Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Screening for irradiation vasculopathy by intima-media thickness sonography in head and neck cancer patients.

PURPOSE: Post-irradiation vasculopathy is a severe form of atherosclerosis and affects the prognosis of head and neck cancer survivors. Sonographic intima-media thickness (IMT) precedes stenosis, plaque formation, and cerebrovascular events. Therefore, IMT may be a valuable screening marker for post-irradiation toxicity. However, the critical irradiation dose and the onset of IMT increase remain unclear. METHODS: The cross-sectional study analysed the carotid artery IMT in 96 irradiated patients and 41 controls regarding irradiation dose, post-irradiation-interval, and cardiovascular risk factors. Distinct irradiation doses to the tumour side and the contralateral hemineck enabled detection of dose depended effects within one patient and control of risk factors. RESULTS: Radiotherapy caused a dose-dependent increase in IMT. The toxicity did not have saturation effects for > 60 Gy. The IMT increase occurred in short-term following radiotherapy and the risk for a pathological value (> 0.9 mm) rose significantly. The correlation between IMT and radiotherapy was comparable to established cardiovascular risk factors. CONCLUSION: Radiotherapists should consider the additional toxicity of high doses for non-metastatic head and neck cancer. If neck metastases require radiotherapy with boost, IMT measurement is suitable for early detection of carotid artery damage.

Exposure of remote organs and associated cancer risks from tangential and multi-field breast cancer radiotherapy.

PURPOSE: With the ever-increasing cure rates in breast cancer, radiotherapy-induced cancers have become an important issue. This study aimed to estimate secondary cancer risks for different treatment techniques, taking into account organs throughout the body. MATERIAL AND METHODS: Organ doses were evaluated for a tangential three-dimensional conformal (3D-CRT) and a multi-field intensity-modulated radiotherapy (IMRT) plan using a validated, Monte Carlo-based treatment planning system. Effects of wedges and of forward versus inverse planning were systematically investigated on the basis of phantom measurements. Organ-specific cancer risks were estimated using risk coefficients derived from radiotherapy patients or from the atomic bomb survivors. RESULTS: In the 3D-CRT plan, mean organ doses could be kept below 1 Gy for more remote organs than the lung, heart, and contralateral breast, and decreased to a few cGy for organs in the lower torso. Multi-field IMRT led to considerably higher mean doses in organs at risk, the difference being higher than 50% for many organs. Likewise, the peripheral radiation burden was increased by external wedges. No difference was observed for forward versus inverse planning. Despite the lower doses, the total estimated secondary cancer risk in more remote organs was comparable to that in the lung or the contralateral breast. For multi-field IMRT it was 75% higher than for 3D-CRT without external wedges. CONCLUSION: Remote organs are important for assessment of radiation-induced cancer risk. Remote doses can be reduced effectively by application of a tangential field configuration and a linear accelerator set-up with low head scatter radiation.

The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases.

BACKGROUND: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. METHODS: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. RESULTS: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. CONCLUSION: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

The SBRT database initiative of the German Society for Radiation Oncology (DEGRO): patterns of care and outcome analysis of stereotactic body radiotherapy (SBRT) for liver oligometastases in 474 patients with 623 metastases.

BACKGROUND: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. METHODS: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. RESULTS: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1­4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1­13) and dose per fraction (median: 18.5 Gy; range 3­37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control. CONCLUSION: After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.

Correlation of pain, functional impairment, and health-related quality of life with radiological grading scales of lumbar degenerative disc disease.

BACKGROUND: It is generally believed that radiological signs of lumbar degenerative disc disease (DDD) are associated with increased pain and functional impairment as well as lower health-related quality of life (HRQoL). Our aim was to assess the association of the Modic and Pfirrmann grading scales with established outcome questionnaires and the timed-up-and-go (TUG) test. METHODS: In a prospective two-center study with patients scheduled for lumbar spine surgery, visual analogue scale (VAS) for back and leg pain, Roland-Morris Disability Index, Oswestry Disability Index and HRQoL, as determined by the Short-Form (SF)-12 and the Euro-Qol, were recorded. Functional mobility was measured with the TUG test. Modic type (MOD) and Pfirrmann grade (PFI) of the affected lumbar segment were assessed with preoperative imaging. Uni- and multivariate logistic regression analysis was performed to estimate the effect size of the relationship between clinical and radiological findings. RESULTS: Two hundred eighty-four patients (mean age 58.5, 119 (42 %) females) were enrolled. None of the radiological grading scales were significantly associated with any of the subjective or objective clinical tests. There was a tendency for higher VAS back pain (3.48 vs. 4.14, p = 0.096) and lower SF-12 physical component scale (31.2 vs. 29.4, p = 0.065) in patients with high PFI (4-5) as compared to patients with low PFI (0-3). In the multivariate analysis, patients with MOD changes of the vertebral endplates were 100 % as likely as patients without changes to show an impaired TUG test performance (odds ratio (OR) 1.00, 95 % confidence interval (CI) 0.56-1.80, p = 0.982). Patients with high PFI were 145 % as likely as those with low PFI to show an impaired TUG test performance (OR 1.45, 95 % CI 0.79-2.66, p = 0.230). CONCLUSIONS: There was no association between established outcome questionnaires of symptom severity and two widely used radiological classifications in patients undergoing surgery for lumbar DDD.

