Reliability of temperature and SAR measurements at oesophageal tumour locations.

INTRODUCTION: For treatment of oesophageal cancer, neo-adjuvant locoregional hyperthermia (HT) has been applied in combination with chemotherapy (ChT) +/- radiotherapy (RT) at the institute. Until now, 26 patients were treated within a completed phase I study combining HT with ChT and 29 patients within an ongoing phase II study combining HT with ChT + RT. METHODS: HT was given with the 70 MHz AMC-4 waveguide system. Initially, oesophageal temperatures were measured using multi-sensor thermocouple probes (TCs) inside a nasogastric tube (NT), but the question arose whether these measurements were reliable enough to quantify the achieved tumour temperatures accurately. Presently, TCs are mounted on the outside of an inflatable balloon catheter (BC) for better intra-luminal fixation and better contact with the tumour. During 14 treatment sessions in four patients TCs inside a NT and mounted on a BC were used simultaneously. Data from these 14 treatment sessions were used to compare temperature and Specific Absorption Rate (SAR) measurements ('DeltaT-measurements') using NTs or BCs. To determine the predictive value of the local SAR for the tumour temperatures achieved during treatment, the relation between the initial DeltaT and steady state temperature (SST) was evaluated. RESULTS: There was a strong correlation between the temperature measured in the NT (Ttube) and the temperature measured with a BC (Tballoon): R = 0.88 +/- 0.13. However, Ttube was on average approximately 1 degrees C higher than Tballoon and there was a large variation between the different treatments in the relation between both measurements, rendering Ttube a probably unreliable measure for tumour temperatures. The correlation between the DeltaT measured in the NT (DeltaTtube) and with a BC (DeltaTballoon) was rather weak: R = 0.46 +/- 0.25. The correlation between the initial DeltaT and the SST was much stronger for the BC measurements, R = 0.78 +/- 0.19, than for the NT measurements, R = 0.61 +/- 0.23. Thus, DeltaTballoon has a higher predictive value for the achieved tumour temperatures than DeltaTtube. Both DeltaT and SST were generally higher for the NT measurements than for the BC measurements, suggesting an over-estimation of tumour temperatures. Averaged over all treatments in the phase I trial using a NT (20 treatments) or a BC (45 treatments), T90 was significantly higher when measured with a NT. CONCLUSION: Oesophageal temperature and SAR (DeltaT) measurements inside a NT are less reliable than BC measurements. These artefacts are due to bad thermal contact with the tumour tissue and are, therefore, not specific for thermocouple thermometry. For reliable temperature or SAR measurements inside lumina or cavities good thermal contact must be assured, e.g. by using a balloon catheter.     

Evolving connections between molecular chaperones and neuronal function

Background: In the Academic Medical Center (AMC) Amsterdam, locoregional hyperthermia for oesophageal tumours is applied using the 70?MHz AMC-4 phased array system. Due to the occurrence of treatment-limiting hot spots in normal tissue and systemic stress at high power, the thermal dose achieved in the tumour can be sub-optimal. The large number of degrees of freedom of the heating device, i.e. the amplitudes and phases of the antennae, makes it difficult to avoid treatment-limiting hot spots by intuitive amplitude/phase steering.

Aim: Prospective hyperthermia treatment planning combined with high resolution temperature-based optimization was applied to improve hyperthermia treatment of patients with oesophageal cancer.

Methods: All hyperthermia treatments were performed with ‘standard’ clinical settings. Temperatures were measured systemically, at the location of the tumour and near the spinal cord, which is an organ at risk. For 16 patients numerically optimized settings were obtained from treatment planning with temperature-based optimization. Steady state tumour temperatures were maximized, subject to constraints to normal tissue temperatures. At the start of 48 hyperthermia treatments in these 16 patients temperature rise (ΔT) measurements were performed by applying a short power pulse with the numerically optimized amplitude/phase settings, with the clinical settings and with mixed settings, i.e. numerically optimized amplitudes combined with clinical phases. The heating efficiency of the three settings was determined by the measured ΔT values and the ΔT-ratio between the ΔT in the tumour (ΔT_oes) and near the spinal cord (ΔT_cord). For a single patient the steady state temperature distribution was computed retrospectively for all three settings, since the temperature distributions may be quite different. To illustrate that the choice of the optimization strategy is decisive for the obtained settings, a numerical optimization on ΔT-ratio was performed for this patient and the steady state temperature distribution for the obtained settings was computed.

