Why Concurrent CDDP and Radiotherapy Has Synergistic Antitumor Effects: A Review of In Vitro Experimental and Clinical-Based Studies.

Chemo-radiotherapy, which combines chemotherapy with radiotherapy, has been clinically practiced since the 1970s, and various anticancer drugs have been shown to have a synergistic effect when used in combination with radiotherapy. In particular, cisplatin (CDDP), which is often the cornerstone of multi-drug combination cancer therapies, is highly versatile and frequently used in combination with radiotherapy for the treatment of many cancers. Therefore, the mechanisms underlying the synergistic effect of CDDP and radiotherapy have been widely investigated, although no definitive conclusions have been reached. We present a review of the combined use of CDDP and radiotherapy, including the latest findings, and propose a mechanism that could explain their synergistic effects. Our hypothesis involves the concepts of overlap and complementation. "Overlap" refers to the overlapping reactions of CDDP and radiation-induced excessive oxidative loading, which lead to accumulating damage to cell components, mostly within the cytoplasm. "Complementation" refers to the complementary functions of CDDP and radiation that lead to DNA damage, primarily in the nucleus. In fact, the two concepts are inseparable, but conceptualizing them separately will help us understand the mechanism underlying the synergism between radiation therapy and other anticancer drugs, and help us to design future radiosensitizers.

Evaluation of Temperature Distribution Around the Probe in Cryoablation of Lipiodol-Mixed-Tissue Phantom.

PURPOSE: To determine whether lipiodol, which has low thermal conductivity, influences ice ball formation during cryoablation of a lipiodol-mixed-tissue phantom. MATERIALS AND METHODS: Lipiodol-mixed-tissue phantoms were created by injecting lipiodol (4-6 ml) into the renal arteries of ex vivo porcine kidneys (lipiodol group). A cryoprobe (CryoHit™ Needle S) with a holder that was set with thermocouples at various positions around the cryoprobe was inserted. After freezing for 300 s, the followings were evaluated: ice ball size on CT, temperature distribution around the cryoprobe, and calculated distances at 0 °C and - 20 °C. Each variable was compared between lipiodol group (n = 6) those obtained in a control group without lipiodol injection (n = 6). RESULTS: Mean ice ball diameter (width/length) on CT was 22.1 ± 2.3/22.9 ± 2.3 mm in the lipiodol group and 21.6 ± 0.7/22.2 ± 1.3 mm in the control group. Mean cryoprobe temperature was - 118 ± 3.0 °C in the lipiodol group and - 117 ± 2.6 °C in the control group. In both groups, temperature at the 3 mm thermocouple reached approximately - 50 °C and was < 0 °C within ~ 10 mm of the cryoprobe. Temperature of 0/- 20 °C occurred at a mean distance from the cryoprobe of 11.1 ± 0.5/6.9 ± 0.4 mm in the lipiodol group and 11.0 ± 0.2/6.9 ± 0.2 mm in the control group. There was no significant difference in any variable between the groups. CONCLUSION: The inclusion of lipiodol in a tissue phantom had no negative effects on ice ball formation that were related to thermal conductivity.

Fundamental Evaluation of Thermophysical Properties of Lipiodol Associated with Cryoablation: Freezing Experiments Using Lipiodol Phantom.

