Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product.

Circulating Tumor Cells (CTCs), interrogated by sampling blood from patients with cancer, contain multiple analytes, including intact RNA, high molecular weight DNA, proteins, and metabolic markers. However, the clinical utility of tumor cell-based liquid biopsy has been limited since CTCs are very rare, and current technologies cannot process the blood volumes required to isolate a sufficient number of tumor cells for in-depth assays. We previously described a high-throughput microfluidic prototype utilizing high-flow channels and amplification of cell sorting forces through magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from patients with metastatic cancer, with a median of 2,799 CTCs purified per patient. Isolation of many CTCs from individual patients enables characterization of their morphological and molecular heterogeneity, including cell and nuclear size and RNA expression. It also allows robust detection of gene copy number variation, a definitive cancer marker with potential diagnostic applications. High-volume microfluidic enrichment of CTCs constitutes a new dimension in liquid biopsies.

Circulating and Imaging Biomarkers of Radium-223 Response in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Radium-223 improves overall survival (OS) and reduces skeletal events in patients with bone metastatic castration-resistant prostate cancer (CRPC), but relevant biomarkers are lacking. We evaluated automated bone scan index (aBSI) and circulating tumor cell (CTC) analyses as potential biomarkers of prognosis and activity. PATIENTS AND METHODS: Patients with bone metastatic CRPC were enrolled on a prospective single-arm study of standard radium-223. 99mTc-MDP bone scan images at baseline, 2 months, and 6 months were quantitated using aBSI. CTCs at baseline, 1 month, and 2 months were enumerated and assessed for RNA expression of prostate cancer-specific genes using microfluidic enrichment followed by droplet digital polymerase chain reaction. RESULTS: The median OS was 21.3 months in 22 patients. Lower baseline aBSI and minimal change in aBSI (<+0.7) from baseline to 2 months were each associated with better OS (P = .00341 and P = .0139, respectively). The higher baseline CTC count of ≥5 CTC/7.5 mL was associated with worse OS (median, 10.1 v 32.9 months; P = .00568). CTCs declined at 2 months in four of 15 patients with detectable baseline CTCs. Among individual genes in CTCs, baseline expression of the splice variant AR-V7 was significantly associated with worse OS (hazard ratio, 5.20 [95% CI, 1.657 to 16.31]; P = .00195). Baseline detectable AR-V7, higher aBSI, and CTC count ≥5 CTC/7.5 mL continued to have a significant independent negative impact on OS after controlling for prostate-specific antigen or alkaline phosphatase. CONCLUSION: Quantitative bone scan assessment with aBSI and CTC analyses are prognostic markers in patients treated with radium-223. AR-V7 expression in CTCs is a particularly promising prognostic biomarker and warrants validation in larger cohorts.

Predictability alters information flow during action observation in human electrocorticographic activity.

The action observation network (AON) has been extensively studied using short, isolated motor acts. How activity in the network is altered when these isolated acts are embedded in meaningful sequences of actions remains poorly understood. Here we utilized intracranial electrocorticography to characterize how the exchange of information across key nodes of the AON-the precentral, supramarginal, and visual cortices-is affected by such embedding and the resulting predictability. We found more top-down beta oscillation from precentral to supramarginal contacts during the observation of predictable actions in meaningful sequences compared to the same actions in randomized, and hence less predictable, order. In addition, we find that expectations enabled by the embedding lead to a suppression of bottom-up visual responses in the high-gamma range in visual areas. These results, in line with predictive coding, inform how nodes of the AON integrate information to process the actions of others.

Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer.

PURPOSE: There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. EXPERIMENTAL DESIGN: We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation. RESULTS: With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells. CONCLUSIONS: Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts.

Increased toxicities associated with dose escalation of stereotactic body radiation therapy in prostate cancer: results from a phase I/II study.

