Search

Background In recent years, the use of Indocyanine Green (ICG) fluorescence-guided surgery during open and laparoscopic procedures has exponentially expanded across various clinical settings. The European Association of Endoscopic Surgery (EAES) initiated a consensus development conference on this topic with the aim of creating evidence-based statements and recommendations for the surgical community. Methods An expert panel of surgeons has been selected and invited to participate to this project. Systematic reviews of the PubMed, Embase and Cochrane libraries were performed to identify evidence on potential benefits of ICG fluorescence-guided surgery on clinical practice and patient outcomes. Statements and recommendations were prepared and unanimously agreed by the panel; they were then submitted to all EAES members through a two-rounds online survey and results presented at the EAES annual congress, Barcelona, November 2021. Results A total of 18,273 abstracts were screened with 117 articles included. 22 statements and 16 recommendations were generated and approved. In some areas, such as the use of ICG fluorescence-guided surgery during laparoscopic cholecystectomy, the perfusion assessment in colorectal surgery and the search for the sentinel lymph nodes in gynaecological malignancies, the large number of evidences in literature has allowed us to strongly recommend the use of ICG for a better anatomical definition and a reduction in post-operative complications. Conclusions Overall, from the systematic literature review performed by the experts panel and the survey extended to all EAES members, ICG fluorescence-guided surgery could be considered a safe and effective technology. Future robust clinical research is required to specifically validate multiple organ-specific applications and the potential benefits of this technique on clinical outcomes.

Purpose Because most previous data on proton therapy for hepatocellular carcinoma (HCC) were retrospectively collected from inoperable or previously treated cases, our aim was to evaluate the outcome of image-guided proton therapy (IGPT) for operable or radiofrequency ablation–treatable primary HCC. Methods and Materials This phase 2 study prospectively investigated the efficacy and safety of IGPT and quality of life (QoL) after IGPT for operable/ablatable HCC. The primary endpoint was overall survival, and the secondary endpoints were local control, incidence of grade ≥3 adverse events, and changes in QoL. Toxicities were evaluated with Common Terminology Criteria for Adverse Events, version 4.0. QoL scores were assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0, and Quality of Life Questionnaire-Hepatocellular Carcinoma/Primary Liver Cancer Module. IGPT was performed using respiratory-gated techniques. Results Forty-five patients (median age: 68 years; range, 36-80 years) were enrolled between June 2013 and February 2016; 38 were considered operable and 14 were indicated for radiofrequency ablation. The major underlying liver diseases were hepatitis B (n = 16), hepatitis C (n = 13), alcoholic hepatitis (n = 3), and nonalcoholic fatty liver disease (n = 13). The Child-Pugh score was A5 in 32 patients, A6 in 9 patients, and B7 in 4 patients. Thirty-seven patients with a peripherally located tumor were given 66 Gy relative biological effectiveness in 10 fractions, and 8 patients with a centrally located tumor received 72.6 Gy relative biological effectiveness in 22 fractions. The median follow-up period of surviving patients was 60 months (range, 42-75 months). Two- and 5-year overall survival rates were 84% (95% confidence interval [CI], 74%-95%) and 70% (95% CI, 56%-84%), respectively, and local control rates were 95% (95% CI, 89%-100%) and 92% (95% CI, 84%-100%), respectively. Grade 3 radiation-induced liver disease was observed in 1 patient. No significant changes were noted in QoL scores 1 year after treatment, except for body image. Conclusions Although the primary endpoint did not meet statistical significance as planned in the study design, IGPT is a safe and effective treatment for solitary primary HCC and may become a treatment option.

Purpose This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC). Methods and Materials The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m2) on day 1 and S-1 (∼40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented. Results Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia. Conclusions CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC.

