Involved-field radiotherapy in older patients with superficial thoracic esophageal squamous cell carcinoma: long-term outcomes and recurrence patterns.

PURPOSE: An optimal radiotherapy field for superficial esophageal carcinoma is yet to be established. We evaluated the long-term outcomes and recurrence patterns of involved-field radiotherapy (IFRT) in older patients with superficial thoracic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Fifty-four patients (49 men and 5 women; mean age, 77 [range: 66-90] years) who underwent IFRT for superficial thoracic ESCC between January 2003 and January 2019 were retrospectively reviewed. Concurrent chemotherapy was administered at the discretion of the attending physician. The primary endpoint was overall survival. The secondary endpoints were progression-free survival and complete response rate. RESULTS: The tumors were localized in the upper, middle, and lower thoracic esophagus in 2, 40, and 12 patients, respectively. All patients underwent IFRT using anteroposterior and anterior-posterior oblique opposed beams (off-cord). The prescribed total doses were 50.4, 59.4-61.2, and 66-70 Gy for 6, 40, and 8 patients, respectively. Concurrent chemotherapy was administered to 33 patients. The median follow-up duration was 57 months. The median overall survival was 115 months. The 5-year overall and progression-free survival rates were 71.7% and 60.1%, respectively. Forty-nine patients had a complete response at one month after IFRT (complete response rate: 90.7%). Twenty patients had recurrence; there were 13 in-field and 7 out-of-field recurrence cases. The radiation-related adverse events were generally mild. Grade 3 late toxicity was observed in one patient. CONCLUSIONS: The efficacy of IFRT was suggested to be comparable to that of standard treatments. Therefore, IFRT can be a promising approach for treating superficial ESCC in older adults, especially those with severe comorbidities.

A long-term survival case of bladder cancer with distant metastases: abscopal effect of brain metastases after stereotactic radiotherapy with immune checkpoint blockade therapy to lung metastases.

Brain metastases from bladder cancer are rare, with a poor prognosis. There is no standard treatment for bladder cancer with brain metastases; thus, palliative therapy is generally provided. We report a case of abscopal effect in a single brain metastasis from bladder cancer in a patient treated with focal stereotactic radiotherapy (total dose = 52 Gy, administered in eight fractions) with immune checkpoint blockade therapy for lung metastases, who achieved long-term disease-free survival (> 4 years). To our knowledge, although there have been some reports on abscopal effects in bladder cancer, there are no previous reports on patients with brain metastases. To date, the brain metastasis, which showed an "abscopal effect," continues to maintain complete regression.

Relationship between changes in quality of life and genitourinary toxicity grade after brachytherapy with I-125 alone for localised prostate cancer.

Background: The relationship between the grading of toxicities based on toxicity criteria and longitudinal changes in quality of life (QOL) scores after permanent prostate brachytherapy (PPB) for localized prostate cancer remains unclear. This study aimed to evaluate these relationships. Materials and methods: We assessed 107 patients treated with PPB using Iodine-125 alone from May 2007 to April 2010. Disease-specific QOL scores before PPB and at 1, 3, 6, 12, and 24 months after PPB were retrospectively evaluated with the Expanded Prostate Cancer Index Composite (EPIC), focusing on urinary domains. Toxicities were graded using the Radiation therapy oncology group and the European organization for research and treatment of cancer toxicity criteria. Results: The median follow-up duration was 116 (range 18-148) months. Thirty-four patients (31.8%) developed grade ≥ 2 acute genitourinary (GU) toxicities; six (5.6%) developed grade ≥ 2 late GU toxicities. The general urinary domain score dropped significantly at 1 month (77.1 ± 14.1) post-PPB compared to the baseline score (92.2 ± 8.2), and then gradually returned to the baseline level by 12 months (93.7 ± 8.3) post-PPB. Reductions in the general urinary domain scores, including its subscale scores at 1, 3, and 6-months post-PPB were significantly greater among patients with grade ≥ 2 GU toxicity than among those with grade 0-1 GU toxicity. Changes in urinary domain scores demonstrated a close relationship with acute GU toxicity grades after PPB. Conclusions: Longitudinal assessments of the EPIC QOL scores provided additional information regarding time-course changes in GU toxicities after PPB.

Predictors of Adverse Gastrointestinal Events After Stereotactic Body Radiation Therapy for Liver Tumors.

