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Purpose: To report the oncological outcomes and the tolerance between 6 instillations and more than 6 cycles of hyperthermic intravesical chemotherapy(HIVEC) in patients with non-muscle invasive bladder cancer(NMIBC). Methods: This is a multicenter retrospective study from a national database including 9 expert centers. All patients treated with HIVEC between 2016 and 2023 for NMIBC were included. Patients were classified into two groups according to the total number of HIVEC instillations, including induction plus maintenance. Kaplan-Meier curves were computed to present survival outcomes. Results: 261 patients with a median follow-up of 25.5 months were included. 199(76.2%) and 62(23.8%) were treated by 6 and more than 6 cycles of HIVEC, respectively. The 2-years RFS(40.2% vs. 34.4%,p = 0.3) and the 2-years PFS(86% vs. 87%,p = 0.85) were similar between group treated with 6 and more than 6 instillations. 2-years CSS and OS were also similar between both groups. Univariate Cox regression showed no association between the number of bladder instillation and RFS (HR = 1.2 95%CI[0.8–1.84], p = 0.3) or PFS (HR = 0.8 95%CI[0.29–2.02], p = 0.2). In the group treated with more than 6 cycles, 2-years RFS and 2-years PFS were similar between patients who received induction plus maintenance compared to those treated with induction only. Finally, hematuria and urinary burning were significantly higher in the group treated by more than 6 cycles (21% vs. 8.5%(p < 0.01),and 29% vs. 17% (p = 0.03), respectively). Serious side effects(grade ≥ 3) are rare(3.1%) and similar in both groups. Conclusions: Results show no significant difference in two years RFS, PFS, CSS and OS according to number of instillations received, while toxicity profile seems better in the group receiving six instillations only. [ABSTRACT FROM AUTHOR]

Gemcitabine (GEM)‐based chemotherapy represents the first choice for locally unresectable advanced pancreatic cancer, while the benefit is limited due to acquired chemoresistance or drug delivery insufficiency. Hyperthermia treatment potentially improves the clinical efficacy of GEM. However, the underlying mechanism is incompletely revealed. Our study aims to investigate the effect and involved mechanism of thermochemotherapy on cell survival. Pancreatic cancer cells PANC‐1 and ASPC‐1 were either treated with GEM or thermochemotherapy, then cell viability, apoptosis, migration, invasion, reactive oxygen species (ROS) production, and Sp1 expression were evaluated. The results showed that GEM dose and time‐dependently affected cell viability, and 30 μM GEM achieved favorable effect in suppressing cancer cell growth. Meanwhile, hyperthermia preconditioning (43°C for 60 min) 24 h before GEM treatment yielded superior effect than other treatment sequence. GEM caused significant cell apoptosis and proapoptotic genes of both cancer cells, and thermochemotherapy further promoted apoptosis and genes transcription, accompanied by excessive ROS production. Thermochemotherapy was superior to GEM in suppressing cell migration and invasion of pancreatic cancer cells. Meanwhile, GEM significantly reduced Sp1 mRNA and protein and its downstream gene Cox‐2, and thermochemotherapy further suppressed their expressions. ROS elimination with N‐acetyl‐l‐cysteine notably neutralizes the suppressive effect of GEM and thermochemotherapy on cell growth and expressions of Sp1 and Cox‐2. In conclusion, thermochemotherapy inhibited pancreatic cell viability, migration and invasion, and promoted cell apoptosis by inducing excessive ROS production, which subsequently suppressed Sp1 expression and the downstream Cox‐2. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease that progresses from inflammation to cartilage destruction. Inspired by the similar characteristics of inflammatory granulation tissue to those of tumors, the newly emerged tumor therapy called thermochemotherapy is proposed to treat RA. Meanwhile, the repair of cartilage injury via tissue engineering is paid attention simultaneously. A first‐line antirheumatic drug (MTX; methotrexate) and transforming growth factor β1 (TGF‐β1) are loaded in nano‐Fe3O4 composite chitosan‐polyolefin to construct a multifunctional hydrogel (DN‐Fe‐MTX‐TGFβ1). The mechanical properties of the hydrogel are equivalent to that of articular cartilage to guarantee its role as a scaffold. A long‐term release ability and the magnetocaloric properties of the hydrogel assure its effect to provide sustained local thermochemotherapy. The effective ability of the hydrogel for both anti‐inflammation and cartilage repair is demonstrated. This work indicates a promising way to combine thermochemotherapy and tissue engineering for the effective treatment of RA for the first time. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and safety of a novel thermochemotherapy scheme and the instillation of pirarubicin (THP) without hyperthermia in patients with intermediate- and high-risk nonmuscle-invasive bladder cancer (NMIBC). Materials and methods: Between June 2012 and December 2016, 300 patients with urothelial carcinoma of the bladder undergoing intravesical adjuvant therapy with THP after transurethral resection of bladder tumors (TURBT) were enrolled in the study. These patients were divided into the CTHC group (thermochemotherapy composed of three consecutive sessions in which only the second hyperthermia was combined with THP, followed by intravesical instillation with THP without using hyperthermia) and the THP group (instillation of THP without hyperthermia). Cystoscopy and urinary cytology were repeated every 3 months. The primary endpoint was 24-month recurrence-free survival (RFS). Secondary endpoints included 24-month progression-free survival (PFS) and adverse event (AE) rates. Results: Baseline characteristics of the CTHC (n = 76) and THP (n = 85) groups were well-balanced. The 24-month RFS was 82.9% in the CTHC group and 63.5% in the THP group (log-rank p = .008). A significantly higher percentage of patients in the CTHC group achieved PFS than in the THP group (97.4% versus 87.1%; log-rank p = .011). There was no significant difference in AEs between the two groups (p > .05). Based on Cox proportional hazards models, CTHC was the only factor that contributed independently to improved RFS (hazard ratio, 0.422; 95% confidence interval, 0.214–0.835; p = .013). Conclusion: The CTHC scheme is a safe and effective adjuvant treatment option after TURBT for patients with intermediate- and high-risk NMIBC.

