Safety of high-dose-rate brachytherapy in patients with prostate cancer and inflammatory bowel disease: A case series.

Introduction: Inflammatory bowel disease (IBD) is a relative contraindication to external beam radiation therapy (EBRT) for prostate cancer patients due to fear of increased risk of gastrointestinal (GI) toxicity. High-dose-rate (HDR) brachytherapy, capable of minimizing radiation dose to surrounding tissues, is a feasible alternative. Given limited data, this study examined the safety profile of HDR brachytherapy in this setting. Material and methods: We conducted a retrospective review of patients with localized prostate cancer and IBD treated with HDR brachytherapy at the University of California San Francisco (UCSF), between 2010 and 2022. Eligibility criteria included biopsy-proven prostate cancer, no distant metastases, absence of prior pelvic radiotherapy, IBD diagnosis, and at least one follow-up visit post-treatment. Results: Eleven patients were included, with a median follow-up of 28.7 months. The median dose administered was 2700 cGy (range, 1500-3150 cGy) over 2 fractions (range, 1-3 fractions). Two patients also received EBRT. Rectal spacers (SpaceOAR) were applied in seven patients. All patients experienced acute genitourinary (GU) toxicity, ten of which were grade 1 and one was grade 2. Eight patients experienced late grade 1 GU toxicity, and three patients had late grade 2 GU toxicity. GI toxicities were similarly low-grade, with six grade 1 acute toxicity, no grade 2 or higher acute toxicity, six grade 1 late toxicity, and one late grade 2 GI toxicity. No grade 3 or higher acute or late GI or GU toxicities were reported. Conclusions: HDR brachytherapy appears to be a safe and tolerable treatment modality for patients with prostate cancer and IBD, with minimal acute and late GI and GU toxicity. These findings warrant multi-institutional validation due to small sample size.

Safety of high-dose rate (HDR) brachytherapy for patients with prostate cancer and history of prior chemoradiation for rectal cancer: A case series.

PURPOSE: A history of prior pelvic radiation therapy (RT) for rectal cancer is a relative contraindication for definitive RT for prostate cancer. High-dose-rate (HDR) brachytherapy can significantly limit the dose to surrounding tissues compared to external beam RT. However, there is limited data surrounding its safety in patients with prior pelvic RT. METHODS AND MATERIALS: A retrospective chart review was performed at the University of California, San Francisco to identify patients diagnosed with prostate cancer with a history of pelvic RT for rectal cancer who were treated with high-dose-rate brachytherapy (HDR-BT) between 2006 and 2022. Inclusion criteria were biopsy-confirmed prostate cancer with no evidence of distant disease on clinical examination or imaging, and at least one post-treatment clinic appointment. RESULTS: Seven patients were treated with salvage HDR-BT at a median interval of 17.7 years after RT for rectal cancer. HDR-BT doses included 3600 cGy in six fractions (n = 5), 2700 cGy in 2 fractions (n=1), or 2800 cGy in four fractions (n = 1). There was no acute grade ≥2 gastrointestinal toxicity, and 1 patient developed late grade 2 rectal bleeding. Two patients developed acute grade 2 genitourinary toxicity consisting of urinary frequency and urgency, which persisted through long-term follow up. At a median follow up of 29.5 months after HDR brachytherapy, one patient developed regional and distant failure, and another had seminal vesicle recurrence. CONCLUSIONS: HDR-BT is a safe treatment for patients with prostate cancer who previously received RT for rectal cancer. Further studies are needed to better characterize the long-term toxicity of HDR-RT in this population.

Contrast-Enhanced Liver Magnetic Resonance Image Synthesis Using Gradient Regularized Multi-Modal Multi-Discrimination Sparse Attention Fusion GAN.