BACKGROUND/AIM: To identify predictors of adverse gastrointestinal (GI) events related to stereotactic body radiation therapy (SBRT) for liver tumors. PATIENTS AND METHODS: We retrospectively analyzed 56 patients who underwent SBRT for liver tumors at our institution between 2016 and 2021. The α/ß ratio of the GI tract (stomach, duodenum, and large intestine) was assumed to be 3 Gy in the Linear-Quadratic model (LQ model). The dose to the GI tract, that is, the biologically effective dose 3 (BED3) was converted to a 2 Gy equivalent dose (Gy2/3=2 Gy equivalent dose, α/ß=3). Using this 2 Gy equivalent dose, predictors of adverse GI events of Grade 2 or higher were investigated. RESULTS: The median observation period was 10 months (0-40 months) and median age was 77 years (range=29-93 years). Forty-three of the 56 patients had hepatocellular carcinoma and the other 13 had metastatic liver tumors. Tumors were irradiated with 30-54 Gy/5-18 fractions of planning target volume D95% prescription (80% isodose). Eight of the 56 patients had Grade 2 or higher adverse GI events. By univariate analysis, GI D1cc, Dmax, V20, V25, V30, and V35 were all significant predictors of Grade 2 or higher adverse GI events. Among these, gastrointestinal V35 was the most significant predictor of Grade 2 or higher adverse GI events. CONCLUSION: For SBRT of liver tumors, GI V35 was the best predictor of Grade 2 or higher adverse GI events.

[Questionnaire Survey of Japanese Medical Physicists on Working Conditions in 2020].

The questionnaire survey was conducted in 2020 to investigate the working conditions of qualified medical physicists in Japan. We developed a web-based system for administering the questionnaire and surveyed 1,228 qualified medical physicists. The number of received responses was 405. We summarized the results of the survey by job category. The obtained results showed that most of the people working as certified medical physicists met the following conditions: (1) position of healthcare occupation, (2) direct supervisor is a medical doctor or a medical physicist, (3) licensed or passed an examination for a Class I Radiation Protection Supervisor, (4) without the license of professional radiotherapy technologist, (5) master's or doctor's degree, (6) being assigned to the section that is different from the radiological technologist section. The average annual salary was approximately 600,000 yen higher for those employed as medical physicists than for those employed as radiotherapy technologists. The percentage of work performed by a certified medical physicist in radiation therapy greatly varies depending on whether the physicist is dedicated to treatment planning and equipment quality control. Alternatively, the proportion of the true duties of medical physicists in charge of radiation therapy, as considered by qualified medical physicists in radiation therapy, was the same regardless of whether they were working full-time or not. The results of this survey updated the working status of certified medical physicists in Japan. We will continue to conduct the survey periodically and update the information to contribute to the improvement of the working conditions of medical physicists and policy recommendations.

Risk of secondary malignancy after radiotherapy for breast cancer: long-term follow-up of Japanese patients with breast cancer.

PURPOSE: There have been very few reports of secondary malignancies after breast cancer treatment in Asia, particularly in Japan. This study aimed to evaluate the risk of secondary malignancies after radiotherapy (RT) in Japanese breast cancer patients. METHODS: This single-center retrospective study included patients who underwent RT between July 1961 and September 2006 for postoperative breast cancer. A total of 702 patients with a follow-up period of more than 5 years were analyzed. All malignancies observed at more than 5 years after the start of RT were defined as secondary malignancies. To calculate the relative risk (RR) of secondary malignancies, we applied data from the National Cancer Center in Japan. RESULTS: The median observation period was 9.7 (interquartile range 7.1-18.2) years. The cumulative person-years of observation were 6879.4. The RR of contralateral breast cancer increased by 1.85-fold (95% confidence interval [CI] 1.05-3.26) among patients compared with that among the general population; however, the difference was not significant (p = 0.053). The RR of secondary malignancies other than breast cancer increased by 2.71-fold (95% CI 1.99-3.70, p < 0.001) among the patients compared with the general population. Even when only malignancies detected more than 10 years after RT were defined as secondary malignancies, the RR of secondary malignancies other than breast cancer was 1.91 (95% CI 1.33-2.73, p < 0.001). CONCLUSION: The incidence of secondary malignancies after RT may be somewhat higher in Japanese patients with breast cancer than in the general population.

