Invasive mucormycosis during treatment for acute lymphoblastic leukaemia-successful management of two life-threatening diseases.

A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).

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.

Comparative proteomic analysis of ductal and lobular invasive breast carcinoma.

Breast cancer is the second most common cancer worldwide and the first among women. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two major histological subtypes, and the clinical and molecular differences between them justify the search for new markers to distinguish them. As proteomic analysis allows for a powerful and analytical approach to identify potential biomarkers, we performed a comparative analysis of IDC and ILC samples by using two-dimensional electrophoresis and mass spectrometry. Twenty-three spots were identified corresponding to 10 proteins differentially expressed between the two subtypes. ACTB, ACTG, TPM3, TBA1A, TBA1B, VIME, TPIS, PDIA3, PDIA6, and VTDB were upregulated in ductal carcinoma compared to in lobular carcinoma samples. Overall, these 10 proteins have a key role in oncogenesis. Their specific functions and relevance in cancer initiation and progression are further discussed in this study. The identified peptides represent promising biomarkers for the differentiation of ductal and lobular breast cancer subtypes, and for future interventions based on tailored therapy.

[Normal and Adventitious Breath Sounds]. / Atemgeräusche und Atem-Nebengeräusche.

Auscultation of the lung is an inexpensive, noninvasive and easy-to-perform tool. It is an important part of the physical examination and is help ful to distinguish physiological respiratory sounds from pathophysiological events. Computerized lung sound analysis is a powerful tool for optimizing and quantifying electronic auscultation based on the specific lung sound spectral characteristics. The automatic analysis of respiratory sounds assumes that physiological and pathological sounds are reliably analyzed based on special algorithms. The development of automated long-term lungsound monitors enables objective assessment of different respiratory symptoms.

PDIA3 and PDIA6 gene expression as an aggressiveness marker in primary ductal breast cancer.

Changes in the expression of the protein disulfide isomerase genes PDIA3 and PDIA6 may increase endoplasmic reticulum stress, leading to cellular instability and neoplasia. We evaluated the expression of PDIA3 and PDIA6 in invasive ductal carcinomas. Using reverse transcription-quantitative polymerase chain reaction, we compared the mRNA expression level in 45 samples of invasive ductal carcinoma with that in normal breast samples. Increased expression of the PDIA3 gene in carcinomas (P = 0.0009) was observed. In addition, PDIA3 expression was increased in tumors with lymph node metastasis (P = 0.009) and with grade III (P < 0.02). The PDIA6 gene showed higher expression levels in the presence of lymph node metastasis (U = 99.00, P = 0.0476) and lower expression for negative hormone receptors status (P = 0.0351). Our results suggest that alterations in PDIA3/6 expression levels may be involved in the breast carcinogenic process and should be further investigated as a marker of aggressiveness.

[What is Important for Diagnosis and Therapy Follow-up in Chronic Cough?]. / Was ist für die Diagnostik und Therapieverlaufskontrolle von chronischem Husten wichtig?

Within the last years there has been significant progress in the field of chronic cough. So far, the analysis and evaluation of chronic cough was done mainly on the basis of subjective methods such as manual counts of cough events, questionnaires and diaries. Testing cough hypersensitivity and monitoring 24 h cough represent objective criteria. Validated questionnaires on cough frequency and quality of life represent the impact of chronic cough. Cough frequency monitoring, the preferred tool to objectively assess cough, should be used as primary end-point in clinical trials. It will also be possible to discriminate between productive and non-productive cough. The relationship with subjective measures of cough is weak. In the future, cough and its therapy should therefore be assessed with a combination of subjective and objective tools.

A family of secreted pathogenesis-related proteins in Candida albicans.

Analysing culture supernatants of yeast and hyphal cells of Candida albicans, we found two close homologues of pathogenesis-related (PR-) 1 proteins, Rbe1p and Rbt4p, in the secretome. Due to sequence homology, three additional, yet not characterized open reading frames, ORF19.6200, ORF19.2787 and ORF19.2336, together with RBE1 and RBT4 were assigned to a novel family of CaPRY proteins. In a Δrbe1/Δrbt4 deletion strain, genome-wide transcriptional analysis revealed differential transcription of only a limited set of genes implicated in virulence and oxidative stress response. Single deletion of RBE1 or RBT4 in a clinical C. albicans isolate resulted in a moderate but significant attenuation in virulence in a mouse model for disseminated candidiasis. However, a synergistic effect was observed in a Δrbe1/Δrbt4 double deletion strain, where virulence was strongly affected. Remarkably, transcription of RBT4 and RBE1 was each upregulated in blastospores of Δrbe1 or hyphae of Δrbt4 deletion strains respectively, indicating functional complementation thereby compensating a potential virulence defect in the single deletion strains. Furthermore, the double deletion strain showed increased sensitivity to attack by polymorphonuclear leucocytes. Therefore, the crucial contribution of both C. albicans pathogenesis-related proteins to virulence might be vested in protection against phagocyte attack.

