Importance of Central Imaging Review in a Pediatric Hodgkin Lymphoma Trial Using Positron Emission Tomography Response Adapted Radiation Therapy.

PURPOSE: We investigated the effects of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) for pediatric patients with high-risk Hodgkin lymphoma. METHODS AND MATERIALS: Per protocol, after 2 cycles of systemic therapy, patients underwent iPET, with visual response assessment by 5-point Deauville score (DS) at their treating institution and a real-time central review, with the latter considered the reference standard. An area of disease with a DS of 1 to 3 was considered a rapid-responding lesion, whereas a DS of 4 to 5 was considered a slow-responding lesion (SRL). Patients with 1 or more SRLs were considered iPET positive, whereas patients with only rapid-responding lesions were considered iPET negative. We conducted a predefined exploratory evaluation of concordance in iPET response assessment between institutional and central reviews of 573 patients. The concordance rate was evaluated using the Cohen κ statistic (κ > 0.80 was considered very good agreement and κ > 0.60-0.80, good agreement). RESULTS: The concordance rate (514 of 573 [89.7%]) had a κ of 0.685 (95% CI, 0.610-0.759), consistent with good agreement. In terms of the direction of discordance, among the 126 patients who were considered iPET positive by institutional review, 38 (30.2%) were categorized as iPET negative by central review, preventing overtreatment with radiation therapy. Conversely, among the 447 patients who were considered iPET negative by institutional review, 21 patients (4.7%) were categorized as iPET positive by the central review and would have been undertreated without radiation therapy. CONCLUSIONS: Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education about DS are needed.

Factors Associated with Transfer from an Acute Geriatric Unit to a Post-Acute Care Facility among Community-Dwelling Patients: Results from the DAMAGE Cohort.

Background: Acute geriatric units (AGUs) require efficient discharge planning tools. Risk factors for discharge from an AGU to post-acute care (PAC) have not previously been investigated in detail. Methods: The objective is to identify risk factors for PAC transfer. The DAMAGE (prospective multicenter cohort) consecutively included more than 3500 subjects aged 75 or older and admitted to an AGU. The patients underwent a comprehensive geriatric assessment (CGA) during their stay in the AGU. Only community-dwelling patients admitted to the AGU from the emergency department were included in the analysis. We recorded the characteristics of the care pathway and identified risk factors for discharge to home or to a PAC facility. Results: 1928 patients were included. Loss of functional independence (a decrease in the Katz activities of daily living (ADL) score between 1 month prior to admission and AGU admission), living alone, social isolation, a high Katz ADL score at home, a low Katz ADL on admission, and delirium on admission were risk factors for transfer to PAC. Obesity, an elevated serum albumin level, and community-acquired infection were associated with discharge to home. Neither sex nor age was a risk factor for home discharge or transfer to PAC. Conclusion: The present results might help clinicians and discharge planning teams to identify patients at risk of transfer to PAC more reliably and promptly in AGUs.

Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A Pediatric Normal Tissue Effects in the Clinic Normal Tissue Outcomes Comprehensive Review.

PURPOSE: Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation. METHODS AND MATERIALS: A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. RESULTS: The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya, or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%). CONCLUSIONS: Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.

Transition to Comfort Care Only and End-of-Life Trajectories in an Acute Geriatric Unit: A Secondary Analysis of the DAMAGE Cohort.