BACKGROUND: This dose-escalation study evaluated the toxicity and efficacy of different stereotactic body radiation therapy (SBRT) doses for selecting an optimal dose for prostatic adenocarcinoma (PCa). MATERIALS AND METHODS: This clinical trial was registered at UMIN (UMIN000014328). Patients with low- or intermediate-risk PCa were equally assigned to 3 SBRT dose levels: 35, 37.5, and 40 Gy per 5 fractions. The primary endpoint was the occurrence rate of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events at 2 years, while the secondary endpoint was the 2-year biochemical relapse-free (bRF) rate. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Seventy-five patients (median age, 70 years) were enrolled from March 2014 to January 2018, of whom 10 (15%) and 65 (85%) had low- and intermediate-risk PCa, respectively. The median follow-up time was 48 months. Twelve (16%) patients received neoadjuvant androgen deprivation therapy. The 2-year occurrence rates of grade 2 late GU and GI toxicities were 34 and 7% in all cohorts, respectively (35 Gy: 21 and 4%; 37.5 Gy: 40 and 14%; 40 Gy: 42 and 5%). The occurrence risk of GU toxicities significantly increased with dose escalation (p = 0.0256). Grades 2 and 3 acute GU toxicities were observed in 19 (25%) and 1 (1%), respectively. Grade 2 acute GI toxicity was observed in 8 (11%) patients. No grade ≥3 GI or ≥4 GU acute toxicity or grade ≥3 late toxicity was observed. Clinical recurrence was detected in 2 patients. CONCLUSIONS: An SBRT dose of 35 Gy per 5 fractions is less likely to cause adverse events in patients with PCa than 375- and 40-Gy SBRT doses. Higher doses of SBRT should be applied with caution.

Dosimetric comparison between volumetric modulated arc therapy planning techniques for prostate cancer in the presence of intrafractional organ deformation.

The purpose of this study was to compare single-arc (SA) and double-arc (DA) treatment plans, which are planning techniques often used in prostate cancer volumetric modulated arc therapy (VMAT), in the presence of intrafractional deformation (ID) to determine which technique is superior in terms of target dose coverage and sparing of the organs at risk (OARs). SA and DA plans were created for 27 patients with localized prostate cancer. ID was introduced to the clinical target volume (CTV), rectum and bladder to obtain blurred dose distributions using an in-house software. ID was based on the motion probability function of each structure voxel and the intrafractional motion of the respective organs. From the resultant blurred dose distributions of SA and DA plans, various parameters, including the tumor control probability, normal tissue complication probability, homogeneity index, conformity index, modulation complexity score for VMAT, dose-volume indices and monitor units (MUs), were evaluated to compare the two techniques. Statistical analysis showed that most CTV and rectum parameters were significantly larger for SA plans than for DA plans (P < 0.05). Furthermore, SA plans had fewer MUs and were less complex (P < 0.05). The significant differences observed had no clinical significance, indicating that both plans are comparable in terms of target and OAR dosimetry when ID is considered. The use of SA plans is recommended for prostate cancer VMAT because they can be delivered in shorter treatment times than DA plans, and therefore benefit the patients.

Radiation Therapy Alone for Human Papillomavirus-Related Squamous Cell Carcinoma of the Oropharynx: A Single-Arm, Phase 2 Study.

PURPOSE: Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OPSCC) is extremely radiosensitive. Radiation therapy plus high-dose cisplatin remains the standard of care but causes long-term toxicity. Treatment deintensification approaches that reduce toxicity while maintaining survival are desirable for HPV-related OPSCC. METHODS AND MATERIALS: We conducted a single-arm, multicenter, phase 2 trial. Patients with newly diagnosed, biopsy-proven, American Joint Committee on Cancer (seventh edition) stage III or IV OPSCC positive for both p16 and HPV DNA were eligible. Patients with T4, N3, or T1N1 disease were excluded. Smoking history was not included in eligibility criteria. Patients received intensity modulated radiation therapy (IMRT) of 70 Gy in 35 fractions or 70.4 Gy in 32 fractions without chemotherapy. The primary endpoint was complete response or complete metabolic response 10 weeks after IMRT completion. RESULTS: Between September 13, 2013, and November 15, 2016, 39 patients were enrolled according to a 2-stage Simon design. Twenty-three patients (59%) had smoked for more than10 pack-years. Thirty-six patients (92%) had tumors genotyped as HPV16. Thirty-seven patients (95%) received full-dose radiation therapy and 35 (90%) had complete response or complete metabolic response. Median follow-up was 51 months (interquartile range, 41-63 months). One patient (3%) had regional recurrence and 3 (8%) had distant metastasis. One patient died of disease. The 2-year progression-free survival rate was 94% (95% CI, 81%-99%), and the 2-year overall survival rate was 100%. Common grade 3 adverse events during IMRT included mucositis in 10 patients (26%) and dysphagia in 7 patients (18%). No patients were dependent on a feeding tube at 1 month after IMRT completion. No grade 3 or 4 late adverse events were observed. CONCLUSIONS: IMRT alone is associated with excellent response as well as reduced toxicity and could be a treatment option for carefully selected patients with locally advanced "true" HPV-related OPSCC. Further studies are warranted.

