The Effectiveness of Hypnoanalgesia Using Conventional and Placebo Hypnosis Induction.

The effectiveness of hypnosis-based pain management is well-established. However, mechanisms of action and specific effective components are not well understood. The sociocognitive theory of hypnosis proposes that the effectiveness of hypnosis for pain management is determined by the nonspecific features of response expectancy and context. We tested this claim by contrasting the effectiveness of 2 hypnoanalgesia procedures in a within subjects design using the cold pressor task. The 2 procedures were identical, including analgesic suggestions, except for the hypnosis induction used. One condition involved a well-established hypnosis induction, including suggestions for focused attention, relaxation, and deepening. The other condition included a sham induction procedure using only white noise. In our confirmatory analysis (N = 46), we found that pain tolerance increased compared to baseline equivalently in the conventional and sham induction conditions (mean increase 13.7 and 12.4 seconds respectively, average within subject difference -1.27 seconds, 90% confidence interval [CI] = -8.46, 5.90). This finding supports the claim of the sociocognitive theory considering that response expectancy for pain reduction was also equivalent between the conditions (average difference 2.30, 90% CI = -2.23, 6.84). However, self-reported hypnosis depth was greater in the conventional induction condition (average difference -.78, 90% CI: -1.36, -.07), which contradicts sociocognitive predictions. Our findings indicate that conventional procedural elements of hypnosis inductions, such as suggestions for focused attention, relaxation, and deepening, may not be necessary to achieve acute pain reduction in an experimental setting when the hypnosis intervention includes analgesic suggestions. PERSPECTIVE: This study assessed the necessary effective components of hypnosis-based analgesia interventions. Our findings suggest that procedural features such as suggestions for focused attention, relaxation, and deepening may not be necessary for hypnoanalgesia as long as pain relief suggestions are present, and the hypnosis context and response expectancy are established. TRIAL REGISTRATION: This trial was registered on Open Science Framework with the registry number e96xk, available at https://osf.io/e96xk.

Exploring the Use of Raman Spectroscopy and Covariate-Adjusted Multivariate Analysis for the Detection of Irradiated Blood.

Biological dosimetry is a key technique for retrospective radiation dosimetry that provides individual estimates of absorbed dose of ionizing radiation, applicable for use in a large scale radiological/nuclear event. Current techniques for biodosimetry are labor intensive and time consuming and not high through-put. In this proof-of-concept study, we developed a new approach for detecting irradiated blood based on Raman spectroscopy of blood combined with multivariate analysis. Peripheral blood samples from 8 healthy male and female, anonymous donors, were exposed to either 5 Gy X ray radiation or unirradiated (0 Gy). At 3 h postirradiation, the blood was immediately frozen at -80°C. Raman spectra were measured from thawed blood using a portable spectrometer system. Data were preprocessed and analyzed using principal component analysis (PCA) to observe trends in the data, and by using partial least squares-discriminant analysis (PLS-DA) to build a model to discriminate between Raman spectra of control (0 Gy) and irradiated (5 Gy) blood. We found strong evidence of inter-donor variability in the form of donor-wise clustering of PCA scores corresponding to the control Raman spectra, in addition to the poor separation of PLS-DA scores associated with Raman intensities of 0 Gy vs. 5 Gy spectra. However, after adjustment for donor covariates using a linear mixed-effects model, we obtained a better separation between control and irradiated blood using PLS-DA. Evaluation of the coefficients of the PLS-DA loading vectors indicated radiation-induced changes in proteins, lipids and hemoglobin to be major contributors for this discrimination. This pilot study demonstrates the potential of application of Raman spectroscopy to support biodosimetry of blood and blood components.

Development of a flow cell based Raman spectroscopy technique to overcome photodegradation in human blood.

Raman spectroscopy of blood offers significant potential for label-free diagnostics of disease. However, current techniques are limited by the use of low laser power to avoid photodegradation of blood; this translates to a low signal to noise ratio in the Raman spectra. We developed a novel flow cell based Raman spectroscopy technique that provides reproducible Raman spectra with a high signal to noise ratio and low data acquisition time while ensuring a short dwell time in the laser spot to avoid photodamage in blood lysates. We show that our novel setup is capable of detecting minute changes in blood lysate spectral features from natural aging. Moreover, we demonstrate that by rigorously controlling the experimental conditions, the aging effect due to natural oxidation does not confound the Raman spectral measurements and that blood treated with hydrogen peroxide to induce oxidative stress can be discriminated from normal blood with a high accuracy of greater than 90% demonstrating potential for use in a clinical setting.

Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation.

Recent findings in populations exposed to ionizing radiation (IR) indicate dose-related lens opacification occurs at much lower doses (<2 Gy) than indicated in radiation protection guidelines. As a result, research efforts are now being directed towards identifying early predictors of lens degeneration resulting in cataractogenesis. In this study, Raman micro-spectroscopy was used to investigate the effects of varying doses of radiation, ranging from 0.01 Gy to 5 Gy, on human lens epithelial (HLE) cells which were chemically fixed 24 h post-irradiation. Raman spectra were acquired from the nucleus and cytoplasm of the HLE cells. Spectra were collected from points in a 3 × 3 grid pattern and then averaged. The raw spectra were preprocessed and principal component analysis followed by linear discriminant analysis was used to discriminate between dose and control for 0.25, 0.5, 2, and 5 Gy. Using leave-one-out cross-validation accuracies of greater than 74% were attained for each dose/control combination. The ultra-low doses 0.01 and 0.05 Gy were included in an analysis of band intensities for Raman bands found to be significant in the linear discrimination, and an induced repair model survival curve was fit to a band-difference-ratio plot of this data, suggesting HLE cells undergo a nonlinear response to low-doses of IR. A survival curve was also fit to clonogenic assay data done on the irradiated HLE cells, showing a similar nonlinear response.

Raman micro-spectroscopy applied to treatment resistant and sensitive human ovarian cancer cells.

Despite the many advances intended to enhance the response to treatment, the survival rate of patients with ovarian cancer has only marginally improved in the past few decades. One major cause for this, is the lack of diagnostics for platinum-resistant disease. The goal of this study was to determine whether Raman micro-spectroscopy in conjunction with multivariate statistical analysis could discriminate between chemically fixed cisplatin-resistant (A2780cp) and cisplatin-sensitive (A2780s) human ovarian carcinoma cells. Raman spectra collected from individual cells were pre-processed and subsequently analyzed with Principal Component Analysis - Linear Discriminant Analysis (PCA-LDA). Statistically significant differences (P <  0.0001) were observed between the Raman spectra of A2780s and A2780cp cells. A diagnostic accuracy of 82% was obtained using the PCA-LDA classifier model for the discrimination between the A2780s and A2780cp cells. The loading plot analysis suggests that relative increases in proteins and glutathione in the cisplatin-resistant cells compared to the cisplatin-sensitive cells are most likely the major source of discrimination between the two types of cells. These results support the potential application of Raman spectroscopy in the identification of chemo-resistant tumors prior to treatment.

Proposal of a post-prostatectomy clinical target volume based on pre-operative MRI: volumetric and dosimetric comparison to the RTOG guidelines.

BACKGROUND: Recurrence rates following radiotherapy for prostate cancer in the post-operative adjuvant or salvage setting remain substantial. Previous work from our institution demonstrated that published prostate bed CTV guidelines frequently do not cover the pre-operative MRI defined prostate. Inadequate target delineation may contribute to the high recurrence rates, but increasing target volumes may increase dose to organs at risk. METHODS: We propose guidelines for delineating post-prostatectomy target volumes based upon an individual's co-registered pre-operative MRI. MRI-based CTVs and PTVs were compared to those created using the RTOG guidelines in 30 patients. Contours were analysed in terms of absolute volume, intersection volume (Jaccard Index) and the ability to meet the RADICALS and QUANTEC rectal and bladder constraints (tomotherapy IMRT plans with PTV coverage of V98% ≥98%). RESULTS: CTV MRI was a mean of 18.6% larger than CTV RTOG: CTV MRI mean 138 cc (range 72.3 - 222.2 cc), CTV RTOG mean 116.3 cc (range 62.1 - 176.6 cc), (p < 0.0001). The difference in mean PTV was only 4.6%: PTV MRI mean 386.9 cc (range 254.4 - 551.2), PTV RTOG mean 370 cc (range 232.3 - 501.6) (p = 0.05). The mean Jaccard Index representing intersection volume between CTVs was 0.72 and 0.84 for PTVs. Both criteria had a similar ability to meet rectal and bladder constraints. Rectal DVH: 77% of CTV RTOG cases passed all RADICALS criteria and 37% all QUANTEC criteria; versus 73% and 40% for CTV MRI (p = 1.0 for both). Bladder DVH; 47% of CTV RTOG cases passed all RADICALS criteria and 67% all QUANTEC criteria, versus 57% and 60% for CTV MRI (p = 0.61for RADICALS, p = 0.79 for QUANTEC). CTV MRI spares more of the lower anterior bladder wall than CTV RTOG but increases coverage of the superior lateral bladder walls. CONCLUSION: CTV contours based upon the patient's co-registered pre-operative MRI in the post-prostatectomy setting may improve coverage of the individual's prostate bed without substantially increasing the PTV size or dose to bladder/ rectum compared to RTOG CTV guidelines. Further evaluation of whether the use of pre-operative MRI improves local control rates is warranted.