OBJECTIVES: Comfort care for a dying patient increases the quality of the end of life. End-of-life situations are frequently managed in acute geriatric units (AGUs), and transition to comfort care only is often necessary. However, the frequency of transition to comfort care and the latter's putative link with the end-of-life trajectory (sudden death, cancer, organ failure, and frailty with or without dementia) have not previously been studied in acute geriatric units. We sought to (1) describe end-of-life trajectories and the transition to comfort care only, and (2) analyse the relationship between the two, prior to death in an AGU. DESIGN: A secondary analysis of a subgroup of the DAMAGE cohort (a prospective multicentre cohort of 3509 patients aged 75 years and over and admitted consecutively to an AGU). SETTING/PARTICIPANTS: DAMAGE patients who died in an AGU after a stay of at least 48 hours. METHODS: Data on the end-of-life trajectory and the transition to comfort care only were extracted from medical records. RESULTS: Of the 177 included patients, 123 (69.5%) transitioned to comfort care only in the AGU. A frailty trajectory (in patients living with dementia or not) accounted for nearly 70% of deaths. Paradoxically, only frailty among people living without dementia was not significantly associated with a more frequent transition to comfort care [odds ratio (95% confidence interval): 1.44 (0.44-4.76), relative to a patient dying suddenly]. CONCLUSIONS AND IMPLICATIONS: Transition to comfort care only is frequent in AGUs and is linked to the end-of-life trajectory (except for frail patients living without dementia). The frailty trajectory is one of the most frequent, and, therefore, physicians must be aware of the need to improve practice in this context.

Development of a Predictive Score for Mortality at 3 and 12 Months After Discharge From an Acute Geriatric Unit as a Trigger for Advanced Care Planning.

BACKGROUND: There is a need for a mortality score that can be used to trigger advanced care planning among older patients discharged from acute geriatric units (AGUs). OBJECTIVE: We developed a prognostic score for 3- and 12-month mortality after discharge from an AGU, based on a comprehensive geriatric assessment, in-hospital events, and the exclusion of patients already receiving palliative care. METHODS: Devenir Après la Médecine Aigue Gériatrique (DAMAGE) is a French multicenter, prospective, cohort study. The broad inclusion criteria ensured that the cohort is representative of patients treated in an AGU. The DAMAGE participants underwent a comprehensive geriatric assessment, a daily clinical checkup, and follow-up visits 3 and 12 months after discharge. Multivariable logistic regression models were used to develop a prognostic score for the derivation and validation subsets. RESULTS: A total of 3 509 patients were assessed and 3 112 were included. The patient population was very old and frail or dependant, with a high proportion of deaths at 3 months (n = 455, 14.8%) and at 12 months (n = 1 014, 33%). The score predicted an individual risk of mortality ranging from 1% to 80% at 3 months and between 5% and 93% at 12 months, with an area under the receiving operator characteristic curve in the validation cohort of 0.728 at 3 months and 0.733 at 12 months. CONCLUSIONS: Our score predicted a broad range of risks of death after discharge from the AGU. Having this information at the time of hospital discharge might trigger a discussion on advanced care planning and end-of-life care with very old, frail patients. Clinical Trials Registration Number: NCT02949635.

Diagnosis Yield and Safety of Surgical Biopsy in Interstitial Lung Diseases: A Prospective Study.

BACKGROUND: Surgical lung biopsy is essential in the diagnostic algorithm of interstitial lung disease (ILD) of unknown cause. Safety concerns have been recently reiterated. This study prospectively assessed the yield of diagnosis and safety of video-assisted thoracoscopic surgical lung biopsy (VATS-LB) for ILD diagnosis. METHODS: This prospective study, conducted in 6 ILD-referral Paris hospitals, included 103 patients with ILD. VATS-LB was proposed after initial multidisciplinary discussion. A final diagnosis was made after the procedure, during a second multidisciplinary discussion. The main outcome was to determine the final diagnoses and their proportion after VATS-LB. Other outcomes were the percentage of change in diagnosis and treatment propositions after VATS-LB and adverse events during 3 months after the operation, postoperative pulmonary function, quality of life, and pain. RESULTS: A definite diagnosis was reached in 87 patients (84.4%), and 16 remained unclassifiable (15.6%). After VATS-LB, the hypothesized diagnosis changed in 65 patients (63.1%) and treatment changed in 41 patients (39.8%). One patient died of acute exacerbation. In-hospital complications were predicted by a shorter preoperative 6-minute walking test distance and by forced vital capacity lower than 77%. Postoperative quality of life was not modified at 3 months, whereas forced vital capacity decreased slightly. Postoperative neuropathic pain was revealed in 5% of patients at 1 month and in 2% at 3 months. CONCLUSIONS: VATS-LB dramatically changed preoperative hypothetical diagnoses and treatment in ILD of unknown cause, with good patient survival in ILD referral centers.