Hyperthermia, i.e. heating the tumor to a temperature of 40–43 °C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5 yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12 months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42 °C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will depend on the thermal sensitization of the tumor cells for the applied drug. In contrast to free drugs, experimental animal studies combining hyperthermia and thermo-sensitive liposomal (TSL) drugs delivery have demonstrated to result in a substantial increase of the drug concentration in the tumor. For TSL based chemotherapy, hyperthermia is critical to both increase perfusion and extravasation as well as to trigger TSL drug release, whereby the temperature controlled induction of a local high drug concentration in a highly permeable vessel is driving the enhanced drug uptake in the tumor. Increased drug concentrations up to 26 times have been reported in rodents. Good control of the tissue temperature is required to keep temperatures below 43 °C to prevent vascular stasis. Further, careful timing of the drug application relative to the start of heating is required to benefit optimal from the combined treatment. From the available experimental data it follows that irrespective whether chemotherapy is applied as free drug or using a thermal sensitive liposomal carrier, the optimal thermal dose for thermochemotherapy should be 40–42 °C for 30–60 min, i.e. equivalent to a CEM43 of 1–15 min. Timing is critical: most free drug should be applied simultaneous with heating, whereas TSL drugs should be applied 20–30 min after the start of hyperthermia. Unlabelled Image [ABSTRACT FROM AUTHOR]

Convection-enhanced delivery (CED) is a promising technique leveraging pressure-driven flow to increase penetration of infused drugs into interstitial spaces. We have developed a fiberoptic microneedle device for inducing local sub-lethal hyperthermia to further improve CED drug distribution volumes, and this study seeks to quantitatively characterize this approach in agarose tissue phantoms. Infusions of dye were conducted in 0.6% (w/w) agarose tissue phantoms with isothermal conditions at 15 °C, 20 °C, 25 °C, and 30 °C. Infusion metrics were quantified using a custom shadowgraphy setup and image-processing algorithm. These data were used to build an empirical predictive temporal model of distribution volume as a function of phantom temperature. A second set of proof-of-concept experiments was conducted to evaluate a novel fiberoptic device capable of generating local photothermal heating during fluid infusion. The isothermal infusions showed a positive correlation between temperature and distribution volume, with the volume at 30 °C showing a 7-fold increase at 100 min over the 15 °C isothermal case. Infusions during photothermal heating (1064 nm at 500 mW) showed a similar effect with a 3.5-fold increase at 4 h over the control (0 mW). These results and analyses serve to provide insight into and characterization of heat-mediated enhancement of volumetric dispersal.

Bladder cancer is the ninth-most prevalent cancer worldwide. Most patients with urothelial cell carcinoma of the bladder present with non-muscle-invasive disease and are treated with bacillus Calmette-Guérin (BCG) intravesical therapy. Many of these patients experience disease recurrence after BCG failure. Radical cystectomy is the recommended treatment for high-risk patients failing BCG. However, many patients are unfit for or unwilling to undergo this procedure. We searched the published literature on the treatment of non-muscle-invasive bladder cancer (NMIBC) after BCG failure. We review current evidence regarding intravesical therapy with gemcitabine, mitomycin combined with thermo-chemotherapy, docetaxel, nab-paclitaxel, photodynamic therapy (PDT), BCG with interferon (IFN), and combination sequentially administered chemotherapy.

Graphical abstract Abstract Metal-based photothermal therapy has been widely used in the biomedicine field and includes gold nanoparticles, silver nanoparticles and copper sulfide nanoparticles. Furthermore, the coordination bonding-based metal nanocomplex is a new generation of photothermal agents for cancer therapy due to its high photothermal transduction efficiency, good biocompatibility, biodegradation and bioactivity. In this study, we designed a coordination bonding-based copper (Cu(II))-carboxylate ternary architecture, which consists of a conjugate dopamine-modified nontoxic hyaluronic acid, copper ions and citric acid. When the Cu(II) coordinated with the carboxyl groups, the splitting d orbitals energy gap of Cu(II) and the capability of electron transition were enhanced, which can increase the extinction ability in the near-infrared region for enhancing photothermal therapy. Moreover, the degradation of hyaluronic acid by hyaluronidase highly expressed in the tumor microenvironment led to the release of Cu-citric acid complexes, thus exhibiting an additional chemotherapeutic effect. The nanocomplexes possessed high-performance photothermal conversion, determined to be 21.3%. The solution could be easily heated to above 42 °C, which was sufficient to ablate the cancer cells. An obvious decrease in cell viability was observed in B16F10 cells incubated with the nanocomplexes under laser at the lower concentration of 20 μg/mL Cu(II). Upon near-infrared laser irradiation, the nanocomplexes showed high photothermal therapy and chemotherapeutic efficacy for breast cancer in vivo. This study demonstrated that the Cu(II)-carboxylate coordination nanocomplex is a promising new effective and facilely prepared thermochemotherapy agent for combination therapy against cancer. [ABSTRACT FROM AUTHOR]

The paper discusses whether palliative treatment using a developed treatment option can be used in patients with regional metastases from malignant head and neck tumors. An analysis of the results of treating 115 patients has established that modified local thermochemotherapy should be performed, which can improve the immediate results of treatment.