Two self-referencing methods for the measurement of beam spot position.

PURPOSE: Two quantitative methods of measuring electron beam spot position with respect to the collimator axis of rotation (CAOR) are described. METHODS: Method 1 uses a cylindrical ion chamber (IC) mounted on a jig corotational with the collimator making the relationship among the chamber, jaws, and CAOR fixed and independent of collimator angle. A jaw parallel to the IC axis is set to zero and the IC position adjusted so that the IC signal is approximately 50% of the open field value, providing a large dose gradient in the region of the IC. The cGy∕MU value is measured as a function of collimator rotation, e.g., every 30°. If the beam spot does not lie on the CAOR, the signal from the ion chamber will vary with collimator rotation. Based on a measured spatial sensitivity, the distance of the beam spot from the CAOR can be calculated from the IC signal variation with rotation. The 2nd method is image based. Two stainless steel rods, 3 mm in diameter, are mounted to a jig attached to the Linac collimator. The rods, offset from the CAOR, lay in different planes normal to the CAOR, one at 158 cm SSD and the other at 70 cm SSD. As the collimator rotates the rods move tangent along an envelope circle, the centers of which are on the CAOR in their respective planes. Three images, each at a different collimator rotation, containing the shadows of both rods, are acquired on the Linac EPID. At each angle the shadow of the rods on the EPID defines lines tangent to the projection of the envelope circles. From these the authors determine the projected centers of the two circles at different heights. From the distance of these two points using the two heights and the source to EPID distance, the authors calculate the distance of the beam spot from the CAOR. Measurements with all two techniques were performed on an Elekta Linac. Measurements were performed with the beam spot in nominal clinical position and in a deliberately offset position. Measurements were also performed using the Flexmap image registration∕ball-bearing test. RESULTS: Within their uncertainties, both methods report the same beam spot displacement. In clinical use, a total of 203 monthly beam spot measurements on 14 different beams showed an average displacement of 0.11 mm (σ = 0.07 mm) in-plane and 0.10 mm (σ = 0.07 mm) cross-plane with maximum displacement of 0.37 mm in-plane and 0.34 mm cross-plane. CONCLUSIONS: The methods described provide a quantitative measure of beam spot position, are easy to use, and provide another tool for Linac setup and quality assurance. Fundamental to the techniques is that they are self-referencing-i.e., they do not require the user to independently define the CAOR.

Postoperative radiotherapy for prostate cancer: a comparison of four consensus guidelines and dosimetric evaluation of 3D-CRT versus tomotherapy IMRT.

PURPOSE: Despite the benefits of adjuvant radiotherapy after radical prostatectomy, approximately one-half of patients relapse. Four consensus guidelines have been published (European Organization for Research and Treatment of Cancer, Faculty of Radiation Oncology Genito-Urinary Group, Princess Margaret Hospital, Radiation Therapy Oncology Group) with the aim of standardizing the clinical target volume (CTV) delineation and improve outcomes. To date, no attempt has been made to compare these guidelines in terms of treatment volumes or organ at risk (OAR) irradiation. The extent to which the guideline-derived plans meet the dosimetric constraints of present trials or of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) trial is also unknown. Our study also explored the dosimetric benefits of intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 20 patients treated with postoperative RT were included. The three-dimensional conformal radiotherapy (3D-CRT) plans were applied to cover the guideline-generated planning target volumes (66 Gy in 33 fractions). Dose-volume histograms (DVHs) were analyzed for CTV/planning target volume coverage and to evaluate OAR irradiation. The OAR DVHs were compared with the constraints proposed in the QUANTEC and Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trials. 3D-CRT plans were compared with the tomotherapy plans for the Radiation Therapy Oncology Group planning target volume to evaluate the advantages of IMRT. RESULTS: The CTV differed significantly between guidelines (p < 0.001). The European Organization for Research and Treatment of Cancer-CTVs were significantly smaller than the other CTVs (p < 0.001). Differences in prostate bed coverage superiorly accounted for the major volumetric differences between the guidelines. Using 3D-CRT, the DVHs rarely met the QUANTEC or RADICALS rectal constraints, independent of the guideline used. The RADICALS bladder constraints were met most often by the European Organization for Research and Treatment of Cancer consensus guideline (14 of 20). The tomotherapy IMRT plans resulted in significant OAR sparing compared with the 3D-CRT plans; however, the RADICALS and QUANTEC criteria were still missed in a large percentage of cases. CONCLUSION: Treatment volumes using the current consensus guidelines differ significantly. For the four CTV guidelines, the rectal and bladder DVH constraints proposed in the QUANTEC and RADICALS trials are rarely met with 3D-CRT. IMRT results in significant OAR sparing; however, the RADICALS dose constraints are still missed for a large percentage of cases. The rectal and bladder constraints of RADICALS should be modified to avoid a reduction in the CTVs.