Late inflammatory and thrombotic changes in irradiated hearts of C57BL/6 wild-type and atherosclerosis-prone ApoE-deficient mice.

BACKGROUND AND PURPOSE: Radiation-induced heart disease represents a late complication of thoracic radiotherapy. We investigated the inflammatory and thrombotic response after local heart irradiation in wild-type and atherosclerosis-prone mice. MATERIAL AND METHODS: Atherosclerosis-prone ApoE(-/-) and C57BL/6 wild-type mice were sacrificed 20, 40, and 60 weeks after irradiation with 0.2, 2, 8, or 16 Gy. The expression of CD31, vascular cell adhesion molecule-1 (VCAM-1), thrombomodulin (TM), and CD45 were quantified by immunofluorescence staining of heart tissue sections. RESULTS: Microvascular density decreased at 40 weeks after 16 Gy in C57BL/6 but not in ApoE(-/-) mice. CD31 expression declined in C57BL/6 mice at 40 weeks (8 Gy), but increased in ApoE(-/-) mice at 20 (2/8/16 Gy) and 60 weeks (16 Gy). Capillary area decreased in C57BL/6 at 40 weeks (8/16 Gy) but increased in ApoE(-/-) mice at 20 weeks (16 Gy). Endocardial VCAM-1 expression remained unchanged. TM-positive capillaries decreased at 40 weeks (8/16 Gy) in C57BL/6 and at 60 weeks (2/16 Gy) in ApoE(-/-) mice. Leukocyte infiltration transiently rose 40 weeks after 8 Gy (only ApoE(-/-)) and 16 Gy. After receiving a low irradiation dose of 0.2 Gy, no significant changes were observed in any of the mouse models. CONCLUSION: This study demonstrated that local heart irradiation affects microvascular structure and induces inflammatory/thrombotic responses in mice in a dose- and time-dependent manner. Thereby, significant prothrombotic changes were found in both strains, although they were progressive in ApoE(-/-) mice only. Proinflammatory responses, like the increase of adhesion molecules and leukocyte infiltration, were more pronounced and occurred at lower doses in ApoE(-/-) vs. C57BL/6 mice. These findings indicate that metabolic risk factors, such as decreased ApoE lipoproteins, may lead to an enhanced proinflammatory and prothrombotic late response in locally irradiated hearts.

[Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation]. / Perampanel in der Behandlung eines Patienten mit Glioblastoma multiforme ohne IHD-1-Mutation und ohne MGMT-Promotor-Methylierung.

Malignant gliomas like glioblastoma multiforme (GBM) release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. We report the case of a patient with GBM treated with the AMPA receptor blocker Perampanel (PER) in combination therapy for partial seizures. Histological work-up of a biopsy showed the tissue of a GBM without mutation of the isocitrate dehydrogenase 1 (IDH1) and without promotor methylation of the O6-methylguanine-DNA methyltransferase (MGMT). In a group of patients with IDH 1 wild type and non-methylated MGMT a median survival of 199 days after surgery (i. e. 6.5 months) was described. Our patient lived about one year longer. PER rendered our patient seizure-free for at least the last seven months of his life. It was well tolerated and did not increase the toxicity of temozolomide. When choosing an antiepileptic drug (AED) for the treatment of seizures in patients with malignant brain tumors, the efficacy, the tolerability and perhaps possible effects on tumor progression of the AED should be taken into account.

Late effects of local irradiation on the expression of inflammatory markers in the Arteria saphena of C57BL/6 wild-type and ApoE-knockout mice.