Most photothermal converting systems are not biodegradable, which bring the uneasiness when they are administered into human body due to the uncertainty of their fate. Hereby, we developed a mussel-inspired PLGA/polydopamine core-shell nanoparticle for cancer photothermal and chemotherapy. With the help of an anti-EGFR antibody, the nanoparticle could effectively enter head and neck cancer cells and convert near-infrared light to heat to trigger drug release from PLGA core for chemotherapy as well as ablate tumors by the elevated temperature. Due to the unique nanoparticle concentration dependent peak working-temperature nature, an overheating or overburn situation can be easily prevented. Since the nanoparticle was retained in the tumor tissue and subsequently released its payload inside the cancer cells, no any doxorubicin-associated side effects were detected. Thus, the developed mussel-inspired PLGA/polydopamine core-shell nanoparticle could be a safe and effective tool for the treatment of head and neck cancer. Statement of Significance The described EGFR targeted PLGA/polydopamine core-shell nanoparticle (PLGA/PD NP) is novel in the following aspects: Different from most photothermal converting nanomaterials, PLGA/PD NP is biodegradable, which eliminates the long-term safety concerns thwarting the clinical application of photothermal therapy. Different from most photothermal nanomaterials, upon NIR irradiation, PLGA/PD NP quickly heats its surrounding environment to a NP concentration dependent peak working temperature and uniquely keeps that temperature constant through the duration of light irradiation. Due to this unique property an overheating or overburn situation for the adjacent healthy tissue can be easily avoided. The PLGA/PD NP releases its payload through detaching PD shell under NIR laser irradiation. The EGFR-targeted doxorubicin-loaded PLGA/PD NP effectively eradicate head and neck tumor in vivo through the synergism of photothermal therapy and chemotherapy while not introducing doxorubicin associated cardiotoxicity. [ABSTRACT FROM AUTHOR]

Nanodevices for multimodal tumor theranostics have shown great potentials for noninvasive tumor diagnosis and therapy, but the libraries of multimodal theranostic building blocks should be further stretched. In this work, Cu(II) ions are doped into polyaniline (Pani) nanoshuttles (NSs) to produce Cu-doped Pani (CuPani) NSs, which are demonstrated as new multimodal building blocks to perform tumor theranostics. The CuPani NSs are capable of shortening the longitudinal relaxation (T 1 ) of protons under magnetic fields and can help light up tumors in T 1 -weighted magnetic resonance imaging. In addition, the released Cu(II) ions from CuPani NSs lead to cytotoxicity, showing the behavior of chemotherapeutic agent. The good photothermal performance of CuPani NSs also makes them as photothermal agents to perform thermochemotherapy. By combining near-infrared laser irradiation, a complete tumor ablation is achieved and no tumor recurrence is observed. [ABSTRACT FROM AUTHOR]

Objectives: To retrospectively assess the efficacy of regional thermochemotherapy (TCT) compared with hepatic arterial infusion chemotherapy (HAIC)-alone for palliative treatment of advanced hilar cholangiocarcinoma (HC) and to determine the prognostic factors associated with survival.Methods: Forty-three consecutive patients with advanced HC underwent regional TCT (TCT group) and HAIC (HAIC group). We analyzed baseline characteristics, overall survival (OS), progression-free survival (PFS), stent patency time (SPT), adverse events (AEs), and prognostic factors for OS between the two groups.Results: OS of patients treated with regional TCT was significantly longer compared to that of patients treated with HAIC (median OS: 20.3 vs. 13.2 months, P = 0.004), and SPT and PFS were significantly increased in the TCT group compared with the HAIC group (median SPT: 26.5 vs. 10.5 months, P < 0.001; median PFS: 16.5 vs. 10.2 months, P = 0.001). TCT and metal stent insertion were two independent prognostic factors associated with survival. The treatment-related AEs were tolerable and similar in the two groups, except for hilar pain (34.6 %) and skin rashes (24.6 %) in the TCT group.Conclusions: Our results show that regional TCT is safe and more effective than HAIC-alone and may be a promising option for palliative treatment of advanced HC. Metal stenting before TCT appears to improve patients' OS.Key Points: • Regional TCT is a novel combination for palliative treatment of advanced HC • Our data showed significantly promising outcomes in the TCT group • HC patients with metal stenting appeared to derive greater benefit from TCT. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer is a challenging disease, even given its superficial nature. It is prone to multiple recurrences and progression to muscle-invasive cancer. These features of this disease contribute significantly to reduced quality of life as well as creating significant morbidity and even mortality. Randomised trials demonstrate that when hyperthermia is added to conventional mitomycin-C treatment that local control rates and progression-free survival are substantially improved. In this review we consider how hyperthermia can exert such beneficial effects. Some of the mechanisms presented are theoretical, while others are facts. It is hoped that this review will contribute rationale for further examination of mechanisms, because an understanding of such mechanisms may lead to even better chemotherapeutic approaches, as well as potential biomarkers for predicting and monitoring treatment success. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) is characterised by a high risk of recurrence for the present standard treatment of transurethral resection of the bladder (TURB) followed by intravesical instillation of Mitomycin-C (MMC) or bacillus Calmette–Guérin (BCG). To decrease this high recurrence rate, alternative treatments are studied. Intravesical MMC combined with hyperthermia could be an interesting alternative active treatment for intermediate- and high-risk NMIBC, and has been investigated in the past years. Hyperthermia, raising tumour temperatures to 40–44 °C, can be achieved with several hyperthermia systems, based on three different techniques: 1) intravesical microwave induced heating, 2) conductive heating, and 3) loco-regional, using external radiofrequency antennas. In this review an overview is given of the available hyperthermia systems and the reported outcomes. Future directions are discussed. Optimal implementation of a combined regimen of MMC and hyperthermia requires further clinical trials to identify patients who will benefit most from this treatment, to optimise treatment schedules and to compare the efficacy of different hyperthermia devices. [ABSTRACT FROM AUTHOR]

Background Despite adjuvant intravesical therapy, recurrences in non–muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data. Objective To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC. Design, setting, and participants Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov ( NCT00384891 ). Outcome measurements and statistical analysis The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients ( n = 147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided. Results and limitations The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group ( p = 0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group ( p = 0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias. Conclusions CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC. Patient summary Recurrences in non–muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy. [ABSTRACT FROM AUTHOR]