Results: A higher ΔT_oes was measured with the mixed settings compared to the calculated and clinical settings; ΔT_cord was higher with the mixed settings compared to the clinical settings. The ΔT-ratio was ～1.5 for all three settings. These results indicate that the most effective tumour heating can be achieved with the mixed settings. ΔT is proportional to the Specific Absorption Rate (SAR) and a higher SAR results in a higher steady state temperature, which implies that mixed settings are likely to provide the most effective heating at steady state as well. The steady state temperature distributions for the clinical and mixed settings, computed for the single patient, showed some locations where temperatures exceeded the normal tissue constraints used in the optimization. This demonstrates that the numerical optimization did not prescribe the mixed settings, because it had to comply with the constraints set to the normal tissue temperatures. However, the predicted hot spots are not necessarily clinically relevant. Numerical optimization on ΔT-ratio for this patient yielded a very high ΔT-ratio (～380), albeit at the cost of excessive heating of normal tissue and lower steady state tumour temperatures compared to the conventional optimization.

Conclusion: Treatment planning can be valuable to improve hyperthermia treatments. A thorough discussion on clinically relevant objectives and constraints is essential.     

On verification of hyperthermia treatment planning for cervical carcinoma patients

Purpose: The aim of this study was to verify hyperthermia treatment planning calculations by means of measurements performed during hyperthermia treatments. The calculated specific absorption rate (SAR_calc) was compared with clinically measured SAR values, during 11 treatments in seven cervical carcinoma patients.

Methods: Hyperthermia treatments were performed using the 70?MHz AMC-4 waveguide system. Temperatures were measured using multisensor thermocouple probes. One invasive thermometry catheter in the cervical tumour and two non-invasive catheters in the vagina were used. For optimal tissue contact and fixation of the catheters, a gynaecological tampon was inserted, moisturized with distilled water (4 treatments), or saline (6 treatments) for better thermal contact. During one treatment no tampon was used. At the start of treatment the temperature rise (ΔT_meas) after a short power pulse was measured, which is proportional to SAR_meas. The SAR_calc along the catheter tracks was extracted from the calculated SAR distribution and compared with the ΔT_meas-profiles.

Results: The correlation between ΔT_meas and SAR_calc was on average R?=?0.56?±?0.28, but appeared highly dependent on the wetness of the tampon (preferably with saline) and the tissue contact of the catheters. Correlations were strong (R?～?0.85–0.93) when thermal contact was good, but much weaker (R?～?0.14–0.48) for cases with poor thermal contact.

Conclusion: Good correlations between measurements and calculations were found when tissue contact of the catheters was good. The main difficulties for accurate verification were of clinical nature, arising from improper use of the gynaecological tampon. Poor thermal contact between thermocouples and tissue caused measurement artefacts that were difficult to correlate with calculations.     

Umbilical temperature correlation with core and skin temperatures at rest,in the heat and during physical activity

Purpose: to determine the correlation of umbilical temperatures (T_umb) with simultaneously recorded chest wall temperature (T_chest) and rectal temperature (T_rectal) in adults during rest, heat exposure and exercise.

Methods: A total of 28 healthy men, wearing different types of clothing (athletic garb, a spandex full body heating garment, firefighter bunker gear) had average and peak umbilical, chest wall and rectal temperature measurements taken during sedentary temperature stabilisation stages, heat exposure periods and active exercise phases.

