Selecting the optimal radiation modality in prostate cancer.

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. Classic clinical trials have established the basic tenets of treatment approaches, and emerging data have generated new potential avenues of treatment that optimize the therapeutic ratio by increasing prostate cancer tumor control while minimizing treatment-related toxicity. In the definitive setting, the selection of the optimal radiation therapy approach depends largely on the appropriate up-front risk stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. Hormonal therapy should be selectively deployed based on prognostic information derived from the National Comprehensive Cancer Network risk group and biologic tumor aggressiveness informed by genomic classifiers. Moreover, treatment intensification and target volume delineation are increasingly informed by molecular imaging and multiparametric magnetic resonance imaging. Herein, we perform a critical appraisal of the literature focusing on the optimal selection of radiation therapy modality for localized prostate cancer. Collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based radiation therapies when clearly indicated and for supporting shared decision-making when the evidence is incomplete.

Delivering Bad News Badly.

In this narrative medicine essay, a resident physician practicing how to deliver bad diagnostic news to patients struck a balance upon learning that authenticity and presence were more important than the exact words he chose.

Evaluating the Impact of Race and Ethnicity on Health-Related Quality of Life Disparities in Patients with Esophageal Cancer: A SEER-MHOS National Database Study.

BACKGROUND: It is unclear whether health-related quality of life (HRQOL) disparities exist between racial/ethnic groups in older patients with esophageal cancer, pre- and post-diagnosis. METHODS: Using the SEER-MHOS (Surveillance, Epidemiology, and End Results and Medicare Health Outcomes Survey) national database, we included patients ages 65-years-old or greater with esophageal cancer diagnosed from 1996 to 2017. HRQOL data within 36 months before and after diagnosis were measured by the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores from the SF-36 and VR-12 instruments. Total combined score (TCS) was reflected by both PCS and MCS. RESULTS: We identified 1,312 patients, with evaluable data on 873 patients pre-diagnosis and 439 post-diagnosis. On pre-diagnosis cohort MVA, the MCS was better for White over Hispanic patients (54.1 vs. 48.6, P = 0.012). On post-diagnosis cohort MVA, PCS was better for Hispanic compared with White (39.8 vs. 34.5, P = 0.036) patients, MCS was better for Asian compared with White (48.9 vs. 40.9, P = 0.034) patients, and TCS better for Asian compared with White (92.6 vs. 76.7, P = 0.003) patients. CONCLUSIONS: In older patients with esophageal cancer, White patients had better mental HRQOL as compared with Hispanic patients pre-diagnosis. However, post-diagnosis, White patients had worse mental and physical HRQOL compared with Asian and Hispanic patients, respectively, suggesting a greater negative impact on self-reported HRQOL in White patients with esophageal cancer. IMPACT: To our knowledge, this study is the first to explore HRQOL differences in patients with esophageal cancer of various racial and ethnic groups and warrants further validation in future studies.

Impact of Prediagnosis Risk of Major Depressive Disorder and Health-Related Quality of Life on Treatment Choice for Stage II-III Rectal Cancer.

PURPOSE: We hypothesized that depressive symptoms and health-related quality of life (HRQOL) reported by patients before their cancer diagnoses would be associated with treatment choice for stage II and III rectal cancer, specifically whether patients underwent surgery. METHODS: The Surveillance, Epidemiology, and End Results and Medicare Health Outcomes Survey linked data set was used to identify patients with stage II-III rectal adenocarcinoma diagnosed between 2004 and 2013 who had completed the health outcomes survey within 36 months before their cancer diagnoses. Risk for major depressive disorder (MDD) was determined on the basis of responses to screening questions for depressive disorders. HRQOL was assessed using the Mental Component Summary and Physical Component Summary of the 36-Item Short Form Survey and Veterans RAND 12-Item Health Survey. Using univariable and multivariable analyses, we assessed for associations between health survey responses and ultimate treatment modality. RESULTS: We identified 142 evaluable patients, of whom 109 (76.8%) underwent surgery. Thirty patients (21.1%) met criteria for being at risk for MDD before their cancer diagnoses. Patients at risk for MDD underwent surgery less often than those not at risk (P = .0499), and this association strengthened after adjusting for patient characteristics (odds ratio, 0.17; 95% CI, 0.04 to 0.82; P = .027). There was a nonsignificant trend between higher Mental Component Summary scores (indicating higher self-reported mental HRQOL) and increased frequency of undergoing surgery (P = .081). There were no significant associations between the Physical Component Summary and treatment modality. CONCLUSION: In Medicare beneficiaries with stage II-III rectal cancer, those at risk for MDD underwent standard-of-care treatment with surgery less frequently. Further studies are warranted to assess the effect of mental health on clinical decision making in this patient population.