Since sexual function and testosterone levels after image-guided proton therapy (IGPT) have not yet been examined in detail, we prospectively evaluated changes before and after IGPT. Among patients treated with IGPT with or without combined androgen blockade (CAB) therapy between February 2013 and September 2014, patients who agreed to participate in the study and were followed up for >3 years after IGPT were evaluated. Serum testosterone levels were regularly measured together with prostate-specific antigen (PSA) levels before and after IGPT. The Erection Hardness Score (EHS) and the sexual domain summary, function subscale and bother subscale of the sexual domain in the Expanded Prostate Cancer Index Composite (EPIC) were assessed. There were 38 low-risk, 46 intermediate-risk and 43 high- or very-high-risk patients (NCCN classification). Although serum testosterone levels in low-risk patients did not decrease after IGPT, reductions were observed in the average EHS and the sexual domain summary score of the EPIC. In intermediate-, high- and very-high-risk patients, testosterone and PSA levels both increased following the termination of CAB after IGPT, and the average EHS increased. The sexual domain summary score gradually increased, but not above minimally important differences. In intermediate-risk patients, the function subscale increased from 4.4 to 14.8 (P < 0.05) 12 months after IGPT and reached a plateau after 60 months. The results of the present study would suggest the potential of IGPT, and further prospective studies to directly compare IGPT with other modalities are warranted.

Spin dynamics of the spin-1/2 kagome lattice antiferromagnet Cs$_2$Cu$_3$SnF$_{12}$ was studied using high-resolution, time-of-flight inelastic neutron scattering. The flat mode, a characteristic of the frustrated kagome antiferromagnet, and the low-energy dispersive mode, which is dominated by magnons, can be well described by the linear spin-wave theory. However, the theory fails to describe three weakly dispersive modes between 9 and 14 meV. These modes could be attributed to two-spinon bound states, which decay into free spinons away from the zone center and at a high temperature, giving rise to continuum scattering., 4 figures and Supplementary Information

Background Interstitial pneumonia (IP) is a disease with a poor prognosis. In addition, IP patients are more likely to develop lung cancer. Since IP patients frequently develop toxicities during cancer treatment, minimally invasive cancer treatment is warranted for such patients to maintain their quality of life. This study retrospectively investigated the efficacy and safety of proton therapy (PT) for non-small cell lung cancer (NSCLC) in patients with IP. Methods Twenty-nine NSCLC patients with IP were treated with PT between September 2013 and December 2019. The patients had stage IA to IIIB primary NSCLC. Ten of the 29 patients exhibited the usual interstitial pneumonia pattern. The prescribed dose was 66–74 Grays (relative biological effectiveness) in 10–37 fractions. Results The median follow-up period was 21.1 months [interquartile range (IQR), 15.6–37.3] for all patients and 37.2 months (IQR, 24.0–49.9) for living patients. The median patient age was 77 years (IQR, 71–81). The median planning target volume was 112.0 ml (IQR, 56.1–246.3). The 2-year local control, progression-free survival, and overall survival rates were 85% (95% confidence interval: 57–95), 30% (15–47), and 45% (26–62), respectively. According to the Common Terminology Criteria for Adverse Events (version 4.0), grade 3 acute radiation pneumonitis (RP) was observed in 1 patient. Two patients developed grade 3 late RP, but no other patients experienced serious toxicities. The patients’ quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 and SF-36) scores had not changed after 3 months. Conclusions PT may be a relatively safe treatment for NSCLC patients with IP, without deteriorating quality of life scores within 3 months.

Aim: To evaluate sorafenib treatment in Latin American patients with unresectable hepatocellular carcinoma in the real-world GIDEON study. Patients & methods: Sorafenib administration, safety and efficacy were analyzed by Child–Pugh status. Results: Of 90 evaluable patients (37% Child–Pugh A, 46% Child–Pugh B and 3% Child–Pugh C at study entry), 97% started sorafenib at 800 mg/day. Patients with Child–Pugh B7 had the longest median treatment duration of sorafenib (33.1 weeks). Sorafenib-related adverse events occurred in 58% of patients with Child–Pugh A (21% grade 3/4) and 46% with Child–Pugh B (7% grade 3/4). Conclusion: Sorafenib had a similar safety profile across patients with Child–Pugh A and B and is a treatment option for both groups.

