Stereospecific Nitrogen Insertion Using Amino Diphenylphosphinates: An Aza-Baeyer-Villiger Rearrangement.

Amino diphenylphosphinates, which are commercially available or easily prepared from hydroxylamine, undergo ring expansion of cyclobutanones toward γ-lactams under mild conditions. A reaction pathway profoundly different from the common Beckmann reaction is achieved through the ambivalent character of the aminating agent. Thus, rearrangement occurs from a Criegee-like intermediate prior to the formation of the oxime species, which is corroborated by mechanistic experiments. Based on this observation, the migrating aptitude of the adjacent groups is analyzed and found to be in line with the parent Baeyer-Villiger reaction rendering a regioselective (up to >99:1 rr), stereospecific (>99% enantiospecificity), and chemoselective (>99%) insertion process possible. The method thus qualifies for late-stage skeletal editing as showcased by the synthesis of Rolipram and its N-alkylated analogs.

Radioprotective Effects of Dermatan Sulfate in a Preclinical Model of Oral Mucositis-Targeting Inflammation, Hypoxia and Junction Proteins without Stimulating Proliferation.

Oral mucositis is the most frequently occurring early side effect of head-and-neck cancer radiotherapy. Systemic dermatan sulfate (DS) treatment revealed a significant radioprotective potential in a preclinical model of oral mucositis. This study was initiated to elucidate the mechanistic effects of DS in the same model. Irradiation comprised daily fractionated irradiation (5 × 3 Gy/week) over two weeks, either alone (IR) or in combination with daily dermatan sulfate treatment of 4 mg/kg (IR + DS). Groups of mice (n = 5) were sacrificed every second day over the course of 14 days in both experimental arms, their tongues excised and evaluated. The response to irradiation with and without DS was analyzed on a morphological (cell numbers, epithelial thickness) as well as on a functional (proliferation and expression of inflammation, hypoxia and epithelial junction markers) level. The mucoprotective activity of DS can be attributed to a combination of various effects, comprising increased expression of epithelial junctions, reduced inflammation and reduced hypoxia. No DS-mediated effect on proliferation was observed. DS demonstrated a significant mucositis-ameliorating activity and could provide a promising strategy for mucositis treatment, based on targeting specific, radiation-induced, mucositis-associated signaling without stimulating proliferation.

Primer extension based quantitative polymerase chain reaction reveals consistent differences in the methylation status of the MGMT promoter in diffusely infiltrating gliomas (WHO grade II-IV) of adults.

Diffusely infiltrating gliomas (WHO grade II-IV) are the most common primary brain tumours in adults. These tumours are not amenable to cure by surgery alone, so suitable biomarkers for adjuvant modalities are required to guide therapeutic decision-making. Epigenetic silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene by promoter methylation has been associated with longer survival of patients with high-grade gliomas who receive alkylating chemotherapy; and molecular testing for the methylation status of the MGMT promoter sequence is regarded as among the most relevant of such markers. We have developed a primer extension-based assay adapted to formalin-fixed paraffin-embedded tissues that enables quantitative assessment of the methylation status of the MGMT promoter. The assay is very sensitive, highly reproducible, and provides valid test results in nearly 100% of cases. Our results indicate that oligodendrogliomas, empirically known to have a relatively favourable prognosis, are also the most homogeneous entities in terms of MGMT promoter methylation. Conversely, astrocytomas, which are more prone to spontaneous progression to higher grade malignancy, are significantly more heterogeneous. In addition, we show that the degree of promoter methylation correlates with the prevalence of loss of heterozygosity on chromosome arm 1p in the oligodendroglioma group, but not the astrocytoma group. Our results may have potentially important implications for clinical molecular diagnosis.

Primary tumors of the submandibular glands: a retrospective study based on 41 cases.

We report our experience on the diagnostic approach, treatment, and follow-up of primary submandibular gland tumors. Retrospective review. Tertiary referral center. Forty-one adult patients, 22 male and 19 female, with primary submandibular gland tumors, 20 benign and 21 malignant. Age, gender, clinical findings, cyto- and histopathology, treatment and outcome were analyzed. Most tumors presented as a painless submandibular mass. Thirty three patients underwent a fine needle aspiration, the sensitivity, specificity and accuracy of which--in detecting malignant tumors--were 79%, 100% and 88%, respectively. Preoperative radiological imaging was performed in 30 cases. Patients with benign tumors were treated with surgery. Most malignant tumors were treated with a combined modality, including neck dissection and radiation therapy. Five patients developed a postoperative complication. Recurrent disease was encountered in 5 malignant tumors. The 2, 5 and 10 year disease-specific survival of patients with malignancy were 84%, 75% and 41%, respectively. The preoperative assessment of the nature of submandibular gland tumors remains challenging. Aggressive treatment of patients with malignant disease may help to avoid poor prognosis.

miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer.

