On the sympatric evolution and evolutionary stability of coexistence by relative nonlinearity of competition

If two species exhibit different nonlinear responses to a single shared resource, and if each species modifies the resource dynamics such that this favors its competitor, they may stably coexist. This coexistence mechanism, known as relative nonlinearity of competition, is well understood theoretically, but less is known about its evolutionary properties and its prevalence in real communities. We address this challenge by using adaptive dynamics theory and individual-based simulations to compare community stabilization and evolutionary stability of species that coexist by relative nonlinearity. In our analysis, evolution operates on the species' density-compensation strategies, and we consider a trade-off between population growth rates at high and low resource availability. We confirm previous findings that, irrespective of the particular model of density dependence, there are many combinations of overcompensating and undercompensating density-compensation strategies that allow stable coexistence by relative nonlinearity. However, our analysis also shows that most of these strategy combinations are not evolutionarily stable and will be outcompeted by an intermediate density-compensation strategy. Only very specific trade-offs lead to evolutionarily stable coexistence by relative nonlinearity. As we find no reason why these particular trade-offs should be common in nature, we conclude that the sympatric evolution and evolutionary stability of relative nonlinearity, while possible in principle, seems rather unlikely. We speculate that this may, at least in part, explain why empirical demonstrations of this coexistence mechanism are rare, noting, however, that the difficulty to detect relative nonlinearity in the field [...]Comment: PLOS ONE, in pres

Study protocol of the German "Registry for the Detection of Late Sequelae after Radiotherapy in Childhood and Adolescence" (RiSK)

<p>Abstract</p> <p>Background</p> <p>Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. However, these analyses are limited due to little information regarding organ dose levels in many cases. To overcome this limitation, the German Group of Paediatric Radiation Oncology (APRO) established the „Registry for the evaluation of late side effects after radiation in childhood and adolescence” (RiSK). The study protocol and the documentation forms are given in this publication.</p> <p>Methods/Design</p> <p>Radiation parameters including detailed organ doses as well as toxicity evaluations are collected prospectively from centres all over Germany. Standardized documentation forms are used. These forms are given in an English and German version as additional files to this publication. Documentation is planned for all children who receive radiotherapy in one of the therapy trials of the "German Society of Paediatric Oncology and Haematology (GPOH)". The study started in a pilot phase in June 2001 in few centres. Since 2004 documentation has been performed all over Germany and is still on-going.</p> <p>Discussion</p> <p>To our knowledge, "RiSK" is the only multi-centre study that evaluates radiation associated side effects prospectively with detailed information about organ dose levels. With ongoing recruitment and prolongation of follow-up powerful data will be obtained in a few years. A broad use and international cooperation are welcome.</p

Temporal muscle thickness is an independent prognostic marker in melanoma patients with newly diagnosed brain metastases.

OBJECTIVES: The purpose of this study was to evaluate the prognostic relevance of temporal muscle thickness (TMT) in melanoma patients with newly diagnosed brain metastases. METHODS: TMT was retrospectively assessed in 146 melanoma patients with newly diagnosed brain metastases on cranial magnetic resonance images. Chart review was used to retrieve clinical parameters, including disease-specific graded prognostic assessment (DS-GPA) and survival times. RESULTS: Patients with a TMT > median showed a statistically significant increase in survival time (13 months) compared to patients with a TMT < median (5 months; p < 0.001; log rank test). A Cox regression model revealed that the risk of death was increased by 27.9% with every millimeter reduction in TMT. In the multivariate analysis, TMT (HR 0.724; 95% 0.642-0.816; < 0.001) and DS-GPA (HR 1.214; 95% CI 1.023-1.439; p = 0.026) showed a statistically significant correlation with overall survival. CONCLUSION: TMT is an independent predictor of survival in melanoma patients with brain metastases. This parameter may aid in patient selection for clinical trials or to the choice of different treatment options based on the determination of frail patient populations

Survival prediction using temporal muscle thickness measurements on cranial magnetic resonance images in patients with newly diagnosed brain metastases.