From lazy to rich to exclusive task representations in neural networks and neural codes.

Neural circuits-both in the brain and in "artificial" neural network models-learn to solve a remarkable variety of tasks, and there is a great current opportunity to use neural networks as models for brain function. Key to this endeavor is the ability to characterize the representations formed by both artificial and biological brains. Here, we investigate this potential through the lens of recently developing theory that characterizes neural networks as "lazy" or "rich" depending on the approach they use to solve tasks: lazy networks solve tasks by making small changes in connectivity, while rich networks solve tasks by significantly modifying weights throughout the network (including "hidden layers"). We further elucidate rich networks through the lens of compression and "neural collapse", ideas that have recently been of significant interest to neuroscience and machine learning. We then show how these ideas apply to a domain of increasing importance to both fields: extracting latent structures through self-supervised learning.

Retrospective examination of pseudoprogression in IDH mutant gliomas.

Background: Tumor surveillance of isocitrate dehydrogenase (IDH) mutant gliomas is accomplished via serial contrast MRI. When new contrast enhancement (CEnew) is detected during postsurgical surveillance, clinicians must assess whether CEnew indicates pseudoprogression (PsP) or tumor progression (TP). PsP has been better studied in IDH wild-type glioblastoma but has not been well characterized in IDH mutant gliomas. We conducted a retrospective study evaluating the incidence, predictors, natural history, and survival of PsP patients in a large cohort of IDH mutant glioma patients treated at a single institution. Methods: We identified 587 IDH mutant glioma patients treated at UCLA. We directly inspected MRI images and radiology reports to identify CEnew and categorized CEnew into TP or PsP using MRI or histopathology. Results: Fifty-six percent of patients developed CEnew (326/587); of these, 92/326 patients (28% of CEnew; 16% of all) developed PsP and 179/326 (55%) developed TP. All PsP patients had prior radiation, chemotherapy, or chemoradiotherapy. PsP was associated with longer overall survival (OS) versus TP patients and similar OS versus no CEnew. PsP differs from TP based on earlier time of onset (median 5.8 vs 17.4 months from treatment, P < .0001) and MRI features that include punctate enhancement and enhancement location. Conclusion: PsP patients represented 28% of CEnew patients and 16% of all patients; PsP patients demonstrated superior outcomes to TP patients, and equivalent survival to patients without CEnew. PsP persists for <1 year, occurs after treatment, and differs from TP based on time of onset and radiographic features. Poor outcomes after CEnew are driven by TP.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Transtympanic Visualization of Cochlear Implant Placement With Optical Coherence Tomography: A Pilot Study.

OBJECTIVE: This study aimed to evaluate the ability of transtympanic middle ear optical coherence tomography (ME-OCT) to assess placement of cochlear implants (CIs) in situ. PATIENT: A 72-year-old man with bilateral progressive heredodegenerative sensorineural hearing loss due to work-related noise exposure received a CI with a slim modiolar electrode for his right ear 3 months before his scheduled checkup. INTERVENTION: A custom-built swept source ME-OCT system (λo = 1550 nm, ∆λ = 40 nm) designed for transtympanic middle ear imaging was used to capture a series of two- and three-dimensional images of the patient's CI in situ. Separately, transtympanic OCT two-dimensional video imaging and three-dimensional imaging were used to visualize insertion and removal of a CI with a slim modiolar electrode in a human cadaveric temporal bone through a posterior tympanotomy. MAIN OUTCOME MEASURE: Images and video were analyzed qualitatively to determine the visibility of implant features under ME-OCT imaging and quantitatively to determine insertion depth of the CI. RESULTS: After implantation, the CI electrode could be readily visualized in the round window niche under transtympanic ME-OCT in both the patient and the temporal bone. In both cases, characteristic design features of the slim modiolar electrode allowed us to quantify the insertion depth from our images. CONCLUSIONS: ME-OCT could potentially be used in a clinic as a noninvasive, nonionizing means to confirm implant placement. This study shows that features of the CI electrode visible under ME-OCT can be used to quantify insertion depth in the postoperative ear.

Autoencoder networks extract latent variables and encode these variables in their connectomes.