Results: Curvilinear relationships were noted between T_chest and T_umb compared with T_rectal and their association became noticeably positive and linear at approximately 35.5?°C. Polynomial regression analysis of T_rectal with linear and quadratic forms of T_chest and T_umb indicated an overall R² of 0.657 and 0.767, respectively. Bivariate analysis of a restricted data set (where T_chest and T_umb?≥35.5°), indicated that T_umb was significantly associated with T_rectal (r_average?=?0.710, p?<0.001; r_peak =?0.841, p?<0.001) and T_chest was also significantly associated with T_rectal, but less so (r_average?=?0.570, p?<0.001; r_peak?=?0.699, p?<0.001).

Conclusions: the umbilicus offers a non-invasive, peripheral site for measurement of temperature that more closely correlated with body core temperature than T_chest when core temperature was ≥35.5?°C.     

Relation between body size and temperatures during locoregional hyperthermia of oesophageal cancer patients

Purpose. To analyse the relation between patients’ body size and temperatures during locoregional hyperthermia for oesophageal cancer.

Methods. Patients were treated with neo-adjuvant chemoradiotherapy plus hyperthermia, given with the AMC-4 waveguide system. Temperatures were measured at tumour location in the oesophageal lumen using multisensor thermocouple probes. Systemic temperature rise (ΔT_syst) was monitored rectally. Steady-state tumour temperatures were expressed in terms of T₉₀, T₅₀ and T₁₀, averaged over the five hyperthermia sessions, and correlated with patients’ body mass, dorsoventral and lateral diameter and fat layer thickness, measured at tumour level using a CT scan made in treatment position. Fat percentage (Fat%) was estimated using diameters and fat layer thickness. Effective tumour perfusion (W_b) was estimated from the temperature decay during the cool-down period.

Results. Temperatures were inversely related to body mass, diameters, fat layer thickness, and fat percentage. The strongest univariate correlations were found with lateral fat layer thickness, lateral diameter, and body mass. An increase in lateral diameter (28→42 cm), or in lateral fat layer thickness (0→40 mm) or in body mass (50→120 kg) all yielded a ～1.5°C decrease in tumour temperature rise. Multivariate correlation analysis proved that the combination of Fat%, ΔT_syst and W_b was most predictive for the achieved tumour temperatures, accounting for 81 ± 12% of the variance in temperatures.

Conclusions. Intra-oesophageal temperatures during locoregional hyperthermia are inversely related to patients’ body size parameters, of which fat percentage is the most significant prognostic factor. These findings could be used to define inclusion criteria of new studies on intrathoracic hyperthermia.     

Intra-luminal thermometry: Is tissue type assignment a necessity for thermal analysis?

Introduction: Tissue type assignment, i.e. differentiation tumour from normal tissue, is a normal procedure for interstitial thermometry. In our department, thermometry in patients with a tumour in the lower pelvis is usually restricted to the intra-luminal tracks. It is unknown whether discrimination between normal and tumour tissue is relevant for deep regional hyperthermia thermal dosimetry using only intra-luminal tumour contact and tumour adjacent thermometry. This study has analysed the acquired temperature data in order to answer this question.

Patients and methods: Seventy-five patients with locally advanced cervical carcinoma were selected randomly. Patients were treated with a two or three modality combination, i.e. radiotherapy?+hyperthermia or radiotherapy?+?hyperthermia?+?chemotherapy from October 1997 to September 2003. The first 100 hyperthermia treatments fulfilling the only selection criterion: no displacement of the thermometry catheter along the insertion length during the treatment, were included in the study, resulting in 43 patients with one-to-five treatments/patient (median 2). Using RHyThM (Rotterdam Hyperthermia Thermal Modulator), for each single treatment tissue type, was defined on the basis of information given by a CT scan in radiotherapy position. A step change in the slope of the profile of the first temperature map was identified to verify the insertion length of the catheter.

Results: The average T₅₀ (median temperature) in bladder tumour indicative, vagina tumour contact and rectum tumour indicative was 40.9?±?0.9°C, 39.7?±?0.9°C and 40.6?±?0.8°C, respectively. The average normal tissue T₅₀ in bladder, vagina and rectum was 40.8?±?0.9°C, 40.1?±?0.9°C and 40.7?±?0.8°C, respectively. The differences between bladder tumour indicative T₅₀ and bladder normal tissue T₅₀ and also between vagina tumour contact T₅₀ and vagina normal tissue T₅₀ were significant (?p?=?0.0001). No statistical difference was found between rectum tumour indicative T₅₀ and rectum normal tissue T₅₀.