Recurrent non muscle invasive bladder cancer (NMIBC) represents a therapeutic challenge, especially in the case of Bacillus Calmette Guerin (BCG)-failures. Chemohyperthermia (CHT) has been tested as adjuvant therapy in selected categories of patients with promising results. The aim of this systematic review is to explore the current role of CHT and its future perspectives. The review process was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. After the selection process, 30 articles were used in this review. Treatment with CHT is safe and quite well tolerated. CHT seems to be effective in low and intermediate risk bladder cancer. Moreover CHT could be offered to selected categories of high risk patients and BCG failures NMIBC. Further trials are needed in order to better identify the categories of patients which could benefit from this therapy and to standardise the right schedule of treatment. [ABSTRACT FROM PUBLISHER]

Purpose: We report for the first time the activity and safety of Unithermia (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). Methods: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. Results: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59 %). Among the 14/34 (41 %) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18 % progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5 %, respectively. Toxicity did not go beyond grade 2 except in five cases. Conclusions: Initial experience with MMC-HT with Unithermia showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC. [ABSTRACT FROM AUTHOR]

Constructing novel multimodal antitumor therapeutic nanoagents has attracted tremendous recent attention. In this work, a new drug-delivery vehicle based on human-serum-albumin (HSA)-coated Prussian blue nanoparticles (PB NPs) is synthesized. It is demonstrated that doxorubicin (DOX)/HSA is successfully loaded after in situ polymerization of dopamine onto PB NPs, and the PB@PDA/DOX/HSA NPs are highly compatible and stable in various physiological solutions. The NPs possess strong near-infrared (NIR) absorbance, and excellent capability and stability of photothermal conversion for highly efficient photothermal therapy applications. Furthermore, a bimodal on-demand drug release sensitively triggered by pH or NIR irradiation has been realized, resulting in a significant chemotherapeutic effect due to the preferential uptake and internalization of the NPs by cancer cells. Importantly, the thermochemotherapy efficacy of the NPs has been examined by a cell viability assay, revealing a remarkably superior synergistic anticancer effect over either monotherapy. Such multifunctional drug-delivery systems composed of approved materials may have promising biomedical applications for antitumor therapy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of thermochemotherapy with mitomycin C (MMC) on normal rabbit bladder urothelium and to compare it with standard intravesical MMC and hyperthermia with normal saline. Methods: Twenty-four male New Zealand rabbits, with a mean weight of 2.7 kg (in weight of 2.1-4.3 kg), were divided into three groups, each containing eight rabbits. Thermotherapy with only normal saline was performed in the first group, standard intravesical MMC was performed in the second group, and thermotherapy with MMC was performed in the last group. A week after the primary procedure, total cystectomy was performed and tissue samples were evaluated. Results: The presence of epithelial vacuolar degeneration ( p = 0.001), epithelial hyperplasia ( p = 0.000), subepithelial fibrosis ( p = 0.001) and hemorrhagic areas in the connective tissue ( p = 0.002) was observed statistically significantly higher in the standard MMC group than in thermotherapy with normal saline group. There was almost a significant difference among standard MMC and normal saline group in terms of vascular congestion in the connective tissue ( p = 0.08). Presence of epithelial vacuolar degeneration ( p = 0.002), epithelial hyperplasia ( p = 0.002), subepithelial fibrosis ( p = 0.030), hemorrhagic areas ( p = 0.011) and vascular congestion ( p = 0.36) in the connective tissue was observed statistically significantly higher in the thermochemotherapy with MMC group than in standard intravesical MMC group. Polymorphonuclear cell infiltration was not considerable in any of the groups, and there was no significant difference between each groups ( p = 0.140). Conclusion: Administration of intravesical MMC causes a toxic effect on the normal urothelium of the bladder rather than an inflammatory reaction. Heating MMC significantly increased this effect. [ABSTRACT FROM AUTHOR]

Bladder cancer is the ninth‑most prevalent cancer worldwide. Most patients with urothelial cell carcinoma of the bladder present with non‑muscle‑invasive disease and are treated with bacillus Calmette‑Guérin (BCG) intravesical therapy. Many of these patients experience disease recurrence after BCG failure. Radical cystectomy is the recommended treatment for high‑risk patients failing BCG. However, many patients are unfit for or unwilling to undergo this procedure. We searched the published literature on the treatment of non‑muscle‑invasive bladder cancer (NMIBC) after BCG failure. We review current evidence regarding intravesical therapy with gemcitabine, mitomycin combined with thermo‑chemotherapy, docetaxel, nab‑paclitaxel, photodynamic therapy (PDT), BCG with interferon (IFN), and combination sequentially administered chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives To prospectively evaluate the outcome of combined microwave-induced bladder wall hyperthermia and intravesical mitomycin C instillation (thermochemotherapy) in patients with recurrent non-muscle-invasive bladder cancer. Methods Between 2003 and 2009, 21 patients (median age 70 years, range 35-95 years) with recurrent non-muscle-invasive bladder cancer ( pTaG1-2 n = 9; pTaG3 n = 3; pT1 n = 9; concurrent p Tis n = 8) were prospectively enrolled. Of 21 patients, 15 (71%) had received previous intravesical instillations with bacillus Calmette- Guérin, mitomycin C and/or farmorubicin. Thermochemotherapy using the Synergo system was carried out in 11 of 21 patients (52%) with curative intent, and in 10 of 21 patients (48%) as prophylaxis against recurrence. Results The median number of thermochemotherapy cycles per patient was six (range 1-12). Adverse effects were frequent and severe: urinary urgency/frequency in 11 of 21 patients (52%), pain in eight of 21 patients (38%) and gross hematuria in five of 21 patients (24%). In eight of 21 patients (38%), thermochemotherapy had to be abandoned because of the severity of the adverse effects (pain in 3/8, severe bladder spasms in 2/8, allergic reaction in 2/8, urethral perforation in 1/8). Overall, six of 21 patients (29%) remained free of tumor after a median follow up of 50 months (range 1-120), six of 21 patients (29%) had to undergo cystectomy because of multifocal recurrences or cancer progression and seven of 21 patients (33%) died (2/7 of metastatic disease, 5/7 of non-cancer related causes). Conclusions Given the high rate of severe side-effects leading to treatment discontinuation, as well as the limited tumor response, thermochemotherapy should be offered only in highly selected cases of recurrent non-muscle-invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: A new pH-sensitive and thermosensitive dual drug delivery system consisting of thin lipid layer encapsulated mesoporous magnetite nanoassemblies (MMNA) has been developed which can deliver two anticancer drugs simultaneously. The formulation of lipid layer used is 5:2:2:2w/w, DPPC:cholesterol:DSPE-PEG2000:MMNA. The structure, morphology and magnetic properties of MMNA and lipid coated MMNA (LMMNA) were thoroughly characterized. This hybrid system was investigated for its ability to carry two anticancer drugs as well as its ability to provide heat under an alternating current magnetic field (ACMF). A very high loading efficiency of up to ∼81% of doxorubicin hydrochloride (DOX) with an ∼0.02mgmg−1 loading capacity and ∼60% of paclitaxel (TXL) with an ∼0.03mgmg−1 loading capacity are obtained with LMMNA. A sustained release of drug is observed over a period of 172h, with better release, of ∼88:53% (DOX:TXL), at pH 4.3 compared to the ∼28:26% (DOX:TXL) in physiological conditions (pH 7.4). An enhanced release of ∼72 and ∼68% is recorded for DOX and TXL, respectively, during the first hour with the application of an ACMF (∼43°C). A greater in vitro cytotoxic effect is observed with the two drugs compared to them individually in HeLa, MCF-7 and HepG2 cancer cells. With the application of an ACMF for 10min, the cell killing efficiency is improved substantially due to simultaneous thermo- and chemotherapy. Confocal microscopy confirms the internalization of drug loaded MMNA and LMMNA by cells and their morphological changes during thermochemotherapy. [Copyright &y& Elsevier]