Measurement of biological washout rates depending on tumor vascular status in15O in-beam rat-PET.

Objective.The biological washout of positron emitters should be modeled and corrected in order to achieve quantitative dose range verification in charged particle therapy based on positron emission tomography (PET). This biological washout effect is affected by physiological environmental conditions such as blood perfusion and metabolism, but the correlation to tumour pathology has not been studied yet.Approach.The aim of this study was to investigate the dependence of the biological washout rate on tumour vascular status in rat irradiation. Two types of tumour vascularity conditions, perfused and hypoxic, were modelled with nude rats. The rats were irradiated by a radioactive15O ion beam and time activity curves were acquired by dynamic in-beam PET measurement. Tumour tissue sections were obtained to observe the histology as well. The biological washout rate was derived using a single-compartment model with two decay components (medium decay,k2mand slow decay,k2s).Main results.Allk2mvalues in the vascular perfused tumour tissue were higher than the values of the normal tissue. Allk2mvalues in the hypoxic tumour tissue were much lower than the values of the vascular perfused tumour tissue and slightly lower than the values of the normal tissue.Significance.The dependency of the biological washout on the tumour vasculature conditions was experimentally shown.

Combining Carbon-Ion Irradiation and PARP Inhibitor, Olaparib Efficiently Kills BRCA1-Mutated Triple-Negative Breast Cancer Cells.

Background: Triple-negative breast cancer (TNBC) exhibits poor prognosis due to the lack of targets for hormonal or antibody-based therapies, thereby leading to limited success in the treatment of this cancer subtype. Poly (ADP-ribose) polymerase 1 (PARP1) is a critical factor for DNA repair, and using PARP inhibitor (PARPi) is one of the promising treatments for BRCA-mutated (BRCA mut) tumors where homologous recombination repair is impaired due to BRCA1 mutation. Carbon ion (C-ion) radiotherapy effectively induces DNA damages in cancer cells. Thus, the combination of C-ion radiation with PARPi would be an attractive treatment for BRCA mut TNBC, wherein DNA repair systems can be severely impaired on account of the BRCA mutation. Till date, the effectiveness of C-ion radiation with PARPi in BRCA mut TNBC cell killing remains unknown. Purpose: Triple-negative breast cancer cell lines carrying either wild type BRCA1, BRCA wt, (MDA-MB-231), or the BRCA1 mutation (HCC1937) were used, and the effectiveness of PARPi, olaparib, combined with C-ion beam or the conventional radiation, or X-ray, on TNBC cell killing were investigated. Methods: First, effective concentrations of olaparib for BRCA mut (HCC1937) cell killing were identified. Using these concentrations of olaparib, we then investigated their radio-sensitizing effects by examining the surviving fraction of MDA-MB-231 and HCC1937 upon X-ray or C-ion irradiation. In addition, the number of γH2AX (DSB marker) positive cells as well as their expression levels were determined by immunohistochemistry, and results were compared between X-ray irradiated or C-ion irradiated cells. Furthermore, PARP activities in these cells were also observed by performing immunohistochemistry staining for poly (ADP-ribose) polymer (marker for PARP activity), and their expression differences were determined. Results: Treatment of cells with 25 nM olaparib enhanced radio-sensitivity of X-ray irradiated HCC1937, whereas lower dose (5 nM) olaparib showed drastic effects on increasing radio-sensitivity of C-ion irradiated HCC1937. Similar effect was not observed in MDA-MB-231, not possessing the BRCA1 mutation. Results of immunohistochemistry showed that X-ray or C-ion irradiation induced similar number of γH2AX-positive HCC1937 cells, but these induction levels were higher in C-ion irradiated HCC1937 with increased PARP activity compared to that of X-ray irradiated HCC1937. Elevated induction of DSB in C-ion irradiated HCC937 may fully activate DSB repair pathways leading to downstream activation of PARP, subsequently enhancing the effectiveness of PARPi, olaparib, with lower doses of olaparib exerting noticeable effects in cell killing of C-ion irradiated HCC1937. Conclusions: From this study, we demonstrate that C-ion irradiation can exert significant DSB in BRCA mut TNBC, HCC1937, with high PARP activation. Thus, PARPi, olaparib, would be a promising candidate as a radio-sensitizer for BRCA mut TNBC treatment, especially for C-ion radiotherapy.