Conclusion: At present the cause of the temperature difference is not known. However, as the difference between tumour (indicative/contact) and normal tissue is very small and considering also the inaccuracy in the tissue type assignment it can be stated that this study does not provide sufficient evidence to conclude that the statistical difference has clinical relevance. Therefore, it was concluded that at this time there is no need to differentiate between normal and tumour tissue in intra-luminal thermometry.     

Cardiac and respiratory effects of deep regional hyperthermia using an 8 MHz radiofrequency-capacitive device on patients with cancer

Purpose: Hyperthermia (HT), an adjuvant therapy for variable cancers, may cause physiological changes in the patients, which may lead to cardiovascular problems. Among various HT treatments, the physiological effects of deep regional HT are still unclear. We examined the physiological alterations throughout deep regional HT to improve the HT safety.

Materials and methods: Thirty-one patients (age: 61?±?12 years) with cancer received HT in the thoracic or upper abdominal regions using an 8-MHz radiofrequency-capacitive-device for 50?min. Rectal temperature (T_rec), systolic and diastolic blood pressures (SBP and DBP), pulse rate (PR), respiratory rate (RR), percutaneous oxygen saturation (SpO₂) and sweating volume were evaluated throughout HT.

Results: At 50?min after starting HT, T_rec, PR and RR were significantly increased compared with the baseline values (T_rec: 38.2?±?1.4 vs. 36.3?±?0.8?°C, p?p?p?p?p?2 on average.

Conclusions: Deep regional HT increased the deep body temperature and resulted in an increase of sweating with peripheral vasodilatation. Consequently, a significant reduction in BP would be induced on standing after HT. Careful attention is needed for patients receiving HT, especially when standing after HT.     

Analysis of clinical data to determine the minimum number of sensors required for adequate skin temperature monitoring of superficial hyperthermia treatments

Purpose: Tumor response and treatment toxicity are related to minimum and maximum tissue temperatures during hyperthermia, respectively. Using a large set of clinical data, we analyzed the number of sensors required to adequately monitor skin temperature during superficial hyperthermia treatment of breast cancer patients.

Methods: Hyperthermia treatments monitored with >60 stationary temperature sensors were selected from a database of patients with recurrent breast cancer treated with re-irradiation (23?×?2?Gy) and hyperthermia using single 434?MHz applicators (effective field size 351–396?cm²). Reduced temperature monitoring schemes involved randomly selected subsets of stationary skin sensors, and another subset simulating continuous thermal mapping of the skin. Temperature differences (ΔT) between subsets and complete sets of sensors were evaluated in terms of overall minimum (T_min) and maximum (T_max) temperature, as well as T90 and T10.

Results: Eighty patients were included yielding a total of 400 hyperthermia sessions. Median ΔT was?<0.01?°C for T90, its 95% confidence interval (95%CI) decreased to ≤0.5?°C when?>50 sensors were used. Subsets of?<10 sensors result in underestimation of T_max up to ?2.1?°C (ΔT 95%CI), which decreased to ?0.5?°C when?>50 sensors were used. Thermal profiles (8–21 probes) yielded a median ΔT?T_max, with a 95%CI of ?0.2?°C and 0.4?°C, respectively. The detection rate of T_max?≥43?°C is?≥85% while using?>50 stationary sensors or thermal profiles.

Conclusions: Adequate coverage of the skin temperature distribution during superficial hyperthermia treatment requires the use of?>50 stationary sensors per 400?cm² applicator. Thermal mapping is a valid alternative.     

Clinical integration of software tool VEDO for adaptive and quantitative application of phased array hyperthermia in the head and neck

Abstract

Background and purpose: In Rotterdam, patient-specific hyperthermia (HT) treatment planning (HTP) is applied for all deep head and neck (H&N) HT treatments. In this paper we introduce VEDO (the Visualisation Tool for Electromagnetic Dosimetry and Optimisation), the software tool required, and demonstrate its value for HTP-guided online complaint-adaptive (CA) steering based on specific absorption rate (SAR) optimisation during a H&N HT treatment.