PURPOSES: To provide abdominal contrast-enhanced MR image synthesis, we developed an gradient regularized multi-modal multi-discrimination sparse attention fusion generative adversarial network (GRMM-GAN) to avoid repeated contrast injections to patients and facilitate adaptive monitoring. METHODS: With IRB approval, 165 abdominal MR studies from 61 liver cancer patients were retrospectively solicited from our institutional database. Each study included T2, T1 pre-contrast (T1pre), and T1 contrast-enhanced (T1ce) images. The GRMM-GAN synthesis pipeline consists of a sparse attention fusion network, an image gradient regularizer (GR), and a generative adversarial network with multi-discrimination. The studies were randomly divided into 115 for training, 20 for validation, and 30 for testing. The two pre-contrast MR modalities, T2 and T1pre images, were adopted as inputs in the training phase. The T1ce image at the portal venous phase was used as an output. The synthesized T1ce images were compared with the ground truth T1ce images. The evaluation metrics include peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mean squared error (MSE). A Turing test and experts' contours evaluated the image synthesis quality. RESULTS: The proposed GRMM-GAN model achieved a PSNR of 28.56, an SSIM of 0.869, and an MSE of 83.27. The proposed model showed statistically significant improvements in all metrics tested with p-values < 0.05 over the state-of-the-art model comparisons. The average Turing test score was 52.33%, which is close to random guessing, supporting the model's effectiveness for clinical application. In the tumor-specific region analysis, the average tumor contrast-to-noise ratio (CNR) of the synthesized MR images was not statistically significant from the real MR images. The average DICE from real vs. synthetic images was 0.90 compared to the inter-operator DICE of 0.91. CONCLUSION: We demonstrated the function of a novel multi-modal MR image synthesis neural network GRMM-GAN for T1ce MR synthesis based on pre-contrast T1 and T2 MR images. GRMM-GAN shows promise for avoiding repeated contrast injections during radiation therapy treatment.

Metaplastic breast cancer: A review.

Metaplastic breast cancer (MpBC) is an uncommon aggressive malignancy that is associated with a poor prognosis. Due to its rarity, the relationships between the clinical and pathological features of MpBC, treatment approach, and clinical outcomes remain underexplored. In the following review article, we synthesize the existing data on the clinical, pathological and genomic features, management, and outcomes of MpBC. We also identify potential targets for future clinical trials.

The impact of clinical uncertainty in the graduate medical education (GME) learning environment: A mixed-methods study.

BACKGROUND: Uncertainty is ubiquitous in medicine. Studies link intolerance of uncertainty to burnout, ineffective communication, cognitive bias, and inappropriate resource use. Little is known about how uncertainty manifests in the clinical learning environment. We aimed to explore the perceptions and experiences of uncertainty among residents and attendings. METHODS: We conducted a mixed-methods study including a survey, semi-structured interviews, and ethnographic observations during rounds with residents and attendings at an academic medical center. The survey included three validated instruments: Physicians' Reaction to Uncertainty Scale; Maslach Burnout Inventory 2-item; and Educational Climate Inventory. RESULTS: 35/60 (58%) of eligible residents and 14/21 (67%) attendings completed the survey. Residents reported higher anxiety due to uncertainty than attendings, higher concern about bad outcomes, and greater reluctance to disclose uncertainty to patients. Residents reported increased symptoms of burnout (p < .05). Perceiving the learning environment as more competitive correlated with reluctance to disclose uncertainty (r = -0.44; p < .01). Qualitative themes included: recognizing and facing uncertainty, and consequences for the learning environment. Observations revealed senior clinicians have greater comfort acknowledging uncertainty. CONCLUSIONS: Medical curricula should be developed to promote recognition and acknowledgement of uncertainty. Greater acknowledgement of uncertainty, specifically by attendings and senior residents, may positively impact the clinical learning environment.

Contrast-enhanced 4D-MRI for internal target volume generation in treatment planning for liver tumors.

BACKGROUND: Liver tumors are often invisible on four-dimensional commuted tomography (4D-CT). Imperfect imaging surrogates are used to estimate the tumor motion. Here, we assessed multiple 4D magnetic resonance (MR) binning algorithms for directly visualizing liver tumor motion for radiotherapy planning. METHODS: Patients were simulated using a 3 Tesla MR and CT scanner. Three prototype binning algorithms (phase, amplitude, and two-directional) were applied to the 4D-MRIs, and the image quality was assessed using a qualitative clarity score and quantitative sharpness score. Radiation plans were generated for internal target volumes (ITVs) derived using 4D-MRI and 4D-CT, and the dosimetry of targets were compared. Paired t-tests were used to compare sharpness scores and dosimetric data. RESULTS: Twelve patients with 17 liver tumors were scanned between May and November 2021. Compared to phase binning, two-directional demonstrated equal or better clarity and sharpness scores (end-expiration: 0.33 vs 0.38, p = 0.018, end-inspiration: 0.28 vs 0.31, p = 0.010). Compared to amplitude binning, two-directional binning captured hysteresis of ≥ 3 mm in 35 % of patients. Evaluation of dosimetry CT-optimized plans revealed that PTV coverage of MR-derived targets were significantly lower than CT-derived targets (PTV receiving 90 % of prescription: 75.56 % vs 89.38 %, p = 0.002). CONCLUSION: Using contrast-enhanced 4D-MRI is feasible for directly delineating liver tumors throughout the respiratory cycle. The current standard of using radiation plans optimized for 4D-CT-derived targets achieved lower coverage of directly visualized MRI targets, suggesting that adopting MRI for motion management may improve radiation treatment of liver lesions and reduce the risk of marginal misses.