MicroRNAs (miRNA) are negative regulators of gene expression at the posttranscriptional level, which are involved in tumorigenesis. Two miRNAs, miR-15a and miR-16, which are located at chromosome 13q14, have been implicated in cell cycle control and apoptosis, but little information is available about their role in solid tumors. To address this question, we established a protocol to quantify miRNAs from laser capture microdissected tissues. Here, we show that miR-15a/miR-16 are frequently deleted or down-regulated in squamous cell carcinomas and adenocarcinomas of the lung. In these tumors, expression of miR-15a/miR-16 inversely correlates with the expression of cyclin D1. In non-small cell lung cancer (NSCLC) cell lines, cyclins D1, D2, and E1 are directly regulated by physiologic concentrations of miR-15a/miR-16. Consistent with these results, overexpression of these miRNAs induces cell cycle arrest in G(1)-G(0). Interestingly, H2009 cells lacking Rb are resistant to miR-15a/miR-16-induced cell cycle arrest, whereas reintroduction of functional Rb resensitizes these cells to miRNA activity. In contrast, down-regulation of Rb in A549 cells by RNA interference confers resistance to these miRNAs. Thus, cell cycle arrest induced by these miRNAs depends on the expression of Rb, confirming that G(1) cyclins are major targets of miR-15a/miR-16 in NSCLC. Our results indicate that miR-15a/miR-16 are implicated in cell cycle control and likely contribute to the tumorigenesis of NSCLC.

Orbital manifestation of whipple's disease: an atypical case.

BACKGROUND: Whipple's disease is a systemic disorder caused by an infection with a gram-positive bacillus, Tropheryma whipplei. Almost every organ system can be affected in Whipple's disease, resulting in varying clinical symptoms. CASE REPORT: As far as we are aware, this report of a 61-year-old male is the first presenting with a periorbital manifestation of the disease, with severe exophthalmos and optic nerve involvement, leading to rapid visual loss. This emergency case was successfully treated by a surgical orbital decompression combined with systemic use of antibiotics and steroids. CONCLUSION: Whipple's disease can affect the periorbital tissues and the optic nerve, causing massive exophthalmos and serious transient visual loss. In such a case surgical decompression of the affected orbit combined with antibiotics and steroids is a recommended valid treatment option.

Objective response to radiation therapy and long-term survival of patients with WHO grade II astrocytic gliomas with known LOH 1p/19q status.

BACKGROUND: WHO grade II gliomas are often approached by radiation therapy (RT). However, little is known about tumor response and its potential impact on long-term survival. PATIENTS AND METHODS: Patients subjected to RT were selected from the own database of WHO grade II gliomas diagnosed between 1991 and 2000. The volumetric tumor response after RT was assessed based on magnetic resonance imaging and graded according to standard criteria as complete, partial (PR, >or= 50%), or minor (MR, 25% to <50%). RESULTS: There were 24 astrocytomas and three oligoastrocytomas. 21 patients (78%) were dead at follow-up (mean survival 74 months). None of the patients had chemotherapy. Objective response occurred in 14 patients (52%, five PR and nine MR) but was not associated with overall survival. The vast majority of the tumors had no loss of heterozygosity (LOH) 1p and/or 19q (86%). CONCLUSION: Approximately 50% of patients with astrocytic WHO grade II gliomas respond to RT despite the absence of LOH for 1p/19q. The potential predictive factors for response and the impact of response on overall survival remain unclear.

Rosette-forming glioneuronal tumor of the fourth ventricle: report of two cases with a differential diagnostic overview.

We report on clinicopathological findings in two cases of rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) occurring in females aged 16 years (Case 1) and 30 years (Case 2). Symptoms included vertigo, nausea, cerebellar ataxia, as well as headaches, and had been present for 4-months and 1 week, respectively. Magnetic resonance imaging (MRI) indicated a cerebellar-based tumor of 1.8 cm (Case 1) and 5 cm (Case 2) diameter each, bulging into the fourth ventricle. Case 2 involved a cyst-mural-nodule configuration. In both instances, the solid component appeared isointense on T(1) sequences, hyperintense in the T(2) mode, and enhanced moderately. Gross total resection was achieved via suboccipital craniotomy. However, functional recovery was disappointing in Case 1. On microscopy, both tumors comprised an admixture of low-grade astrocytoma interspersed with circular aggregates of synaptophysin-expressing round cells harboring oligodendrocyte-like nuclei. The astrocytic moiety in Case 1 was nondescript, and overtly pilocytic in Case 2. The architecture of neuronal elements variously consisted of neurocytic rosettes, of pseudorosettes centered on a capillary core, as well as of concentric ribbons along irregular lumina. Gangliocytic maturation, especially "floating neurons", or a corresponding immunoreactivity for neurofilament protein was absent. Neither of these populations exhibited atypia, mitotic activity, or a significant labeling for MIB-1. Cerebellar parenchyma included in the surgical specimen did not reveal any preexisting malformative anomaly. Despite sharing some overlapping histologic traits with dysembryoplastic neuroepithelial tumor (DNT), the presentation of RGNT with respect to both patient age and location is consistent enough for this lesion to be singled out as an autonomous entity.