Background To compare the feasibility of transrectal and transperineal fiducial marker placement for prostate cancer before proton therapy. Materials and Methods From 2013 to 2015, the first 40 prostate cancer patients that were scheduled for proton therapy underwent transrectal fiducial marker placement, and the next 40 patients underwent transperineal fiducial marker placement (the first series). Technical and clinical success and pain scores were evaluated. In the second series (n = 280), the transrectal or transperineal approach was selected depending on the presence/absence of comorbidities, such as blood coagulation abnormalities. Seven patients refused to undergo the procedure. Thus, the total number of patients across both series was 353 (262 and 91 underwent the transrectal and transperineal approach, respectively). Technical and clinical success, complications, marker migration and the distance between the two markers were evaluated. Results In the first series, the technical and clinical success rates were 100% in both groups. The transrectal group exhibited lower pain scores than the transperineal group. The overall technical success rates of the transrectal and transperineal groups were 100% (262/262) and 99% (90/91), respectively (P > 0.05). The overall clinical success rate was 100% in both groups, and there were no major complications in either group. The migration rates of the two groups did not differ significantly. The mean distance between the two markers was 25.6 ± 7.1 mm (mean ± standard deviation) in the transrectal group and 31.9 ± 5.2 mm in the transperineal group (P Conclusion Both the transrectal and transperineal fiducial marker placement methods are feasible and safe.

Tractional remodeling of collagen fibrils by fibroblasts requires long cell extensions that mediate fibril alignment. The formation of these cell extensions involves flightless I (FliI), an actin-binding protein that contains a leucine-rich-repeat (LRR), which binds R-ras and may regulate cdc42. We considered that FliI interacts with small GTPases and their regulators to mediate assembly of cell extensions. Mass spectrometry analyses of FliI immunoprecipitates showed abundant Ras GTPase-activating-like protein (IQGAP1), which in immunostained samples colocalized with FliI at cell adhesions. Knockdown of IQGAP1 reduced the numbers of cell extensions and the alignment of collagen fibrils. In experiments using dominant negative mutants, cdc42 activity was required for the formation of short extensions while R-ras was required for the formation of long extensions. Immunoprecipitation of wild-type and mutant constructs showed that IQGAP1 associated with cdc42 and R-ras; this association required the GAP-related domain (1004-1237 aa) of IQGAP1. In cells transfected with FliI mutants, the LRR of FliI, but not its gelsolin-like domains, mediated association with cdc42, R-ras, and IQGAP1. We conclude that FliI interacts with IQGAP1 and co-ordinates with cdc42 and R-ras to control the formation of cell extensions that enable collagen tractional remodeling.

X-ray and gamma-ray photons are widely used for imaging but require a mathematical reconstruction step, known as tomography, to produce cross-sectional images from the measured data. Theoretically, the back-to-back annihilation photons produced by positron–electron annihilation can be directly localized in three-dimensional space using time-of-flight information without tomographic reconstruction; however, this has not yet been demonstrated due to the insufficient timing performance of available radiation detectors. Here we develop techniques based on detecting prompt Cherenkov photons, which, when combined with a convolutional neural network for timing estimation, resulted in an average timing precision of 32 ps, corresponding to a spatial precision of 4.8 mm. We show this is sufficient to produce cross-sectional images of a positron-emitting radionuclide directly from the detected coincident annihilation photons, without using any tomographic reconstruction algorithm. The reconstruction-free imaging demonstrated here directly localizes positron emission and frees the design of an imaging system from the geometric and sampling constraints that are normally present for tomographic reconstruction. Positron emission imaging without tomographic reconstruction is demonstrated. A Cherenkov radiation detector detects gamma rays produced by positron–electron annihilation. The position of a positron source is determined with a precision of 4.8 mm.