Risk Factors for Hospital Readmission and Death After Discharge of Older Adults from Acute Geriatric Units: Taking the Rank of Admission into Account.

OBJECTIVE: To analyze the impact of the number of hospital readmissions on the risks of further hospital readmission and death after adjustment for a range of risk factors. METHODS: We performed a multicentre prospective study of the DAMAGE cohort in the Hauts-de-France region of France. Patients aged 75 and over hospitalized initially in an acute geriatric unit (AGU) were included and followed up for 12 months. The risk of hospital readmission was analyzed using a Cox model, and its extension for recurrent events and the risk of death were analyzed using a Cox model for time-dependent variables. RESULTS: A total of 3081 patients were included (mean (SD) age: 86.4 (5.5)). In the multivariate analysis, the relative risk (95% confidence interval [CI]) of hospital readmission rose progressively to 2.66 (1.44; 5.14), and the risk of death rose to 2.01 (1.23; 3.32) after five hospital admissions, relative to a patient with no hospital readmissions. The number of hospital readmissions during the follow-up period was the primary risk factor and the best predictor of the risk of hospital readmission and the risk of death. CONCLUSION: Hospital readmission is the primary risk factor for further hospital readmissions and for death in older subjects discharged from an AGU.

Visual lung damage CT score at hospital admission of COVID-19 patients and 30-day mortality.

OBJECTIVES: Chest CT has been widely used to screen and to evaluate the severity of COVID-19 disease in the early stages of infection without severe acute respiratory syndrome, but no prospective data are available to study the relationship between extent of lung damage and short-term mortality. The objective was to evaluate association between standardized simple visual lung damage CT score (vldCTs) at admission, which does not require any software, and 30-day mortality. METHODS: In a single-center prospective cohort of COVID-19 patients included during 4 weeks, the presence and extent of ground glass opacities(GGO), consolidation opacities, or both of them were visually assessed in each of the 5 lung lobes (score from 0 to 4 per lobe depending on the percentage and out of 20 per patient = vldCTs) after the first chest CT performed to detect COVID-19 pneumonia. RESULTS: Among 210 confirmed COVID-19 patients, the number of survivors and non-survivors was 162 (77%) and 48 (23%), respectively at 30 days. vldCTs was significantly higher in non-survivors, and the AUC of vldCTs to distinguish survivors and non-survivors was 0.72 (95%CI 0.628-0.807, p < 0.001); the best cut-off vldCTs value was 7. During follow-up, significant differences in discharges and 30-day mortality were observed between patients with vldCTs ≥ 7 versus vldCTs < 7: (98 [85.2%] vs 49 [51.6%]; p < 0.001 and 36 [37.9%] vs 12 [12.4%]; p < 0.001, respectively. The 30-day mortality increased if vldCTs ≥ 7 (HR, 3.16 (1.50-6.43); p = 0.001), independent of age, respiratory rate and oxygen saturation levels, and comorbidities at admission. CONCLUSIONS: By using chest CT in COVID-19 patients, extensive lung damage can be visually assessed with a score related to 30-day mortality independent of conventional risk factors of the disease. KEY POINTS: • In non-selected COVID-19 patients included prospectively during 4 weeks, the extent of ground glass opacities(GGO) and consolidation opacities evaluated by a simple visual score was related to 30-day mortality independent of age, respiratory rate, oxygen saturation levels, comorbidities, and hs-troponin I level at admission. • This severity score should be incorporated into risk stratification algorithms and in structured chest CT reports requiring a standardized reading by radiologists in case of COVID-19.