Combined action of irradiation (IR), shear stress, and high blood pressure is well recognized to induce damage to vasculature, while data on pathological effects of IR in large peripheral vessels with low blood pressure are scarce. The purpose of the present study was hence to investigate time- and dose-dependent effects of local IR on inflammatory and prothrombotic processes in the Arteria (A.) saphena of C57BL/6 wild-type and apolipoprotein E (ApoE)-knockout mice. Single doses of 2, 5, 8, 10, or 16 Gy were locally delivered to the A. saphena of the left leg of the animals. The expression of CD31, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and thrombomodulin (TM) was quantified by semiautomatic TissueFax fluorescence analysis in frozen arterial sections. Follow-up periods were 3, 6, 9, 12, or 18 months. Protein expression in the arterial wall displayed dose-dependent changes. Proinflammatory reactions were observed for CD31, E-selectin, ICAM, and VCAM already at doses of 2 Gy. Anti-inflammatory changes were detected for MCP-1 and TM. The effects were more pronounced in wild-type versus ApoE(-/-) mice. Changes remain mostly transient up to 16 Gy. Dose- and time-dependent changes in inflammatory and thrombotic mediators in the wall of the A. saphena were found after local IR but did not transform into histopathological consequences.

Role of choline PET/CT in guiding target volume delineation for irradiation of prostate cancer.

Choline PET/CT has shown limitations for the detection of primary prostate cancer and nodal metastatic disease, mainly due to limited sensitivity and specificity. Conversely in the restaging of prostate cancer recurrence, choline PET/CT is a promising imaging modality for the detection of local regional and nodal recurrence with an impact on therapy management. This review highlights current literature on choline PET/CT for radiation treatment planning in primary and recurrent prostate cancer. Due to limited sensitivity and specificity in differentiating between benign and malignant prostatic tissues in primary prostate cancer, there is little enthusiasm for target volume delineation based on choline PET/CT. Irradiation planning for the treatment of single lymph node metastases on the basis of choline PET/CT is controversial due to its limited lesion-based sensitivity in primary nodal staging. In high-risk prostate cancer, choline PET/CT might diagnose lymph node metastases, which potentially can be included in the conventional irradiation field. Prior to radiation treatment of recurrent prostate cancer, choline PET/CT may prove useful for patient stratification by excluding distant disease which would require systemic therapy. In patients with local recurrence, choline PET/CT can be used to delineate local sites of recurrence within the prostatic resection bed allowing a boost to PET-positive sites. In patients with lymph node metastases outside the prostatic fossa and regional metastatic lymph nodes, choline PET/CT might influence radiation treatment planning by enabling extension of the target volume to lymphatic drainage sites with or without a boost to PET-positive lymph nodes. Further clinical randomized trials are required to assess treatment outcomes following choline-based biological radiation treatment planning in comparison with conventional radiation treatment planning.

Calcifying pseudoneoplasms of the neuraxis (CAPNON): clinical features and therapeutic options.

INTRODUCTION: Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare, slow-growing lesions occurring anywhere in the central nervous system (CNS). Since their first description in 1978, only 39 cases have been reported in the literature. METHODS: The cases of two patients with histopathologically verified diagnoses of CAPNON are presented. Thereafter, we review all reports published so far with respect to study type, number of patients, anatomical area (intracranial, spinal, or both), clinical presentation, radiological presentation, therapy, duration of follow-up, incidence and type of complication, and outcome. Furthermore, current recommendations for the management of spinal and cerebral CAPNON are discussed. RESULTS: A total of 19 retrospective articles were identified and selected for review: 6 case series (31.6 %) and 13 reports of single cases (68.4 %). The 19 articles and our two additional cases added up to a total of 19 patients with spinal CAPNON and 22 patients with intracranial CAPNON. All patients were treated surgically. A follow-up was provided in 13 patients with spinal (68.4 %) and in 16 patients with intracranial CAPNON (72.7 %), respectively. The follow-up showed no signs of recurrence in 12 of 13 patients with spinal CAPNON (92.3 %) and in 15 of 16 patients with intracranial CAPNON (93.7 %). One-tailed Fisher's exact test revealed no significant difference between complete and incomplete resection in terms of disease recurrence (spinal: p = 0.6842; intracranial: p = 0.3749). Analysis of the literature did not reveal any deaths directly associated with CAPNON. CONCLUSIONS: Calcifying pseudoneoplasms are rare benign lesions of the CNS of yet unknown origin. Because of the increasing number of reports, this clinical entity should be taken into consideration in the differential diagnosis of intracranial and intraspinal calcified lesions.

[Radiation-related caries: etiology and possible preventive strategies. What should the radiotherapist know?]. / Radiogene Karies: Ätiologie und Möglichkeiten der Prävention. Was sollte der Strahlentherapeut wissen?