BL-774 is a control, data acquisition, and online analysis platform for addressing the requirements in future beamline experiments at SPring-8-II. To date, we have achieved implementations related to “robustness and flexibility” and “configuration management”. These implementations were made possible by the two-phase development workflow. The two-phase development is characterized by a dedicated rapid application development environment that beamline scientists can use rapidly and easily in real beamline environments, and web-based graphical user interfaces that BL-774 software developers have incorporated the achievements of the beamline scientists as part of the official release of the beamline control software. BL-774 has been introduced in two beamlines to date, and we plan to implement it in more beamlines while adding more features. We plan to integrate BL-774 seamlessly with other systems that are currently under development in the facility, such as two-dimensional detector systems and SPring-8 data centers. By introducing BL-774 in conjunction with other infrastructure in the facility, more advanced experimental operations, such as feedback operations based on online data analysis or remote operations from outside the beamlines, are to be expected. This paper presents the design and implementation of BL-774 and its introduction into a beamline at SPring-8.

Coincidence time resolution (CTR) of 10 ps is an ultimate goal toward reconstruction-less positron emission tomography (PET). One of the ways to enhance the timing performance of the PET detector is to make use of Cherenkov photons which is promptly emitted on the order of picosecond. A Cherenkov detector composed of a Cherenkov radiator and a fast photo-detector, such as a microchannel plate photomultiplier tube (MCP-PMT) can reach the CTR better than 100 ps full width at half maximum (FWHM). Previously, we have developed the Cherenkov detector where the Cherenkov radiator is integrated with the MCP-PMT to enhance the timing performance, and the CTR of 41.9 ps FWHM was obtained. In this study, we performed two types of experiments; (1) increasing statistics roughly ten times larger than the previous study to precisely determine the timing performance of the detector, (2) stepping a 22Na point source and validating transitions of timing histograms according to the source positions. As a result, the CTR of 41.7 ps FWHM was obtained. Moreover, the CTR between the radiator and the MCP direct interaction was also investigated and approximately 55 ps FWHM was obtained. The transitions of the timing histograms according to the source positions were successfully observed. Finally, we show physical components affecting the CTR and potential capability toward the ultimate goal of 10 ps CTR is discussed.

To investigate optimal treatment planning using proton beams for non-squamous cell carcinoma of the head and neck (NSCHN), the dose distributions of plans involving pencil beam scanning (PBS) with or without a patient-specific aperture system (PSAS), passive-scattering proton therapy (PSPT) and X-ray intensity-modulated radiotherapy (IMRT) were compared. As clinical results, toxicities of PBS with PSAS, including changes in quality of life, were reported. Between April 2014 and August 2016, a total of 30 patients were treated using PBS with PSAS. In 20 patients selected at random, the dose distributions of PBS with or without the PSAS, PSPT and IMRT plans were compared. Neutron exposure by proton therapy was calculated using a Monte Carlo simulation. Toxicities were scored according to CTCAE ver. 4.0. Patients completed EORTC quality of life survey forms (QLQ-C30 and QLQ-HN35) before and 0–12 months after proton therapy. The 95% conformity number of PBS with the PSAS plan was the best, and significant differences were detected among the four plans (P < 0.05, Bonferroni tests). Neutron generation by PSAS was ~1.1-fold higher, but was within an acceptable level. No grade 3 or higher acute dermatitis was observed. Pain, appetite loss and increased weight loss were more likely at the end of treatment, but recovered by the 3 month follow-up and returned to the pretreatment level at the 12 month follow-up. PBS with PSAS reduced the penumbra and improved dose conformity in the planning target volume. PBS with PSAS was tolerated well for NSCHN.