Advanced Integrated Science Courses: Building a Skill Set to Engage With the Interface of Research and Medicine.

Scientific research has been changing medical practice at an increasing pace. To keep up with this change, physicians of the future will need to be lifelong learners with the skills to engage with emerging science and translate it into clinical care. How medical schools can best prepare students for ongoing scientific change remains unclear. Adding to the challenge is reduced time allocated to basic science in curricula and rapid expansion of relevant scientific fields. A return to science with greater depth after clinical clerkships has been suggested, although few schools have adopted such curricula and implementation can present challenges. The authors describe an innovation at Harvard Medical School, the Advanced Integrated Science Courses (AISCs), which are taken after core clerkships. Students are required to take 2 such courses, which are offered in a variety of topics. Rather than factual content, the learning objectives are a set of generalizable skills to enable students to critically evaluate emerging research and its relationship to medical practice. Making these generalizable skills the defining principle of the courses has several important advantages: it allows standardization of acquired skills to be combined with diverse course topics ranging from basic to translational and population sciences; students can choose courses and projects aligned with their interests, thereby enhancing engagement, curiosity, and career relevance; schools can tailor course offerings to the interests of local faculty; and the generalizable skills delineate a unique purpose of these courses within the overall medical school curriculum. For the 3 years AISCs have been offered, students rated the courses highly and reported learning the intended skill set effectively. The AISC concept addresses the challenge of preparing students for this era of rapidly expanding science and should be readily adaptable to other medical schools.

Residents-as-Teachers Curriculum for Radiation Oncology: A Targeted Needs Assessment.

PURPOSE: Achieving competency as educators is increasingly recognized as a critical part of residents' training in graduate medical education across specialties. In addition to teaching medical students, radiation oncology residents often play a vital role in peer and interprofessional education. We conducted a survey to identify the needs of radiation oncology residents for developing skills in teaching. METHODS AND MATERIALS: An anonymous, web-based survey was developed and distributed to resident physicians at US radiation oncology programs. Analyses describe respondent demographics, experiences with teaching, and interest in various aspects of a formal "residents-as-teachers" curriculum. RESULTS: There were 171 completed survey responses (27.5% response rate). A total of 146 residents (85.4%) reported receiving no formal training in teaching before residency, and 121 (70.8%) reported no formal training during residency. Residents who had formal training in teaching were significantly more likely to be "quite" or "extremely" confident about teaching compared with residents who had no prior formal training (76.0% vs 51.4%; P = .022). Residents most commonly taught other residents and medical students (163 [95.3%] and 160 [93.6%] respondents, respectively). The most common settings for teaching were one-on-one teaching (164 respondents [95.9%]), small-group lectures (135 respondents [78.9%]), and intradepartmental lectures (136 respondents [79.5%]). In response to open-ended questions regarding desired teaching opportunities and domains for teaching development, many residents expressed a lack of confidence in teaching and were interested in improvement across many aspects of teaching. CONCLUSIONS: Radiation oncology residents are expected and desire to teach in a multitude of settings across a wide variety of audiences. However, a significant proportion of radiation oncology residents lack formal training and rarely receive feedback for their teaching skills. The results of this national survey support the development of a residents-as-teachers curriculum for radiation oncology residents that would address the needs for and significant interest in this area.

Proton Radiation Therapy for Pediatric Craniopharyngioma.

BACKGROUND: Radiation therapy (RT) is used for pediatric craniopharyngioma in the definitive, adjuvant, or salvage settings. Proton RT may be useful owing to tumor proximity to eloquent anatomy. We report clinical outcomes for a large cohort treated with proton therapy. METHODS: We conducted a retrospective review of pediatric patients (≤21 years) treated with surgery and proton therapy for craniopharyngioma between August 2002 and October 2018. Clinical characteristics, treatment course, and outcomes were recorded. Acute toxicity was graded using Common Terminology Criteria for Adverse Events, version 5.0. Late toxicity was assessed using neuroendocrine, neuro-ophthalmologic, and neuropsychological testing. RESULTS: Among 77 patients, median age at diagnosis was 8.6 years (range, 1.3-20); median age at radiation was 9.6 years (range, 2.3-20.5). Most common presenting symptoms were headache (58%), visual impairment (55%), and endocrinopathy (40%). Patients underwent a median of 2 surgical interventions (range, 1-7) before protons. At initial surgery, 18% had gross total resection, 60% had subtotal resection, and 22% had biopsy/cyst decompression. Median RT dose was 52.2 Gy (relative biologic effectiveness). Common acute toxicities were headache (29%), fatigue (35%), and nausea/vomiting (12%). Only 4% developed any acute grade 3 toxicity. Nine patients experienced cyst growth requiring replanning or surgical decompression. At a median of 4.8 years from RT (range, 0.8-15.6), there were 6 local failures and 3 deaths, 2 related to disease progression. Effect of tumor and treatment contributed to late toxicity including Moyamoya syndrome (13%), visual impairment (40%), and endocrine deficiency requiring hormone replacement (94%). Subclinical decline in functional independence and adaptive skills in everyday life was detected at follow-up. CONCLUSIONS: Surgery and proton therapy results in excellent disease control for pediatric craniopharyngioma. Severe acute toxicity is rare. Late toxicities from tumor, surgery, and radiation remain prevalent. Endocrine and ophthalmology follow-up is necessary, and neuropsychological testing may identify patients at risk for treatment-related cognitive and adaptive functioning changes.