Primary renal neuroblastoma metastasizing into liver and lungs with tumor thrombus extension into the right atrium.

Neuroblastomas are malignant tumors of the sympathetic nervous system. Areas of manifestation most commonly involve the abdomen, neck, thorax and pelvis. Primary renal neuroblastomas are extremely rare, only a few case reports exist worldwide, and even those are discussed controversially.We present the case of a 6-year-old girl with a renal tumor and a tumor thrombus extending into the right atrium, which radiologically appeared to be a Wilms tumor. Since the lesion did not respond to nephroblastoma-specific therapy, a biopsy from one of the liver metastases was taken, revealing the revised diagnosis of a clear cell renal cell carcinoma. Histopathology of the reference center, however, described a primary renal neuroblastoma. After adjusting the chemotherapy tumornephrectomy including the complete venous thrombus could be performed without any complications.Neuroblastoma originating from a kidney is an absolute rarity that can easily be misdiagnosed as Wilms tumor, especially, if a typical tumor thrombus with extension into the inferior vena cava is seen. Therefore neuronspecific enolase in serum as well as vanillylmandelic acid and homovanillic acid in the urine should be determined in all patients when Wilms tumor is assumed. To the best of our knowledge, this is the first published case of a primary renal neuroblastoma with a tumor thrombus extending into the right atrium.

Novel case of combination antibiotic therapy for treatment of a complicated polymicrobial urinary tract infection with one organism harboring a metallo-ß-lactamase (MBL) in a pregnant patient.

Carbapenem resistance due to metallo-beta-lactamases (MBLs) is a global phenomenon and an important challenge for antibiotic therapy (Boyd et al., 2020 [1]). While previous reports have demonstrated both in vitro and in vivo synergy using the combination of ceftazidime-avibactam and aztreonam against Stenotrophomonas maltophilia, an MBL-harboring organism, this treatment strategy has not been reported during pregnancy (Mojic et al., 2017 [2], [3], Mojica et al., 2016 [4], Alexander et al., 2020 [5]). We describe a 33-year-old pregnant female with polymicrobial, bilateral pyelonephritis caused by Stenotrophomonas maltophilia and other gram-negative bacteria. The organisms were eradicated with the combination of ceftazidime-avibactam and aztreonam followed by successful delivery with no observed adverse effects in either mother or child post-partum.

Incidence and clinical course of radionecrosis in children with brain tumors. A 20-year longitudinal observational study.

Radionecrosis (RN) in children treated for brain tumors represents a potentially severe long-term complication. Its diagnosis is challenging, since magnetic resonance imaging (MRI) cannot clearly discriminate between RN and tumor recurrence. A retrospective single-center study was undertaken to describe the incidence and clinical course of RN in a cohort of 107 children treated with external radiotherapy (RT) for various brain tumors between 1992 and 2012. During a median follow-up of 4.6 years (range 0.29-20.1 years), RN was implied by suspicious MRI findings in in 5 children (4.7 %), 5-131 months after RT. Suspicion was confirmed histologically (1 patient) or substantiated by FDG positron-emission tomography (FDG-PET, 2 patients) or by FDG-PET and MR spectroscopy (1 patient). Before developing RN, all 5 patients had received cytotoxic chemotherapy in addition to RT. In addition to standard treatment protocols, 2 patients had received further chemotherapy for progression or relapse. Median radiation dose expressed as the biologically equivalent total dose applied in 2 Gy fractions (EQD2) was 51.7 Gy (range 51.0-60.0 Gy). At RN onset, 4 children presented with neurological symptoms. Treatment of RN included resection (n = 1), corticosteroids (n = 2) and a combination of corticosteroids, hyperbaric oxygen (HBO) and bevacizumab (n = 1). One patient with asymptomatic RN was not treated. Complete radiological regression of the lesions was observed in all patients. Clinical symptoms normalized in 3 patients, whereas 2 developed permanent severe neurological deficits. RN represents a severe long-term treatment complication in children with brain tumors. The spectrum of clinical presentation is wide; ranging from asymptomatic lesions to progressive neurological deterioration. FDG-PET and MR spectroscopy may be useful for distinguishing between RN and tumor recurrence. Treatment options in patients with symptomatic RN include conservative management (steroids, HBO, bevacizumab) and surgical resection.

