Real-time gated proton therapy with a reduced source to imager distance: Commissioning and quality assurance.

INTRODUCTION: Real-time gated proton therapy (RGPT) is a motion management technique unique to the Hitachi particle therapy system. It uses pulsed fluoroscopy to track an implanted fiducial marker. There are currently no published guidelines on how to conduct the commissioning and quality assurance. In this work we reported on our centre's commissioning workflow and our daily and monthly QA procedures. METHODS: Six commissioning measurements were designed for RGPT. The measurements include imaging qualities, fluoroscopic exposures, RGPT marker tracking accuracy, temporal gating latency, fiducial marker tracking fidelity and an end-to-end proton dosimetry measurement. Daily QA consists of one measurement on marker localization accuracy. Four months daily QA trends are presented. Monthly QA consists of three measurementson the gating latency, fluoroscopy imaging quality and dosimetry verification of gating operation with RGPT. RESULTS: The RGPT was successfully commissioned in our centre. The air kerma rates were within 15 % from specifications and the marker tracking accuracies were within 0.245 mm. The gating latencies for turning the proton beam on and off were 119.5 and 50.0 ms respectively. The 0.4x10.0 mm2 Gold AnchorTM gave the best tracking results with visibility up to 30 g/cm2. Gamma analysis showed that dose distribution of a moving and static detectors had a passing rate of more than 95 % at 3 %/3mm. The daily marker localization QA results were all less than 0.2 mm. CONCLUSION: This work could serve as a good reference for other upcoming Hitachi particle therapy centres who are interested to use RGPT as their motion management solution.

Repurposing DailyQA3 for an efficient and spot position sensitive daily quality assurance tool for proton therapy.

INTRODUCTION: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3. METHODS: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented. RESULTS: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries. CONCLUSION: With the proposed approach, we can perform four QA items in the TG224 within 10 min.

Pulsed low-dose rate radiotherapy for recurrent bone sarcomas: case reports and brief review.

PURPOSE: Re-irradiation for bulky recurrent sarcoma carries significant risks. Pulsed low-dose rate radiotherapy (PLDR) is an attractive option for re-irradiation due to inherent radiobiological advantages. MATERIALS AND METHODS: We present two patients who underwent reirradiation using PLDR technique, followed by a literature review. RESULTS: The first case is that of a 76-year-old male who developed an in-field recurrence of a bulky pelvic bone high-grade chondrosarcoma after he was treated with definitive radiotherapy using helical TomoTherapy with a total dose of 66 Gy. The patient was re-irradiated using PLDR with a shrinking field technique; 50 Gy in 2 Gy fractions followed by a boost of 20 Gy in 2 Gy fractions. The patient remains disease-free without significant toxicity 60 months post-irradiation. The second case is that of an 82-year-old female who was treated with a definitive irradiation of 66 Gy in 33 fractions for a right shoulder grade II chondrosarcoma. She developed an in-field recurrence 28 months later and presented with bulky disease causing brachial plexopathy and lymphedema. The patient was re-irradiated with a palliative intent to a total dose of 50 Gy in 2 Gy fractions over 5 weeks using PLDR. Brachial plexopathy resolved shortly after re-irradiation, but local progression near the surface was evident 8 months later. She passed away from unrelated causes 11 months later. CONCLUSION: We present two cases highlighting our early experience with PLDR, which was effective in the reirradiation of recurrent bony sarcoma. Our study highlights PLDR as an option for reirradiation in recurrent unresectable tumors.

First clinical experience following the consensus guide for calibrating a proton stopping power ratio curve in a new proton centre.

