During the coronavirus disease 2019 (COVID‐19) pandemic, providers and patients must engage in shared decision making regarding the pros and cons of early versus delayed interventions for localized ...skin cancer. Patients at highest risk of COVID‐19 complications are older; are immunosuppressed; and have diabetes, cancer, or cardiopulmonary disease, with multiple comorbidities associated with worse outcomes. Physicians must weigh the patient's risk of COVID‐19 complications in the event of exposure against the risk of worse oncologic outcomes from delaying cancer therapy. Herein, the authors have summarized current data regarding the risk of COVID‐19 complications and mortality based on age and comorbidities and have reviewed the literature assessing how treatment delays affect oncologic outcomes. They also have provided multidisciplinary recommendations regarding the timing of local therapy for early‐stage skin cancers during this pandemic with input from experts at 11 different institutions. For patients with Merkel cell carcinoma, the authors recommend prioritizing treatment, but a short delay can be considered for patients with favorable T1 disease who are at higher risk of COVID‐19 complications. For patients with melanoma, the authors recommend delaying the treatment of patients with T0 to T1 disease for 3 months if there is no macroscopic residual disease at the time of biopsy. Treatment of tumors ≥T2 can be delayed for 3 months if the biopsy margins are negative. For patients with cutaneous squamous cell carcinoma, those with Brigham and Women's Hospital T1 to T2a disease can have their treatment delayed for 2 to 3 months unless there is rapid growth, symptomatic lesions, or the patient is immunocompromised. The treatment of tumors ≥T2b should be prioritized, but a 1‐month to 2‐month delay is unlikely to worsen disease‐specific mortality. For patients with squamous cell carcinoma in situ and basal cell carcinoma, treatment can be deferred for 3 months unless the individual is highly symptomatic.
During the coronavirus disease 2019 (COVID‐19) pandemic, providers must help patients to make informed decisions regarding skin cancer management and assess the risk of potential COVID‐19–associated morbidity and/or mortality versus primary skin cancer morbidity and/or mortality. In this article, the authors summarize current data regarding the risk of COVID‐19 complications and mortality based on age and comorbidities, and review the literature assessing how treatment delays affect oncologic outcomes. They provide multidisciplinary recommendations regarding the timing of local therapy for patients with early‐stage skin cancers.
Introduction La perte de masse osseuse pendant la grossesse et l’allaitement peut atteindre 1 % par mois, mais réversible. La sommation des événements génitaux peut conduire à l’expression de ...l’ostéoporose. L’objectif était d’étudier l’effet de la parité et de l’allaitement sur le risque fracturaire chez les femmes ménopausées de plus de 60 ans. Méthodologie Il s’agissait d’une étude cas-témoin, réalisée à partir du registre « Qualité de l’Os en Lorraine ». Les cas concernaient 434 femmes ≥ 60 ans avec une fracture de fragilité après l’âge de 45 ans. Les témoins concernaient 422 patientes recrutées dans la même population mais sans fracture. Étaient non incluses celles présentant une cause secondaire d’ostéoporose ou de fracture. Les données recueillies étaient relatives aux facteurs de risque d’ostéoporose et l’histoire génitale. Résultats L’âge moyen était de 73,09 ± 8,8 ans. Le surpoids et l’obésité affectaient 47,7 %, le tabagisme 19 %, l’éthylisme 15,3 %, une consommation ≥ 2 portions de calcium 51 %. En analyse univariée, seule une durée de lactation ≥ 5 mois était associée à un risque fracturaire majoré (OR = 1,6 1,1–2,2). En analyse multivariée, la durée de la lactation ≥ 5 mois était toujours associée à un risque plus élevé (OR = 1,5 1,1–2,2) alors qu’une longue période génitale ≥ 39 ans était associée à un risque fracturaire moindre (OR = 0,7 0,5–0,9). L’association avec le surpoids et l’obésité se rapprochait de la significativité (OR = 1,3 0,9–1,7). Conclusion La lactation semble être un facteur de risque de fracture alors qu’une longue période génitale est protectrice.
Objective: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. ...Patients: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. Results: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. Conclusion: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.
We demonstrate the experimental feasibility of probing the fully nonperturbative regime of quantum electrodynamics with a 100 GeV-class particle collider. By using tightly compressed and focused ...electron beams, beamstrahlung radiation losses can be mitigated, allowing the particles to experience extreme electromagnetic fields. Three-dimensional particle-in-cell simulations confirm the viability of this approach. The experimental forefront envisaged has the potential to establish a novel research field and to stimulate the development of a new theoretical methodology for this yet unexplored regime of strong-field quantum electrodynamics.