With the upgradation of detector components, such as scintillators and photodetectors , the PET-image signal-to-noise ratio of time-of-flight positron emission tomography (TOF-PET) systems has been improved, compared to those of ordinary nonTOF-PET systems. A TOF-PET with an ultrahigh time resolution, for example a coincidence time resolution (CTR) better than few tens of picoseconds, can not only improve the image quality, but also remove the image reconstruction process, significantly impacting medical imaging. Therefore, it is crucial to develop a high-time resolution PET detector. We focus on the prompt emission of Cherenkov radiation , owing to the instantaneousness of which, a high time resolution can be expected. One of the candidates for the Cherenkov radiator is lead fluoride (PbF 2 ) due it has excellent properties, including transparency toward the ultraviolet region, high refractive index (n = 1.82), and high density (7.77 g/cm 3). Moreover, it does not contain radioisotopes, unlike lutetium-based scintillators, which are commonly used in the currently available TOF-PET detectors. In this work, we experimentally investigate the timing performance of PbF2-based Cherenkov detectors, breaking down the timing performance into physical components. 3 × 3 × 5 mm3 and 9.6 × 9 . 6 × 5 mm3 PbF2 crystals are used as Cherenkov radiators; both are attached to a microchannel plate photomultiplier tube (MCP-PMT) because the single channel MCP-PMT is one of the best photodetectors in terms of the SPTR, which is 25 ps full width at half maximum (FWHM). All the surfaces, except the end surface where the MCP-PMT is connected, are wrapped in black tape to suppress the reflections of the Cherenkov photons in the crystal. The CTR is measured by placing a detector pair face-to-face, using an 22 Na point source, and an oscilloscope at 20 GS/s with a set bandwidth of 4.2 GHz. A CTR of 46.9 ps FWHM, corresponding to a position resolution of 7.0 mm, is obtained, consistent with our simulation results.

Purpose Suppression of respiratory movement of the liver would be desirable for high-precision radiation therapy for liver tumors. We aimed to investigate the effect of our original device-free compressed shell fixation method and breathing instruction on suppression of respiratory movement. The characteristics of liver motion based on the movement of a fiducial marker were also analyzed. Methods and Materials First, respiratory amplitudes of the liver with the device-free compressed shell were analyzed from the data of 146 patients. The effect of this shell fixing method on liver movement was evaluated. Second, as another cohort study with 166 patients, interfractional internal motion of the liver for patients fixed in the shell was calculated using the fiducial marker coordinate data of images for position setting before daily irradiation. Third, in another 12 patients, intrafractional internal motion was calculated from the fiducial marker coordinate data using x-ray images before and after irradiation. Results The median respiratory movement without the shell, after fixing with the shell, and after instructing on the breathing method with the shell was 14.2 (interquartile range, 10.7-19.8), 11.5 (8.6-17.5), and 10.4 mm (7.3-15.8), respectively. Systematic and random errors of interfractional internal motion were all ≤2 mm in the left-right and anteroposterior directions and 3.7 and 3.0 mm, respectively, in the craniocaudal direction. Systematic and random errors of intrafractional internal motion were all ≤1.3 mm in the left-right and anteroposterior directions and 0.8 and 2.4 mm, respectively, in the craniocaudal direction. Conclusions The device-free compressed shell fixation method was effective in suppressing the respiratory movement of the liver. Irradiation position matching using the fiducial marker can correct the interfractional internal motion on each day, which would contribute to the reduction of the margin to be given around the target.