Stereotactic Body Radiation Therapy and High-Dose-Rate Brachytherapy Boost in Combination With Intensity Modulated Radiation Therapy for Localized Prostate Cancer: A Single-Institution Propensity Score Matched Analysis.

PURPOSE: To perform a propensity-score matched analysis comparing stereotactic body radiation therapy (SBRT) boost and high-dose-rate (HDR) boost for localized prostate cancer. METHODS AND MATERIALS: A single-institution retrospective chart review was conducted of men treated with pelvic external beam radiation therapy (EBRT) and SBRT boost (21 Gy and 19 Gy in 2 fractions) to the prostate for prostate cancer. A cohort treated at the same institution with HDR brachytherapy boost (19 Gy in 2 fractions) was compared. Propensity-score (PS) matching and multivariable Cox regression were used for analysis. Outcomes were biochemical recurrence freedom (BCRF) and metastasis freedom (MF). RESULTS: One hundred thirty-one men were treated with SBRT boost and 101 with HDR boost with median follow-up of 73.4 and 186.0 months, respectively. In addition, 68.8% of men had high-risk and 26.0% had unfavorable-intermediate disease, and 94.3% received androgen deprivation therapy. Five- and 10-year unadjusted BCRF was 88.8% and 85.3% for SBRT and 91.8% and 74.6% for HDR boost (log-rank P = .3), and 5- and 10-year unadjusted MF was 91.7% and 84.3% for SBRT and 95.8% and 82.0% for HDR (log-rank P = .8). After adjusting for covariates, there was no statistically significant difference in BCRF (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.37-1.79; P = .6) or MF (HR 1.07; 95% CI, 0.44-2.57; P = .9) between SBRT and HDR boost. Similarly, after PS matching, there was no statistically significant difference between SBRT and HDR (BCRF: HR 0.66, 0.27-1.62, P = .4; MF: HR 0.84, 0.31-2.26, P = .7). Grade 3+ genitourinary and gastrointestinal toxicity in the SBRT cohort were 4.6% and 1.5%, and 3.0% and 0.0% in the HDR cohorts (P = .4, Fisher exact test). CONCLUSIONS: SBRT boost plus pelvic EBRT for prostate cancer resulted in similar BCRF and MF to HDR boost in this single institution, PS matched retrospective analysis. Toxicity was modest. Prospective evaluation of SBRT boost for the treatment of unfavorable-intermediate and high-risk prostate cancer is warranted.

The Impact of an Introductory Radiation Oncology Curriculum (IROC) for Radiation Oncology Trainees Across the United States and Canada.

PURPOSE: Despite interest from both radiation oncology residents and program directors, many residency training programs lack a formalized introductory curriculum to orient incoming radiation oncology residents to the specialty. METHODS AND MATERIALS: Using the 6-step model for medical education curriculum development, a structured introductory radiation oncology curriculum (IROC) was created for incoming post-graduate year 2 (PGY-2) radiation oncology residents to address foundational concepts including patient simulation, contouring, and plan evaluation. The curriculum was distributed to 55 training programs across the United States and Canada at the start of the 2018 to 2019 and 2019 to 2020 academic years. Feasibility of curriculum dissemination was assessed via a survey of participating program directors. Curriculum effectiveness was assessed using an anonymous survey of participating residents administered pre- and postcurriculum and consisting of both subjective and objective knowledge-based questions. RESULTS: A total of 236 residents participated in IROC at the start of the 2018 to 2019 and 2019 to 2020 academic years. Of those, 228 of 236 (97%) completed both the pre- and postcurriculum surveys. Of participating residents, the median residency program size was 10 (range, 2-28), and the median number of residents in each program per year was 3 (range, 1-7). At baseline, most PGY-2s (142 of 228, 62%) reported being "not at all" or "slightly" prepared to function in the radiation oncology clinic, and after IROC most (188 of 228, 82%) felt "moderately," "quite," or "extremely" prepared. Objective knowledge improved pre- to postcurriculum on a multiple-choice test from 70% to 81% (P < .0001) correct, with improvements observed across all question items. Program directors also reported that the curriculum was easier to use and more effective than prior orientation materials. CONCLUSIONS: The implementation of an international introductory curriculum for PGY-2 radiation oncology residents is both feasible and effective. Similar strategies should be employed to enhance and standardize radiation oncology educational initiatives across training programs.