Purpose: The aim of this paper is to report thermal dosimetry characteristics of external deep regional pelvic hyperthermia combined with intravesical mitomycin C (MMC) for treating bladder cancer following transurethral resection of bladder tumour, and to use thermal data to evaluate reliability of delivering the prescribed hyperthermia dose to bladder tissue. Materials and methods: A total of 14 patients were treated with MMC and deep regional hyperthermia (BSD-2000, Sigma Ellipse or Sigma 60). The hyperthermia objective was 42° ± 2 °C to bladder tissue for ≥40 min per treatment. Temperatures were monitored with thermistor probes and recorded values were used to calculate thermal dose and evaluate treatment. Anatomical characteristics were examined for possible correlations with heating. Results: Combined with BSD-2000 standard treatment planning and patient feedback, real-time temperature monitoring allowed thermal steering of heat sufficient to attain the prescribed thermal dose to bladder tissue within patient tolerance in 91.6% of treatments. Mean treatment time for bladder tissue >40 °C was 61.9 ± 11.4 min and mean thermal dose was 21.3 ± 16.5 CEM43. Average thermal doses obtained in normal tissues were 1.6 ± 1.2 CEM43 for the rectum and 0.8 ± 1.3 CEM43 in superficial normal tissues. No significant correlation was seen between patient anatomical characteristics and thermal dose achieved in bladder tissue. Conclusions: This study demonstrates that a hyperthermia prescription of 42° ± 2 °C for 40-60 min can be delivered safely to bladder tissue with external radiofrequency phased array applicators for a typical range of patient sizes. Using the available thermometry and treatment planning, the BSD-2000 hyperthermia system was shown to be an effective method of focusing heat regionally around the bladder with good patient tolerance. [ABSTRACT FROM AUTHOR]

Purpose: This paper aimed to evaluate the effects of a combination of paclitaxel and cisplatin on osteosarcoma (OS) cell lines in the presence of hyperthermia and to investigate the related mechanism. Materials and methods: Two types of OS cell lines (OS732 and MG63) were treated with paclitaxel and cisplatin in the presence of hyperthermia. The survival rate was measured by MTT assay, and the clonogenic rate was measured by a clonogenic assay. The cellular changes were observed with an inverted phase contrast microscope and a fluorescence microscope. The apoptotic effect was analysed with flow cytometry (FCM). Fas expression by the OS cell lines was measured by western blot. Fas expression in OS tissue was measured by immunohistochemistry. Results: Our study indicated that 1 h after the application of a combination of 10 μg/mL paclitaxel and 5 μg/mL cisplatin to OS cells at 43 °C, the survival rate of the OS cells was 11.96%, which was significantly lower than when either 10 μg/mL paclitaxel (45.02%) or 5 μg/mL cisplatin (48.69%) was applied alone ( p < 0.01). Additionally, the clonogenic assay demonstrated that the clonogenic survival rate in the OS cells of the combination group was lower than that in the individual groups. Moreover, the cellular changes and apoptosis rates indicated that apoptosis in the combined application group was much greater than when either drug was applied individually. Fas expression by OS cell lines was increased by the combination of paclitaxel and cisplatin under hyperthermic conditions. More importantly, our study revealed low Fas expression in OS, which better explained the up-regulation of Fas achieved by the combination of paclitaxel and cisplatin in the presence of hyperthermia. Conclusions: The combination of paclitaxel and cisplatin increases the effects of thermochemotherapy on OS cell lines, primarily through the induction of apoptosis by the up-regulation of Fas expression. [ABSTRACT FROM AUTHOR]

Thermotherapy and thermochemotherapy have been used in clinics to treat patients with malignant diseases, including colon cancer, and their efficacy has been well proved. Heat shock proteins (HSPs), especially Hsp70, play important roles in neutralizing their efficacy. It has been reported that quercetin can suppress cancer by inhibiting the intratumoral expression of Hsp70. This study was designed to investigate whether quercetin could enhance sensitivity to thermotherapy and thermochemotherapy. Soluble quercetin liposome was used in this study. The effects of quercetin were investigated in vitro and in mouse colon cancer models of subcutaneous tumor and peritoneal carcinomatosis. The results showed that quercetin liposome inhibited the upregulation of Hsp70 and enhanced apoptosis induced by hyperthermia and thermochemotherapy. Systemic administration of quercetin liposome can sensitize CT26 cells to thermotherapy and chemothermotherapy. This study suggests that quercetin liposome might be potentially applied for clinical cancer therapy. [ABSTRACT FROM PUBLISHER]