PURPOSE: To elucidate the basic thermophysical properties at low temperatures of lipiodol, which is used as a marker by transarterial injection before CT-guided cryoablation for solid tumors, by fundamental experiments with pure lipiodol phantom. MATERIALS AND METHODS: The freezing point of lipiodol was measured using differential scanning calorimeter (DSC) by detecting differences in the heating rate during heating from - 30 °C. Freezing experiments were conducted using pure lipiodol and a tissue phantom, which were prepared in an acrylic container at 37 °C. The growth of the frozen region was observed for 10 min. Temperatures were monitored at the cryoprobe surface and designated positions around the cryoprobe. RESULTS: The DSC experiment showed that freezing was observed between - 5 and - 30 °C, which indicated that the freezing point was approximately - 5 °C. Freezing experiments revealed that the diameter of frozen region in the lipiodol was smaller than that in the tissue phantom (5 mm vs 24 mm) after 10-min freezing. The temperature at the probe surface was - 130 °C in lipiodol, which was 25 °C lower than that in the tissue phantom. There was a larger temperature gradient near the cryoprobe in lipiodol due to lower thermal conductivity. CONCLUSIONS: The present results suggest that an extremely high concentration of lipiodol (close to pure lipiodol) potentially reduces frozen region because of its lower freezing point and smaller thermal conductivity. However, since lipiodol concentrations in clinical cases differ from the current model, further studies using models that are close to clinical conditions are required. LEVEL OF EVIDENCE: No level of evidence, laboratory investigation.

Is the Cessation of Blood Flow Faster than the Polymerization of an n-Butyl Cyanoacrylate-Lipiodol Mixture? An In Vitro Phantom Study.

PURPOSE: To compare the polymerization time of n-butyl cyanoacrylate (NBCA) and lipiodol mixture in a static model and a pulsating flow model simulating embolization procedure of small caliber arteries. MATERIALS AND METHODS: The polymerization time of NBCA-lipiodol mixture was measured by the morphological changes of a glue droplet in a petri dish. For the flow model, we used a 2-mm-inner-diameter polyvinyl alcohol tube connected to a pulsation pump. Bovine serum was supplied from the pump and circulated into the system at 30 ml/min and 60 bpm. A 0.64-mm-inner-diameter silicon microcatheter was inserted into this system, and then, 0.5 ml of glue was injected into the tube. The flow cessation time was defined as the time it took to stop the serum draining from the end of the tube. Six samples of 100, 66, 50, 40, 33, and 20 vol% NBCA were assessed. RESULTS: The median polymerization times for each concentration were 0.12, 3.72, 12.30, 27.41, 57.68, and 63.67 s, respectively. The median flow cessation times were 0.28, 0.78, 1.43, 3.75, 4.50, and 9.29 s, respectively. The flow cessation time was significantly shorter than the polymerization time for all samples except for 100 vol% cyanoacrylate (p < 0.05). CONCLUSION: The flow cessation time of cyanoacrylate glue was significantly shorter than the polymerization time in an in vitro experiment. The injected glue possibly stops the blood flow before the completion of polymerization in the vascular system.

Preoperative lipiodol marking and its role on survival and complication rates of CT-guided cryoablation for small renal masses.

BACKGROUND: Partial nephrectomy for small renal masses (SRM) may be useful for preserving renal function, but is technically more difficult than radical nephrectomy. Cryoablation may be performed under local anesthesia. The objective of the present study is to assess the safety and therapeutic efficacy of cryoablation with lipiodol marking for SRM. METHODS: Cryoablation therapy was performed on 42 patients under local anesthesia. Their median age was 74 years (31-91). The median tumor diameter was 21 mm (10-42). Responses to the treatment were evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST) by contrast-enhanced CT. In six patients (14.3%) for whom it was not possible to use contrast medium, plain CT findings were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty-nine (69%) and five (12%) patients achieved complete responses (CR) and partial responses (PR), respectively, while four (10%) and four (10%) patients each had stable disease (SD) and progressive disease (PD) after the first course of therapy. A second course of cryoablation therapy with lipiodol marking was performed on three out of four patients with PD after the first course of therapy, and resulted in a total of 32 patients achieving CR (76%). Four (36.4%) out of 11 patients for whom lipiodol marking was not conducted had PD, whereas none of the 31 patients for whom lipiodol marking was conducted had PD. All grade complications were reported in 11 (24.4%) patients while grade 3 in two (4.4%) patients. 11 (24.4%) A significant difference was observed in postoperative hemorrhagic events in all grades (18% in patients undergoing cryoablation without lipiodol marking vs. 0% in patients undergoing cryoablation without lipiodol marking). CONCLUSIONS: Although further studies involving more patients are needed in order to evaluate long-term results, cryoablation therapy appears to be a useful treatment option for SRM. Preoperative marking with lipiodol was helpful for improving complication and survival rates with cryoablation.