OBJECTIVES: To evaluate the prognostic relevance of temporal muscle thickness (TMT) in brain metastasis patients. METHODS: We retrospectively analysed TMT on magnetic resonance (MR) images at diagnosis of brain metastasis in two independent cohorts of 188 breast cancer (BC) and 247 non-small cell lung cancer (NSCLC) patients (overall: 435 patients). RESULTS: Survival analysis using a Cox regression model showed a reduced risk of death by 19% with every additional millimetre of baseline TMT in the BC cohort and by 24% in the NSCLC cohort. Multivariate analysis included TMT and diagnosis-specific graded prognostic assessment (DS-GPA) as covariates in the BC cohort (TMT: HR 0.791/CI [0.703-0.889]/p < 0.001; DS-GPA: HR 1.433/CI [1.160-1.771]/p = 0.001), and TMT, gender and DS-GPA in the NSCLC cohort (TMT: HR 0.710/CI [0.646-0.780]/p < 0.001; gender: HR 0.516/CI [0.387-0.687]/p < 0.001; DS-GPA: HR 1.205/CI [1.018-1.426]/p = 0.030). CONCLUSION: TMT is easily and reproducibly assessable on routine MR images and is an independent predictor of survival in patients with newly diagnosed brain metastasis from BC and NSCLC. TMT may help to better define frail patient populations and thus facilitate patient selection for therapeutic measures or clinical trials. Further prospective studies are needed to correlate TMT with other clinical frailty parameters of patients. KEY POINTS: • TMT has an independent prognostic relevance in brain metastasis patients. • It is an easily and reproducibly parameter assessable on routine cranial MRI. • This parameter may aid in patient selection and stratification in clinical trials. • TMT may serve as surrogate marker for sarcopenia

High correlation of temporal muscle thickness with lumbar skeletal muscle cross-sectional area in patients with brain metastases.

OBJECTIVES: This study aimed to assess the correlation of temporal muscle thickness (TMT), measured on routine cranial magnetic resonance (MR) images, with lumbar skeletal muscles obtained on computed tomography (CT) images in brain metastasis patients to establish a new parameter estimating skeletal muscle mass on brain MR images. METHODS: We retrospectively analyzed the cross-sectional area (CSA) of skeletal muscles at the level of the third lumbar vertebra on computed tomography scans and correlated these values with TMT on MR images of the brain in two independent cohorts of 93 lung cancer and 61 melanoma patients (overall: 154 patients) with brain metastases. RESULTS: Pearson correlation revealed a strong association between mean TMT and CSA in lung cancer and melanoma patients with brain metastases (0.733; p<0.001). The two study cohorts did not differ significantly in patient characteristics, including age (p = 0.661), weight (p = 0.787), and height (p = 0.123). However, TMT and CSA measures differed significantly between male and female patients in both lung cancer and melanoma patients with brain metastases (p<0.001). CONCLUSION: Our data indicate that TMT, measured on routine cranial MR images, is a useful surrogate parameter for the estimation of skeletal muscle mass in patients with brain metastases. Thus, TMT may be useful for prognostic assessment, treatment considerations, and stratification or a selection factor for clinical trials in patients with brain metastases. Further studies are needed to assess the association between TMT and clinical frailty parameters, and the usefulness of TMT in patients with primary brain tumors

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Background Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. Methods We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Results Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. Conclusion TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastom

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer—A Secondary Analysis of the PET Plan Trial

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1–5, 29–33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1–5, 29–33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician’s discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias

Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma

Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH

Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in intermediate- and advanced-stage children and adolescents with classic Hodgkin lymphoma: a titration study with an embedded non-inferiority randomised controlled trial

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m(2) vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m(2) etoposide taken intravenously on days 1–5; 60 mg/m(2) prednisone taken orally on days 1–15; and 40 mg/m(2) doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m(2) cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m(2) vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m(2) prednisone taken orally on days 1 to 15; and 100 mg/m(2) procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m(2) dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7–71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5–92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1–92·8) for COPP (n=444) versus 86·1% (82·9–89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was −3·7% (−8·0 to 0·6). The most common grade 3–4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK

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