Multiple spinal extradural meningeal cysts presenting as acute paraplegia. Case report and review of the literature.

Multiple spinal extradural meningeal cysts are rare. To the authors' knowledge, there have been only four reported cases in the world literature. The authors report a case of multiple spinal extradural meningeal cysts in a 31-year-old woman presenting with acute paraplegia. Magnetic resonance imaging of the thoracolumbar spine revealed multiple extradural cystic lesions extending from T-7 to T-8 and from T-12 to L-3. Intraoperative findings demonstrated a white, fibrous, and tense cyst filled with cerebrospinal fluid-like colorless fluid. Excision of the posterior wall of the symptomatic cyst was followed by immediate neurological improvement. The examination of the pathological specimen showed a thick duralike layer of collagen and an inner membrane of arachnoid that is often not found in these lesions. The final diagnosis was based on combined imaging, intraoperative, and histopathological findings. The authors review the literature and discuss the etiological, diagnostic, and therapeutic aspects of this lesion.

[Extraordinary manifestation of a gastric carcinoma by leptomeningeal carcinomatosis and spinal metastasis]. / Aussergewöhnliche Manifestation eines Magenkarzinoms mit Meningeosis carcinomatosa und spinaler Metastase.

BACKGROUND: Leptomeningeal carcinomatosis is a rare complication of solid tumors, e. g., breast, lung and gastrointestinal carcinomas. Clinical manifestations are variable with radicular pains with or without neurologic deficiencies as well as headache and hallucinations. CASE REPORT: The rare case of a 57-year-old patient with neurologic symptoms caused by a leptomeningeal carcinomatosis and a spinal metastasis of an asymptomatic signet-ring cell gastric carcinoma is reported. In spite of combined radiochemotherapy the patient died already 4 weeks after discharge from hospital due to an intracerebral hemorrhage. CONCLUSION: Until today, prognosis of leptomeningeal carcinomatosis is poor with a median survival between 3-4 months independently of the primary tumor.

Loss of heterozygosity 1p36 and 19q13 is a prognostic factor for overall survival in patients with diffuse WHO grade 2 gliomas treated without chemotherapy.

PURPOSE: This study was conducted to elucidate the impact of loss of heterozygosity (LOH) for chromosomes 1p36 and 19q13 on the overall survival of patients with diffusely infiltrating WHO grade 2 gliomas treated without chemotherapy. PATIENTS AND METHODS: We assessed the LOH status of tumors from patients harboring WHO grade 2 gliomas diagnosed between 1991 and 2000. Patients were either followed after initial biopsy or treated by surgery and/or radiation therapy (RT). Overall survival, time to malignant transformation, and progression-free survival were last updated as of March 2005. RESULTS: Of a total of 79 patients, LOH 1p36 and LOH 19q13 could be assessed in 67 and 66 patients, respectively. The median follow-up after diagnosis was 6 years. Loss of either 1p or 19q, in particular codeletion(s) at both loci, was found to positively impact on both overall survival (log-rank P < .01), progression-free survival, and survival without malignant transformation (P < .05). Tumor volume (P < .0001), neurologic deficits at diagnosis (P < .01), involvement of more than one lobe (P < .01), and absence of an oligodendroglial component (P < .05) were also predictors of shorter overall survival. The extent of surgery was similar in patients with or without LOH 1p and/or 19q; RT was more frequently resorted to for patients without than for patients with LOH 1p/19q (30% v 60%). CONCLUSION: The presence of LOH on either 1p36 or 19q13, and in particular codeletion of both loci is a strong, nontreatment-related, prognostic factor for overall survival in patients with diffusely infiltrating WHO grade 2 gliomas.

Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p.

PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Papillary glioneuronal tumor.

The descriptive term papillary glioneuronal tumor (PGNT) has been repeatedly applied to a morphologic subset of low-grade mixed glial-neuronal neoplasia of juvenile and young adult patients. We report on a 13-year-old boy with PGNT of the left temporal lobe, who presented with headaches and a single generalized seizure. On magnetic resonance imaging, tumor was seen as a large, moderately enhancing paraventricular mass with cyst-mural nodule configuration and slight midline shift. Perifocal edema was virtually absent. Gross total resection could be performed, followed by an uneventful recovery. Histologically, the tumor exhibited similar, if not identical, features as reported previously. These comprised a patterned biphasic mixture of sheets of synaptophysin-expressing small round cells and pseudorosettes of GFAP-positive rudimentary astrocytes along vascular cores. Focally, the latter imprinted a pseudopapillary aspect on this otherwise solid lesion. Both cellular components expressed non-polysialylated neural cell adhesion molecule (NCAM)-L species, and several overlapping areas of synaptophysin and GFAP immunoreactivity were present. The mean MIB-1 labeling index remained below 1%. Signs of anaplasia, in particular mitotic figures, endothelial proliferation, or necrosis were consistently lacking. We perceive PGNT as a clinically and morphologically well-delineated subgroup of extraventricular neurocytic neoplasia, whose paradigmatic presentation may allow for consideration as an entity.