Self-management of diabetes is essential to reducing the risks of associated disabilities. But effective self-management is often short-lived. Peers can provide the kind of ongoing support that is ...needed for sustained self-management of diabetes. In this context, peers are nonprofessionals who have diabetes or close familiarity with its management. Key functions of effective peer support include assistance in daily management, social and emotional support, linkage to clinical care, and ongoing availability of support. Using these four functions as a template of peer support, project teams in Cameroon, South Africa, Thailand, and Uganda developed and then evaluated peer support interventions for adults with diabetes. Our initial assessment found improvements in symptom management, diet, blood pressure, body mass index, and blood sugar levels for many of those taking part in the programs. For policy makers, the broader message is that by emphasizing the four key peer support functions, diabetes management programs can be successfully introduced across varied cultural settings and within diverse health systems.
Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain ...barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.
The vast majority of QED results are obtained in relatively weak fields and so in the framework of perturbation theory. However, forthcoming laser facilities providing extremely high fields can be ...used to enter not-yet-studied regimes. Here, a scheme is proposed that might be used to reach a supercritical regime of radiation reaction or even the fully non-perturbative regime of quantum electrodynamics. The scheme considers the collision of a 100 GeV-class electron beam with a counterpropagating ultraintense electromagnetic pulse. To reach these supercritical regimes, it is unavoidable to use a pulse with ultrashort duration. Using two-dimensional particle-in-cell simulations, it is therefore shown how one can convert a next-generation optical laser to an ultraintense (I ≈ 2.9 × 10
Wcm
) attosecond (duration ≈ 150 as) pulse. It is shown that if the perturbation theory persists in extreme fields, the spectrum of secondary particles can be found semi-analytically. In contrast, a comparison with experimental data may allow differentiating the contribution of high-order radiative corrections if the perturbation theory breaks.
The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal ...residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.
We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point.
utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.
Radiation oncology (RO) has seen declines in Medicare reimbursement (MCR). However, there are no recent studies analyzing the contributions of specific billing codes to overall RO reimbursement. We ...compared total MCR for specific Healthcare Common Procedure Coding System (HCPCS) codes in 2019 with MCR for those codes in 2010 and 2015, corrected for inflation, to see how the same basket of RO services in 2019 would have been reimbursed in 2010 and 2015 (adjusted MCR).
The Centers for Medicare & Medicaid Services Physician/Supplier Procedure Summary database was used to obtain MCR data for RO HCPCS codes in 2010, 2015, and 2019. For each code, the total allowed charge was divided by the number of submitted claims to calculate the average MCR per claim in 2010, 2015, and 2019. The 2019 billing frequency for each code was then multiplied by the inflation-adjusted average MCR for those codes in 2010 and 2015 to determine what the MCR would have been in 2010 and 2015 using 2019 dollars and utilization rates. Results were compared with actual 2019 MCR to calculate the projected difference.
Total inflation-adjusted RO MCR was $2281 million (M), $1991 M, and $1848 M in 2010, 2015, and 2019 respectively. This represents a cut of $433 M (19%) and $143 M (7%) from 2010 and 2015, respectively, to 2019. After utilization adjustment, total reimbursement was $2534 M, $2034 M, and $1848 M for 2010, 2015, and 2019, respectively, representing a cut of $686 M (27%) and $186 M (9%) from 2010 and 2015, respectively, to 2019. Intensity modulated radiation therapy (IMRT) treatment delivery and planning accounted for $917 M (36%), $670 M (33%), and $573 M (31%) of the adjusted MCR in 2010, 2015, and 2019, respectively.
Medicare reimbursement decreased substantially from 2010 to 2019. A decline in IMRT treatment reimbursement was the primary driver of MCR decline. When considering further cuts, policymakers should consider these trends and their consequences for health care quality and access.
Excessive daytime sleepiness (EDS) and fatigue are common symptoms after traumatic brain injury (TBI), but there is no specific treatment for affected patients. With this pilot study, we aimed at ...studying the effect of daily modafinil on posttraumatic EDS and fatigue.
We conducted a prospective, double-blind, randomized, placebo-controlled pilot study in 20 patients with TBI who had fatigue or EDS or both. After baseline examinations (questionnaires including the Epworth Sleepiness Scale to assess EDS and the Fatigue Severity Scale to assess fatigue, actigraphy, polysomnography, maintenance of wakefulness test, and psychomotor vigilance test), 10 patients received 100 to 200 mg modafinil every morning, and 10 patients were treated with placebo. After a 6-week treatment period, all examinations were repeated.
EDS improved significantly in patients with TBI who were treated with modafinil, compared with the placebo group. Similarly, the ability to stay awake on the maintenance of wakefulness test improved only in the modafinil group. Modafinil, however, had no impact on posttraumatic fatigue. Clinically relevant side effects were not observed.
This study indicates that modafinil is effective and well tolerated in the treatment of posttraumatic EDS but not of fatigue.
This study provides Class I evidence that modafinil (100-200 mg daily) improves posttraumatic EDS compared with placebo. This study provides Class I evidence that modafinil (100-200 mg daily) does not improve posttraumatic fatigue compared with placebo.
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