OBJECTIVES: To give an updated review concerning the role of combined regimen (CT) based on microwave- induced hyperthermia (MwHT, CT-MwHT) with intravesical chemotherapy (ICT) as a treatment for non-muscle invasive bladder cancer (NMIBC). EVIDENCE ACQUISITION: The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also included. The primary end-point was the time to recurrence. Secondary end-points included time to progression, bladder preservation rate, and adverse event (AE) rate. EVIDENCE SYNTHESIS: A total of 24 studies met inclusion criteria and underwent data extraction. When feasible, data were combined using random-effects meta-analytic techniques. Recurrence was seen 59% less after CT-MwHT than after MMC alone, however, due to the short follow-up, no definitive conclusions can be drawn about the impact on the time to recurrence and progression. The overall bladder preservation rate after CT-MwHT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies could not be drawn due to the absence of randomized trials in neo-adjuvant settings. AEs were higher with CT-MwHT than with MMC alone, but this difference was not statistically significant. cOnclusiOns: Published data suggest that recurrence rates for chemo-hyperthermia are substantially reduced compared with chemotherapy alone in adjuvant settings. Patients with refractory disease fare worse than those being treated with chemo-hyperthermia for their first tumor. Progression rates to muscle-invasive disease are markedly lower after combination treatment than after chemotherapy alone, with very high rates of bladder preservation. Tolerability is good, with few dropouts in the clinical trials. The results support CT-MwHT in the future as a standard procedure for high-risk recurrent patients, for subjects in whom the treatment with Bacillus Calmette-Guérin is contraindicated, and those unsuitable for radical cystectomy. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer is a common urinary malignancy whose management is a challenge: strong evidence supports the use of passive intravesical chemotherapy in the management of this tumor. Despite current guidelines, the treatment is suboptimal as illustrated by the high risk of recurrence and progression. Bacillus Calmette-Guérin (BCG) is the gold standard for the treatment of high-grade non-muscle-invasive bladder cancer, but in case of disease persistence, after 2 consecutive induction courses of BCG, patients must undergo radical cystectomy. We discuss options for second-line adjuvant therapy for non-muscle-invasive bladder cancer in standard treatment non-responder patients. We investigated the use and application of device-assisted therapy for the intravesical treatment of bladder cancer, such as thermochemotherapy (TCT) and electromotive drug administration (EMDA). Many studies demonstrate their synergistic therapeutic effect, greater than the single treatment with chemotherapy, inducing an increased absorption of the chemo-therapeutic agent (Mitomycin C) to the urothelium. TCT and EMDA are safe and effective in terms of outcomes. For the future it will be important to encourage the use of the existing technology within the appropriate clinical indications. [ABSTRACT FROM AUTHOR]

There is significant interest in recent years in developing magnetic nanoparticles (MNPs) having multifunctional characteristics with complimentary roles. In this study, methotrexate (MTX) was conjugated on the iron oxide magnetic nanoparticles surface via a poly(ethyleneimine) self-assembled monolayer (MTX-MNPs). The novel platform combined cancer chemotherapy, hyperthermia and potential monitoring of the progression of disease through magnetic resonance imaging (MRI). The conjugation of MTX on the magnetite surface was confirmed by Fourier transform infrared spectroscopy and change of zeta potential. Transmission electron microscope (TEM) showed that MTX-MNPs were morphologically spherical. The average diameter of MTX-MNPs was 30.1 ± 5.2 nm determined by dynamic light scattering. Magnetic measurements revealed that the saturation magnetization of MTX-MNPs reached 68.8 emu/g and the nanoparticles were superparamagnetic. The MTX-MNPs had good heating properties in an alternating magnetic field. TEM results showed that a larger number of MTX-MNPs were internalized into the MCF-7 cellular cytoplasm compared with the MNPs. The MTX-MNPs demonstrated highly synergistic antiproliferative effects of simultaneous chemotherapy and hyperthermia in MCF-7 breast cancer cells. A significant negative contrast enhancement was observed with magnetic resonance phantom imaging for MCF-7 cells over L929cells, when both were cultured with the nanoconjugate. The MTX-MNPs with combined characteristics of thermochemotherapy and MRI could be of high clinical significance in the treatment of tumor. [ABSTRACT FROM AUTHOR]

Objectives: Non-muscle-invasive bladder cancer is characterized by a high recurrence rate after primary transurethral resection. In case of bacillus Calmette-Guérin-refractory neoplasms, cystectomy is the gold standard. In this study the effects of thermochemotherapy with mitomycin C were evaluated in high-risk bladder cancer nonresponders to previous therapy. Patients and Methods: Between January 2006 and December 2009, 30 patients were enrolled with recurrent stage carcinoma in situ, Ta and T1, grade G1 to G3 non-muscle-invasive bladder cancer refractory to chemotherapy or immunotherapy and so becoming suitable for radical cystectomy. All patients underwent endovesical thermochemotherapy: 16 patients underwent a prophylactic scheme and 14 patients underwent an ablative scheme. Results: All the patients completed the study. The mean follow-up for all the patients enrolled was 14 months. Thirteen of 30 patients (43.30%) were disease free and 17 patients (56.70%) had recurrence. In the prophylactic group, 7 of 16 patients (43.75%) were disease free and 9 patients (46.25%) had tumor recurrence; no progression was observed. In the ablative group, 3 patients (17, 64%) had progression to muscle-invasive disease. Side effects were generally mild. Conclusions: Thermochemotherapy could be considered an additional tool in patients refractory to intravesical therapies before considering early cystectomy. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the relationship between thermochemotherapy-induced apoptosis and the expressions of the Bcl-2 and Bax proteins in maxillofacial squamous cell carcinomas. Fifteen patients with maxillofacial squamous cell carcinomas were treated with microwave hyperthermia (43°C for 40 min) following the intravenous injection of pingyangmycin (Bleomycin A5 Hydrochloride for Injection) (8 mg). Subsequently, the tumors were surgically resected. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling method was used to assess the apoptosis in the carcinoma cells, and immunohistochemistry was performed using the streptavidin-peroxidase method to determine the expression levels of the Bcl-2 and Bax proteins, and quantitative analysis was employed. The number of apoptotic cells increased markedly ( P < 0.001). The protein expression of Bcl-2 was downregulated ( P < 0.001), while that of Bax was markedly upregulated ( P < 0.001). Thermochemotherapy induces apoptosis in maxillofacial squamous cell carcinoma cells by downregulating the protein expression of Bcl-2 and upregulating that of Bax. [ABSTRACT FROM AUTHOR]