BACKGROUND AND PURPOSE: This work introduces the first assessment of CT calibration following the ESTRO's consensus guidelines and validating the HLUT through the irradiation of biological material. METHODS: Two electron density phantoms were scanned with two CT scanners using two CT scan energies. The stopping power ratio (SPR) and mass density (MD) HLUTs for different CT scan energies were derived using Schneider's and ESTRO's methods. The comparison metric in this work is based on the Water-Equivalent Thickness (WET) difference between the treatment planning system and biological irradiation measurement. The SPR HLUTs were compared between the two calibration methods. To assess the accuracy of using MD HLUT for dose calculation in the treatment planning system, MD vs SPR HLUT was compared. Lastly, the feasibility of using a single SPR HLUT to replace two different energy CT scans was explored. RESULTS: The results show a WET difference of less than 3.5% except for the result in the Bone region between Schneider's and ESTRO's methods. Comparing MD and SPR HLUT, the results from MD HLUT show less than a 3.5% difference except for the Bone region. However, the SPR HLUT shows a lower mean absolute percentage difference as compared to MD HLUT between the measured and calculated WET difference. Lastly, it is possible to use a single SPR HLUT for two different CT scan energies since both WET differences are within 3.5%. CONCLUSION: This is the first report on calibrating an HLUT following the ESTRO's guidelines. While our result shows incremental improvement in range uncertainty using the ESTRO's guideline, the prescriptional approach of the guideline does promote harmonization of CT calibration protocols between different centres.

US state laws on medical freedom and investigational stem cell procedures: a call to focus on state-based legislation.

The premature marketing of investigational stem cell interventions (SCIs) is a growing market in the US. Several US states have passed legislation to permit and promote unproven and experimental SCIs for individuals with terminal or chronic diseases. These SCI medical freedom laws, which are largely based on right-to-try legislation, increase access to experimental SCIs with little to no oversight. They undermine federal regulatory authority and can compromise patient safety and informed decision-making. SCI medical freedom laws have gone largely unnoticed by scientific societies interested in the responsible translation of stem cell medicine. In this article, we analyze state SCI medical freedom laws and describe their detrimental impact on patients and society. We contend that scientific and medical societies are uniquely poised to advocate against state-based policy promoting unproven SCIs but recognize resource and other constraints to advocate for or against legislation in 50 states. We recommend societies establish coalitions and share resources to address state-based SCI medical freedom laws and other legislation surrounding unproven SCIs.

Implementing dispersion measurement as part of scanning proton therapy commissioning and quality assurance.

Introduction. Dispersion in an accelerator quantifies the deviation of the proton trajectory when there is a momentum deviation. We present for the first time a safe method of measuring dispersion in the clinic, using a scintillator detector and the momentum deviations within a spill. This is an important accelerator quantity as we found that this is the reason behind the large dose fluctuation in our absolute dosimetry measurement.Methods. Dispersions are measured for nine energies in a Hitachi ProBeat system at three locations (isocenter and at two profile monitors) and at two gantry angles (0 and 90 degrees) by first measuring the spot position and momentum drift within a spill. The spot position drift is measured by the XRV-4000 at the isocenter, and by the two profile monitors located at 0.57 and 2.27 m from the isocenter. The momentum drift is calculated from the intra-spill range drift which is measured using the Ranger accessory. The dispersion at isocenter and its gradient are calculated using the weighted least square regression on the measured dispersions at the three locations. A constraint is formulated on the dispersion and its gradient to ensure minimal intra-spill spot position deviation around the isocenter.Results. The measured intra-spill range and spot positional drift at isocenter are less than0.25mmand0.7mmrespectively. The momentum spread calculated from the range drift are less than 0.08%. The dispersion at the isocenter ranged from0.50to4.30mand the zero-crossing happens upstream of isocenter for all energies. 2 of the 9 energies (168.0 and 187.5 MeV) violated the constraint and has an intra-spill spot positional deviation greater than1.0within5cmfrom the isocenter.Conclusion. This measurement is recommended as part of commissioning and annual quality assurance for accelerator monitoring and to ensure intra-spill spot deviations remain low.

Designing persuasive health education for patients seeking unproven stem cell interventions.

Misinformation among clinics advertising unproven stem cell interventions (SCIs) is pervasive and has resulted in patient and societal harms. Most bioethics commentaries have centered on advancing regulatory approaches to curtail the supply side of the market, but insufficient attention has been paid to considering strategies influencing patient demand. In this article, we offer an ethical justification for the design and deployment of persuasive patient education on unproven SCIs and distinguish it from didactic and manipulative education frames. Persuasive education should aim to correct and inoculate against misinformation about unproven SCIs and instill a sense of caution among patients considering experimental interventions outside of a clinical trial. We outline various communication strategies to effectively correct or inoculate against SCI misinformation. The stem cell community needs to invest in understanding patients' informational sources, attitudes, and beliefs about SCIs to develop and implement evidence-based persuasive education to promote informed decision-making about these therapies.