Secondary cancers after carbon-ion radiotherapy and photon beam radiotherapy for uterine cervical cancer: A comparative study.

BACKGROUND: There are limited studies on the risk of secondary cancers after carbon-ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period. METHODS: This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated. RESULTS: The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person-years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6-2.1) in the CIRT group and 1.4 (95% CI, 1.0-2.1) in the photon RT group. The 10-year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0-21.5) in the CIRT group and 9.4% (95% CI, 6.2-14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268). CONCLUSIONS: The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long-term observation is warranted.

Study of feasible and safe condition for total body irradiation using cardiac implantable electronic devices.

Cardiac implantable electronic devices (CIEDs) were believed to have a tolerance dose and that direct irradiation has to be avoided. Thus, no clinical guidelines have mentioned the feasibility of total body irradiation (TBI) with a CIED directly. The purpose of this work was to study a feasible and safe condition for TBI using a CIED. Eighteen CIEDs were directly irradiated by a 6-MV X-ray beam, where a non-neutron producible beam was employed for the removal of any neutron contribution to CIED malfunction. Irradiation up to 10 Gy in accumulated dose was conducted with a 100-cGy/min dose rate, followed by up to 20 Gy at 200 cGy/min. An irradiation test of whether inappropriate ventricular shock therapy was triggered or not was also performed by using a 6-MV beam of 5, 10, 20 and 40 cGy/min to two CIEDs. No malfunction was observed during irradiation up to 20 Gy at 100 and 200 cGy/min without activation of shock therapy. These results were compared with typical TBI, suggesting that a CIED in TBI will not encounter malfunction because the prescribed dose and the dose rate required for TBI are much safer than those used in this experiment. Several inappropriate shock therapies were, however, observed even at 10 cGy/min if activated. The present result suggested that TBI was feasible and safe if a non-neutron producible beam was employed at low dose-rate without activation of shock therapy, where it was not inconsistent with clinical and non-clinical data in the literature. The feasibility of TBI while using a CIED was discussed for the first time.

Plastic scintillation dosimeter with a conical mirror for measuring 3D dose distribution.

PURPOSE: To test the measurement technique of the three-dimensional (3D) dose distribution measured image by capturing the scintillation light generated using a plastic scintillator and a scintillating screen. METHODS: Our imaging system constituted a column shaped plastic scintillator covered by a Gd2 O2 S:Tb scintillating screen, a conical mirror and a cooled CCD camera. The scintillator was irradiated with 6 MV photon beams. Meanwhile, the irradiated plan was prepared for the static field plans, two-field plan (2F plan) and the conformal arc plan (CA plan). The 2F plan contained 16 mm2 and 10 mm2 fields irradiated from gantry angles of 0° and 25°, respectively. The gantry was rotated counterclockwise from 45° to 315° for the CA plan. The field size was then obtained as 10 mm2 . A Monte Carlo simulation was performed in the experimental geometry to obtain the calculated 3D dose distribution as the reference data. Dose response was acquired by comparing between the reference and the measurement. The dose rate dependence was verified by irradiating the same MU value at different dose rates ranging from 100 to 600 MU/min. Deconvolution processing was applied to the measured images for the correction of light blurring. The measured 3D dose distribution was reconstructed from each measured image. Gamma analysis was performed to these 3D dose distributions. The gamma criteria were 3% for the dose difference, 2 mm for the distance-to-agreement and 10% for the threshold. RESULTS: Dose response for the scintillation light was linear. The variation in the light intensity for the dose rate ranging from 100 to 600 MU/min was less than 0.5%, while our system presents dose rate independence. For the 3D dose measurement, blurring of light through deconvolution processing worked well. The 3D gamma passing rate (3D GPR) for the 10 × 10 mm2 , 16 × 16 mm2 , and 20 × 20 mm2 fields were observed to be 99.3%, 98.8%, and 97.8%, respectively. Reproducibility of measurement was verified. The 3D GPR results for the 2F plan and the CA plan were 99.7% and 100%, respectively. CONCLUSIONS: We developed a plastic scintillation dosimeter and demonstrated that our system concept can act as a suitable technique for measuring the 3D dose distribution from the gamma results. In the future, we will attempt to measure the 4D dose distribution for clinical volumetric modulated arc radiation therapy (VMAT)-SBRTplans.

Denoising PET images for proton therapy using a residual U-net.