Stereotactic Body Radiotherapy Using CyberKnife® for Localized Low- and Intermediate-risk Prostate Cancer: Initial Report on a Phase I/II Trial.

BACKGROUND: The present study aimed to evaluate the toxicity and efficacy of stereotactic body radiotherapy (SBRT) for localized prostate cancer. PATIENTS AND METHODS: We investigated 25 patients treated with SBRT of 35 Gy per five fractions from May 2014 to March 2015. RESULTS: The median age of patients was 70 years, four (16%) patients were low risk and 21 (84%) were intermediate risk. Seven (28%) patients received neoadjuvant androgen-deprivation therapy. The median follow-up time was 53 months. Grade 2 acute and late genitourinary toxicities were observed in five (20%) and two (8%) patients and there were no Grade 2 gastrointestinal toxicities. There were no Grade 3 or higher acute or late toxicities at 2 years follow-up. The biochemical relapse-free survival rate at 2 years was 100%. CONCLUSION: SBRT of 35 Gy per five fractions is a promising treatment method in the short term for prostate cancer.

Dihydroouabain, a novel radiosensitizer for cervical cancer identified by automated high-throughput screening.

BACKGROUND AND PURPOSE: Radiotherapy plays a crucial role in the treatment of cervical cancer, but existing radiosensitizers have limited efficacy in clinical applications. The aims of this study were to establish and verify an efficient method for identifying new radiosensitizers, to use this to identify candidate radiosensitizers for cervical cancer, and to investigate the specific mechanisms of these when used in combination with radiotherapy. MATERIALS AND METHODS: An automated platform for identifying radiosensitizers for cervical cancer was created based on high-throughput screening technology. The radiosensitizing effects of candidate compounds from the LOPAC1280 chemical library were evaluated in radiosensitive and radioresistant cervical cancer cells using a clonogenic survival assay, with cell cycle analyses, and western blot analyses performed for both cell lines. RESULTS: The automated high-throughput screening approach identified four hit compounds. One of the most potent candidates was dihydroouabain (DHO), an inhibitor of Na+/K+-ATPase that has not previously been classified as a radiosensitizer. DHO significantly enhanced radiosensitivity in cervical cancer cells. It also abrogated radiation-induced S phase arrest in cervical cancer cells. Combination treatment significantly caused the inhibition of Chk1 and increased DNA double-strand breaks (DSB). CONCLUSIONS: DHO is a novel radiosensitizer for the treatment of cervical cancer. The automated high-throughput screening platform developed in this study proved to be powerful and effective, with the potential to be widely used in the future identification of radiosensitizers.

Assessment of Daily Replanning and Geometrical Variation of High-dose-rate Brachytherapy for the Prostate.

BACKGROUND: The present study aimed to estimate geometric changes in applicators and prostate over 3 days in patients with high-dose-rate brachytherapy (HDR-BT) and to assess the need for daily replanning. PATIENTS AND METHODS: This study retrospectively investigated 18 patients who underwent HDR-BT as monotherapy from February 2016 to October 2018. RESULTS: Without replanning, the planning target volume coverage significantly worsened on day 2 (p<0.001) and day 3 (p=0.003). The minimum dose distributed to the highest irradiated rectal volume of 5 cc became significantly higher on day 2 (p=0.02), and the maximum dose distributed to the urethra became significantly higher on day 2 (p=0.01). CONCLUSION: Conformal, high-dose delivery of HDR-BT is impaired without replanning not only on the second day but also on the third day. Daily replanning is required for achieving accuracy of HDR-BT.

The short-term outcomes of pulmonary metastasectomy or stereotactic body radiation therapy for pulmonary metastasis from epithelial tumors.

