Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET ≥ 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH-HD2002 trial.

PURPOSE: In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH-HD2002 trial for pediatric Hodgkin lymphoma (PHL). PATIENTS/METHODS: Pairwise FDG-PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. RESULTS: Patients with a qPET value ≥ 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%). CONCLUSION: Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given.

[The innate immune system in oropharyngeal squamous cell carcinoma : Immune modulation by HPV]. / Das angeborene Immunsystem beim Oropharynxkarzinom : Immunmodulation durch HPV.

Based on clinical and experimental data, oropharyngeal squamous cell carcinomas (OPSCC) associated with human papillomavirus (HPV) have been recognized as a distinct entity of head and neck cancers. However, outside of clinical trials, HPV status currently has no impact on treatment. The natural replication cycle of HPV takes place in epithelial cells, and is thus spatially separated from cytotoxic immune cells in the epidermis. Dendritic cells (Langerhans cells, LC), however, are frequent in this upper dermal layer. The ability of LC to process antigens, migrate, and, ultimately activate T cells is inhibited by the activity of the viral oncoproteins (E5-E7). Downregulation of functional human leukocyte antigen I (HLA-I) epithelial cell surface expression contributes to LC inhibition. However, due to their absence in upper skin layers, corresponding activation of natural killer (NK) cells via missing-self recognition is not relevant. Genome-wide analyses have revealed specific expression signatures for HPV-associated OPSCC that are distinct from HPV-negative cancers. Interestingly, aberrations in HLA-I genes were common in HPV-associated OPSCC. Our own findings indicate more frequent infiltration of HPV-associated OPSCC by CD56-positive (CD56+) NK cells, which might be related to HLA-I downregulation during HPV-associated carcinogenesis. In patients with OPSCC, CD56 positivity correlates with improved prognosis after conventional therapy. This could be evidence for HPV-associated OPSCC being especially eligible for novel immune-based therapies and an indication that immunological data should be included in the design of clinical trials.

[Disseminated osteolytic lesions in a 28-year-old refugee]. / Disseminierte osteolytische Läsionen bei einem 28-jährigen Flüchtling.

A 28-year-old Syrian refugee presented with right-sided knee pain and progressive deterioration of the general condition over the past months. Laboratory diagnostics revealed severe hypercalcemia due to primary hyperparathyroidism, and computed tomography (CT) scanning demonstrated disseminated osteolytic lesions throughout the skeleton. Histologically, these lesions were characterized by multinuclear giant cells (defining these lesions as so-called brown tumors). Finally, surgical removal of a jugular mass allowed the histopathologic diagnosis of a sporadic parathyroid carcinoma. In the patient, this condition was associated with a mutation in the HPRT2 gene locus.

Lévy Flights due to Anisotropic Disorder in Graphene.

We study transport properties of graphene with anisotropically distributed on-site impurities (adatoms) that are randomly placed on every third line drawn along carbon bonds. We show that stripe states characterized by strongly suppressed backscattering are formed in this model in the direction of the lines. The system reveals Lévy-flight transport in the stripe direction such that the corresponding conductivity increases as the square root of the system length. Thus, adding this type of disorder to clean graphene near the Dirac point strongly enhances the conductivity, which is in stark contrast with a fully random distribution of on-site impurities, which leads to Anderson localization. The effect is demonstrated both by numerical simulations using the Kwant code and by an analytical theory based on the self-consistent T-matrix approximation.

PTPIP51 levels in glioblastoma cells depend on inhibition of the EGF-receptor.

Protein tyrosine phosphatase interacting protein 51 (PTPIP51) is upregulated in glioblastoma multiforme (GBM) and expression levels correlate with the grade of malignancy in gliomas. A similar correlation was reported for its interacting partner 14-3-3ß, which has been shown to facilitate the interaction of PTPIP51 with cRAF (Raf1). Since the interaction of these signalling partners stimulates growth factor signalling downstream of the epidermal growth factor receptor (EGFR), a major drug target in GBM, we here investigated the impact of EGFR inhibition by small molecule inhibitors or monoclonal antibody on PTPIP51. The effect of EGFR inhibition on PTPIP51 mRNA, protein expression and its interaction profile in GBM was analyzed using the U87 cell line as model system. The transferability of the results to in vivo conditions was evaluated in cultured tumour cells from GBM patients. Cells were treated either to the small molecule tyrosine kinase inhibitor of EGFR Gefitinib or the monoclonal antibody Cetuximab in a time and dose dependent manner. Gefitinib treatment decreased the proliferation rate and induced apoptosis in U87 and primary tumour cells. The PTPIP51 interaction profile changed in correlation to the applied Gefitinib. Despite unchanged mRNA levels PTPIP51 protein was reduced. In contrast, treatment with Cetuximab had no effects on PTPIP51 expression. In conclusion, our results demonstrate the impact of EGFR inhibition by Gefitinib on PTPIP51 protein expression, a downstream regulator of MAPK signalling. These data will serve as a basis to unravel the precise role of PTPIP51-mediated signalling in GBM and its potential implications for Gefitinib-mediated therapy in future studies.