Materials and methods: VEDO integrates CA steering, visualisation of the SAR patterns and mean tumour SAR (SAR_target) optimisation in a single screen. The pre-calculated electromagnetic fields are loaded into VEDO. During treatment, VEDO shows the SAR pattern, overlaid on the patients’ CT-scan, corresponding to the actually applied power settings and it can (re-)optimise the SAR pattern to minimise SAR at regions where the patient senses discomfort while maintaining a high SAR_target.

Results: The potential of the quantitative SAR steering approach using VEDO is demonstrated by analysis of the first treatment in which VEDO was used for two patients using the HYPERcollar.

These cases show that VEDO allows response to power-related complaints of the patient and to quantify the change in absolute SAR: increasing either SAR_target from 96 to 178?W/kg (case 1); or show that the first SAR distribution was already optimum (case 2).

Conclusion: This analysis shows that VEDO facilitates a quantitative treatment strategy allowing standardised application of HT by technicians of different HT centres, which will potentially lead to improved treatment quality and the possibility of tracking the effectiveness of different treatment strategies.     

A method to convert MRI images of temperature change into images of absolute temperature in solid tumours

Abstract

Purpose: During hyperthermia (HT), the therapeutic response of tumours varies substantially within the target temperature range (39–43?°C). Current thermometry methods are either invasive or measure only temperature change, which limits the ability to study tissue responses to HT. This study combines manganese-containing low temperature sensitive liposomes (Mn-LTSL) with proton resonance frequency shift (PRFS) thermometry to measure absolute temperature in tumours with high spatial and temporal resolution using MRI.

Methods: Liposomes were loaded with 300?mM MnSO₄. The phase transition temperature (T_m) of Mn-LTSL samples was measured by differential scanning calorimetry (DSC). The release of manganese from Mn-LTSL in saline was characterised with inductively coupled plasma atomic emission spectroscopy. A 2T GE small animal scanner was used to acquire dynamic T₁-weighted images and temperature change images of Mn-LTSL in saline phantoms and fibrosarcoma-bearing Fisher-344 rats receiving hyperthermia after Mn-LTSL injection.

Results: The T_m of Mn-LTSL in rat blood was 42.9?±?0.2?°C (DSC). For Mn-LTSL samples (0.06?mM–0.5?mM Mn²⁺ in saline) heated monotonically from 30?°C to 50?°C, a peak in the rate of MRI signal enhancement occurred at 43.1°?±?0.3?°C. The same peak in signal enhancement rate was observed during heating of fibrosarcoma tumours (N?=?3) after injection of Mn-LTSL, and the peak was used to convert temperature change images into absolute temperature. Accuracies of calibrated temperature measurements were in the range 0.9–1.8?°C.

Conclusion: The release of Mn²⁺ from Mn-LTSL affects the rate of MR signal enhancement which enables conversion of MRI-based temperature change images to absolute temperature.     

A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery

This phase I–II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70?MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15–60?min of heating to 41°C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999–February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6?cm. The maximum tumour temperature failed to reach at least 41°C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right?=?1:3:3:3, with a power range of 800–1000?W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T₉₀?=?39.3°C, T₅₀?=?40°C, T₁₀?=?40.7°C and a median T_max?=?41.9°C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia.     