BACKGROUND: After radiation treatment of head-and-neck cancer, the impairment of patient's quality of life still remains an issue. After completion of the treatment course, a substantial number of patients develop so-called radiation caries. In addition, almost 50% of all cases of infectious osteoradionecrosis (iORN) of the jaws are directly associated with radiation caries. This review addresses our current knowledge on the etiology and pathogenesis of radiation caries including possible preventive strategies. MATERIALS AND METHODS: A PubMed search using the terms "radiation caries" ("radiation related caries", "radiation related damage to dentition") and "radiogenic caries" ("postradiation caries", "dental complications and radiotherapy") was performed. The analysis of its content focused on the etiology, the pathogenesis, and the available knowledge on prophylaxis as well as treatment of radiation caries. RESULTS: For this review, 60 publications were selected. As main causal factors for radiogenic caries, either indirect impairment, resulting from alterations in the oral environment (e.g., radiation-induced xerostomia) or direct radiation-induced damage in teeth hard tissues are discussed. Radiation caries remains a lifelong threat and, therefore, requires permanent prevention programs. CONCLUSION: To enable optimal medical care of the patients during the time course of radiotherapy as well as afterwards, close interdisciplinary cooperation between radiotherapists, oral surgeons, otorhinolaryngologists, and dentists is absolutely essential.

Chemoradiotherapy duration correlates with overall survival in limited disease SCLC patients with poor initial performance status who successfully completed multimodality treatment.

BACKGROUND AND PURPOSE: Limited data concerning treatment-related prognostic factors in limited disease (LD) small-cell lung cancer (SCLC) patients with poor initial performance status (PS) who successfully completed chemoradiotherapy (CRT) are available. PATIENTS AND METHODS: A total of 125 patients with initial PS WHO 2-3 who successfully completed CRT were retrospectively reviewed. Thoracic radiation therapy (TRT) was applied in the concurrent (group 1) or sequential (group 2) mode. Influence of treatment type, time from diagnosis to start of TRT, number of chemotherapy cycles, prophylactic cranial irradiation (PCI), occurrence of brain metastases (BMs), and duration of CRT on overall survival (OS) were analyzed. RESULTS: Median duration of CRT was 156 days in group 1 and 195 days in group 2 (p < 0.001). Median progression-free survival and OS were 11.6 (95% confidence interval (CI) 10-13.2) and 14.9 (95% CI 11.7-17.6) months with no difference between the groups. The 2- and 3-year survival rates were 37.9 ± 6.9% and 22.7 ± 6.3% in group 1 and 22.4 ± 4.9% and 15.2 ± 4.3% in group 2, respectively. Duration of CRT was only treatment-related factor predicting OS in the uni- (p < 0.014) and multivariate (p < 0.025) analyses. Short dose-dense CRT was associated with improved OS. CONCLUSION: Duration of CRT affects OS in LD SCLC patients with poor initial performance status who successfully completed multimodality treatment.

Radiosensitizing effect of epothilone B on human epithelial cancer cells.

BACKGROUND: A combined modality treatment employing radiation and chemotherapy plays a central role in the management of solid tumors. In our study, we examined the cytotoxic and radiosensitive effect of the microtubule stabilizer epothilone B on two human epithelial tumor cell lines in vitro and its influence on the microtubule assembly. METHODS: Cancer cells were treated with epothilone B in proliferation assays and in combination with radiation in colony-forming assays. For the analysis of ionizing radiation-induced DNA damage and the influence of the drug on its repair a γH2AX foci assay was used. To determine the effect of epothilone B on the microtubule assembly in cells and on purified tubulin, immunofluorescence staining and tubulin polymerization assay, respectively, were conducted. RESULTS: Epothilone B induced a concentration- and application-dependent antiproliferative effect on the cells, with IC(50) values in the low nanomolar range. Colony forming assays showed a synergistic radiosensitive effect on both cell lines which was dependent on incubation time and applied concentration of epothilone B. The γH2AX assays demonstrated that ionizing radiation combined with the drug resulted in a concentration-dependent increase in the number of double-strand breaks and suggested a reduction in DNA repair capacity. Epothilone B produced enhanced microtubule bundling and abnormal spindle formation as revealed by immunofluorescence microscopy and caused microtubule formation from purified tubulin. CONCLUSION: The results of this study showed that epothilone B displays cytotoxic antitumor activity at low nanomolar concentrations and also enhances the radiation response in the tumor cells tested; this may be induced by a reduced DNA repair capacity triggered by epothilone B. It was also demonstrated that epothilone B in fact targets microtubules in a more effective manner than paclitaxel.