The use of proton therapy has the advantage of high dose concentration as it is possible to concentrate the dose on the tumor while suppressing damage to the surrounding normal organs. However, the range uncertainty significantly affects the actual dose distribution in the vicinity of the proton range, limiting the benefit of proton therapy for reducing the dose to normal organs. By measuring the annihilation gamma rays from the produced positron emitters, it is possible to obtain a proton induced positron emission tomography (pPET) image according to the irradiation region of the proton beam. Smoothing with a Gaussian filter is generally used to denoise PET images; however, this approach lowers the spatial resolution. Furthermore, other conventional smoothing processing methods may deteriorate the steep region of the pPET images. In this study, we proposed a denoising method based on a Residual U-Net for pPET images. We conducted the Monte Carlo simulation and irradiation experiment on a human phantom to obtain pPET data. The accuracy of the range estimation and the image similarity were evaluated for pPET images using the Residual U-Net, a Gaussian filter, a median filter, the block-matching and 3D-filtering (BM3D), and a total variation (TV) filter. Usage of the Residual U-Net yielded effective results corresponding to the range estimation; however, the results of peak-signal-to-noise ratio were identical to those for the Gaussian filter, median filter, BM3D, and TV filter. The proposed method can contribute to improving the accuracy of treatment verification and shortening the PET measurement time.

Abscopal complete regression of hepatocellular carcinoma with multiple pleural metastases.

Hepatocellular carcinoma (HCC) with extrahepatic metastasis is rare, and its prognosis is extremely poor. There is no standard treatment for HCC with extrahepatic metastasis. We report a case of abscopal effect in HCC with multiple pleural metastases in a patient who was treated with focal radiotherapy to extrahepatic metastasis, and achieved long-term survival. We performed radiotherapy only to the tumor in inferior vena cava and the proximal pleural tumor. The regimen comprised a total dose of 30 Gy administered in ten fractions to these tumors, followed by 12 Gy administered in four fractions (a total of 42 Gy in 14 fractions) as boost irradiation to the remaining tumor, and a complete regression was achieved. There have been some case reports on abscopal effects in HCC, but no reports on patients with multiple pleural metastases. To our knowledge, this is the first case report on the abscopal effect of focal radiotherapy resulting in complete regression of distant multiple pleural metastases.

Ipsilateral breast tumor control following hypofractionated and conventional fractionated whole-breast irradiation for early breast cancer: a long-term follow-up.

PURPOSE: Long-term follow-up of Japanese women with breast cancer who underwent hypofractionated whole-breast irradiation (HF-WBI) has not been well documented. Therefore, we compared the treatment results of HF-WBI and conventional fractionated (CF)-WBI. METHODS: Patients with stage 0-II breast cancer receiving partial mastectomy were eligible for this prospective observational study. The HF-WBI consisted of 43.2 Gy in 16 fractions to the whole breast, with an additional tumor-bed boost of 8.1 Gy in three fractions for patients with positive or less than 5 mm surgical margins. A total of 615 patients (400: HF-WBI and 215: CF-WBI) who were treated between 2006 and 2008 were investigated. Propensity score matching was conducted based on age, tumor grade, and margin status, and 372 matched cases were investigated for examining factors relating to intrabreast tumor recurrence (IBTR). RESULTS: With a median follow-up period of 9.4 years, age and margin status were independent factors associated with IBTR occurrence (P = 0.006 and 0.016, respectively). The 10-year ipsilateral breast tumor control (IBTC) rates after HF-WBI and CF-WBI were 96.5% and 95.3%, respectively (P = 0.606). The 10-year IBTC rates according to margin status were 88.0% with positive margins, 94.9% with 5 mm margins, and 98.0% with negative margins (P = 0.014). CONCLUSIONS: There was no difference in IBTC between CF-WBI and HF-WBI in our patients. Positive surgical margin was a risk factor independently associated with IBTC rates after CF-WBI and HF-WBI. Further investigation is required to establish adequate treatment strategies for patients with positive surgical margins.

A clinical study of curative partial breast irradiation for stage I breast cancer using carbon ion radiotherapy.

