Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system. In this article, we report the results of a pilot trial adding rituximab to the established regimen consisting of methotrexate, procarbazine, and lomustine (R-MCP). DESIGN AND METHODS: PCNSL patients ≥65 years without Karnofsky performance score (KPS) limit were included. R-MCP regimen consisted of rituximab (375 mg/m(2) i.v. on days -6, 1, 15, and 29), methotrexate (3 g/m(2) i.v., days 2, 16, and 30) followed by folinic rescue, procarbazine (60 mg/m(2) orally, days 2-11), and lomustine (110 mg/m(2) orally, day 2). A maximum of three 43-day cycles were applied. Primary end point was response to treatment obtained by magnetic resonance imaging. Secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Twenty-eight patients were included (median age 75, median KPS 60%). Best documented response: complete remission in 18 of 28 (64%), partial remission in 5 of 28 (18%), stable disease in 1 of 28 (4%), and progressive disease in 2 of 28 (7%) patients. Response was not assessed in two patients. Two treatment-associated deaths were observed. After a median follow-up of 36 months, the 3-year PFS and OS was 31%. CONCLUSION: R-MCP regimen is well tolerated and active in elderly patients with newly diagnosed PCNSL.

Obstructive sleep apnea and type 2 diabetes.

Type 2 diabetes and obstructive sleep apnea (OSA) are diseases with high prevalence and major public health impact. There is evidence that regular snoring and OSA are independently associated with alterations in glucose metabolism. Thus, OSA might be a risk factor for the development of type 2 diabetes. Possible causes might be intermittent hypoxia and sleep fragmentation, which are typical features of OSA. OSA might also be a reason of ineffective treatment of type 2 diabetes. There is further evidence that the treatment of OSA by continuous positive airway pressure (CPAP) therapy might correct metabolic abnormalities in glucose metabolism. It is assumed that this depends on therapy compliance to CPAP. On the other hand, there are also hints in the literature that type 2 diabetes per se might induce sleep apnea, especially in patients with autonomic neuropathy. Pathophysiological considerations open up new insights into that problem. Based on the current scientific data, clinicians have to be aware of the relations between the two diseases, both from the sleep medical and the diabetological point of view. The paper summarizes the most important issues concerning the different associations of OSA and type 2 diabetes.

DKC1 overexpression associated with prostate cancer progression.

BACKGROUND: Dyskerin encoded by the DKC1 gene is a predominantly nucleolar protein essential for the formation of pseudouridine in RNA and the telomerase RNA subunit hTR. Inherited mutations inactivating dyskerin cause dyskeratosis congenita, a syndrome with progeroid features characterised by skin defects and haematopoiesis failure, as well as cancer susceptibility. In this study, we report DKC1 overexpression in prostate cancers. METHODS: Expression of DKC1 was measured by quantitative RT-PCR in prostate cancer tissues in relation to hTR and the proliferation marker MKI67. Effects of dyskerin downregulation on proliferation, apoptosis and senescence of prostate cancer cell lines were determined. RESULTS: DKC1 was significantly overexpressed in prostate cancers, particularly in high-stage and recurring cases, correlating moderately with hTR and MKI67. Dyskerin downregulation in prostate carcinoma cell lines by siRNA diminished cell proliferation, but elicited neither apoptosis nor senescence. Apoptosis induction by TNF-alpha or tunicamycin was not enhanced. Long-term downregulation led predominantly to cell shrinking and loss of adhesion. INTERPRETATION: DKC1 upregulation in prostate cancers is common and likely to be necessary for extensive tumour growth. The phenotype of prostate carcinoma cell lines after dyskerin downregulation suggests that its most critical function is sustaining protein biosynthesis. Intriguingly, compromised function and overexpression of dyskerin can both contribute to cancer development.

Disruption of the FA/BRCA pathway in bladder cancer.

Bladder carcinomas frequently show extensive deletions of chromosomes 9p and/or 9q, potentially including the loci of the Fanconi anemia (FA) genes FANCC and FANCG. FA is a rare recessive disease due to defects in anyone of 13 FANC genes manifesting with genetic instability and increased risk of neoplasia. FA cells are hypersensitive towards DNA crosslinking agents such as mitomycin C and cisplatin that are commonly employed in the chemotherapy of bladder cancers. These observations suggest the possibility of disruption of the FA/BRCA DNA repair pathway in bladder tumors. However, mutations in FANCC or FANCG could not be detected in any of 23 bladder carcinoma cell lines and ten surgical tumor specimens by LOH analysis or by FANCD2 immunoblotting assessing proficiency of the pathway. Only a single cell line, BFTC909, proved defective for FANCD2 monoubiquitination and was highly sensitive towards mitomycin C. This increased sensitivity was restored specifically by transfer of the FANCF gene. Sequencing of FANCF in BFTC909 failed to identify mutations, but methylation of cytosine residues in the FANCF promoter region was demonstrated by methylation-specific PCR, HpaII restriction and bisulfite DNA sequencing. Methylation-specific PCR uncovered only a single instance of FANCF promoter hypermethylation in surgical specimens of further 41 bladder carcinomas. These low proportions suggest that in contrast to other types of tumors silencing of FANCF is a rare event in bladder cancer and that an intact FA/BRCA pathway might be advantageous for tumor progression.