The effect of spill change on reliable absolute dosimetry in a synchrotron proton spot scanning system.

BACKGROUND: Absolute dosimetry measurement is an integral part of Treatment Planning System (TPS) commissioning and it involves measuring the integrated absorbed dose to water for all energies in a pencil beam scanning delivery system. During the commissioning of Singapore's first proton therapy center, a uniform scanned field with an Advanced Markus chamber method was employed for this measurement, and a large dose fluctuation of at least 5% was observed for 10% of the energy layers during repeated measurements. PURPOSE: This study aims to understand the root cause of this fluctuation by relating the actual delivered spot information in the log file with the charge measurement by the ion chambers. METHODS: A dedicated pencil beam dose algorithm was developed, taking into account the log file parameters, to calculate the dose for a single energy layer in a homogeneous water phantom. Three energies, 70.2, 182.7, and 228.7 MeV were used in this study, with the 182.7 MeV energy exhibiting large dose fluctuation. The dose fluctuation was investigated as a function of detector's sizes (pinpoint 3D, Advanced Markus, PTW 34070, and PTW 34089) and water depth (2 , 6, and 20 cm). Twelve ion chambers measurements were performed for each chamber and depth. The comparison of the theoretically predicted integrated dose and the charge measurement served as a validation of the algorithm. RESULTS: About 5.9% and 9.6% dose fluctuation were observed in Advanced Markus and pinpoint 3D measurements at 2 cm depth for 182.7 MeV, while fluctuation of 1.6% and 1.1% were observed in Advanced Markus with 228.7 and 70.2 MeV at similar depth. Fluctuation of less than 0.1% was observed for PTW34070 and PTW 34089 for all energies. The fluctuation was found to diminish with larger spot size at 20 cm depth to 1.3% for 182.7 MeV. The theoretical and measured charge comparison showed a high linear correlation of R 2 > 0.80 ${R^2} > 0.80$ for all datasets, indicating the fluctuation originated from the delivered spot characteristics. The cause of fluctuation was identified to be due to the spill change occurring close to the detector, and since the spot positional deviation profiles were different between two spills, this resulted in local hot spots between columns of spots. The actual position of spill change varies randomly during measurement, which led to a random occurrence of hot spot within the detector's sensitive volume and a fluctuating dose measurement. CONCLUSION: This is the first report of a dose fluctuation greater than 5% in absolute dosimetry measurement with a uniform scanned field and the cause of the fluctuation has been conclusively determined. It is important to choose the MU and scanning pattern carefully to avoid spill change happening when the spot delivery is near the detector.

ISSCR Education Committee syllabus and learning guide for enhancing stem cell literacy.

The rapidly evolving stem cell field puts much stress on developing educational resources. The ISSCR Education Committee has created a flexible stem cell syllabus rooted in core concepts to facilitate stem cell literacy. The free syllabus will be updated regularly to maintain accuracy and relevance.

The two-bucket problem of unproven stem cell interventions.

The two-bucket problem of unproven stem cell interventions (SCIs) continues to bifurcate good (ethical) from bad (unethical) practices in the translation of stem cell medicine in ways that divert attention from other salient and challenging questions. It causes scholars to focus narrowly on reprimanding bad actors through legal and regulatory approaches and distracts from other important considerations such as how best to balance evidence with unmet patient needs and address misinformation about unproven stem cell interventions potentially changing patient behavior. The stem cell science community needs to consider a range of ethical practices and aim to address important questions that have yet not received sufficient consideration.

Prescribing unproven cancer drugs: physician perspectives on expanded access and right to try.