Quality of Life: A Prospective Randomized Trial of Palliative Volumetric Arc Therapy Versus 3-Dimensional Conventional Radiation Therapy.

PURPOSE: Volumetric arc therapy (VMAT) is a radiation therapy (RT) technique that spares normal tissues from high and intermediate RT doses but increases the volume of tissues receiving low doses of RT compared with 3-dimensional conformal RT (3DCRT). We hypothesized that palliative VMAT would reduce the detriment to patient quality of life (QOL) compared with palliative 3DCRT. METHODS AND MATERIALS: This phase 2 trial randomized patients to palliative RT using VMAT or 3DCRT to 1 painful site of metastatic disease in the trunk. Treating physicians could choose 8 Gy in 1 fraction or 20 Gy in 5 fractions to stratify randomization. The primary endpoint was the change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) global health status QOL subscale at 1 week after RT. Repeated measures analysis of variance was used to assess the relationship of patient QOL over time with other factors. RESULTS: From July 2014 to November 2017, 37 patients who underwent 3DCRT and 32 patients who underwent VMAT were randomized into the study. Median overall survival was 9 months. Overall pain responses to RT were equivalent (P = .53) between the techniques. Patient compliance in returning QOL questionnaires was 94%, 81%, and 69% at baseline, 1 week after RT, and 1 month after RT, respectively. At 1 week after RT, change in global QOL was not significantly (P = .31) different between VMAT versus 3DCRT. At 4 weeks after RT, VMAT induced significantly (P = .049) less global QOL deterioration than 3DCRT did. Patients who underwent VMAT maintained better physical (P = .012), role (P = .041), and social (P = .025) functioning, but they reported more diarrhea symptoms (P = .017) than in the 3DCRT group. CONCLUSIONS: Palliative VMAT and 3DCRT did not differ in their ability to control pain; however, palliative VMAT induced fewer QOL detriments than 3DCRT did at 4 weeks after RT.

Unshifting the baseline: a framework for documenting historical population changes and assessing long-term anthropogenic impacts.

Ecological baselines-reference states of species' distributions and abundances-are key to the scientific arguments underpinning many conservation and management interventions, as well as to the public support to such interventions. Yet societal as well as scientific perceptions of these baselines are often based on ecosystems that have been deeply transformed by human actions. Despite increased awareness about the pervasiveness and implications of this shifting baseline syndrome, ongoing global assessments of the state of biodiversity do not take into account the long-term, cumulative, anthropogenic impacts on biodiversity. Here, we propose a new framework for documenting such impacts, by classifying populations according to the extent to which they deviate from a baseline in the absence of human actions. We apply this framework to the bowhead whale (Balaena mysticetus) to illustrate how it can be used to assess populations with different geographies and timelines of known or suspected impacts. Through other examples, we discuss how the framework can be applied to populations for which there is a wide diversity of existing knowledge, by making the best use of the available ecological, historical and archaeological data. Combined across multiple populations, this framework provides a standard for assessing cumulative anthropogenic impacts on biodiversity. This article is part of a discussion meeting issue 'The past is a foreign country: how much can the fossil record actually inform conservation?'

Forgotten Mediterranean calving grounds of grey and North Atlantic right whales: evidence from Roman archaeological records.

Right whales (Eubalaena glacialis) were extirpated from the eastern North Atlantic by commercial whaling. Grey whales (Eschrichtius robustus) disappeared from the entire North Atlantic in still-mysterious circumstances. Here, we test the hypotheses that both species previously occurred in the Mediterranean Sea, an area not currently considered part of their historical range. We used ancient DNA barcoding and collagen fingerprinting methods to taxonomically identify a rare set of 10 presumed whale bones from Roman and pre-Roman archaeological sites in the Strait of Gibraltar region, plus an additional bone from the Asturian coast. We identified three right whales, and three grey whales, demonstrating that the ranges of both of these species historically encompassed the Gibraltar region, probably including the Mediterranean Sea as calving grounds. Our results significantly extend the known range of the Atlantic grey whale, and suggest that 2000 years ago, right and grey whales were common when compared with other whale species. The disappearance of right and grey whales from the Mediterranean region is likely to have been accompanied by broader ecosystem impacts, including the disappearance of their predators (killer whales) and a reduction in marine primary productivity. The evidence that these two coastal and highly accessible species were present along the shores of the Roman Empire raises the hypothesis that they may have formed the basis of a forgotten whaling industry.

