microwave radiation in the Synergo® systems was based on previous experience, as well as on articles already published by other researchers.

Richmond A. Owusu et. al describes the effect and mechanism of hyperthermia together with intravescical chemotherapy in his recently published paper (Owusu et al. 2013)."HT has cytotoxic effects on tumour cells via several mechanisms including improved anti-tumour immunity and by direct cytotoxic effects. Heat plays a role in causing cytotoxicity to tumours (additive effect), enhancing drug toxicity to tumours (synergistic effect), and thermosensitization by noncytotoxic drugs....”
Studies, showing the effect of the Synergo® RITE were performed in the 90's by Paroni (Paroni et al. 1997; Paroni et al. 2001). The findings indicated the clinical effectiveness benefits of RF hyperthermia associated with chemotherapy. The marked effect on bladder wall permeability resulted in enhanced MMC penetration through the urothelium and the tissue layers. It also showed that the dose administered in the Synergo treatment with hyperthermia, consisting of two 30-minute dwell periods of 20 mg MMC each, actually represented a total dose of not less than 40 mg for the 60 minutes treatment. The same study also showed that the MMC solution is not affected by the RITE method.
The re-fueling of the bladder with a fresh instillation of 20 mg MMC solution (following 30 minutes of treatment) after the bladder is drained of residual urine – eliminates the dilution of the drug with urine and thereby maintains a more optimal and homogeneous drug dose throughout the entire treatment duration. This technique also minimizes the inter-patient variability of parameters such as concentration in residual urine and bladder MMC concentration.
Another study made on animals, showed that indeed bladder walls are heated while adjacent organs are not (Rath-Wolfson et al. 2003). It also showed the evenly distributed heating and that the thermometers of the Synergo® reflect faithfully and accurately the temperature of the tissue and not of the liquid in the bladder vault.
In a 2004 study van der Heijden at al. assessed the effect of hyperthermia on mitomycin C-induced cytotoxicity in bladder cancer cell lines (van der Heijden et al. 2004) showing a decrease in cell proliferation after treatment with increasing concentrations MMC. The apparent synergy of chemotherapeutics and hyperthermia was further addressed by the same group demonstrating a similar phenomenon for epirubicin, EO9, mitomycin C and, to a lesser extent, gemcitabine (van der Heijden et al. 2005).

Owusu RA, Abern MR, Inman BA. 2013. Hyperthermia as Adjunct to Intravesical Chemotherapy for Bladder Cancer. BioMed Research International 2013: 7. Paroni R, Arcelloni C, De Vecchi E, Fermo I, Mauri D, Colombo R. 1997. Plasma mitomycin C concentrations determined by HPLC coupled to solid-phase extraction. Clinical chemistry 43: 615-618. Paroni R, Salonia A, Lev A, Da Pozzo LF, Cighetti G, Montorsi F, Rigatti P, Colombo R. 2001. Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. British journal of clinical pharmacology 52: 273-278. Rath-Wolfson L, Moskovitz B, Dekel Y, Kugel V, Koren R. 2003. Combined intravesical hyperthermia and mitomycin chemotherapy: a preliminary in vivo study. International journal of experimental pathology 84: 145-152. van der Heijden AG, Jansen CF, Verhaegh G, O'Donnell M A, Schalken JA, Witjes JA. 2004. The effect of hyperthermia on mitomycin-C induced cytotoxicity in four human bladder cancer cell lines. European urology 46: 670-674. van der Heijden AG, Verhaegh G, Jansen CF, Schalken JA, Witjes JA. 2005. Effect of hyperthermia on the cytotoxicity of 4 chemotherapeutic agents currently used for the treatment of transitional cell carcinoma of the bladder: an in vitro study. The Journal of urology 173: 1375-1380.

Thursday, 30 January 2014

Bladder cancer and Synergo latest updates


Bladder Cancer  

Bladder cancer is the fourth most common non-dermatological cancer in men in the UK. In 2005, the estimated male and female crude incidence rates of bladder cancer were 24.6 and 9.3 per 100,000 population with 6091 and 2403 new cases, respectively, in England. In Wales the incidence is 43.0 and 17.2 per 100,000 population, that is 619 and 260 new cases, respectively. Altogether, more than 10,000 people in the UK are newly diagnosed with bladder cancer each year. Around 75–85% of these patients have non-muscle-invasive bladder cancer (NMIBC) including carcinoma in situ (CIS).

NMIBC has a probability of recurrence at 5 years of up to 80% and a probability of progression of between 0.8% and 30% after initial treatment (depending on the stage and grade of disease). A combined analysis of 2596 patients from seven EORTC Trials with stage Ta T1 Bladder Cancer indicated a 70% recurrence within 3 years (Sylvester R. Eur Urol 2006)

Patients with bladder cancer are differentiated into one of three groups: (1) those with low risk disease in whom the main risk is recurrent low-risk papillary disease with a small chance of dying of the disease; (2) those with intermediate and high-risk non-muscle-invasive disease and CIS in whom there is a high chance of disease progression and subsequent death from bladder cancer; and (3) those with muscle-invasive disease in whom there is imminent risk of death from bladder cancer.

The goals of current treatment for patients with non-muscle-invasive bladder cancer are to prevent disease recurrence or progression to muscle-invasive disease, to avoid cystectomy and, ultimately, to enhance survival.

Transurethral resection of the bladder tumour (TURBT) is the first-line treatment for patients with NMIBC. Unfortunately, the high rate of recurrence and progression after TURBT necessitates the use of adjuvant treatments. This entails instillation of a chemotherapeutic agent, usually mitomycin (MMC), or immunotherapeutic agents such as BCG, either alone or in various combinations.

Intravesical BCG is the an effective treatment but patients who fail BCG treatment are often treated again with low probability to remain disease-free and are often referred to cystectomy. Some patients are unable to tolerate BCG and/or are refractory to treatment and some patients cannot receive treatment due to impaired immune system (e.g. lung/kidney transplants).

Synergo technology has become a therapy option[1] in many centres throughout Europe for:
·         intermediate and high-risk patients with recurrent tumours, especially after failed BCG treatment
·         patients who are unsuitable or refuse radical cystectomy
·         patients who are unfit for operation
·         patients for whom BCG treatment is contraindicated.

[1] Lammers RJ, Witjes JA, Inman BA, Leibovitch I, Laufer M, Nativ O, Colombo R: The Role of a Combined Regimen With Intravesical Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol 2011, 60:81-93