Advances in electron microscopy and data processing techniques are leading to increasingly large and complete microscale connectomes. At the same time, advances in artificial neural networks have produced model systems that perform comparably rich computations with perfectly specified connectivity. This raises an exciting scientific opportunity for the study of both biological and artificial neural networks: to infer the underlying circuit function from the structure of its connectivity. A potential roadblock, however, is that - even with well constrained neural dynamics - there are in principle many different connectomes that could support a given computation. Here, we define a tractable setting in which the problem of inferring circuit function from circuit connectivity can be analyzed in detail: the function of input compression and reconstruction, in an autoencoder network with a single hidden layer. Here, in general there is substantial ambiguity in the weights that can produce the same circuit function, because largely arbitrary changes to input weights can be undone by applying the inverse modifications to the output weights. However, we use mathematical arguments and simulations to show that adding simple, biologically motivated regularization of connectivity resolves this ambiguity in an interesting way: weights are constrained such that the latent variable structure underlying the inputs can be extracted from the weights by using nonlinear dimensionality reduction methods.

Predictive learning as a network mechanism for extracting low-dimensional latent space representations.

Artificial neural networks have recently achieved many successes in solving sequential processing and planning tasks. Their success is often ascribed to the emergence of the task's low-dimensional latent structure in the network activity - i.e., in the learned neural representations. Here, we investigate the hypothesis that a means for generating representations with easily accessed low-dimensional latent structure, possibly reflecting an underlying semantic organization, is through learning to predict observations about the world. Specifically, we ask whether and when network mechanisms for sensory prediction coincide with those for extracting the underlying latent variables. Using a recurrent neural network model trained to predict a sequence of observations we show that network dynamics exhibit low-dimensional but nonlinearly transformed representations of sensory inputs that map the latent structure of the sensory environment. We quantify these results using nonlinear measures of intrinsic dimensionality and linear decodability of latent variables, and provide mathematical arguments for why such useful predictive representations emerge. We focus throughout on how our results can aid the analysis and interpretation of experimental data.

Ventricular fibrillation arrest due to Brugada syndrome in a coronavirus disease 2019 patient with negative procainamide challenge: a case report.

BACKGROUND: Pharmacologic challenge test is often used to diagnose Brugada syndrome (BrS) when spontaneous electrocardiograms (ECG) do not show type I Brugada pattern but reported sensitivity varies. The role of the exercise stress test in diagnosing Brugada syndrome is not well-established. CASE SUMMARY: A patient had a type I Brugada pattern ECG during the recovery phase of exercise stress test but had a negative procainamide challenge test. He had a loop recorder implanted and later survived a ventricular fibrillation (VF) arrest provoked by coronavirus disease 2019 (COVID-19). Electrocardiogram on arrival showed type 1 Brugada pattern. He was discharged after implantable cardioverter-defibrillator implantation. He later underwent genetic testing and was found to be heterozygous for c.844C>G (p.Arg282Gly) mutation in the SCN5A gene. DISCUSSION: Type 1 Brugada pattern ECG may be unmasked by ST-segment augmentation during recovery from exercise. Exercise stress test may play a role in the diagnosis of Brugada syndrome when suspicion for Brugada syndrome remains after a negative procainamide challenge test or if the patient has exercise-related symptoms. COVID-19 can unmask BrS and trigger a VF cardiac arrest.

Elective Nodal Irradiation for Limited-stage Small-cell Lung Cancer: Survey of US Radiation Oncologists on Practice Patterns.

BACKGROUND: Traditionally, elective nodal irradiation (ENI) has been used in clinical trials that have established thoracic radiotherapy as instrumental in improving survival for patients with limited-stage small-cell lung cancer (LS-SCLC). However, several reports have suggested that the omission of ENI might be appropriate. Current US practice patterns are unknown regarding ENI for patients with LS-SCLC. MATERIALS AND METHODS: We surveyed US radiation oncologists via an institutional review board-approved questionnaire. The questions covered demographics, treatment recommendations, and self-assessed knowledge of key clinical trials. χ2 and Cochran-Armitage tests were used to evaluate for statistically significant correlations between responses. RESULTS: We received 309 responses. Of the respondents, 21% recommended ENI for N0 LS-SCLC, 29% for N1, and 30% for N2; 64% did not recommend ENI for any of these clinical scenarios. The respondents who recommended ENI were more likely to have been practicing for > 10 years (P < .001), more likely to be in private practice (P = .04), and less likely to be familiar with the ongoing Cancer and Leukemia Group B 30610 trial (P = .04). Almost all respondents (93%) prescribed the same radiation dose to the primary disease and involved lymph nodes. When delivering ENI, 36% prescribed the same dose to the involved and elective nodes, and 64% prescribed a lower dose to the elective nodes. CONCLUSION: Nearly two thirds of respondents did not recommend ENI, which represents a shift in practice. A recent large clinical trial that omitted ENI reported greater overall survival than previously reported and lower-than-expected radiation toxicities, lending further evidence that omitting ENI should be considered a standard treatment strategy.