Obstructive sleep apnea syndrome: the effect of diabetes and autonomic neuropathy.

Several studies indicate an association between obstructive sleep apnea syndrome (OSAS) and diabetic autonomic neuropathy (DAN). Observed frequency of OSAS in diabetic patients with DAN varies between 26% and 30%. Excessive daytime sleepiness is one of the major clinical symptoms of sleep disordered breathing. Diabetics with autonomic neuropathy might have abnormal control of respiration during sleep, probably resulting in a reduced daytime sleepiness. We investigated the impact of autonomic diabetic neuropathy on clinical symptoms (e.g., daytime sleepiness, measured by Epworth Sleepiness Scale, ESS) in patients with suspected OSAS. We examined 196 patients suspected of sleep apnea (52 female, 144 male, mean age 58.7 yrs, mean BMI 30.57 kg/m2). All patients underwent overnight polysomnography and were tested for autonomic neuropathy by a method of measuring heart rate variabilty and heart rate response to the Valsalva maneuver, standing and deep breathing using a computerized data analysis system. Eighty diabetic subjects: 52 DAN-, 28 DAN+; 116 subjects without diabetes: 101 without autonomic neuropathy (AN), 15 AN+. The group of diabetics with DAN+ had a mean apnoea/hypopnea index (AHI) of 38.6/h, mean oxygen desaturation: 77.5%, mean ESS-Score: 9.86. Diabetic patients DAN-: mean AHI:30.4/h, mean oxygen desaturation: 79.3%, mean ESS-Score 9.73. Defining OSAS as AHI>5/h and ESS-Score>9, 46% of the diabetic patients DAN+ were positive, whereas in the DAN- group 61% met the criteria (non-diabetic patients without AN 50.5%; with AN: 60%). Although the group of diabetic patients with autonomic neuropathy had the lowest percentage of OSAS, statistical analysis showed no significance in comparisons between DAN-/DAN+ or diabetic/non-diabetic. In conclusion, although this study did not give statistical evidence, there is reason to assume that patients with diabetic autonomic neuropathy show fewer clinical symptoms of OSAS than those without it. The examination for OSAS might be indicated even without excessive daytime sleepiness because of elevated cardiovascular risk.

Non-invasive ventilation: comparison of effectiveness, safety, and management in acute heart failure syndromes and acute exacerbations of chronic obstructive pulmonary disease.

Continuous positive airway pressure ventilation (CPAP) and non-invasive positive pressure ventilation (NPPV) are accepted treatments in acute cardiogenic pulmonary edema (ACPE) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The aim of the study was a comparison of effectiveness, safety, and management of NPPV in ACPE and AECOPD trying to find an approach for standard management in intensive care. Thirty patients with acute respiratory failure (14 due to ACPE, 16 due to AECOPD) were prospectively included into the study. If clinical stability could not be achieved by standard therapy (pharmacological therapy and oxygen) patients were treated by non-invasive ventilation (NPPV) using a BiPAP-Vision device in S/T-mode. During the first 90 min after the onset of NPPV respiratory and vital parameters were documented every 30 min. Additional relevant outcome parameters (need for intubation, duration of ICU stay, complications and mortality) were monitored. We found that 85.7% of the ACPE patients and 50.0% of the AECOPD patients were treated successfully with NPPV. Intubation rate was 31.2% in the AECOPD group and 14.3% in the ACPE group. 78.6% of the ACPE patients and 43.8% of the AECOPD patients were regularly discharged from hospital in a good condition. In the first 90 min of NIV, there was a significant amelioration of respiratory and other vital parameters. In ACPE patients there was a significant increase in PaO2 from 58.9 mmHg to 80.6 mmHg and of oxygen saturation (SaO2) from 85.1% to 93.1% without changing the inspiratory O2 concentration. This effect was comparable in the AECOPD group, but only could be achieved by increasing the inspiratory ventilation pressure. In the ACPE group inspiratory ventilation pressure could be reduced. In conclusion, in acute respiratory failure, ACPE patients comparably profit from NPPV as do patients with AECOPD, but the algorithm of titration for non-invasive ventilation pressure is different.

[Von Hippel-Lindau disease. Interdisciplinary patient care]. / Von-Hippel-Lindau-Erkrankung. Interdisziplinäre Patientenversorgung.