[Epithelial neuroendocrine tumors of the upper respiratory tract: New entities, new perspectives]. / Neuroendokrine epitheliale Tumoren des oberen Respirationstrakts : Neue Entitäten, neue Blickwinkel.

Epithelial neuroendocrine tumors of the upper respiratory tract are rare and are classified as typical and atypical carcinoid versus small cell neuroendocrine carcinoma. Furthermore, a giant cell variant of neuroendocrine carcinoma is suggested corresponding to the bronchopulmonary system as well as a recently described subtype of oropharyngeal small cell neuroendocrine carcinoma associated with human papillomavirus. Many arguments relying on clinical as well as on molecular findings indicate that the distinction between carcinoid and poorly differentiated neuroendocrine carcinoma does not only reflect different degrees of differentiation of otherwise related tumors but indicates the existence of substantially different types of neoplasms.

Quantum Hall criticality and localization in graphene with short-range impurities at the Dirac point.

We explore the longitudinal conductivity of graphene at the Dirac point in a strong magnetic field with two types of short-range scatterers: adatoms that mix the valleys and "scalar" impurities that do not mix them. A scattering theory for the Dirac equation is employed to express the conductance of a graphene sample as a function of impurity coordinates; an averaging over impurity positions is then performed numerically. The conductivity σ is equal to the ballistic value 4e2/πh for each disorder realization, provided the number of flux quanta considerably exceeds the number of impurities. For weaker fields, the conductivity in the presence of scalar impurities scales to the quantum-Hall critical point with σ≃4×0.4e2/h at half filling or to zero away from half filling due to the onset of Anderson localization. For adatoms, the localization behavior is also obtained at half filling due to splitting of the critical energy by intervalley scattering. Our results reveal a complex scaling flow governed by fixed points of different symmetry classes: remarkably, all key manifestations of Anderson localization and criticality in two dimensions are observed numerically in a single setup.

[A 75-year-old female patient with pleural effusion and gastric metastases of a poorly differentiated carcinoma]. / 75-jährige Patientin mit Pleuraerguss und gastralen Metastasen eines wenig differenzierten Karzinoms.

A 75-year-old woman was found to have left-sided pleural effusion and endoscopy revealed the rare entity of adenoid cystic carcinoma metastases in the gastric mucosa. Approximately 20% of patients with this carcinoma suffer from distant metastases. For the initial staging detection of adenoid cystic carcinoma metastasis with positron emission tomography (PET) or PET computed tomography (CT) is recommended. The recurrent t(6;9)(q22-23;p23-24) translocation that results in a fusion of the two transcription factor genes MYB and NFIB is detectable in half of the cases. As in our case molecular pathology can confirm the correct diagnosis and identification of the localization of the primary tumor.

[Splenomegaly with multiple unclear parenchymal lesions. Splenomegaly]. / Splenomegalie mit multiplen unklaren Parenchymläsionen. Littoralzellangiom.

A 53-year-old female patient presented with splenomegaly, uncertain lesions of the spleen, pancytopenia and suspected aortitis. Reduced strength and muscular pain but no B symptoms were also present. Alterations of the spleen had been known for a long time. Blood examination, laboratory tests and magnetic resonance imaging (MRI) confirmed an aortitis. Concerning the splenic changes neither ultrasound nor MRI could provide conclusive or even pathognomonic findings. Because of an existing pancytopenia and diagnostic obscurity, the patient underwent splenectomy. The histological diagnosis was finally concluded as multifocal littoral cell angioma.

[Significance of frozen section diagnosis for the management of laryngeal tumors]. / Bedeutung der Schnellschnittdiagnostik für das Management laryngealer Tumoren.