Background: While Preservation of NAC is concerned to increase the risk of local recurrences in the retroareolar glandular tissue, nipple sparing mastectomy (NSM) is increasing in patients with breast cancer and has been shown to result in better cosmetic outcome and the benefit for quality-of-life. It is necessary to predict accurately NAC involvement in order to select which patients may be candidates to NSM. The distance from the nipple to the tumor (DNT) is proposed as one of the best criteria to select the patient. The purpose of this study is to identify the predictors of NAC involvement retrospectively and to develop a clinical predictive model to select the patients who can be offered preservation of NAC.Methods: A total of 168 patients with primary operable breast cancer who received subcutaneous mastectomy for breast reconstruction at Saitama Medical Center during July 2013 to December 2017 were selected from the hospital's surgical database. NAC involvement was defined by the presence of invasive carcinoma and/or ductal carcinoma in situ at the subareolar margin. Results: Of the 148 patients who were preserved NAC, 89.9% (133/148) were NAC involvement negative and 10.1% (15/148) were positive in permanent pathological specimens. Of the 20 patients who were resected NAC, NAC involvement positivity was only 50.0% (10/20). This revealed that NAC involvement with a sensitivity (SN) of 40.0%, a specificity (SP) of 93.0%, a positive predictive value (PPV) of 50.0% and a negative predictive value (NPV) of 89.9% (AUC=0.665, 95%CI: 0.5345-0.796). In 140 patients who were performed intraoperative sub-nipple frozen section biopsy, the findings was significantly associated with NAC involvement (P Citation Format: Seki H, Sakurai T, Shimizu K, Mizuno S, Tokuda T, Kaburagi T, Seki M, Karahashi T, Nakajima K. A novel nipple aleolar complex involvement predictive index (NACPI) for indicating nipple sparing mastectomy in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-09.

The light yield (LY) and decay kinetics of a single crystal scintillator of Gd 3 Al 2 Ga 3 O12(GAGG):Ce were measured for 0.662 MeV γ - and 5.48 MeV α -rays between −100 °C and room temperature. As the temperature decreased, the LY increased by 20% for γ -rays, reaching its maximum at around −70 °C, and increased monotonously by 50% for α -rays. Both the rise and decay times increased gradually. Furthermore, the results indicate that pulse shape discrimination is most effective at room temperature.

In the CANDLES experiment aiming to search for the very rare neutrino-less double beta decays (0νββ) using 48Ca, we introduced a new shielding system for high energy γ-rays from neutron captures in massive materials near the detector, in addition to the background reduction for 232Th decays in the 0νββ target of CaF2 crystals. The method of background reduction and the performance of newly installed shielding system are described.

We present neutrino-based options for verifying that the nuclear reactors at North Korea's Yongbyon Nuclear Research Center are no longer operating or that they are operating in an agreed manner, precluding weapons production. Neutrino detectors may be a mutually agreeable complement to traditional verification protocols because they do not require access inside reactor buildings, could be installed collaboratively, and provide persistent and specific observations. At Yongbyon, neutrino detectors could passively verify reactor shutdowns or monitor power levels and plutonium contents, all from outside the reactor buildings. The monitoring options presented here build on recent successes in basic particle physics. Following a dedicated design study, these tools could be deployed in as little as one year at a reasonable cost. In North Korea, cooperative deployment of neutrino detectors could help redirect a limited number of scientists and engineers from military applications to peaceful technical work in an international community. Opportunities for scientific collaboration with South Korea are especially strong. We encourage policymakers to consider collaborative neutrino projects within a broader program of action toward stability and security on the Korean Peninsula.

We designed and fabricated a microwave transmitting antenna that uses an HTS thick disk as a patch antenna with a resonant frequency of around 5.0 GHz. The reflection property S 11, electromagnetic fields, current distributions, and far-field of several resonant modes in the antenna were analyzed using the CST studio suite. We compared the properties in several resonance modes and selected the TM11 mode, which has the smallest resonator size and the highest directivity. The antenna was assembled using a GdBCO thick disk, sapphire substrates, Cu housing, and SMA connector. We measured the S 11 using a vector network analyzer and pulse tube refrigerator and found that it had a resonant frequency of 4.996 GHz and a Q u of 405 at the temperature of 48 K. These measured properties were in good agreement with the simulated results.