BACKGROUND: Stereotactic body radiation therapy (SBRT) has recently been widely performed for relatively small-volume tumors. We analyzed the short-term outcomes of pulmonary metastasectomy (PM) or SBRT for pulmonary metastases. METHODS: This study was a retrospective analysis of 82 patients with pulmonary metastasis from epithelial tumors who underwent PM or SBRT between 2013 and 2016. RESULTS: Fifty-nine patients underwent PM, 21 patients underwent SBRT, and 2 patients underwent combined PM and SBRT. The mean age of the PM group was significantly lower than that of the SBRT group (60.6 vs 67.4 years, p = 0.03). The most frequent types of primary tumor in the PM and SBRT groups were colorectal cancer (n = 27, 46%) and head and neck squamous cell carcinoma (n = 8, 38%), respectively. The rate of treatment-associated complications did not differ between the two groups to a statistically significant extent (20% vs 24%, p = 0.76). The 3-year local control rates of the two groups were similar (PM group, 88%; SBRT group, 92%; p = 0.48). The 3-year progression-free survival (PFS) rate of the PM group were better than that of SBRT groups (42% vs 11%, p = 0.01). The 3-year overall survival (OS) rates of the PM and SBRT groups were 77 and 52% respectively; although the rate of the PM group was higher, the difference was not statistically significant (p = 0.10). CONCLUSIONS: SBRT provides a favorable 3-year local control rate. The 3-year OS rate of the SBRT group tended to be lower than that of the PM group, despite the difference was not statistically significant. PM and SBRT play complementary roles in patients with pulmonary metastases.

Ro 90-7501 Is a Novel Radiosensitizer for Cervical Cancer Cells that Inhibits ATM Phosphorylation.

BACKGROUND/AIM: Ro 90-7501 has been reported as an inhibitor of the amyloid ß42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. MATERIALS AND METHODS: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. RESULTS: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. CONCLUSION: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.

Feasibility of virtual starshot analysis providing submillimeter radiation isocenter accuracy: A long-term multi-institutional analysis.

PURPOSE: We developed a technique to calculate the offset between room lasers and the radiation isocenter using a digital Winston-Lutz (WL) test with a starshot technique. We have performed isocenter localization quality assurance (QA) with submillimeter accuracy for a long period. Here we evaluated the feasibility and accuracy of this virtual starshot (VS) analysis for isocenter localization QA. METHODS: A 6-MV photon beam with a square multileaf collimator field was used to irradiate a WL sphere positioned at the intersection of the room lasers. Images were acquired using an electronic portal imaging device. A four-field WL test was performed, and the path of each beam was calculated from the offset between the beam and sphere. Virtual starshot analysis was used to analyze the radiation isocenter, which calculates the center of the beam paths by using a least-squares method, similar to the starshot analysis. Then, eight coplanar and 12 noncoplanar beams were irradiated to evaluate isocenter localization accuracy. RESULTS: Several VS analyses, using different WL spheres, were performed at three institutions, and the calculated accuracies were within 0.1 mm at all institutions. Long-term analysis showed that the isocenter localization accuracy was appropriately managed with three-dimensional accuracy within ± 0.5 mm for 90 months after the first laser adjustments. The offset between each beam and the room laser was within 0.6 mm and within 1.0 mm for eight coplanar and 12 noncoplanar beams, respectively, for 90 months. Cone-beam computed tomography images, acquired after verification beams, showed that the offset between the radiation isocenter and the imaging center was within 0.66 mm for 90 months. The isocenter localization accuracy within 1 mm was kept for long period at other four institutions. CONCLUSIONS: Long-term analysis showed the feasibility of VS analysis for isocenter localization QA, including room laser re-alignment, noncoplanar irradiation verification, and image guidance accuracy.

Feasibility of Salvage Re-irradiation With Stereotactic Radiotherapy for Recurrent Glioma Using CyberKnife.