Background: For gravely ill patients who have no treatment options and who are ineligible for clinical trials, the US Food and Drug Administration (FDA) established the Expanded Access Program (EAP). Motivated by efforts to weaken FDA regulation and sold as providing greater access to experimental drugs, the federal Right to Try Act (RTT) was passed in 2017. It reduces FDA oversight by not requiring physicians to report safety data and foregoes approval of protocols by local institutional review boards. Methods: This study explored the views of 17 neuro-oncologists from 15 different academic medical centers with varying experience with EAP and RTT using convenience sampling. We conducted semi-structured interviews and qualitative analysis to identify emerging themes. Results: Most oncologists were confused between the two pathways, had little familiarity with RTT, and had little knowledge about experimental medicine available through either pathway. Oncologists reported a preference of enrolling patients in clinical trials over off-trial preapproval pathways with scant data. As a result, oncologists revealed concerns over properly evaluating risks for their patients. Conclusion: Our findings suggest that neuro-oncologists need better resources and clearer mechanisms at their institutions to help navigate EAP and RTT in order to counsel patients interested in experimental medicine.

The Direct to Consumer Stem Cell Market and the Role of Primary Care Providers in Correcting Misinformation.

INTRODUCTION: Direct to consumer stem cell and regenerative interventions (SCRIs) for various medical conditions have increased in popularity due to unmet medical needs and the promise of SCRIs to meet those needs. These interventions may have varying levels of safety and efficacy data and many lack sufficient scientific data to be marketed. The direct to consumer SCRI industry has received significant attention due to potential physical, economic, and emotional harms to patients. Patients may seek the counsel of their primary care providers when considering stem cell therapy for their condition. METHODS: Here we describe strategies primary care providers can utilize when counseling patients. RESULTS: Although we recommend constructing these discussions around individual patients' needs, one can utilize a general approach consisting of 4 parts. First, providers should recognize what information the patient is seeking and what is their understanding of stem cell and regenerative medicine. Next, providers should convey evidence-based information at the level of patients understanding so that they are aware of the risks, benefits, and descriptions of possible procedures. Throughout the conversations, attempts should be made to guide patients to a trusted resource that can provide additional information. Finally, providers should make an effort to address misinformation in a way that is nonjudgmental and patient-centered to make the patient feel safe and comfortable. CONCLUSION: Effectively communicating risk information by primary care providers to patients is important given the harms reported from direct-to-consumer SCRIs. Correcting misinformation remains a priority when discussing SCRI's. Providers should strive to offer patients with additional resources such as the opportunity for consultation with a specialist or a consultation service dedicated to informing patients about regenerative medicine.

Modern-era radiotherapy and ischaemic heart disease-related mortality outcomes in Asian breast-cancer patients.

Introduction: Left-sided breast-cancer patients treated with adjuvant radiotherapy (RT) before the 1990s were associated with increased risk of cardiac mortality. Modern RT techniques have since improved, resulting in lower radiation doses to the heart. However, concerns regarding cardiac toxicity remain. In a retrospective cohort study, we compare the ischaemic heart disease (IHD)-related mortality of left-sided versus right-sided breast-cancer patients. We present the results of the cardiac mortality and all-cause mortality risk of Asian breast-cancer survivors treated with RT in Singapore. Material and methods: A total of 14,419 Asian women from a single institution were treated for breast cancer from 2000 to 2016. A systematic mortality follow-up was conducted until December 2015. The effect of breast cancer laterality on IHD-related mortality and on overall mortality was investigated. Mean heart doses were recorded for patients from 2010-2016. Results: In the irradiated group (n = 9556), we found no difference in IHD-related mortality or overall mortality when comparing the left- and right-sided breast cancers. The hazard ratio of cardiac mortality for left-sided versus right-sided RT was 0.94 (95% CI: 0.64-1.38). The hazard ratio for all-cause mortality was 1.03 (95% CI: 0.94-1.13). Conclusions: Our study of Asian cancer patients did not reveal a significant increase in the risk of IHD-related mortality or overall mortality comparing left- vs. right-sided breast cancers in modern-era RT.

Patients seeking stem cell therapies-a prospective qualitative analysis from a Regenerative Medicine Consult Service.