We developed a CANDLES-III system to study the neutrino-less double beta (0$\nu\beta\beta$) decay of $^{48}$Ca. The proposed system employs 96 CaF$_{2}$ scintillation crystals (305 kg) with natural Ca ($^{\rm nat.}$Ca) isotope which corresponds 350\,g of $^{48}$Ca. External backgrounds were rejected using a 4$\pi$ active shield of a liquid scintillator surrounding the CaF$_2$ crystals. The internal backgrounds caused by the radioactive impurities within the CaF$_2$ crystals can be reduced effectively through analysis of the signal pulse shape. We analyzed the data obtained in the Kamioka underground for a live-time of 130.4\,days to evaluate the feasibility of the low background measurement with the CANDLES-III detector. Using Monte Carlo simulations, we estimated the background rate from the radioactive impurities in the CaF$_{2}$ crystals and the rate of high energy $\gamma$-rays caused by the (n, $\gamma$) reactions induced by environmental neutrons. The expected background rate was in a good agreement with the measured rate, i.e., approximately 10$^{-3}$ events/keV/yr/(kg of $^{\rm nat.}$Ca), in the 0$\nu\beta\beta$ window. In conclusion, the background candidates were estimated properly by comparing the measured energy spectrum with the background simulations. With this measurement method, we performed the first search for 0$\nu\beta\beta$ decay in a low background condition using a detector with a Ca isotope, in which the Ca present was not enriched, in a scale of hundreds of kg. The $^{48}$Ca isotope has a high potential for use in 0$\nu\beta\beta$ decay search, and is expected to be useful for the development of a next-generation detector for highly sensitive measurements.

Purpose/objective(s) Although the PACIFIC trial did not suggest that the administration of durvalumab increased the risk of radiation pneumonitis (RP) compared to placebo, the timing of durvalumab administration following concurrent chemo-radiotherapy was various and the method used to evaluate RP including interstitial pneumonia was unclear. Thus, further studies are needed to better understand the development of immune-related adverse event (irAE), in particular RP. In the present study, we performed a preliminary analysis to investigate RP after concurrent chemo-proton therapy (CCPT) followed by durvalumab. Materials/methods Between October 2018 and March 2020, 17 patients were administered durvalumab (mg/kg, q2w) within 14 days after CCPT (70 GyRBE/35 fractions and cisplatin (60 mg/m2) on day 1 and S-1 (w40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 2 cycles). As a control, 47 patients who underwent CCPT in our previous phase II trial conducted between August 2013 and December 2017 were analyzed. These 47 patients were administered adjuvant chemotherapy (same regimen for up to 2 cycles) after CCPT. In patients suspected to have developed RP as a result of irAE, their treatment plans were compared with CT images obtained at the time of RP onset to examine the association between the dose distribution and RP. Results In our previous study, acute grade 2 RP within 3 months after the end of irradiation was observed in 4 patients (8.5%), and no patients developed grade 3 or higher RP. However, all occurred after completion of adjuvant chemotherapy, that is, within 2-3 months after the end of irradiation. On the other hand, 6 patients developed symptomatic grade 2 RP within 1 month of treatment among 17 patients who were administered durvalumab. Unlike CT findings of RP in the control patients, RP in 6 patients who received durvalumab was identified in the areas that received low-to-medium doses of proton irradiation and/or outside of the irradiation field, whereas the areas that received a high dose of proton irradiation exhibited little to no inflammatory response. In 3 patients who were subsequently administered steroids, CT revealed a rapid decrease in the lung volume and inflammatory response that progressed every week, in addition to traction ectasia and rapid progression of fibrosis. For the remaining 3 patients, the symptoms were mild without fever and improved only by stopping durvalmab without using steroids, and the course of CT images were similar. Conclusion Administration of durvalumab soon after CCPT resulted in the unexpected or unusual course of development of RP, which was likely an irAE. Further studies are needed to better understand the cause of immune-related RP.