The efficacy of radio-frequency ablation for metastatic lung or liver tumors of male germ cell tumors as an alternative minimally invasive therapy after salvage chemotherapy.

BACKGROUND: The aim of this study was to assess the efficacy of radio-frequency ablation (RFA) for metastatic lung or liver tumors of germ cell tumors (GCTs) after chemotherapy. METHODS: RFA with computed tomography guidance and monitoring was performed in 24 patients with 48 metastatic lung or liver tumors of GCTs. Group A consisted of 9 patients with tumor marker normalization after salvage chemotherapy and group B consisted of 15 patients without tumor marker normalization in spite ofintensive treatment. RESULTS: Out of 48 tumors, 41 tumors in 21 patients were evaluated for the efficacy of the RFA treatment. Of the 41 tumors, successful ablation was achieved in 34 (82.9 %). The patients in group A had significantly better survival than the patients in group B (p = 0.0003). In group A, all 9 patients are still alive with no evidence of disease (NED). Patients with a solitary tumor had significantly better survival than those with multiple tumors (p = 0.0247). In group B, 2 patients are alive with NED, 1 patient is alive with disease, and the remaining 12 patients have died a tumor-related death. Three cases of pneumothorax requiring intubation were observed. CONCLUSIONS: RFA is less invasive than surgery and is an effective treatment option for curative and palliative therapy as an alternative to invasive salvage surgery for post-chemotherapeutic metastatic lung or liver lesions from GCT.

Permanent prostate brachytherapy and short-term androgen deprivation for intermediate-risk prostate cancer in Japanese men: outcome and toxicity.

OBJECTIVES: To evaluate the interim outcomes of low-dose-rate permanent brachytherapy (PB) combined with short-term androgen deprivation therapy (ADT) in Japanese men with intermediate-risk prostate cancer excluding those with a Gleason score of 4+3. METHODS: The Protocol-intermediate-risk group (Protocol-IRG) was defined as clinical stage T1c-T2c, Gleason score of 3+4, or lower and prostatic-specific antigen (PSA) level lower than 20 ng/mL. A total of 308 patients underwent brachytherapy in the protocol-IRG group (n=152) or in the low-risk group (n=156). Patients in Protocol-IRG had received at least 6 months of ADT before and after PB. Supplemental external beam radiotherapy was not used. Planned followup by PSA was carried out every 3 months for the first 2 years and every 6 months thereafter. The PSA failure was defined as nadir+2 ng/mL. Patients' Expanded Prostate Cancer Index Composite was recorded before and 3 years after treatment. RESULTS: The median followup was 68 and 68 months for the protocol-IRG and the low-risk groups, respectively. The 5-year biological disease-free survival rates in the low-risk and protocol-IRG groups were 94.8 and 94.6%, respectively. As far as survival rates were concerned, there were no significant differences between the two groups. Overall satisfaction and sexual function at 3 years after PB had significantly improved compared with pretreatment (p=0.01 and p=0.01, respectively). CONCLUSIONS: In intermediate-risk prostate patients, excluding those with a biopsy Gleason score of 4+3, brachytherapy with short-term ADT can be an effective treatment option for Japanese men.

Potential risk of alpha-glucosidase inhibitor administration in prostate cancer external radiotherapy by exceptional rectal gas production: a case report.