Predictive Factor Analysis of Response-Adapted Radiation Therapy for Chemotherapy-Sensitive Pediatric Hodgkin Lymphoma: Analysis of the Children's Oncology Group AHOD 0031 Trial.

PURPOSE: To evaluate whether clinical risk factors could further distinguish children with intermediate-risk Hodgkin lymphoma (HL) with rapid early and complete anatomic response (RER/CR) who benefit significantly from involved-field RT (IFRT) from those who do not, and thereby aid refinement of treatment selection. METHODS AND MATERIALS: Children with intermediate-risk HL treated on the Children's Oncology Group AHOD 0031 trial who achieved RER/CR with 4 cycles of chemotherapy, and who were randomized to 21-Gy IFRT or no additional therapy (n=716) were the subject of this study. Recursive partitioning analysis was used to identify factors associated with clinically and statistically significant improvement in event-free survival (EFS) after randomization to IFRT. Bootstrap sampling was used to evaluate the robustness of the findings. RESULT: Although most RER/CR patients did not benefit significantly from IFRT, those with a combination of anemia and bulky limited-stage disease (n=190) had significantly better 4-year EFS with the addition of IFRT (89.3% vs 77.9% without IFRT; P=.019); this benefit was consistently reproduced in bootstrap analyses and after adjusting for other prognostic factors. CONCLUSION: Although most patients achieving RER/CR had favorable outcomes with 4 cycles of chemotherapy alone, those children with initial bulky stage I/II disease and anemia had significantly better EFS with the addition of IFRT as part of combined-modality therapy. Further work evaluating the interaction of clinical and biologic factors and imaging response is needed to further optimize and refine treatment selection.

Barcoding the largest animals on Earth: ongoing challenges and molecular solutions in the taxonomic identification of ancient cetaceans.

Over the last few centuries, many cetacean species have witnessed dramatic global declines due to industrial overharvesting and other anthropogenic influences, and thus are key targets for conservation. Whale bones recovered from archaeological and palaeontological contexts can provide essential baseline information on the past geographical distribution and abundance of species required for developing informed conservation policies. Here we review the challenges with identifying whale bones through traditional anatomical methods, as well as the opportunities provided by new molecular analyses. Through a case study focused on the North Sea, we demonstrate how the utility of this (pre)historic data is currently limited by a lack of accurate taxonomic information for the majority of ancient cetacean remains. We then discuss current opportunities presented by molecular identification methods such as DNA barcoding and collagen peptide mass fingerprinting (zooarchaeology by mass spectrometry), and highlight the importance of molecular identifications in assessing ancient species' distributions through a case study focused on the Mediterranean. We conclude by considering high-throughput molecular approaches such as hybridization capture followed by next-generation sequencing as cost-effective approaches for enhancing the ecological informativeness of these ancient sample sets.This article is part of the themed issue 'From DNA barcodes to biomes'.

Insights from life history theory for an explicit treatment of trade-offs in conservation biology.