Von Hippel-Lindau disease is an important hereditary tumor syndrome with a clear option for effective treatment if diagnosed in time. Interdisciplinary cooperation is the key to successful management. Major components of the disease are retinal capillary hemangioblastomas, hemangioblastomas of cerebellum, brain stem and spine, renal clear cell carcinomas, pheochromocytomas, multiple pancreatic cysts and islet cell carcinomas, tumors of the endolymphatic sac of the inner ear, and cystadenomas of the epididymis and broad ligament. A well structured screening program should be performed at yearly intervals.

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study).

To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m2, days 1, 15, 29), high-dose methotrexate (3 g/m2 days 2, 16, 30), procarbazine (60 mg/m2 days 2-11) and lomustine (110 mg/m2, day 2)-R-MPL protocol. Owing to infectious complications, we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less ⩾grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.

Selective Venous Blood Sampling for Hyperparathyroidism with unclear Localization of the Parathyroid Gland.

Purpose: Evaluation of the benefit of selective venous blood sampling (SVS) for the preoperative identification of parathyroid adenomas with unclear localization in non-invasive diagnostics. Materials and Methods: In a retrospective study, all patients (n = 23) with primary (n = 21) or tertiary (n = 2) hyperparathyroidism were evaluated from 2005 to 2016 at the Hospital Nuremberg-North. These patients all received one (n = 20) or more (n = 3) SVS. 15 patients had one or more previous unsuccessful surgeries (group A), 8 patients received the SVS primarily before the first surgery (group B). Results of SVS were compared with the results of surgery, non-invasive diagnostic procedures and clinical follow up. Results: In 24 out of 26 SVS a significant PTH peak was found. 19 patients underwent surgery after SVS. In 16 of these cases (84 %) the SVS peak was concordant with the intraoperative localization. Thus, SVS of all operated patients had a sensitivity of 94 %. Considering only patients with prior HPT surgery the sensitivity was 89 %. In none of the 26 examinations complications occurred. Conclusion: Our results demonstrate that selective venous blood sampling SVS in cases with unclear imaging of parathyroid adenomas is an effective and low-risk invasive diagnostic method to localize parathyroid adenomas and helps to improve surgical therapy. Key points: • low risk invasive diagnostic procedure to localize parathyroid adenomas• additional step if non-invasive diagnostics are negative or inconclusive• high sensitivity in the detection of parathyroid adenomas Citation Format: • Hader C, Uder M, Loose RWR et al. Selective Venous Blood Sampling for Hyperparathyroidism with unclear Localization of the Parathyroid Gland. Fortschr Röntgenstr 2016; 188: 1144 - 1150.

A rapid method for detection of nongenotoxic carcinogens of environmental pollutants using synchronized V79 cells and flow cytometry.

Synchronized V79 cells were treated before entering mitosis with known and suspicious mitotic arrestants and analyzed by flow cytometry and by light microscopy. Colcemid, nocodazole, vinblastine, diethylstilbestrol, triethyl lead and cadmium sulfate caused a dose dependent mitotic arrest of up to 80%, in comparison with 6% for the controls. Mixtures of polycyclic aromatic hydrocarbons and heterocyclic compounds induced a mitotic arrest of 50%-60%. Extracts of airborne particulates revealed a mitotic arrest of 10%-40%. In contrast, benzoquinone and hydroquinone led to a G2-block rather than to a mitotic arrest. Results of flow cytometry measurements correlated well with those obtained by light microscopy. Cell synchronization in combination with flow cytometry seems to be of considerable value as a rapid method for testing nongenotoxic agents with mitotic arresting activity.

[Clinical and neuroradiological diagnostics in Graves' orbitopathy]. / Klinische und neuroradiologische Diagnostik bei endokriner Orbitopathie.

Early diagnosis of Graves' orbitopathy (GO) is important for a timely treatment of the disease. The diagnosis is based on clinical as well as radiological findings. Detailed assessment and follow-up mainly rely on standardized clinical examinations which register symptoms and signs including inflammation, upper lid retraction, exophthalmos, eye muscle involvement and diplopia, corneal involvement, raised intraocular pressure and optic nerve involvement, the latter representing a particular challenge. Each case of GO is classified in terms of severity and activity allowing suitable therapeutic strategies to be derived.

[Clinical and neuroradiological diagnostics of orbital tumors]. / Klinische und neuroradiologische Diagnostik bei Orbitatumoren.