Hemophagocytic syndrome in children with acute monoblastic leukemia-another cause of fever of unknown origin.

PURPOSE: Intensification of antileukemic treatment and progress in supportive management have improved the survival rates of children with acute myeloid leukemia (AML). However, morbidity and early mortality in these patients are still very high, especially in children with acute monoblastic leukemia (AML FAB M5). Inflammatory syndromes complicating the management of these children after application of cytosine arabinoside and due to hyperleukocytosis at initial presentation have been reported. Hemophagocytic lymphohistiocytosis (HLH) has been described as a serious and life-threatening acute complication during treatment of different oncologic entities; however, data on HLH in children with AML FAB M5 are extremely rare. METHODS: A retrospective study of all children with AML FAB M5 treated at our institution between 1993 and 2013 was performed to describe the clinical characteristics of patients who developed an inflammatory syndrome with HLH during oncologic treatment. RESULTS: Three of 10 children developed an inflammatory syndrome with fever, elevation of C-reactive protein, hyperferritinemia, elevation of soluble interleukin-2, and hemophagocytosis during prolonged aplasia following the first cycle of chemotherapy not responding to broad-spectrum antibiotics. No infectious agents could be identified; the initial symptoms occurred 17, 18, and 28 days after diagnosis of AML, respectively. The children immediately responded to dexamethasone; however, the same syndrome was observed again after the second cycle of chemotherapy and, in one patient, also after the third cycle. CONCLUSIONS: Treating physicians should be aware of an inflammatory syndrome resembling HLH in children with monoblastic leukemia since this problem might extremely complicate management and supportive care of these children. The co-incidence of monoblastic leukemia with HLH might be explained by cytokines released from the monoblastic leukemic cells themselves.

Comparison between fibroblasts and mesenchymal stem cells derived from dermal and adipose tissue.

OBJECTIVE: Stem cells have the ability to renew themselves and differentiate into various cell types. For this reason, numerous research groups have been studying these cells for their therapeutic potential. Some of the therapies, however, are not producing the expected results because of contamination by other cell types, especially by fibroblasts. In the cosmetic industry, stem cells are used to test the efficacy of anti-ageing and rejuvenation products. The purpose of this work was to gain a better understanding of the differences in phenotype, in gene expression associated with stem cells, in the pattern of cell surface proteins and in the differentiation capacity of adipose-derived stem cells, of skin-derived stem cells and of commercially available fibroblasts. METHODS: In this study, we compared fibroblasts with mesenchymal stem cells derived from bone marrow, skin (dermis) and adipose tissue, to assess the differentiation potential of fibroblasts. Dermal and adipose stem cells were isolated from aesthetic surgery patients, and fibroblasts were obtained from a commercial source. The following parameters were used in this study: immunophenotypic profile (positive: CD29, CD73, CD90 and CD105; negative: CD14, CD45 and HLA-DR); differentiation into osteoblastic, chondrogenic and adipogenic cell types; and PCR array to analyse the gene expression of cells isolated from different culture passages. RESULTS: Fibroblasts express the same cell immunophenotypic markers, as well as the genes that are known to be expressed in stem cells, and were shown to be expressed also in adipose and dermis stem cells. Fibroblasts are also able to differentiate into the three cell lineages mentioned above, that is, adipocytes, osteocytes and chondrocytes. CONCLUSION: Human dermal fibroblasts have a potential to adhere to plastic surfaces and differentiate into other cell types. However, for stem cells intended to be used in cosmetics, experiments conducted with contaminated fibroblasts may produce poor or even falsely negative results for the efficacy of the active ingredient or formulation and thus conceal their promising effects as anti-ageing and skin rejuvenation products.

Increased incidence of aberrant DNA methylation within diverse imprinted gene loci outside of IGF2/H19 in Silver-Russell syndrome.

Almost half of the patients with Silver-Russell syndrome (SRS) are affected by DNA hypomethylation of the Imprinting Center Region 1 (ICR1) at the IGF2/H19 locus on 11p15. We searched genome-wide for additional aberrant DNA methylation in such SRS patients that could account for the clinical variability of the disorder. For this purpose, 18 children with SRS (11 with ICR1 hypomethylation) and 9 children small for gestational age (SGA), serving as controls, were recruited. Genomic DNA from whole blood was subjected to microarray analysis with the HumanMethylation27 BeadChip. This array allows investigating 27,500 CpG sites mostly located in the promoter regions of 14,000 genes. Data were validated by the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) technique for the 11p15 region. SRS patients with ICR1 hypomethylation were significantly more frequently affected by DNA hypo- and hypermethylation of CpG sites from diverse imprinted loci than the SGA controls (p = 0.0048). There was no recurrent specific methylation defect outside of IGF2/H19. These findings suggest as causative in SRS a defective mechanism necessary for establishment or maintenance of imprinting marks, which affects imprinted loci in general with low specificity and the IGF2/H19 locus with high specificity, implying the existence of some structural peculiarities at the IGF2/H19 locus.