Despite patient demand for stem cell therapies (SCTs) for musculoskeletal conditions, there remains limited research on why patients seek SCTs or their sources of information. We employ three questions into a consult intake form: (1) Why are you interested in stem cell treatment for your condition? (2) How did you find out about stem cell treatment for your condition? (3) Have you contacted a stem cell clinic? Responses analyzed, using a qualitative content analysis approach to identify themes reveal many patients seek SCTs to treat pain or delay surgery which may align with some current clinical evidence while other patients express motivations as expected outcomes (e.g., SCTs are better than standard of care or can regenerate tissue) which are not supported by current medical evidence. These differences suggests that patient-centered counseling may help patients by addressing misconceptions and increasing health literacy about expected outcomes of SCTs for treating musculoskeletal conditions.

Application of an automated dose accumulation workflow in high-risk prostate cancer - validation and dose-volume analysis between planned and delivered dose.

Inter-fraction organ variations cause deviations between planned and delivered doses in patients receiving radiotherapy for prostate cancer. This study compared planned (DP) vs accumulated doses (DA) obtained from daily cone-beam computed tomography (CBCT) scans in high-risk- prostate cancer with pelvic lymph nodes irradiation. An intensity-based deformable image registration algorithm used to estimate contours for DA was validated using geometrical agreement between radiation oncologist's and deformable image registration algorithm propagated contours. Spearman rank correlations (rs) between geometric measures and changes in organ volumes were evaluated for 20 cases. Dose-volume (DV) differences between DA and DP were compared (Wilcoxon rank test, p < 0.05). A novel region-of-interest (ROI) method was developed and mean doses were analyzed. Geometrical measures for the prostate and organ-at-risk contours were within clinically acceptable criteria. Inter-group mean (± SD) CBCT volumes for the rectum were larger compared to planning CT (pCT) (51.1 ± 11.3 cm3vs 46.6 ± 16.1 cm3), and were moderately correlated with variations in pCT volumes, rs = 0.663, p < 0.01. Mean rectum DV for DA was higher at V30-40 Gy and lower at V70-75 Gy, p < 0.05. Mean bladder CBCT volumes were smaller compared to pCT (198.8 ± 55 cm3vs 211.5 ± 89.1 cm3), and was moderately correlated with pCT volumes, rs = 0.789, p < 0.01. Bladder DA was higher at V30-65 Gy and lower at V70-75 Gy (p < 0.05). For the ROI method, rectum and bladder DA were lower at 5 to 10 mm (p < 0.01) as compared to DP, whilst bladder DA was higher than DP at 20 to 50 mm (p < 0.01). Generated DA demonstrated significant differences in organ-at-risk doses as compared to DP. A well-constructed workflow incorporating a ROI DV-extraction method has been validated in terms of efficiency and accuracy designed for seamless integration in the clinic to guide future plan adaptation.

Oncologists' reflections on patient rights and access to compassionate use drugs: A qualitative interview study from an academic cancer center.

The U.S. Food and Drug Administration (FDA) allows patients with serious illnesses to access investigational drugs for "compassionate use" outside of clinical trials through expanded access (EA) Programs. The federal Right-to-Try Act created an additional pathway for non-trial access to experimental drugs without institutional review board or FDA approval. This removal of oversight amplifies the responsibility of physicians, but little is known about the role of practicing physicians in non-trial access to investigational drugs. We undertook semi-structured interviews to capture the experiences and opinions of 21 oncologists all with previous EA experience at a major cancer center. We found five main themes. Participants with greater EA experience reported less difficulty accessing drugs through the myriad of administrative processes and drug company reluctance to provide investigational products while newcomers reported administrative hurdles. Oncologists outlined several rationales patients offered when seeking investigational drugs, including those with stronger health literacy and a good scientific rationale versus others who remained skeptical of conventional medicine. Participants reported that most patients had realistic expectations while some had unrealistic optimism. Given the diverse reasons patients sought investigational drugs, four factors-scientific rationale, risk-benefit ratio, functional status of the patient, and patient motivation-influenced oncologists' decisions to request compassionate use drugs. Physicians struggled with a "right-to-try" framing of patient access to experimental drugs, noting instead their own responsibility to protect patients' best interest in the uncertain and risky process of off-protocol access. This study highlights the willingness of oncologists at a major cancer center to pursue non-trial access to experimental treatments for patients while also shedding light on the factors they use when considering such treatment. Our data reveal discrepancies between physicians' sense of patients' expectations and their own internal sense of professional obligation to shepherd a safe process for patients at a vulnerable point in their care.