Efficacy of hyperbaric oxygen therapy combined with mild hyperthermia for improving the anti-tumour effects of carboplatin

Abstract

Purpose: The aim of this study was to evaluate the effects of hyperbaric oxygen therapy (HBO) on the enhancement of hyperthermic chemosensitisation to carboplatin at mild temperatures in experimental tumours. Methods: SCCVII carcinoma in C3H/He mice was used to assess tumour growth delay. The mice received intraperitoneal injections of carboplatin. For HBO treatment, the mice were exposed to HBO at 2.0 atmospheres of absolute oxygen for 60?min. For mild hyperthermia (HT), treatment at 41.5?°C for 30?min was performed. The tumour tissue pO₂ levels were measured with a digital pO₂ monitor during and immediately after treatment. Results: The average time taken to reach a threefold relative tumour size was significantly longer after treatment with carboplatin combined with mild HT and HBO than after treatment with carboplatin and mild HT. The relative sizes of the tumours after the combined treatment were smallest when the treatment sequence was carboplatin, mild HT, and HBO. The tumour tissue pO₂ values were significantly higher immediately after mild HT followed by HBO than immediately after HBO followed by mild HT. The tumour tissue pO₂ levels during mild HT and HBO generally increased, although the patterns of the increases varied. Conclusion: The administration of HBO increased the effects of hyperthermic chemosensitisation to carboplatin at mild temperatures on experimental tumours, particularly when given in the sequence of carboplatin, mild HT, and HBO, a finding that supports previous clinical outcomes for a novel combined therapy using carboplatin plus HT and HBO.     

Thermal dosimetry of spinal cord heating in the mouse

Three systems for the localized heating of the spinal cord of the mouse have been evaluated by measuring the temperatures in the spinal canal (T_sp); at a reference location dorsal to the spine (T_do), and by numerically calculating temperature distributions throughout two-dimensional transverse cross-sections through the middle of the heated region. The systems assessed were water bath heating alone, water bath-rf combination and rf heating alone with oblique, dorsally located electrodes. It has been established that (1) for all systems ΔT (where ΔT–T_sp) decreased throughout a 1 h heating period–this was attributed to changes in blood flow; (2) there existed a considerable variation in the experimental value of ΔT, particularly for rf heating. The resulting error in the estimation of T_sp from a measured value of T_do can be reduced by making use of the observed correlation between ΔT and the slope of a temperature decay curve measured at the beginning of the heating period; (3) rf alone best spares adjacent visceral and superficial tissues from significant elevation of temperature.     

Temperature data and specific absorption rates in pelvic tumours: predictive factors and correlations

The system BSD 2000 has been in clinical use for regional hyperthermia for more than 10 years. Several technical details of this hyperthermia system, as well as the results of clinical studies employing this system have been investigated. The intention of this paper is to investigate the correlation between technical efficiency or feasibility of hyperthermia with the BSD 2000, in terms of power densities and temperatures depending upon parameters such as tumour histology, tumour location, patient age, patient sex, and patient cross section. The possible conclusions of predictive factors derived from the above correlations were closely scrutinized. Data acquired from 772 treatment sessions of 190 patients with pelvic tumours, mainly sarcomas and carcinomas of the rectum, cervix, prostate and anus, have been evaluated. For every session, index temperatures T ₉₀ (temperature attained at 90% of tumour related measurement points), cumulative minutes for T₉₀ &gt; T_ref, tumour related power density (SAR: specific absorption rate, in W/kg) and the effective perfusion W_eff (inml/100gmin) were calculated. Temperatures were measured either invasively or endoluminally. The statistics software SPSS was employed subsequently for univariate, as well as multivariate analyses. The results exhibit that index temperatures mainly depend on the power density SAR and the hyperthermia induced effective perfusion. The total power P (in 100W) and, complementarily, the relative power density ||SAR|| (= SAR/P) seem to have lesser influence. Clear differences between the tumour entities were established regarding their index temperatures and temperature distributions. SAR, W_eff and P were correlated with several anatomical, biological and clinical factors. Sessions rendering low index temperatures and SAR values also revealed decreased individual tolerance to the treatment. This clearly displays that powerinduced side effects define the limits of the efficiency of regional hyperthermia. Equivalent relationships and correlations are derived from intratumoural and endoluminal thermometry. Individual limitations of regional hyperthermia caused by anatomical, biological and clinical factors are liable to be difficult to overcome with the rather restricted potentials of the BSD 2000 system to control the SAR distribution.     