Fatal EBV infection and variable clinical manifestations in an XLP-1 pedigree - rapid diagnosis of primary immunodeficiencies may save lives.

Two related boys who died from fulminant infectious mononucleosis were diagnosed with X-linked lymphoproliferative disease type 1 (XLP-1). Family screening (n=17) identified 6 female mutation carriers and 2 more XLP-1 patients in whom, despite recurrent infections, agammaglobulinemia, and Hodgkin's Disease, the genetic basis had been unknown; demonstrating that awareness and early genetic testing are crucial to reveal underlying primary immunodeficiencies and improve outcome. Furthermore, XLP should be included routinely in the differential diagnosis of severe hypogammaglobulinemia and/or lymphoma in males.

Granulomatous amebic encephalitis in a child with acute lymphoblastic leukemia successfully treated with multimodal antimicrobial therapy and hyperbaric oxygen.

Acanthamoeba is the causative agent of granulomatous amebic encephalitis, a rare and usually fatal disease. We report a child with acute lymphoblastic leukemia who developed brain abscesses caused by Acanthamoeba during induction therapy. Multimodal antimicrobial chemotherapy and hyperbaric oxygen therapy resulted in complete resolution of symptoms and of pathology as seen by magnetic resonance imaging.

Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome.

Parvovirus B19 (PVB19) induced severe aplastic anaemia (SAA) or myelodysplastic syndrome (MDS) is rare, and haematopoietic stem cell transplantation (HSCT) in this condition has not been reported so far. 6 children with SAA (n=4) or MDS (n=2) caused by acute PVB19 infection underwent HSCT under the protection of intravenous immunoglobulines. The 4 children with SAA received matched HLA bone marrow from a sibling (n=3) or peripheral unrelated blood stem cells (n=1). 1 patient had delayed erythrocyte engraftment, whereas 3 patients had an uneventful transplantation course. HSCT in one of the 2 children with MDS was complicated by poor graft function, the other patient engrafted without complications. In conclusion, HSCT in children with PVB19 induced SAA or MDS is feasible, even though some patients may develop delayed engraftment or prolonged poor graft function.

Proteomic analysis of non-tumoral breast tissue.

Breast cancer is a complex and heterogeneous disease. In spite of the advances made in recent decades, a better understanding of the intrinsic mechanisms of this disease is crucial. The development of new biomarkers is absolutely necessary to improve diagnosis and prognosis. Research using the proteomic approach has generated interesting results; however, the complexity of the mammary gland and of breast tumors remains a major limitation to the development of new markers. An initial step is to characterize non-tumoral human breast tissue. We present data from classical proteomic analysis based on 2-D electrophoresis and peptide mass fingerprinting identification, which were performed on six non-tumoral samples from patients with invasive ductal breast carcinomas. Forty-four different proteins from 70 spots were identified and classified according to their biological function. Cytoskeleton and associated proteins represent the largest class (30%) followed by the proteins with binding function (27%). Several of the proteins have been described in breast tumors, such as vimentin, endoplasmin, small heat shock beta-6, disulfide isomerase and some cell growth, and proliferation regulators, suggesting the importance of including data on the characterization of non-tumoral breast and to studies on differential expression in cancer tissue.

Novel double beta-lactam therapy for Granulicatella adiacens infective endocarditis.

Granulicatella adiacens, a nutritionally variant streptococci (NVS) is a well described organism associated with endocarditis. Previously communicated cases have documented the use of double beta-lactam therapy with ampicillin and ceftriaxone to treat patients with infective endocarditis due to Enterococcus faecalis and Streptocossus pneumoniae. We describe the first case of Granulicatella adiacens infective endocarditis in a patient successfully treated with the combination of intravenous ampicillin and ceftriaxone and document their synergistic activity.

Edwardsiella tarda, a rare human pathogen isolated from a perihepatic abscess: Implications of transient versus long term colonization of the gastrointestinal tract.

Although gastroenteritis is the most commonly described manifestation of Edwardsiella tarda infection, the pathogenesis and transient or long-term colonization of the gastrointestinal tract of this organism in human disease is not clear. We describe a rare manifestation of E. tarda infection in a perihepatic abscess in the setting of a patient with perforated cholecystitis and its successful eradication following antibiotic treatment.