Helical tomotherapy for locoregional irradiation including the internal mammary chain in left-sided breast cancer: dosimetric evaluation.

PURPOSE: To compare a standard 3- or 4-field technique to intensity modulated radiotherapy with helical tomotherapy (IMRT-HT) in the planning of locoregional breast radiation including the internal mammary chain (IMC). METHODS AND MATERIALS: For 10 women with stage III left-sided breast cancer with a planning target volume (PTV) defined by the breast/chest wall and regional nodes, radiotherapy to a dose of 50 Gy in 25 fractions was planned using a standard 3- or 4-field technique and using IMRT-HT. Various metrics were extracted from dose-volume histograms, and were compared using the paired Student's t-test. RESULTS: The PTV receiving at least 95% of the prescribed dose did not differ between the two plans, but the VD115% was significantly lower with IMRT-HT. The dose conformality was significantly better with IMRT-HT. The cardiac V30(Gy) was reduced with IMRT-HT. The mean lungs dose was lower with IMRT-HT, as well the V20(Gy). With IMRT-HT, a greater volume of contralateral breast was irradiated to 5 Gy, but a smaller volume of soft tissue received dose above 50 Gy. CONCLUSIONS: Compared to a standard technique, IMRT-HT provides similar target coverage, improves dose conformality and dose homogeneity within the PTV, decreases mean lung dose and spares heart, lung and soft tissue from high dose exposure.

TCP isoeffect analysis using a heterogeneous distribution of radiosensitivity.

A formula for the alpha/beta ratio is derived using the heterogeneous (population averaged) tumor control model. This formula is nearly identical to the formula obtained using the homogeneous (individual) tumor control model, but the new formula includes extra terms showing that the alpha/beta ratio, the ratio of the mean value of a divided by the mean value of beta that would be observed in a patient population, explicitly depends on the survival level and heterogeneity. The magnitude of this correction is estimated for prostate cancer, and this appears to raise the mean value of the ratio estimate by about 20%. The method also allows investigation of confidence limits for alpha/beta based on a population distribution of radiosensitivity. For a widely heterogeneous population, the upper 95% confidence interval for the alpha/beta ratio can be as high as 7.3 Gy, even though the population mean is between 2.3 and 2.6 Gy.

Comparison of alpha/beta estimates from homogeneous (individual) and heterogeneous (population) tumor control models for early stage prostate cancer.

Radiobiological parameter estimates for prostate cancer are obtained from both a homogeneous (individual) and heterogeneous (population) tumor control model based on Poisson statistics and the linear quadratic model of cell survival. Parameter estimates for both models are highly correlated: statistically equivalent fits are achievable using either (1) linear quadratic (LQ) parameters with low numbers of radioresistant tumor stem cells, or (2) LQ parameters with corresponding larger number of radiosensitive tumor stem cells. A theoretical framework is developed to explain this correlation. A Monte Carlo error analysis based on binomial statistics is used to estimate confidence intervals for all parameter estimates. It was found that both the homogeneous and heterogeneous models produce approximately equivalent estimates of radiobiological parameters, including the alpha/beta ratio. However, the 95% confidence interval for the alpha/beta ratio derived from the heterogeneous model are considerably larger than those derived from the homogeneous model, which indicate the homogeneous model overestimates the statistical significance of the alpha/beta estimate.