AIM: To evaluate the toxicity and efficacy of re-irradiation with salvage stereotactic radiotherapy (SRT) for recurrent glioma using CyberKnife. PATIENTS AND METHODS: This study retrospectively investigated 35 patients with 48 recurrent grade 2-4 gliomas who received SRT between 1998 and 2011. Six patients (17.1%) had grade 2 gliomas, nine (25.7%) had grade 3 gliomas, and 20 (57.1%) had glioblastomas; all initially underwent surgery and conventional radiotherapy. The median initial and subsequent radiotherapy doses were 60 and 26 Gy, respectively. RESULTS: After a median follow-up period of 9.0 months, the only toxicity of grade 2 or more was radiation-induced brain necrosis in four patients (11.4%). The median overall and progression-free survival periods following re-irradiation were 9.0 and 3.0 months, respectively. Univariate analysis revealed that performance status at salvage re-irradiation was a significant predictor of progression-free survival. CONCLUSION: Salvage re-irradiation using CyberKnife is feasible, with an acceptable toxicity profile, for patients with recurrent glioma.

Influence of transitioning of planning techniques in high-dose-rate brachytherapy monotherapy for clinically localized prostate cancer from two- to three-dimensional planning.

PURPOSE: The purpose of this study was to examine the influence of transitioning treatment planning techniques in high-dose-rate interstitial brachytherapy monotherapy for localized prostate cancer. METHODS AND MATERIALS: We compared 113 patients treated with initial two-dimensional treatment planning (2D: 74% received 54 Gy/nine fractions) to 240 patients treated with three-dimensional planning (3D: 70 CT image-guided 3D [CT-3D]: 84% 45.5 Gy/seven fractions and 170 MRI image-guided [MRI-3D]: 87% received 49 Gy/nine fractions). RESULTS: The actuarial 5-year biochemical failure-free survival rates for 2D and 3D planning were 88.4% and 95.1% (p = 0.0285 between 2D and 3D) (89.4% in CT-3D and 97.5% in MRI-3D), respectively; the rates for 2D and 3D planning were not available and 100% in the low-risk group (100% and 100%), 97.7% and 94.5% (p = 0.7626) (85.1% and 100%) in the intermediate-risk group, and 82.5% and 94.4% (p = 0.0507) (93.8% and 94.7%) for the high-risk group. Late gastrointestinal (GI) toxicity Grade 1, Grade 2, and Grade 3 was found in 13%, 4%, and 1% in 2D, whereas 8%, 2%, and 0% in 3D group (p = 0.0699), respectively. 3D decreased GI toxicity Grade 2 ≤ than 2D (19% and 10%, p = 0.0169). Late genitourinary toxicity Grade 1, Grade 2, and Grade 3 was 21%, 12%, and 3% for 2D and 32%, 18%, and 3% for 3D, respectively (p = 0.0217). CONCLUSIONS: The 3D technique has the potential to reduce GI toxicity and improve biochemical control rate compared to 2D planning, whereas 3D resulted in increased mild genitourinary toxicity.

Impacts of respiratory phase shifts on motion-tracking accuracy of the CyberKnife Synchrony™ Respiratory Tracking System.

PURPOSE: The SynchronyTM Respiratory Tracking System (SRTS) component of the CyberKnife® Robotic Radiosurgery System (Accuray, Inc., Sunnyvale CA) enables real-time tracking of moving targets by modeling the correlation between the targets and external surrogate light-emitting diode (LED) markers placed on the patient's chest. Previous studies reported some cases with respiratory phase shifts between lung tumor and chest wall motions. In this study, the impacts of respiratory phase shifts on the motion-tracking accuracy of the SRTS were investigated. METHODS: A plastic scintillator was used to detect the position of the x-ray beams. The scintillation light was recorded using a camera in a dark room. A moving phantom moved a U-shaped frame on the scintillator with a 4th power of sinusoidal functions. Three metallic markers for motion tracking and four fluorescent tapes were attached to the frame. The fluorescent tapes were used to identify phantom position and respiratory phase for each video frame. The beam positions collected, when considered relative to the phantom motion, represent the degree of tracking error. Beam position was calculated by adding error value to phantom position. Motions with respiratory phase shifts between the target and an extra stage mimicking chest wall motion were also tested for LED markers. Log files of the SRTS were analyzed to evaluate correlation errors. RESULTS: When target and LED marker motions were synchronized with a respiratory cycle of 4 s, the maximum tracking errors for 90% and 95% of beam-on time were 1.0 mm and 1.2 mm, respectively. The frequency of tracking errors increased when LED marker motion phase preceded target motion. Tracking errors that corresponded to 90% beam-on time were within 2.4 mm for 5-15% of phase shifts. In contrast, the tracking errors were very large when the LED marker delayed to the target motions; the maximum errors of 90% beam-on time were 3.0, 3.8, and 7.5 mm for 5%, 10%, and 15% of phase shifts, respectively. The patterns of the tracking errors derived from the scintillation light were very similar to those of the correlation data of the SRTS derived from the log files, indicating that the tracking errors caused mainly due to the errors in modeling the correlation data. With long respiratory cycle of 6 s, the tracking errors were significantly decreased; the maximum tracking errors for 95% beam-on time were 1.6 mm and 2.2 mm for early and delayed LED motion. CONCLUSION: We have investigated the motion-tracking accuracy of the CyberKnife SRTS for cases with the respiratory phase shift between the target and the LED marker. The maximum tracking errors for 90% probability were within 2.4 mm when the target delays to the LED markers. When LED marker delays, however, very large tracking errors were observed. With a long respiratory cycle, the tracking errors were greatly improved to less than 2.2 mm. Coaching slow breathing will be useful for accurate motion tracking radiotherapy.