Radiation Dose and Fractionation for Limited-stage Small-cell Lung Cancer: Survey of US Radiation Oncologists on Practice Patterns.

BACKGROUND: Thoracic radiotherapy (TRT) with concurrent chemotherapy is standard for limited-stage small-cell lung cancer (LS-SCLC). However, the optimal dosing and fractionation remain unclear. The National Comprehensive Cancer Network guidelines have recommended either 45 Gy delivered twice daily (BID) or 60 to 70 Gy delivered once daily (QD). However, the current practice patterns among US radiation oncologists are unknown. MATERIALS AND METHODS: We surveyed US radiation oncologists using an institutional review board-approved questionnaire. The questions covered demographic data, self-rated knowledge of key trials, and treatment recommendations. RESULTS: We received 309 responses from radiation oncologists. Of the 309 radiation oncologists, 60% preferred TRT QD and 76% acknowledged QD to be more common in their practice. The respondents in academic settings were more likely to endorse BID treatment by both preference (P = .001) and actual practice (P = .009). The concordance between preferring QD and administering QD in practice was 100%. In contrast, 40% of respondents who preferred BID actually administered QD more often. Also, 15% of physicians would be unwilling to switch from QD to BID and 3% would be unwilling to switch from BID to QD, even on patient request. Most respondents (88%) recommended a dose of 45 Gy for BID treatment. For QD treatment, the division was greater, with 54% recommending 60 Gy, 30% recommending 63 to 66 Gy, and 10% recommending 70 Gy. CONCLUSION: Substantial variation exists in how US radiation oncologists approach TRT dosing and fractionation for LS-SCLC. Three quarters of our respondents reported administering TRT QD most often. The most common doses were 60 Gy QD and 45 Gy BID. The results of the present survey have provided the most up-to-date information on US practice patterns for LS-SCLC.

Preferential use of imaging modalities in staging newly diagnosed rectal cancer: a survey of US radiation oncologists.

BACKGROUND: Accurate staging is crucial for management of patients with newly diagnosed rectal cancer. Endorectal ultrasound (EUS) has been the standard modality in the United States for decades, with magnetic resonance imaging (MRI) now preferred by national guidelines. Positron emission tomography (PET), conversely, is not recommended. The current utilization of imaging modalities by American radiation oncologists in staging newly diagnosed rectal cancer is unknown. METHODS: American radiation oncologists completed an anonymous institutional review board-approved online survey probing their imaging preferences for initial staging of rectal cancer patients. RESULTS: We received 220 responses from American radiation oncologists, with 39% in academic centers and with 45% seeing more than 10 rectal cancer patients per year. Most respondents utilize all three imaging modalities for rectal cancer staging-EUS, MRI and positron emission tomography/computed tomography (PET/CT). Fifty-two percent and 38% of respondents are high utilizers of EUS and MRI, respectively, defined as ordering these tests at least 75% of the time. Forty seven percent were high PET utilizers. The latter was associated with practice in a private setting (P=0.015) and being within 10 years from residency training completion (P<0.01). CONCLUSIONS: Our analysis reveals a dramatic discordance among national guidelines and the practice patterns among American radiation oncologists. More rely on PET for initial staging of rectal cancer patients than on pelvic MRI. Further research needs to determine the most effective imaging work-up of patients with an initial diagnosis of rectal cancer.

Does a fine line exist between regional and metastatic pelvic lymph nodes in rectal cancer-striking discordance between national guidelines and treatment recommendations by US radiation oncologists.