The frozen section procedure for immediate intraoperative pathological diagnosis represents a pivotal method in tumor diagnosis. In laryngeal tumors the most frequent indication for the use of this method is the documentation of the residual tumor status, while intraoperative consultation with the purpose of primary tumor diagnosis is less common. The specimen management employed in each case should be chosen depending on the clinical question: while the collection of a maximum amount of tissue is advisable for the determination of the residual tumor status, sparing a portion of the remaining tissue for possible future examinations is advisable in the case of primary tumor diagnosis. Moreover, intraoperative frozen section diagnosis with no immediate consequences should be avoided.

[Tumor microenvironment in gastrointestinal tumors]. / "Tumor microenvironment" in gastrointestinalen Tumoren.

The growing potential of modern molecular analysis tools has led to a sharp increase in the understanding of the molecular dimension of pathological processes and, consequently, to a growing influence of pathological diagnoses on the selection of therapeutic approaches. Molecular analysis tools have also led to the understanding that groups of tumors hitherto considered to belong to a single, homogeneous disease entity should rather be divided into subgroups with specific molecular attributes, growth behavior patterns and, consequently, different prognostic characteristics and therapeutic needs. A major factor contributing to the differentiation of these subgroups is the composition of the tumor microenvironment (ME), a compartment that is involved in the control of critical carcinogenetic processes such as angiogenesis and invasive growth. Consequently, the investigation of the ME promises to be a most auspicious field of research for pathologists and there is hope that the increased understanding of the interaction between neoplastic cells and the ME will lead to improved diagnostic tools and novel therapeutic approaches for the treatment of cancer patients.

A human recombinant autoantibody-based immunotoxin specific for the fetal acetylcholine receptor inhibits rhabdomyosarcoma growth in vitro and in a murine transplantation model.

Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) gamma-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA). While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms.

[Adoptive T-cell therapy of rhabdomyosarcoma]. / Adoptive T-Zell-Therapie des Rhabdomyosarkoms.

AIMS: To improve survival of patients with advanced rhabdomyosarcomas (RMS), we aimed to adoptively transfer T-cells with redirected specificity for the fetal acetylcholine receptor (AChR), an RMS-specific cell surface antigen. METHODS: A "second generation" chimeric antigen receptor (CAR) with a combined CD28-CD3ζ signaling domain was derived from our previously described chimeric antigen receptor composed of an extracellular human anti-fAChR antibody fragment, an Fc hinge region, and the intracellular T-cell receptor zeta chain. Lymphocytes from the peripheral blood were modified by retroviral transduction and monitored by FACS analysis. Cytotoxicity of modified T-cells towards RMS cells was recorded by MTT-based viability tests; expression of co-stimulatory molecules and anti-apoptotic genes was studied by FACS and qRT-PCR analysis. RESULTS: Co-stimulatory molecules were expressed in low levels on RMS cells giving the rationale to generate a CD28-CD3ζ signalling CAR (chimeric antigen receptor) for redirecting T-cells. T-cells were successfully engineered with the "second generation" AChR-specific chimeric antigen receptor. Despite of high CAR expression engineered T-cells showed low killing efficiency towards RMS compared to redirected killing of CD20+ lymphoma or CEA-expressing adenocarcinoma cell lines when redirected by CD20- and/or CEA-specific CAR. CONCLUSIONS: Data suggest that RMS cells exhibit resistance to a T-cell attack redirected by a fAChR-specific CAR. Inhibition of anti-apoptotic pathways in those cells may improve sensitivity to conventional as well as T-cell-based therapeutics.

[Multifocal manifestation of Rosai-Dorfman disease. A rare case of purely extranodal sinus histiocytosis in the elderly]. / Multifokale Manifestation einer Rosai-Dorfman-Erkrankung. Seltene, rein extranodale Sinushistiozytose im Erwachsenenalter.

Rosai-Dorfman disease belongs to the group of childhood histiocytoses and was initially described as sinus histiocytosis with massive lymphadenopathy. Its rare purely extranodal manifestation is primarily found in the head and neck region. An atypical primary manifestation in an elderly patient with multifocal extranodal disease is described, and this pathological entity is reviewed. Specific difficulties concerning differential diagnostic aspects as well as individually appropriate treatment strategies are discussed.

[Neurofibroma in Children hand - Case Report and Literature Review]. / Neurofibrome an der kindlichen Hand ­ Fallbericht und Literaturrecherche.

