Synthesis and evaluation of new Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold

Abstract: Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates, gave a new family of 1,4,5-trisubstitued triazole carboxylic acid derivatives that showed high affinity towards Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring, were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstitued triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18; SST0287CL1) was selected for further investigation as the most promising drug candidate

Intracerebral schwannoma. Case report

A case of intraparenchymal schwannoma is presented. A 61-year-old woman, with stigmata of von Recklinghausen's neurofibromatosis (NF-2), presented with a history of weakness of the right lower limb for 2 months. She was investigated by MR which showed a circular mass with a maximum diameter of 5 cm in the right parieto-occipital lobe. The tumor was removed in toto via a left parieto-occipital craniotomy. The patient was discharged two weeks after the operation and remains well now 2 years later. The clinical and neuroradiological findings of reported intraparenchymal schwannomas, including the case reported here, are discussed

Solitary cerebral metastasis from melanoma : value of the "en bloc" resection

The authors report 19 cases of solitary cerebral metastases from malignant malanoma. In 15 patients, the primary lesion was known at the time the metastasis was diagnosed; deltoid-scapular in 4 cases, thoracic in 5, inguinal in 4 and neck in 2. The primary location was unknown in 4 patients. Presenting symptoms were: epileptic seizures in 9 cases, headache in 8, strength deficit of the limbs in 2. In 3 patients (16%) neurological symptoms were the first clinical sign of the systemic tumor; in 16 cases (84%) there was a long interval between treatment of the primary and appearance of the cerebral metastasis (average 3.8 years; median 3.4 years). All patients were submitted to surgery and radiotherapy (whole-brain in 14 and radiosurgery in 5). In 10 cases the lesion was removed ‘en bloc’ (no internal touch technique). Average survival was 9 months (median 8 months) and was influenced by ‘en bloc’ resection and whole-brain irradiation. None of the patients operated by the ‘no touch technique’ presented a recurrence

Radiation-induced sarcoma of the skull: report of two cases.

The authors describe two cases of sarcomas of the skull following cranial irradiation in patients treated for other neoplasms, acute lymphatic leukemia, and astrocytoma, respectively. The patients (one man and one woman: mean age 24.5 years) developed sarcomas within the irradiated field after a mean latency period of 11.5 years. Histologically, the tumor proved to be a fibrosarcoma. Despite aggressive surgery and other therapy, the survival of the patients was short (10 and 8 months, respectively). The pathological and clinical aspects of this unusual complication are analyzed with reference to 41 cases taken from the world literature

Central Neurocytoma:clinical feature of 8 cases

The authors report 8 cases of central neurocytoma with a minimum follow-up of 3 years. Five patients were males and 3 females with average age of 21 years. All patients underwent surgical removal of tumor, and radiotherapy was delivered to 2 of the 3 patients in whom removal had been partial. At an average follow-up of 5 years, all patients are alive and none of them has presented signs of recurrence or progression of the disease. Some typical clinical and histological features of this tumor are pointed

Intracranial meningioma at the site of a previous cranial fracture: Case report and review of the literature

The authors present a case of post-traumatic intracranial meningioma, selected according to the criteria specified in the relevant literature. Assessment of the clinical characteristics of our patient and those reported in the literature seems to confirm that, in some cases, head trauma may be a factor contributing to the development of meningioma

Gliomas of the conus medullaris

AIMS AND BACKGROUND: Gliomas of the conus medullaris often show characteristic clinical, radiological, and intraoperative features which differ from gliomas involving other parts of the spinal cord. METHODS: Eight patients with histologically verified gliomas of the conus medullaris were diagnosed and studied. RESULTS: There were five men and three women ranging in age from 21 to 59 years. Predominant initial symptoms were back pain (4 cases) and leg weakness (4 cases). The most common findings on admission were flaccid paraparesis with impaired sensation and bladder dysfunction. Postoperative magnetic resonance (MR) images with more than 95% removal of a tumour were defined as "subtotal removal" (noted in 4 of 8 cases), and less than 95% as "partial removal" (4 of 8 cases). All patients had postoperative radiotherapy. During the follow-up period ranging from 3 to 10 years, there was no tumour recurrence or regrowth on MR images. CONCLUSIONS: The postoperative radiotherapy in gliomas of the conus medullaris where total resection is not possible seems provide a beneficial effect on preventing tumour regr

[Epidermoid cyst of the cranial vault. Neuroradiological and therapeutic considerations].

AIM: Intradiploic epidermoid cyst is a slow-growing tumor affecting only rarely the cranial bones. PATIENT: The authors describe a case of intradiploic epidermoid cyst of the cranial vault in which there was a predominantly intracranial extension. Roentgenographic and CT findings do not permit a differential diagnosis. Complete removal of the cyst and its capsule was accomplished, with complete recovery. CONCLUSION: Total removal oft the tumor and its capsule is associated with a very good long-term prognosis without recurrence

Multicentric and multifocal primary cerebral tumours. Methods of diagnosis and treatment

Forty patients with multifocal and multicentric cerebral tumours were retrospectively studied. The patients were divided into two groups: ten patients with multicentric tumours (group A), and 30 patients with multifocal tumours. As far as their preoperative clinical history and the incidence of the various symptoms and signs are concerned, there were no significant differences between the two groups. CT permitted a correct diagnosis in 90% of the cases. All of the patients underwent the removal of the tumour(s) and received radiotherapy; 30 patients also received chemotherapy. In group A, nine patients died and one was lost to follow-up one year after treatment; the average survival was ten months from the appearance of the multicentric tumour. In group B, 29 patients died and one is still alive two years after treatment; the average survival was six months. We consider the problems of diagnosis and the long-term follow-up of patients

Medulloblastoma dell'adulto:revisione di 9 casi studiati con la RM

Medulloblastoma is a neuroectodermic, malignant tumor of the cerebellum, most commonly seen in children and accounting for 25% of all intracranial neoplasms and 33% of posterior cranial fossa neoplasms in childhood. In adulthood, medulloblastomas account for 14-30% of medulloblastomas overall and 0.4%-1% of adult brain tumors. This study reviews 9 adult patients in order to characterize the neoplasm with regard to MR features. Five patients had lateral medulloblastoma, 3 paramedian and 1 median. On long TR/long TE images medulloblastomas generally had an intermediate to hyperintense signal; on short TR/short TE images tumor had a low to intermediate signal. Enhanced MR images were heterogeneous in 8 cases, while 1 case showed no enhancement. The vermian medulloblastoma presented no diagnostic problem. Paramedian medulloblastoma often appeared infiltrative. 3 lateral medulloblastomas appeared extra-axial and nimicked other masses of the cerebellopontine angle. In our series, one feature of potential differential importance was the angiographic hypovascularity of the medulloblastomas related to the tentorium. Hydrocephalus was present in 44% of patients. Cystic and/or necrotic changes within the tumor were seen in 33%. We conclude that the MR characteristics of medulloblastomas in adulthood are variable