INTRODUCTION: Radiotherapy is a standard treatment for prostate cancer, and image-guided radiotherapy is increasingly being used to aid precision of dose delivery to targeted tissues. However, precision during radiotherapy cannot be maintained when unexpected intrafraction organ motion occurs. CASE PRESENTATION: We report our experience of internal organ motion caused by persistent gas production in a patient taking an alpha-glucosidase inhibitor. A 68-year-old Japanese man with prostate cancer visited our institution for treatment with helical tomotherapy. He suffered from diabetes mellitus and took an alpha-glucosidase inhibitor. Routine treatment planning computed tomography showed a large volume of rectal gas; an enema was given to void the rectum. Subsequent treatment planning computed tomography again showed a large volume of gas. After exercise (walking) to remove the intestinal gas, a third scan was performed as a test scan without tight fixation, which showed a sufficiently empty rectum for planning. However, after only a few minutes, treatment planning computed tomography again showed extreme accumulation of gas. Therefore, we postponed treatment planning computed tomography and consulted his doctor to suspend the alpha-glucosidase inhibitor, which was the expected cause of his persistent gas. Four days after the alpha-glucosidase inhibitor regimen was suspended, we took a fourth treatment planning computed tomography and made a treatment plan without gas accumulation. Thereafter, the absence of rectal gas accumulation was confirmed using daily megavolt computed tomography before treatment, and the patient received 37 fractions of intensity-modified radiotherapy at 74 Gy without rectal gas complications. In this case study, the alpha-glucosidase inhibitor induced the accumulation of intestinal gas, which may have caused unexpected organ motion, untoward reactions, and insufficient doses to clinical targets. CONCLUSIONS: We suggest that patients who are taking an alpha-glucosidase inhibitor for diabetes should discontinue use of that particular medicine prior to beginning radiotherapy.

Standardizing display conditions of diffusion-weighted images using concurrent b0 images: a multi-vendor multi-institutional study.

PURPOSE: To establish a practical method that uses concurrent b0 images to standardize the display conditions for diffusion-weighted images (DWI) that vary among institutions and interpreters. METHOD: Using identical parameters, we obtained DWI for 12 healthy volunteers at 4 institutions using 4 MRI scanners from 3 vendors. Three operators manually set the window width for the images equal to the signal intensity of the normal-appearing thalamus on b0 images and set the window level at half and then exported the images to 8-bit gray-scale images. We calculated the mean pixel values of the brain objects in the images and examined the variation among scanners, operators, and subjects. RESULT: Following our method, the DWI of the 12 subjects obtained using the 4 different scanners had nearly identical contrast and brightness. The mean pixel values of the brain on the exported images among the operators and subjects were not significantly different, but we found a slight, significant difference among the scanners. CONCLUSION: Determining DWI display conditions by using b0 images is a simple and practical method to standardize window width and level for evaluating diffusion abnormalities and decreasing variation among institutions and operators.

Somatotopic organization of thalamocortical projection fibers as assessed with MR tractography.

PURPOSE: To prospectively evaluate the course of sensory fibers through the supratentorial brain with diffusion-tensor-based tractography. MATERIALS AND METHODS: This study was approved by the institutional review board. Informed consent was obtained. Seven healthy volunteers (five men, two women; age range, 20-55 years) underwent 1.5-T magnetic resonance imaging. Diffusion-tensor images with isotropic voxels (2 x 2 x 2 mm) were obtained by using a single-shot echo-planar imaging technique, with a motion-probing gradient in 15 orientations, a b value of 1000 sec/mm(2), and nine signals acquired. The total imaging time was approximately 30 minutes. Fiber tracking of the sensorimotor pathways was performed with the fiber assignment by continuous tracking method. RESULTS: All the pyramidal tracts rotated anteriorly as they traveled through the centrum semiovale. On the other hand, the sensory tracts rotated posteriorly as they coursed through the centrum semiovale toward the cortex. When the sensorimotor tracts were viewed as a unit, the tracts of the lower extremity formed the axis of rotation around which the other parts of the pyramidal and sensory homunculus rotated. CONCLUSION: Sensorimotor fibers of the lower extremity form an axis of rotation, around which the pyramidal fibers rotate anteriorly and the sensory fibers rotate posteriorly.