The accuracy and precision of two non-invasive,magnetic resonance-guided focused ultrasound-based thermal diffusivity estimation methods

Purpose: The use of correct tissue thermal diffusivity values is necessary for making accurate thermal modelling predictions during magnetic resonance-guided focused ultrasound (MRgFUS) treatment planning. This study evaluates the accuracy and precision of two non-invasive thermal diffusivity estimation methods, a Gaussian temperature method and a Gaussian specific absorption rate (SAR) method. Materials and methods: Both methods utilise MRgFUS temperature data obtained during cooling following a short (<25?s) heating pulse. The Gaussian SAR method can also use temperatures obtained during heating. Experiments were performed at low heating levels (ΔT～10?°C) in ex vivo pork muscle and in vivo rabbit back muscle. The non-invasive MRgFUS thermal diffusivity estimates were compared with measurements from two standard invasive methods. Results: Both non-invasive methods accurately estimated thermal diffusivity when using MR temperature cooling data (overall ex vivo error <6%, in vivo <12%). Including heating data in the Gaussian SAR method further reduced errors (ex vivo error <2%, in vivo <3%). The significantly lower standard deviation values (p?Conclusions: With repeated sonications, either MR-based method could provide accurate thermal diffusivity values for MRgFUS therapies. Fitting to more data simultaneously likely made the Gaussian SAR method less susceptible to noise, and using heating data helped it converge more consistently to the FUS fitting parameters and thermal diffusivity. These effects led to the improved precision of the Gaussian SAR method.     

Thermal diffusivity and perfusion constants from in vivo MR-guided focussed ultrasound treatments: a feasibility study

Purpose: This study investigates the feasibility of non-invasively determining thermal diffusivity (α) and the Pennes perfusion parameter (w) from pre-clinical and clinical magnetic resonance-guided focussed ultrasound (MRgFUS) temperature data.

Materials and methods: Pre-clinical MRgFUS experiments were performed in rabbit muscle (N?=?3, 28 sonications) using three-dimensional MR thermometry. Eight sonications were made in a clinical QA phantom with two-dimensional thermometry. Retrospective property determination was performed on clinical uterine fibroid (N?=?8, 9 sonications) and desmoid tumour (N?=?4, 7 sonications) data. The property determination method fits an analytical solution to MRgFUS temperatures in the coronal MR plane, including all temperatures acquired during heating and one cooling image. When possible, additional cooling data were acquired for property determination.

Results: Rabbit α and w from Heating Data (α?=?0.164?mm²s^?1, w?=?7.9 kg?m^?3?s^?1) and Heating and Cooling Data (α?=?0.146?mm²s^?1, w?=?3.3 kg?m^?3?s^?1) were within the range of gold-standard invasive measurements, with >50% reduction in variability by including cooling data. QA phantom property determination with cooling data yielded properties within 3% of expected values (α?=?0.144?mm²s^?1, w?=?0.0 kg?m^?3?s^?1), a difference that was not statistically significant (p?=?0.053). Uterine fibroid (Heating Data: α?=?0.212?mm²s^?1, w?=?11.0 kg?m^?3?s^?1) and desmoid tumour (Heating &; Cooling Data: α?=?0.245?mm²s^?1, w?=?4.7 kg?m^?3?s^?1) properties are feasible but lack independent verification.

Conclusions: Thermal diffusivity and the Pennes perfusion parameter can be obtained from in vivo data and with clinical MRgFUS protocols. Property values are consistently improved by including cooling data. The utility of this property determination method will increase as clinical protocols implement improved temperature imaging.     

Impact of chemokines CCR5∆32, CXCL12G801A,and CXCR2C1208T on bladder cancer susceptibility in north Indian population