BACKGROUND AND PURPOSE: Our institute initiated carbon ion radiotherapy research for patients with stage I breast cancer in April 2013. The purpose of this article is to evaluate the treatment outcome of cases treated outside clinical trial up to May 2020. MATERIALS AND METHODS: Eligibility criteria of the patients were having untreated stage I breast cancer and being unsuitable for operation for physical or mental reasons. The irradiated volume was defined as the gross tumor including intraductal components. The dose escalation study was initially conducted four times a week for a total of 52.8 Gy [relative biological efficacy (RBE)]. After confirming that adverse effects were within acceptable range, the total dose was increased to 60.0 Gy (RBE). RESULTS: Between April 2013 and November 2015, 14 cases were treated. The median follow up period was 61 months. No adverse toxicities were observed except for grade 1 acute skin reaction in 10 cases. The time required from carbonion radiotherapy to tumor disappearance was 3 months in 1 case, 6 months in 3 cases, 12 months in 4 cases, and 24 months in 5 cases. The third case developed local recurrence 6 months after radiotherapy. Twelve patients with luminal subtype received 5-year endocrine therapy. Thirteen of 14 tumors have been maintaining complete response with excellent cosmetic results. CONCLUSIONS: The time from carbon ion radiotherapy to tumor disappearance was longer than expected, but complete tumor disappearance was observed except for one high-grade case. With careful patient selection, carbonion radiotherapy in patients with stage I breast cancer is deemed effective and safe, and further research is recommended.

Feasibility of image quality improvement for high-speed CBCT imaging using deep convolutional neural network for image-guided radiotherapy in prostate cancer.

PURPOSE: High-speed cone-beam computed tomography (CBCT) scan for image-guided radiotherapy (IGRT) can reduce both the scan time and the exposure dose. However, it causes noise and artifacts in the reconstructed images due to the lower number of acquired projection data. The purpose of this study is to improve the image quality of high-speed CBCT using a deep convolutional neural network (DCNN). METHODS: CBCT images of 36 prostate cancer patients were selected. The CBCT images acquired at normal scan speed were defined as CBCT100%. Simulated high-speed CBCT images acquired at twofold and fourfold scan speed were created, which were defined as CBCT50% and CBCT25%, respectively. The image quality of the CBCT50% was treated as the requirement for IGRT in this study because previous studies reported that its image is sufficient with respect to IGRT. The DCNN model was trained to learn direct mapping from CBCT25% to the corresponding CBCT100%. The performance of the DCNN model was evaluated using the sixfold cross-validation method. CBCT images generated by DCNN (CBCT25%+DCNN) were evaluated for voxel value accuracy and image quality. RESULTS: The DCNN model can process CBCT25% of a new patient within 0.06 s/slice. The CBCT25%+DCNN was comparable to the CBCT50% in terms of both voxel value accuracy and image quality. CONCLUSIONS: We developed a DCNN model to remove noise and artifacts from high-speed CBCT. We emphasize that it is possible to reduce exposure to one quarter and to increase the CBCT scan speed by a factor of four.

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: impact of non-cytotoxic doses of 2-DG on diminishing invasiveness.

BACKGROUND: Metabolic reprogramming is being recognized as a fundamental hallmark of cancer, and efforts to identify drugs that can target cancer metabolism are underway. In this study, we used human breast cancer (BC) cell lines and established their invading phenotype (INV) collected from transwell inserts to compare metabolome differences and evaluate prognostic significance of the metabolome in aggressive BC invasiveness. METHODS: The invasiveness of seven human BC cell lines were compared using the transwell invasion assay. Among these, INV was collected from SUM149, which exhibited the highest invasiveness. Levels of metabolites in INV were compared with those of whole cultured SUM149 cells (WCC) using CE-TOFMS. The impact of glycolysis in INV was determined by glucose uptake assay using fluorescent derivative of glucose (2-NBDG), and significance of glycolysis, or tricarboxylic acid cycle (TCA) and electron transport chain (ETC) in the invasive process were further determined in aggressive BC cell lines, SUM149, MDA-MB-231, HCC1937, using invasion assays in the presence or absence of inhibitors of glycolysis, TCA cycle or ETC. RESULTS: SUM149 INV sub-population exhibited a persistent hyperinvasive phenotype. INV were hyper-glycolytic with increased glucose (2-NBDG) uptake; diminished glucose-6-phosphate (G6P) levels but elevated pyruvate and lactate, along with higher expression of phosphorylated-pyruvate dehydrogenase (pPDH) compared to WCC. Notably, inhibiting of glycolysis with lower doses of 2-DG (1 mM), non-cytotoxic to MDA-MB-231 and HCC1937, was effective in diminishing invasiveness of aggressive BC cell lines. In contrast, 3-Nitropropionic acid (3-NA), an inhibitor of succinate dehydrogenase, the enzyme that oxidizes succinate to fumarate in TCA cycle, and functions as complex II of ETC, had no significant effect on their invasiveness, although levels of TCA metabolites or detection of mitochondrial membrane potential with JC-1 staining, indicated that INV cells originally had functional TCA cycles and membrane potential. CONCLUSIONS: Hyper-glycolytic phenotype of invading cells caters to rapid energy production required for invasion while TCA cycle/ETC cater to cellular energy needs for sustenance in aggressive BC. Lower, non-cytotoxic doses of 2-DG can hamper invasion and can potentially be used as an adjuvant with other anti-cancer therapies without the usual side-effects associated with cytotoxic doses.