BACKGROUND: Management of rectal cancer with involved lateral pelvic lymph nodes (LPLNs) at the time of diagnosis-the stage we refer institutionally to as Stage 3.5-is controversial. The American Joint Committee on Cancer's 7th edition classifies internal iliac lymph nodes (LNs) as regional (Stage III), but both external and common iliac LNs as metastatic (Stage IV). However, in many Asian countries all LPLNs are considered regional and patients are treated with curative intent, with literature supporting improved outcomes with LPLN dissection. Management patterns of these patients by US radiation oncologists (ROs) are unknown. METHODS: American ROs completed an anonymous institutional review board-approved online questionnaire regarding rectal cancer management. RESULTS: Among the 220 completed responses, 45% treat more than 10 patients annually and 39% work in academia. We found 10.5% and 34.2% recommend biopsy of clinically involved internal and common iliac LNs, respectively. The vast majority of responders-98.6% and 94.5%-treat involved internal and common iliac LNs with curative intent, respectively. Respondents recommend treatment intensification to involved internal iliac LNs by dissection of the nodal basin (88.2%) and radiation therapy (RT) boost (59.1%), and treatment intensification to involved common iliac LNs by LN dissection (76.4%) and RT boost (63.6%). CONCLUSIONS: Our analysis reveals that the vast majority of US ROs approach patients with involved LPLNs, both regional (internal iliac) and metastatic (common iliac), with curative intent. They recommend treatment intensification with surgical resection and/or RT boost to involved nodes. Prospective clinical trials need to determine the appropriate management of patients with Stage 3.5 rectal cancer.

Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer: Survey of US Radiation Oncologists on Current Practice Patterns.

PURPOSE: Prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer (LS-SCLC) is considered the standard of care. Meta-analysis of 7 clinical trials indicates a survival benefit to PCI, but all of these trials were conducted in the pre-magnetic resonance imaging (MRI) era. Therefore, routine brain imaging with MRI before PCI-as recommended by National Comprehensive Cancer Network guidelines-is not directly supported by the evidence. Current US practice patterns for patients with LS-SCLC are unknown. MATERIALS AND METHODS: We surveyed practicing US radiation oncologists via an institutional review board-approved online questionnaire. Questions covered demographic information and treatment recommendations for LS-SCLC. RESULTS: We received 309 responses from US radiation oncologists. Ninety-eight percent recommended PCI for patients with LS-SCLC, 96% obtained brain MRI before PCI, 33% obtained serial brain imaging with MRI after PCI to detect new metastases, and 35% recommended memantine for patients undergoing PCI. Recommending memantine was associated with fewer years of practice (P < .001), fewer lung cancer patients treated per year (P = .045), and fewer LS-SCLC patients treated per year (P = .024). CONCLUSION: Almost all responding radiation oncologists recommended PCI and pre-PCI brain MRI for LS-SCLC patients with disease responsive to initial therapy. Only a third of respondents followed these patients with serial brain MRI. Approximately one third provided memantine therapy to try to limit neurocognitive effects of PCI. Further research is warranted to determine the best treatment for patients with LS-SCLC. This survey can inform the development of future trials that depend on participation from radiation oncologists.

Survey results of US radiation oncology providers' contextual engagement of watch-and-wait beliefs after a complete clinical response to chemoradiation in patients with local rectal cancer.

BACKGROUND: Watchful waiting in rectal cancer patients with a complete clinical response (cCR) to chemoradiation therapy (CRT) forgo upfront resection has been proposed. Growing evidence suggests that a watch-and-wait approach using resection for salvage of local recurrence may improve quality of life without jeopardizing outcomes. The current acceptance of watch-and-wait by US radiation oncologists (ROs) is unknown. METHODS: US ROs completed our IRB-approved anonymous e-survey regarding non-surgical management of patients who achieved a cCR to neoadjuvant CRT. Self-ranked knowledge of the OnCoRe Project-UK prospective observational study of watch-and-wait-was tested for its association with ROs' attitudes using the Chi-squared or Fisher's test, as indicated. Supporters of observation are self-identified. RESULTS: Of the 220 respondents, 48% (n=106) of respondents support watchful waiting and 48% claimed familiarity with the OnCoRe Project. Respondents supporting observation were more likely to be familiar with the publication (P=0.029). Among watch-and-wait supporters, 59% (n=62) felt comfortable discussing this approach and 41% preferred the conversation be initiated by other specialists. There was no association between comfort level in discussing watch-and-wait and familiarity with the OnCoRe Project. ROs treating more than 10 locally advanced rectal cancer (LARC) patients annually felt more comfortable discussing watch-and-wait (P=0.015) compared to ROs seeing fewer patients. CONCLUSIONS: Almost half of surveyed US ROs support watch-and-wait, though many do not feel comfortable discussing this paradigm with patients. Knowledge of the OnCoRe Project is associated with support of watch-and-wait, yet not comfort level in leading the discussion. These results inform provider attitudes toward future clinical study participation.