Exophthalmus is the leading sign of space-occupying lesions of the orbit. Patients may further present with lid swelling, impaired ocular motility and optic neuropathy including a relative afferent pupillary defect, compressive optic disc edema or optic atrophy. Orbital tumors can be classified into various categories depending on the etiology, as lymphoproliferative lesions (in particular non-Hodgkin's lymphoma as the most common malignant orbital tumor of adulthood), optic nerve and meningeal lesions, lacrimal gland lesions, secondary orbital tumors which extend to the orbit from neighboring structures and metastases. Slightly less common are vasculogenic and cystic lesions including cavernous hemangioma as the most common benign orbital tumor of adulthood and dermoid cysts as the most common benign orbital tumor of childhood. Rhabdomyosarcoma is the most common malignant orbital tumor of childhood but has a low total incidence. Orbital tumors might not only cause symptoms like pain, diplopia and loss of visual acuity but may also lead to esthetically disfiguring changes. Particular attention should be paid to underlying systemic diseases and generalized tumor diseases. This article illustrates the approach to a detailed clinical and neuroradiological assessment which is mandatory for the care of orbital tumor patients.

Freiburg neuropathology case conference: a midline mass lesion in an infant.

This article presents the case of a 10-month-old baby girl with an atypical teratoid/rhabdoid tumor. The differential diagnosis relied on the findings from magnetic resonance with T1 and T2-weighted imaging as well as histological and immunohistochemical methods. The characteristics of the possible candidate lesions considered for the differential diagnosis are described.

The role of c-FLIP splice variants in urothelial tumours.

Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIP(long) (c-FLIP(L)) and c-FLIP(short) (c-FLIP(S)), which can have opposing functions. We observed diminished expression of the c-FLIP(L) isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIP(S) was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIP(L) to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIP(L) isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours.

Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2.

Overexpression of the forkhead family transcription factor Foxc2 has been shown to activate epithelial-mesenchymal transition (EMT) and correlate with tumor metastasis. In this study, we show that both mRNA and protein levels of Foxc2 increase 1 day after kidney ischemia/reperfusion in sublethally injured tubular cells and that the protein is located in the cytoplasm rather than the nucleus of these cells. in vitro studies of cultured tubular cells confirm the cytoplasmic location of Foxc2 and show that increased cytoplasmic expression of Foxc2 correlates with epithelial differentiation rather than dedifferentiation. Silencing of Foxc2 by RNAi in these cells led to EMT and increased cell migration. In contrast, Foxc2 is found in both the nucleus and cytoplasm of cultured fibroblasts, with RNAi leading to increased expression of epithelial markers and impaired cell migration. Consistent with a subcellular localization dependence of Foxc2 function, overexpression of Foxc2 in renal epithelial cells resulted in de novo nuclear expression of the protein and promotion of a mesenchymal/fibroblast phenotype. These results suggest that Foxc2 may have regulatory functions independent of its nuclear transcriptional activity and that upregulation of endogenous Foxc2 in the cytoplasm of injured tubular cells activates epithelial cell redifferentiation rather than dedifferentiation during organ repair.

CT-guided cervical selective nerve root block with a dorsal approach.

BACKGROUND AND PURPOSE: Cervical transforaminal blocks are frequently performed to treat cervical radicular pain. These blocks are performed mostly under fluoroscopy, but a CT-guided technique has also been described. The aim of this study was to review the results of CT-guided CSNRB by using a dorsal approach, to describe the contrast patterns achieved with this injection technique, and to estimate the degree of specificity and sensitivity. MATERIALS AND METHODS: We used a CT-guided technique with a dorsal approach leading to a more extra-than transforaminal but a selective nerve root block as well. Of 53 blocks, we performed 38 for diagnostic and 15 for therapeutic indications. Pain relief was measured hourly on a VAS. The distribution of contrast and the angle of the trajectory of the injection needle were analyzed as well as the degree of pain relief. RESULTS: Contrast was found in the intraforaminal region in 8 (15%) blocks, extraforaminally in 40 (78%) blocks, and intraspinally in 3 (6%) blocks. The mean angle between the needle and the sagittal plane was 26.6° (range, from 1° to 50°). The mean distance between needle tip and nerve root was 4.43 mm (range, 0-20 mm). Twenty-six (68.4%) of the 38 diagnostic blocks led to a decrease in the pain rating of >50%. There were no complications or unintended side effects, apart from occasional local puncture pain. CONCLUSIONS: We conclude that CT-guided CSNRBs using a dorsal approach are feasible and that they are sensitive and specific.

Essentials and pitfalls in the treatment of CNS hemangioblastomas and von Hippel-Lindau disease.

Hemangioblastomas are rare CNS tumors, which are mostly located in the posterior fossa or spinal cord and occasionally in spinal nerves. They can occur sporadically or as a component tumor of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor syndrome. The limited awareness of several pitfalls in the therapy of these rare lesions results in delayed or suboptimal treatment for many of these patients, especially those with VHL disease. The University of Freiburg serves as a reference center for patients with VHL disease and hemangioblastomas. The current therapeutic strategies for hemangioblastoma patients and typical pitfalls are presented here.