Effect of Androgen Deprivation Therapy on Other-Cause of Mortality in Elderly Patients with Clinically Localized Prostate Cancer Treated with Modern Radiotherapy: Is There a Negative Impact?

The influence of androgen deprivation therapy (ADT) on other-cause of mortality (OCM) was investigated in patients with localized prostate cancer treated with modern high-dose radiotherapy. A retrospective review was conducted on 1125 patients with localized prostate cancer treated with high-dose radiotherapy, including image-guided, intensity-modulated radiotherapy or brachytherapy with a median follow-up of 80.7 months. Overall survival rate was no different between ADT (+) and ADT (-) group in high-, intermediate-, and low-risk groups. OCM was found in 71 patients, consisting of 4% (10/258) in the ADT (-) group and 7% (61/858) in the ADT (+) group (p = 0.0422). The 10-year OCM-free survival rate (OCMFS), if divided by the duration of ADT (ADT naïve (ADT (-)), ADT <2-year, and ADT ≥2-year groups), showed statistical significance, and was 90.7%, 88.2%, and 78.6% (p = 0.0039) for the ADT (-), ADT <2-year, and ADT ≥2-year groups, respectively. In patients aged ≥75 years, 10-year OCMFS for ADT (-), ADT <2-, and ADT ≥2-year groups was 93.5% (at 115.6 months), 85.6%, and 60.7% (p = 0.0189), respectively, whereas it was 90.7%, 89.9%, and 89.0% (p = 0.4716), respectively, in their younger counterparts. In localized prostate cancer patients, treatment with longer ADT for ≥2 years potentially increases the risk of OCM, especially in patients aged ≥75 years.

Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma.

Carbon ion radiotherapy has been utilized even for X-ray resistant tumors. However, control of distant metastasis remains a major challenge in carbon ion irradiation. We investigated whether carbon ion irradiation combined with dual immune checkpoint blockade therapy (anti-PD-L1 and anti-CTLA-4 antibodies [P1C4]) provides anti-tumor efficacy for both local and distant sites. A mouse osteosarcoma cell line (LM8) was inoculated into both hind legs of C3H mice assigned to four groups: no treatment (NoTX), P1C4, 5.3 Gy of carbon ion irradiation to one leg (Cion), and combination (Comb) groups. In the Comb group, tumor growth delay was observed not only in the irradiated tumors but also in the unirradiated tumors. Notably, a complete response of unirradiated tumors was observed in 64% of mice in the Comb group, while only 20% of mice in the P1C4 group showed a complete response. Significant activation of immune cells was observed in the Comb group, with an increase in CD8+/GzmB+ tumor-infiltrating lymphocytes (TILs) in the irradiated tumor, and of CD8+/GzmB+ and CD4+ TILs in the unirradiated tumor, respectively. Depletion of CD8 abolished the tumor growth delay in unirradiated tumors in mice treated by Cion and P1C4. Overall survival was significantly prolonged in the Comb group. HMGB-1 release from irradiated tumors was significantly increased after Cion both in vitro and in vivo. These data suggest that carbon ion therapy enhances P1C4 efficacy against osteosarcoma in both the primary tumor and distant metastases mediated by immune activation.