Association Between Androgen Deprivation Therapy and Patient-reported Depression in Men With Recurrent Prostate Cancer.

BACKGROUND: Previous studies have reported conflicting results on the relationship between androgen deprivation therapy (ADT) and the risk of depression. We assessed whether ADT is associated with depression in a unique data set of men with recurrent prostate cancer. PATIENTS AND METHODS: We studied a cohort of 656 men in the prospective COMPARE (Comprehensive, Multicenter, Prostate Adenocarcinoma) registry who experienced biochemical recurrence after radiation therapy (RT) only, radical prostatectomy (RP) with or without RT, or ADT with RP or RT. Multivariable logistic regression was used to determine the relationship between the modality of treatment and patient-reported depression. RESULTS: Of 656 men, 44 (6.7%) experienced depression. The prevalence of depression stratified by treatment was 3.2% for RT only, 5.9% for RP with or without RT, and 9.1% for ADT plus RP or RT. Compared with RT-only, ADT plus RP or RT was associated with a significantly increased rate of depression (P = .031) and RP with or without RT was not (P = .195). On multivariate analysis adjusting for age and baseline comorbidities, the receipt of ADT was associated with an increased risk of depression (odds ratio, 3.29; 95% confidence interval, 1.11-9.76; P = .032) compared with RT only. No statistically significant difference was found in the risk of depression for men who received RP with or without RT versus RT only (odds ratio, 2.12; 95% confidence interval, 0.68-6.65; P = .19). CONCLUSION: Men with recurrent prostate cancer who underwent ADT were 3 times more likely to report experiencing depression. Treating physicians should discuss depression as a possible side effect when considering the use of ADT and should screen for depression in men who have received ADT.

Dormant Intestinal Stem Cells Are Regulated by PTEN and Nutritional Status.

The cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3K→AKT→mTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3K→AKT→mTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress.

A breath fungal secondary metabolite signature to diagnose invasive aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection. METHODS: Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples. RESULTS: The monoterpenes camphene, α- and ß-pinene, and limonene, and the sesquiterpene compounds α- and ß-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, ß-trans-bergamotene, a ß-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%). CONCLUSIONS: In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.

Cytotoxicity of a Ti(IV) compound is independent of serum proteins.

Titanium(IV) compounds are excellent anticancer drug candidates, but they have yet to find success in clinical applications. A major limitation in developing further compounds has been a general lack of understanding of the mechanism governing their bioactivity. To determine factors necessary for bioactivity, we tested the cytotoxicity of different ligand compounds in conjunction with speciation studies and mass spectrometry bioavailability measurements. These studies demonstrated that the Ti(IV) compound of N,N'-di(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) is cytotoxic to A549 lung cancer cells, unlike those of citrate and naphthalene-2,3-diolate. Although serum proteins are implicated in the activity of Ti(IV) compounds, we found that these interactions do not play a role in [TiO(HBED)](-) activity. Subsequent compound characterization revealed ligand properties necessary for activity. These findings establish the importance of the ligand in the bioactivity of Ti(IV) compounds, provides insights for developing next-generation Ti(IV) anticancer compounds, and reveal [TiO(HBED)](-) as a unique candidate anticancer compound.

A global metabolite profiling approach to identify protein-metabolite interactions.

Understanding the biochemical functions of proteins is an important factor in elucidating their cellular and physiological functions. Due to the predominance of biopolymer interactions in biology, many methods have been designed to interrogate and identify biologically relevant interactions that proteins make to DNA, RNA, and other proteins. Complementary approaches that can elucidate binding interactions between proteins and small molecule metabolites will impact the understanding of protein-metabolite interactions and fill a need that is outside the scope of current methods. Here, we demonstrate the ability to identify natural protein-metabolite interactions from complex metabolite mixtures by combining a protein-mediated small molecule enrichment step with a global metabolite profiling platform.