Abstract: Context: Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings. Objective: To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC. Evidence acquisition: The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate. Evidence synthesis: A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant. Conclusions: Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated. [Copyright &y& Elsevier]

Abstract: Objectives: Non-muscle invasive bladder cancer (NMIBC) classified as T1G3 represents one of the most challenging issues in urologic oncology. Although it is still considered a lesion amenable for conservative management, the risk for recurrence and progression remains high. The aim of this study was to define both recurrence and progression rate in patients with T1G3 UCC treated by complete transurethral resection (TURT) and adjuvant thermochemotherapy approach. Materials and methods: We retrospectively evaluated the clinical data of patients with T1G3 NMIBC who underwent TURT followed by thermochemotherapy (TCT) treatment. Data recorded included age, gender, previous resections, previous intravesical treatment, time to tumor recurrence, and progression. TCT was given once weekly for 6 consecutive weeks, followed by 6 maintenance sessions at 4 to 6 weeks intervals. During each treatment session, 40 mg of mitomycin C (MMC) was instilled into the bladder in combination with bladder wall hyperthermia of 42 ± 2°C for 60 minutes. Follow-up cystoscopy and urinary cytology were performed every 3 months for the first 2 years and than biannually. Results: A total of 56 T1G3 patients were treated with adjuvant TCT treatment at 7 urologic centers. Mean age was 68 years (range 35–91), 10 were females and 46 were males. Twenty-six patients failed on at least 1 previous intravesical treatment. Five patients who dropped out due to adverse events before reaching the first outcome evaluation cystoscopy were referred to another intravesical therapy, and were therefore excluded from the current analysis. A total 51 patients were available for analysis. Median follow-up time of tumor-free patients was 18 months (average 20, range 2–49 months). Seventeen patients (33.3%) had tumor recurrence and 4 of them progressed to muscle invasive disease. The median time to recurrence was 9 months (average 11, range 2–31 months). The Kaplan-Meier estimated recurrence rate for this group is: 42.9% at 2 years, 51.0% at 4 years. Conclusions: TCT can be an effective adjuvant treatment option after TURT to prevent recurrence in patients with T1G3 NMIBC. Progression rate after this treatment was low (7.9%). TCT treatment was documented to be effective also in those who failed previous intravesical BCG. Treatment was confirmed to be safe and well tolerated. [Copyright &y& Elsevier]

Purpose: Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity. Materials and methods: The effect of mild heat (40°C) on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumour cell line. In vivo oxaliplatin was administered at various doses and times before, during and after fever-range thermal therapy (6 h at 40°C) to rats bearing an MTLn3 mammary adenocarcinoma. Tumour growth, survival, and toxicity were measured to determine treatment outcome. Results: Heating halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24 h before thermal therapy were completely immunologically cured, while a further 11% regressed their primary tumour but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumour efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 h before fever-range whole body thermal therapy. Conclusions: When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumours in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life. [ABSTRACT FROM AUTHOR]

Summary: Introduction: The aim of this study was to evaluate the efficacy, functional and aesthetic results, and safety of a novel treatment, thermochemotherapy, for lower lip squamous cell carcinoma (LLSCC) without metastases. Patients and Methods: A combination of local hyperthermia delivered by a 915MHz microwave heating system and the chemotherapy of pingyangmycin (bleomycin A(5) hydrochloride) (PYM) and methotrexate (MTX), was administered to 31 patients of LLSCC twice per week for a period of 4.5–7.5 weeks. Patients with complete response (CR) have been followed up for a full five-year period, whereas partial response (PR) patients were excluded for further analysis. The local control of tumour, functional and cosmetic outcomes, recurrence, regional lymph node and distant metastases, and complications were assessed by clinical and imaging examination. Results: Clinical CR was observed in twenty-nine (93.55%) patients and PR in two (6.45%), the total response rate was 100%, while the adverse effects were extremely minimal and tolerable in all 31 patients including 6 elderly patients with a compromised general condition. All 29 CR, including 8 extensive lesions, achieved excellent cosmetic and functional preservation. During the follow-up period, local relapse was seen in 1 case, 1 patient died, and the remainder obtained a complete remission. Conclusion: This clinical study suggests that thermochemotherapy may be a feasible treatment for primary LLSCC without cervical metastases, especially for patients with extensive lesions and a compromised general condition. [Copyright &y& Elsevier]