Comparison of gamma index based on dosimetric error and clinically relevant dose-volume index based on three-dimensional dose prediction in breast intensity-modulated radiation therapy.

BACKGROUND: Measurement-guided dose reconstruction has lately attracted significant attention because it can predict the delivered patient dose distribution. Although the treatment planning system (TPS) uses sophisticated algorithm to calculate the dose distribution, the calculation accuracy depends on the particular TPS used. This study aimed to investigate the relationship between the gamma passing rate (GPR) and the clinically relevant dose-volume index based on the predicted 3D patient dose distribution derived from two TPSs (XiO, RayStation). METHODS: Twenty-one breast intensity-modulated radiation therapy plans were inversely optimized using XiO. With the same plans, both TPSs calculated the planned dose distribution. We conducted per-beam measurements on the coronal plane using a 2D array detector and analyzed the difference in 2D GPRs between the measured and planned doses by commercial software. Using in-house software, we calculated the predicted 3D patient dose distribution and derived the predicted 3D GPR, the predicted per-organ 3D GPR, and the predicted clinically relevant dose-volume indices [dose-volume histogram metrics and the value of the tumor-control probability/normal tissue complication probability of the planning target volume and organs at risk]. The results derived from XiO were compared with those from RayStation. RESULTS: While the mean 2D GPRs derived from both TPSs were 98.1% (XiO) and 100% (RayStation), the mean predicted 3D GPRs of ipsilateral lung (73.3% [XiO] and 85.9% [RayStation]; p < 0.001) had no correlation with 2D GPRs under the 3% global/3 mm criterion. Besides, this significant difference in terms of referenced TPS between XiO and RayStation could be explained by the fact that the error of predicted V5Gy of ipsilateral lung derived from XiO (29.6%) was significantly larger than that derived from RayStation (- 0.2%; p < 0.001). CONCLUSIONS: GPR is useful as a patient quality assurance to detect dosimetric errors; however, it does not necessarily contain detailed information on errors. Using the predicted clinically relevant dose-volume indices, the clinical interpretation of dosimetric errors can be obtained. We conclude that a clinically relevant dose-volume index based on the predicted 3D patient dose distribution could add to the clinical and biological considerations in the GPR, if we can guarantee the dose calculation accuracy of referenced TPS.

Radiotherapy alone as a possible de-intensified treatment for human papillomavirus-related locally advanced oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is defined by p16 positivity and/or HPV DNA positivity. Because survival of patients with HPV-related OPSCC after chemoradiotherapy is favorable, a de-intensified treatment is expected to lead to less morbidity while maintaining low mortality. The association of tumor p16 and HPV DNA status with survival after radiotherapy alone remains unknown. METHODS: We retrospectively examined survival of 107 patients with locally advanced OPSCC after radiotherapy alone (n = 43) or chemoradiotherapy (n = 64) with respect to tumor p16 and HPV DNA status, using Cox's proportional hazard model. RESULTS: Survival after radiotherapy alone was significantly worse in p16-positive/HPV DNA-negative locally advanced OPSCC than in p16-positive/HPV DNA-positive locally advanced OPSCC. In bivariable analyses that included T category, N category, TNM stage, and smoking history, the survival disadvantage of p16-positive/HPV DNA-negative locally advanced OPSCC remained significant. There was no significant difference in survival after chemoradiotherapy between p16-positive/HPV DNA-positive locally advanced OPSCC and p16-positive/HPV DNA-negative locally advanced OPSCC. Survival in p16-positive/HPV DNA-positive locally advanced OPSCC after radiotherapy alone was similar to that after chemoradiotherapy, which stayed unchanged in bivariable analyses after adjustment of every other covariable. Survival of p16-negative/HPV DNA-negative locally advanced OPSCC was poor irrespective of treatment modality. CONCLUSIONS: Survival in p16-positive locally advanced OPSCC differs depending on HPV DNA status. Radiotherapy alone can serve as a de-intensified treatment for p16-positive/HPV DNA-positive locally advanced OPSCC, but not for p16-positive/HPV DNA-negative locally advanced OPSCC.