As economic and social contexts become more embedded within biodiversity conservation, it becomes obvious that resources are a limiting factor in conservation. This recognition is leading conservation scientists and practitioners to increasingly frame conservation decisions as trade-offs between conflicting societal objectives. However, this framing is all too often done in an intuitive way, rather than by addressing trade-offs explicitly. In contrast, the concept of trade-off is a keystone in evolutionary biology, where it has been investigated extensively. I argue that insights from evolutionary theory can provide methodological and theoretical support to evaluating and quantifying trade-offs in biodiversity conservation. I reviewed the diverse ways in which trade-offs have emerged within the context of conservation and how advances from evolutionary theory can help avoid the main pitfalls of an implicit approach. When studying both evolutionary trade-offs (e.g., reproduction vs. survival) and conservation trade-offs (e.g., biodiversity conservation vs. agriculture), it is crucial to correctly identify the limiting resource, hold constant the amount of this resource when comparing different scenarios, and choose appropriate metrics to quantify the extent to which the objectives have been achieved. Insights from studies in evolutionary theory also reveal how an inadequate selection of conservation solutions may result from considering suboptimal rather than optional solutions when examining whether a trade-off exits between 2 objectives. Furthermore, the shape of a trade-off curve (i.e., whether the relationship between 2 objectives follows a concave, convex, or linear form) is known to affect crucially the definition of optimal solutions in evolutionary biology and very likely affects decisions in biodiversity conservation planning too. This interface between evolutionary biology and biodiversity conservation can therefore provide methodological guidance to support decision makers in the difficult task of choosing among conservation solutions.

Anti-Müllerian hormone screening to assess ovarian reserve among female survivors of childhood cancer.

PURPOSE: Anti-Müllerian hormone (AMH) is an indicator of oocyte reserve in healthy females. The role of AMH testing in oncology remains investigational, although its sensitivity and stability over the menstrual cycle make it an attractive screening test for fertility assessment among female cancer survivors. We measured AMH level in survivors of childhood cancer and evaluated its association with treatment and patient factors. METHODS: Participants were adult female survivors of childhood malignancy treated with chemotherapy. Serum AMH was measured at a random day of the menstrual cycle. Multivariate analysis was used to evaluate the association between AMH level, alkylating agent exposure using the cyclophosphamide equivalent dose (CED), and other covariates. RESULTS: Sixty-six females with a median attained age of 23.3 years were eligible for analysis. Median AMH was 25.5 pM (range 0.5-108.0), at a median time of 11.5 years (range 1.4-25.1) since cancer diagnosis. Twenty-three patients (34.8%) had low AMH, including a significant proportion that reported normal menstrual cycles. Compared to ALL survivors, sarcoma survivors had significantly lower AMH levels. Among alkylating agents evaluated, procarbazine had the greatest adverse effect on AMH. In multivariate analysis, higher CED (p = 0.001), older age at diagnosis (p < 0.001), and use of oral contraceptive pills (p = 0.04) remained significantly associated with lower AMH. CONCLUSIONS: Random AMH can reveal evidence of oocyte depletion among female survivors reporting normal cycles, although low AMH should be interpreted cautiously among those taking oral contraception. Age at exposure and CED can aid identification of those more likely to have low AMH, although CED may underestimate the effect of procarbazine on oocyte reserve. IMPLICATIONS FOR CANCER SURVIVORS: Measurement of AMH can reveal apparent depletion of ovarian reserve in female childhood cancer survivors reporting normal menstrual cycles. Sarcoma survivors and those exposed to procarbazine may benefit from targeted AMH evaluation in an outpatient setting, and thereby allow appropriate fertility counseling before the onset of premature ovarian failure. The cyclophosphamide equivalent dose may facilitate comparison of the potential effect of different regimens on fertility.

Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose.