Neurofibromas rarely occur before the age of 7 in children. They are a rarity on the hand, especially if they are accompanied by sensory disturbances and impairment of the gripping function. We report on a 9-year-old girl with symptomatic neurofibroma of the third and fourth ray of the right palm.

Neurosurgical aspects of childhood hypophosphatasia.

OBJECTIVE: Hypophosphatasia (HPP; MIM241510) is a rare inborn error of bone metabolism of recessive inheritance. It is caused by mutations in the gene encoding the tissue-nonspecific alkaline phosphatase. Apart from problems in bone mineralization, growth failure, and premature loss of decidual teeth, the infantile and the childhood types of HPP are associated with premature fusion of cranial sutures. PATIENTS: We report on seven children affected with infantile and childhood HPP who presented with craniosynostosis. RESULTS: Neurosurgical intervention was necessary in four of them because of intracranial hypertension. In one of these, severe dural calcification posed an unexpected problem during surgery. Secondary ectopia of the cerebellar tonsils were detected in five of the seven patients and caused hydrosyringomyelia in one of them. CONCLUSIONS: Since cranial sutures are frequently involved in infantile and childhood HPP, a multidisciplinary approach for the clinical care is necessary, including long-term neurosurgical surveillance.

Tumor cell dissemination in a human colon cancer animal model: orthotopic implantation or intraportal injection?

BACKGROUND: The development of therapeutic strategies for treatment of metastasized colorectal carcinoma requires biologically relevant and adequate animal models generating both metastases and the dissemination of tumor cells. METHODS: To prove the efficiency of orthotopic implantation concerning induction of minimal residual disease (MRD) colorectal cancer tissue from 10 patients was transplanted orthotopically into nude mice. In the intraportal injection model 1 x 10(6) HT-29 human colon cancer cells were injected. We investigated by histological studies and CK-20 RT-PCR the occurrence of hematogenous metastases and the dissemination of human colon cancer cells in bone marrow. RESULTS: Following orthotopic implantation of human colon cancer tissue the lymph node and hepatic metastasis rates were low. MRD as reflected by CK-20 positivity of the bone marrow was present in 22.2%. The intraportal injection of 1 x 10(6) HT-29 human colon cancer cells produced hepatic metastases in up to 89% of all animals. The intraportal injection of 1 x 10(6) cells also generated MRD in the bone marrow in 63% of animals. CONCLUSIONS: The intraportal injection model represents a biologically relevant and adequate animal model for the induction of both reproducible hepatic metastasis and MRD in the bone marrow. In this regard it seems to be superior to the orthotopic implantation model.

[CUP syndrome: molecular pathogenesis and biology]. / CUP-Syndrom: Molekulare Pathogenese und Biologie.

Carcinoma of unknown primary (CUP) is an intriguing clinical finding defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical workup. CUP is a relatively common clinical entity, accounting for approximately 3-5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. The mechanisms responsible for early metastasis and lack of a detectable primary tumor are largely unknown. Although remarkable tools have been developed for immunohistological classification of CUP on the basis of the likely tissue of origin, data on molecular pathogenesis and biology of this disorder are rare. A wide variety of chromosomal aberrations are seen in CUP, with aberrations of chromosomes 1, 6, 7, and 11 having been most frequently described. 66-75% of CUP express epidermal growth factor receptor while overexpression of Her2/neu seems to be rare. In contrast to most other tumor entities p53 mutations have been found only in a minority of CUP tumors. Recently, several independent studies have demonstrated proof of principle for the use of gene expression microarrays in identifying a primary site for CUP. Therefore, gene expression and also genomic profiling tools represent promising analytical approaches to assist with the management of CUP patients.

Cutaneous dissemination of nasal NK/T-cell lymphoma in a young girl.

In Europe and the USA, the incidence of primary nasal natural killer (NK)/T-cell lymphoma is rare. The skin is one of the predilection sites for dissemination. Cutaneous dissemination is a poor prognostic sign and is consistently fatal. We describe the case of a 17-year-old white German girl with a primary nasal NK/T-cell lymphoma and cutaneous dissemination. She presented with multiple maculopapular patches involving the trunk and thighs, and a 4-week history of headache, fever and fatigue. Biopsies of the skin and the nasal mucosa were taken. Pathological examination of both specimens revealed a NK/T-cell lymphoma. Epstein-Barr virus RNA was detected in the lymphoma cells by in situ hybridization. Unfortunately, the patient died of disease within 1 week.