Chemokines are small inducible pro-inflammatory cytokines. In the present study, we tested association of chemokine single nucleotide polymorphisms (SNPs) viz., CCR5?32, CXCL12G801A and CXCR2C1208T genes in bladder cancer (BC) patients and normal healthy controls of north Indians. Genotyping of the above SNPs were done in 200 BC cases and 200 healthy controls, using RFLP and amplification refractory mutation system–polymerase chain reaction methodology. A significant association was found in CXCL12G801A with BC risk. In case of CXCL12G801A polymorphism, the heterozygous (GA) genotype showed significantly high risk (p?<?0.001, odds ratio (OR)?=?2.72), whereas A allele carrier (GA + AA) also showed risk with BC (p?<?0.001, OR?=?2.44). In CXCR2C1208T polymorphism, the variant genotype (TT) showed significant risk for BC (p?=?0.028, OR?=?1.58). The variant allele (T) of CXCR2C1208T polymorphism was found to be associated with BC risk (p?=?0.003, OR?=?1.29). Interestingly, smoking was also found to modulate 1.16-fold risks for BC in case of CXCR2C1208T, variant genotype (TT). Upon analyzing the gene–gene interaction between CXCR2C1208T and CXCL12G801A, the combination CT-GA showed 4-fold risk for BC (p?=?0.009). Our results indicated that polymorphism in CXCR2C1208T and CXCL12G801A showed high risk for BC in north Indian population. However, CCR5?32 exhibited no association. Study with large sample size and diverse ethnicity are required to validate these observations.     

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors

Abstract

Purpose: To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors.

Materials and methods: Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT?+?ACT (n?=?10), HT?+?ACT?+?anti-PD-1 inhibitor (pembrolizumab) (n?=?11) and HT?+?ACT?+?CT (n?=?12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.

Results: The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR?=?CR?+?PR?+?SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders (p?<?0.05) while IL-6 and IL-10 were elevated among those with progressive disease (p?<?0.05). Peripheral blood CD8⁺/CD28⁺ T cells increased (p?=?0.002), while the CD4⁺/CD25⁺/CD127⁺Treg cells decreased after therapy (p?=?0.012). TCR diversity was substantially increased among the clinical responders.

Conclusions: Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.     

DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: A pilot study

Combined therapies represent a staple of modern medicine. For women treated with neoadjuvant chemotherapy (NA ChT) for locally advanced breast cancer (LABC), early determination of whether the patient will fail to respond can enable the use of alternative, more beneficial therapies. This is even more desirable when the combined therapy includes hyperthermia (HT), an efficient way to improve drug delivery, however, more costly and time consuming. There is data showing that this goal can be achieved using magnetic resonance imaging (MRI) with contrast agent (CA) enhancement. This work for the first time proposes combining the information extracted from pre-treatment MR imaging into a morpho-physiological tumour score (MPTS) with the hypothesis that this score will increase the prognostic efficacy, compared to each of its MR-derived components: morphological (derived from the shape of the tumour enhancement) and physiological (derived from the CA enhancement variance dynamics parameters). The MPTS was correlated with response as determined by both pathologic residual tumour and MRI imaging, and was shown to have potential to predict response. The MPTS was extracted from pre-treatment MRI parameters, so independent of the combined therapy used.

Purpose: To use a novel morpho-physiological tumour score (MPTS) generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict response to treatment.

Materials and methods: A protocol was designed to acquire DCE-MRI images of 20 locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NA ChT) and hyperthermia (HT). Imaging was done over 30 min following bolus injection of gadopentetate-based contrast agent. Parametric maps were generated by fitting the signal intensity to a double exponential curve and were used to derive a morphological characterisation of the lesions. Enhancement-variance dynamics parameters, wash-in and wash-out parameters (WiP, WoP), were extracted. The morphological characterisation and the WiP and WoP were combined into a MPTS with the intent of achieving better prognostic efficacy. The MPTS was correlated with response to NA therapy as determined by pathological residual tumour and MRI imaging.

Results: The contrast agent in all tumours typically peaked in the first 1–4 min. The tumours’ WiP and WoP varied considerably. The MPTS was highly correlated with whether the patients had a pathological response. This scoring system has a specificity of 78% and a sensitivity of 91% for predicting response to NA chemotherapy. The kappa was 0.69 with a 95% confidence interval of [0.38, 1] and a p-value of 0.002.

Conclusions: This pilot study shows that the MPTS derived using pre-treatment MRI images has the potential to predict response to NA ChT and HT in LABC patients. Further prospective studies are needed to confirm the validity of these results.