PURPOSE: Active breathing control (ABC) is emerging as a tool to reduce heart and lung dose for lymphoma patients receiving mediastinal radiation therapy (RT). The objective of this study was to report our early institutional experience with this technique, with emphasis on quantifying the changes in normal tissue dose and exploring factors that could be used to select patients with the greatest benefit. METHODS AND MATERIALS: Patients receiving mediastinal involved-field RT (IFRT) for lymphoma were eligible. The ABC was performed using a moderate deep-inspiration breath-hold (mDIBH) technique. All patients were replanned with free-breathing (FB) computed tomographic data sets and comparisons of lung, cardiac, and female breast tissue doses were made between mDIBH and FB plans. Logistic regression models were used to identify factors associated with improvement in mean lung and heart dose with mDIBH. RESULTS: Forty-seven patients were analyzed; the majority (87.2%) had Hodgkin lymphoma. Median prescribed dose was 30 Gy (range, 20-36 Gy), with 78.7% of cases being treated with parallel-opposed beams. The use of mDIBH significantly improved average mean lung dose (FB: 11.0 Gy; mDIBH: 9.5 Gy; P < .0001), lung V20 (28% vs 22%; P < .0001), and mean heart dose (14.3 Gy vs 11.8 Gy; P = .003), but increased the mean breast dose (FB: 3.0 Gy; mDIBH 3.6 Gy; P = .0005). The magnitude of diaphragmatic excursion on the inhale scan was significantly associated with dosimetric improvement in both heart and lung dose with mDIBH. CONCLUSIONS: Mediastinal IFRT for lymphoma delivered with mDIBH can significantly reduce lung and heart dose compared with FB, although not for all patients, and may increase breast dose in females. Its implementation is achievable in both adult and pediatric populations. Further work is necessary to better predict which patients benefit from this technique.

Evolution of a genetic polymorphism with climate change in a Mediterranean landscape.

Many species show changes in distribution and phenotypic trait variation in response to climatic warming. Evidence of genetically based trait responses to climate change is, however, less common. Here, we detected evolutionary variation in the landscape-scale distribution of a genetically based chemical polymorphism in Mediterranean wild thyme (Thymus vulgaris) in association with modified extreme winter freezing events. By comparing current data on morph distribution with that observed in the early 1970s, we detected a significant increase in the proportion of morphs that are sensitive to winter freezing. This increase in frequency was observed in 17 of the 24 populations in which, since the 1970s, annual extreme winter freezing temperatures have risen above the thresholds that cause mortality of freezing-sensitive morphs. Our results provide an original example of rapid ongoing evolutionary change associated with relaxed selection (less extreme freezing events) on a local landscape scale. In species whose distribution and genetic variability are shaped by strong selection gradients, there may be little time lag associated with their ecological and evolutionary response to long-term environmental change.

A multi-institutional study of factors influencing the use of stereotactic radiosurgery for brain metastases.

PURPOSE: Stereotactic radiosurgery (SRS) for brain metastases is a relatively well-studied technology with established guidelines regarding patient selection, although its implementation is technically complex. We evaluated the extent to which local availability of SRS affected the treatment of patients with brain metastases. METHODS AND MATERIALS: We identified 3030 patients who received whole-brain radiation therapy (WBRT) for brain metastases in 1 of 7 cancer centers in Ontario. Clinical data were abstracted for a random sample of 973 patients. Logistic regression analyses were performed to identify factors associated with the use of SRS as a boost within 4 months following WBRT or at any time following WBRT. RESULTS: Of 898 patients eligible for analysis, SRS was provided to 70 (7.8%) patients at some time during the course of their disease and to 34 (3.8%) patients as a boost following WBRT. In multivariable analyses, factors significantly associated with the use of SRS boost following WBRT were fewer brain metastases (odds ratio [OR] = 6.50), controlled extracranial disease (OR = 3.49), age (OR = 0.97 per year of advancing age), and the presence of an on-site SRS program at the hospital where WBRT was given (OR = 12.34; all P values were <.05). Similarly, availability of on-site SRS was the factor most predictive of the use of SRS at any time following WBRT (OR = 5.98). Among patients with 1-3 brain metastases, good/fair performance status, and no evidence of active extracranial disease, SRS was provided to 40.3% of patients who received WBRT in a hospital that had an on-site SRS program vs 3.0% of patients who received WBRT at a hospital without SRS (P<.01). CONCLUSIONS: The availability of on-site SRS is the factor most strongly associated with the provision of this treatment to patients with brain metastases and appears to be more influential than accepted clinical eligibility factors.