Isolated cerebral manifestation of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges.

We present the case of a 49-year-old male patient with Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) limited to the brain that occurred 6 months after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical symptoms included mental confusion, ataxia, and diplopia. Magnetic resonance imaging (MRI) revealed cerebellar and periventricular lesions consistent with an inflammatory process. Cerebrospinal fluid (CSF) analysis, but not peripheral blood, was positive for EBV-DNA, but no malignant cells were found. Brain biopsy was not feasible because of low platelet counts. As we considered a diagnosis of either EBV-associated encephalitis or PTLD, the patient was treated with rituximab combined with antiviral therapy. However, the cerebral lesions progressed and follow-up CSF testing revealed immunoglobulin H clonality as evidence of a malignant process. Subsequent treatment attempts included 2 donor lymphocyte infusions (DLI). Despite treatment, the patient died from autopsy-proven PTLD within 8 weeks of the onset of symptoms. This case demonstrates the clinical and diagnostic challenges of primary cerebral PTLD in a patient following allogeneic HSCT.

Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia.

T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTMox32E) to suppress CLL IL-10. MTMox32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the Eµ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8+ T-cell proliferation, effector and memory cell prevalence, and interferon-γ production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared to anti-PD-L1 alone. Combination therapy also produced more interferon-γ+, cytotoxic effector KLRG1+, and memory CD8+ T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.

Successful treatment of Scedosporium apiospermum soft tissue abscess with caspofungin and voriconazole in a severely immunocompromised patient with acute myeloid leukemia.

We report the case of a 53-year-old female patient with refractory acute myeloid leukemia developing a necrotic, soft tissue abscess on the right forearm caused by Scedosporium apiospermum during prolonged severe neutropenia (absolute white blood cell count <500/µL for 49 days). In the context of the severely immunocompromised state of the patient and her need for allogeneic hematopoietic stem cell transplantation (HSCT), surgical treatment options were not favored. Therefore, combined antifungal therapy with voriconazole and caspofungin was started, based on the results of the in vitro testing (minimum inhibitory concentrations of voriconazole, posaconazole, and amphotericin B: 1, 4, and >2mg/L, respectively). The local site of infection slowly improved clinically and no spread of S. apiospermum infection to other sites was observed. After HSCT, the soft tissue abscess resolved completely and the patient has remained free of S. apiospermum infection since then. We successfully demonstrate that the use of combined antifungal therapy with voriconazole and casopfungin may further improve the clinical course and provides a promising therapeutic option to treat Scedosporium infections in such patients.

Transgenerational developmental effects and genomic instability after X-irradiation of preimplantation embryos: studies on two mouse strains.

Recent results have shown that irradiation of a single cell, the zygote or 1-cell embryo of various mouse strains, could lead to congenital anomalies in the fetuses. In the Heiligenberger strain, a link between the radiation-induced congenital anomalies and the development of a genomic instability was also suggested. Moreover, further studies showed that in that strain, both congenital anomalies and genomic instability could be transmitted to the next generation. The aim of the experiments described in this paper was to investigate whether such non-targeted transgenerational effects could also be observed in two other radiosensitive mouse strains (CF1 and ICR), using lower radiation doses. Irradiation of the CF1 and ICR female zygotes with 0.2 or 0.4Gy did not result in a decrease of their fertility after birth, when they had reached sexual maturity. Moreover, females of both strains that had been X-irradiated with 0.2Gy exhibited higher rates of pregnancy, less resorptions and more living fetuses. Additionally, the mean weight of living fetuses in these groups had significantly increased. Exencephaly and dwarfism were observed in CF1 fetuses issued from control and X-irradiated females. In the control group of that strain, polydactyly and limb deformity were also found. The yields of abnormal fetuses did not differ significantly between the control and X-irradiated groups. Polydactyly, exencephaly and dwarfism were observed in fetuses issued from ICR control females. In addition to these anomalies, gastroschisis, curly tail and open eye were observed at low frequencies in ICR fetuses issued from X-irradiated females. Again, the frequencies of abnormal fetuses found in the different groups did not differ significantly. In both CF1 and ICR mouse strains, irradiation of female zygotes did not result in the development of a genomic instability in the next generation embryos. Overall, our results suggest that, at the moderate doses used, developmental defects observed after X-irradiation of female zygotes of these two sensitive mouse strains should not be transmitted to the next generation. Paradoxically, other studies would be needed to address the question of a potential increase of fertility after doses lower than 0.2Gy in both strains.