Parathyroid carcinoma in a 13-year-old girl with a long-term survival.

BACKGROUND: Parathyroid carcinoma as a cause of primary hyperparathyroidism in children is extremely rare. We report a case of parathyroid carcinoma which occurred in a 13-year-old girl who survived for more than 45 years after the first operation. CASE PRESENTATION: A woman was admitted to our hospital for the treatment of recurrent parathyroid carcinoma in the neck. She had been diagnosed with primary hyperparathyroidism from a fibula fracture and underwent parathyroidectomy at 13 years old. She had no family history of multiple endocrine neoplasia or jaw tumor syndrome. Genetic testing was not performed, and the histopathological diagnosis of the tumor had been parathyroid adenoma at the time. At 22 years old, she showed hypercalcemia after a femur fracture. Pulmonary metastases of parathyroid carcinoma in the bilateral lungs were found and surgically removed. Regarding the clinical course, her diagnosis was corrected from parathyroid adenoma to parathyroid carcinoma. At 33 years old, re-resection of the lung metastases was performed. For 10 years, her serum calcium level stayed within the normal range. However, her serum calcium level and intact parathyroid hormone eventually began to increase. Two masses suspected of being parathyroid carcinoma recurrence were found in the neck when she was 57 years old. En bloc resection was performed. Pathologically, the tumors were diagnosed as parathyroid adenoma. The serum calcium level and intact parathyroid hormone did not decrease after the operation. A 99mTc-methoxy-isobutyl-isonitrile- and 18F-fluorodeoxyglucose-negative, 11C-methionine-positive tumor was detected at the right side of the trachea in the neck. The tumor was removed, along with the thyroid, muscle, and trachea that were involved. The pathological diagnosis was parathyroid carcinoma recurrence. The serum calcium level and intact parathyroid hormone decreased temporarily but had increased again 8 months later. Methionine-positive tumors were found at the right side of the trachea and suspected of being a recurrence. Denosumab reduced her serum calcium level, and radiation successfully suppressed the growth of the recurrent tumors. CONCLUSION: We have reported a rare case of parathyroid carcinoma in a child who has survived for over 40 years. Positron emission tomography of 11C-methionine was useful for detecting local recurrence. This patient's long-term survival has been attributed to multimodality treatment including repeated surgery, medication, and radiation.

Extension of the ML-EM algorithm for dose estimation using PET in proton therapy: application to an inhomogeneous target.

Positron emission tomography (PET) has been used for in vivo treatment verification, mainly for range verification, in proton therapy. Evaluating the direct dose from PET measurements remains challenging; however, it is highly desirable from a clinical perspective. In this study, a method for estimating the dose distribution from the positron emitter distributions was developed using the maximum likelihood expectation maximization algorithm. The 1D spatial relationship between positron emitter distributions and a dose distribution in an inhomogeneous target was inputted into the system matrix based on a filter framework. In contrast, spatial resolution of the PET system and total variation regularization (as prior knowledge for dose distribution) were considered in the 3D image-space. The dose estimation was demonstrated using Monte Carlo simulated PET activity distributions with substantial noise in a head and neck phantom. This mimicked the single field irradiation of the spread-out Bragg peak beams at clinical dose levels. Besides the simple implementation of the algorithm, this strategy achieved a high-speed calculation (30 s for a 3D dose estimation) and accurate dose and range estimations (less than 10% and 2 mm errors at 1-σ values, respectively). The proposed method could be key for using PET for in vivo dose monitoring.