To study the results of chemotherapy combined with intravesical hyperthermia in patients with mainly BCG-failing carcinoma in situ (CIS). Patients with histologically confirmed CIS were included retrospectively. Outpatient thermochemotherapy treatment was done with mitomycin-C (MMC) and the Synergo® system SB-TS 101 (temperature range between 41 and 44°C), weekly for 6–8 weeks, followed by 4–6 sessions every 6–8 weeks. Fifty-one patients were treated between 1997 and 2005 from 15 European centers. Thirty-four were pre-treated with BCG. Mean age was 69.9 years. Twenty-four patients had concomitant papillary tumors. The mean number of hyperthermia/MMC treatments per patient was 10.0. Of the 49 evaluable patients 45 had a biopsy and cytology proven complete response. In two patients CIS disappeared, but they had persistent papillary tumors. Follow-up of 45 complete responders showed 22 recurrences after a mean of 27 months (median 22): T2 (4), T1 (4), T1/CIS (1), CIS (5), Ta/CIS (2), Ta (5) and Tx (1). Side effects (bladder complaints) were generally mild and transient. In patients with primary or BCG-failing CIS, treatment with intravesical hyperthermia and MMC appears a safe and effective treatment. The initial complete response rate is 92%, which remains approximately 50% after 2 years. [ABSTRACT FROM AUTHOR]

Purpose: To determine an effective triple-agent schedule combining fever-range whole body thermal therapy (FR-WB-TT) with cisplatin and gemcitabine by optimizing the timing of drug with heat, and drug with drug. Materials and methods: Using an orthotopically implanted syngeneic breast adenocarcinoma in an immunologically normal female Fischer rat model, we investigated various schedules of a thermochemotherapy regimen combining FR-WB-TT with chemotherapy agents, cisplatin and gemcitabine. Differently timed combinations of a) cisplatin with FR-WB-TT, b) gemcitabine with FR-WB-TT, and c) cisplatin with gemcitabine were examined for anti-tumor efficacy and toxicity. A combination of the three agents based on the optimal two-agent schedules was then tested. Results: The greatest primary tumor and axillary metastasis growth delay and lowest toxicity was induced with administration of cisplatin 24 h prior to gemcitabine and cisplatin 24 h prior to simultaneous gemcitabine and FR-WB-TT. Administering cisplatin 24 h prior to gemcitabine was more effective and less toxic than giving the two drugs simultaneously or gemcitabine prior to cisplatin. Survival was greatest when gemcitabine and FR-WB-TT were administered 24 h after cisplatin, even with reduced drug doses. One complete cure resulted from the triple agent treatment. Conclusions: The relative timing of agents in multiple modality treatments is critically important in achieving tumor control or cures, and in reducing toxicity. Optimizing the relative timing of multiple agents in thermochemotherapy allows use of lower drug doses to achieve maximal anti-tumor efficacy and minimal toxicity. [ABSTRACT FROM AUTHOR]

Purpose: We investigated whether it is possible to predict the antitumour effects of thermochemotherapy from the results of anticancer agent sensitivity testing. Materials and Methods: We produced a nude mouse cancer model using 4 lung cancer cell lines. Animals were divided into 4 groups: Thermotherapy (HT group), chemotherapy (CT group), thermochemotherapy (HT+CT group), and no therapy (NT group). Comparison of in vivo and in vitro effects were performed using cisplatin (CDDP), doxorubicin (ADR) and vinorelbine (NVB). In vivo thermotherapy was performed using the Thermotron RF IV, and radiofrequency (RF) capacitative hyperthermia device that induces a localised temperature of 42.0°C for 45 min. The collagen gel embedded culture drug sensitivity test (CD-DST) was used for in vitro chemosensitivity analysis of the anticancer agents. In vitro thermochemotherapy was performed using a modified CD-DST method, with the incubator set at 42.0° for the first hour of the 24 hours drug exposure period. Results: A good correlation was seen between in vivo and in vitro treated/control ratios (T/C%) in the HT group (R = 0.91, p = 0.09). Good correlations were also seen between in vivo and in vitro T/C in all cell lines in the CT group (R = 0.759, p = 0.09) and the HT+CT group (R = 0.65, p = 0.02). True positive rate was 87.5% (7/8), and true negative rate was 100% (4/4). Sensitivity, specificity and accuracy were 100% (7/7), 80% (4/5), and 91.7% (11/12) respectively. Conclusion: A modified CD-DST using an exposure temperature of 42°C can be used to predict the antitumour effect of thermochemotherapy. [ABSTRACT FROM AUTHOR]

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window. [ABSTRACT FROM AUTHOR]

Abstract: Children with retinoblastoma have increasingly been treated with carboplatin in the past decade. Ototoxicity is a known, possible, side-effect of carboplatin. Since retinoblastoma patients are very young and frequently have impaired vision, the evaluation of hearing loss is very important. The hearing status of 25 children with retinoblastoma treated with carboplatin (median cumulative dose 2240mg/m2) was evaluated in detail. Median age at first carboplatin administration was 7months. The evaluation of hearing loss was performed by an age-appropriate measurement protocol consisting of tympanometry, otoacoustic emission measurements, auditory brainstem responses and (high-frequency) visual reinforcement audiometry (VRA) or play-audiometry. The median follow-up time after last carboplatin dose was 25months (range 1–94months). In none of the children was hearing loss detected after carboplatin administration. A measurement protocol that includes tympanometry, distortion product otoacoustic emission measurements and high-frequency VRA is recommended for young children receiving carboplatin or other ototoxic drugs. [Copyright &y& Elsevier]

Abstract: Four series of water-based dextran-ferrite (DF) magnetic fluids (MFs) containing Melphalan (MP) were prepared. Their saturation magnetization (M s) was from 0.8 to 7.8kA/m; specific power absorption rates were 240W/g Fe. After nine courses of magnetic fluid thermochemotherapy with MP containing DF MF (M s 7.5kA/m, pH 6.6, ζ+15mV) at 44–46°C for 30min in an AC magnetic field (0.88MHz, 9.3kA/m, 0.3kW), complete P388 tumor regression was seen in 30% of BDF1 mice. Furthermore, a life span increase of 180% was achieved. [Copyright &y& Elsevier]

It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5°C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5°C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T[sub 0] (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37°C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T[sub 0] at 37°C to the T[sub 0] at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed. [ABSTRACT FROM AUTHOR]