CDK9 inhibition as an effective therapy for small cell lung cancer.

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

[The bilateral renal lymphoma: an incurable disease? Case report]. / Il linfoma renale bilaterale: è ancora una malattia incurabile? Case Report.

The bilateral primary renal lymphoma (PRL) is a rare disease with a high mortality rate (75% within the first year). We report the case of a fifty-three years old women observed in January 2011 for renal colic. Ultrasonography showed hypoechoic lobular formations in the kidney. Blood tests showed: creatinine 1.8 mg/dl, urea 75 mg/dl , Creatinine Clerance 35 ml/m, hemoglobinemia 11 g/dl, with blood cells 8.500/mcL, Albumin 2.8 g/dl, Beta -2 micro - 27.3/mL. Proteinuria was 0.3 g/24 hours. The CT scan showed kidneys with larger dimensions and multiple hypodense areas infiltrating the renal parenchyma with contrast-enhanced low in which kidneys had lesions similar to "leopard skin". The CT scan showed no enlarged lymph nodes. Renal biopsy showed: renal parenchyma largely occupied by infiltration of lymphoid elements, small and medium-sized, densely packed with compression of the tubular structures . Immunofluorescence for immunoglobulin (Ig) G, IgA, IgM, C3, C4, C1q, fibrinogen, kappa and lambda were negative. The bone marrow biopsy excluded lymphomatous infiltration. The histological diagnosis was "non-Hodgkin's B-cell lymphoma"; the clinical diagnosis was LRBP. The patient was treated by 6 cycles of R-CHOP-21 protocol (rituximab - endoxan, adriblastina , vincristine, prendnisone), the latter of which practiced in August 2011. The pt is currently in follow-up hematology and nephrology . The first TAC control , in October 2011, showed a complete regression of the lesions infiltrating . This finding was confirmed by two other CT scan performed in February and October 2012. The last blood tests of February 2013 showed : creatinine 1.1 mg / dl , Urea 40 mg/dl, proteinuria absent. Currently, the pt is asymptomatic and is being treated by low dose of ACE inhibitor. The bilateral PRL is considered a severe disease with one-year mortality of 75% . The successful outcome of the case described can be attributed to haematological therapy and to the early diagnosis.

Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many cancer cells without causing toxicity in vivo. However, to date, TRAIL-receptor agonists have only shown limited therapeutic benefit in clinical trials. This can, most likely, be attributed to the fact that 50% of all cancer cell lines and most primary human cancers are TRAIL resistant. Consequently, future TRAIL-based therapies will require the addition of sensitizing agents that remove crucial blocks in the TRAIL apoptosis pathway. Here, we identify PIK-75, a small molecule inhibitor of the p110α isoform of phosphoinositide-3 kinase (PI3K), as an exceptionally potent TRAIL apoptosis sensitizer. Surprisingly, PI3K inhibition was not responsible for this activity. A kinome-wide in vitro screen revealed that PIK-75 strongly inhibits a panel of 27 kinases in addition to p110α. Within this panel, we identified cyclin-dependent kinase 9 (CDK9) as responsible for TRAIL resistance of cancer cells. Combination of CDK9 inhibition with TRAIL effectively induced apoptosis even in highly TRAIL-resistant cancer cells. Mechanistically, CDK9 inhibition resulted in downregulation of cellular FLICE-like inhibitory protein (cFlip) and Mcl-1 at both the mRNA and protein levels. Concomitant cFlip and Mcl-1 downregulation was required and sufficient for TRAIL sensitization by CDK9 inhibition. When evaluating cancer selectivity of TRAIL combined with SNS-032, the most selective and clinically used inhibitor of CDK9, we found that a panel of mostly TRAIL-resistant non-small cell lung cancer cell lines was readily killed, even at low concentrations of TRAIL. Primary human hepatocytes did not succumb to the same treatment regime, defining a therapeutic window. Importantly, TRAIL in combination with SNS-032 eradicated established, orthotopic lung cancer xenografts in vivo. Based on the high potency of CDK9 inhibition as a cancer cell-selective TRAIL-sensitizing strategy, we envisage the development of new, highly effective cancer therapies.

Early experiences of intraoperative ultrasound guided angioplasty of the arterial stenosis during upper limb arteriovenous fistula creation.

In recent years the high prevalence of diabetes and atherosclerosis in elderly uremic patients starting hemodialysis (HD) has led to the increase in the risk of vascular access (VA) failure caused by pre-existing arterial diseases, including both VA slow maturation and early failure, and upper limb ischemic symptoms. Recently, in performing radial (R), brachial (B) and ulnar (U) artery (A) percutaneous transluminal angioplasty (PTA) in HD patients affected by access thrombosis, with insufficient blood flow and severe upper limb ischemia, good outcomes have been reported. Nevertheless, these procedures were performed after arteriovenous fistula (AVF) creation. About 2 years ago, we approached an intra-operative ultrasound-guided transluminal angioplasty (IUTA) performed during AVF creation, using the arterial incision, necessary because of the anastomosis, to introduce the necessary devices for the IUTA. The arterial stenosis having undergone IUTA was diagnosed by a preliminary ultrasound examination. Ultrasound guidance during the procedure is necessary for correct balloon location in the stenosis site. We treated seven patients (four diabetics), mean age 76 + 5 yrs. In all cases, the radial arteries because of hyposphygmia, were unfit for AVF creation. Four distal radio-cephalic AVFs at the wrist were created in patients 1, 3, 4 and 5; in the other three patients (2, 6 and 7), with failure or thrombosis of previous distal AVFs, an immediately upstream anastomosis was performed. In all cases, first, the area selected to perform the AV anastomosis was exposed, then the AR was incised, and the introductory metallic guide wire and the angioplasty catheter (with dimensions decided after PUS), were introduced. The balloon was inflated to 8-13 atm for 30-35 sec. In two patients a stent was also positioned. Later, a side-to-side AVF was created, closing the distal venous vessel. Patient follow-up ranged from 6-22 months. The ultrasound evaluation after IUTA showed the correction of all the stenosis treated. AVF maturation was good, except for the stented ones, which were inadequate. In conclusion, our early experience shows IUTA could be an adequate and effective procedure allowing the use of the stenotic arteries (otherwise unsuitable) for AVF creation. In our experience, stenting after IUTA does not add any other advantages.

Equine pericardium for dural grafts: clinical results in 200 patients.

AIM: Serous sheets are currently used in Neurosurgery as dural substitute. The aim of this study is to demonstrate that the horse pericardium, which has the essential charasteristics of reabsorbable membranes and moreover is BSE-free, is an excellent dural substitute. METHODS: 200 patients, 53 suffering from cranial traumatic conditions and 97 from cranial and craniospinal neoplastic pathologies, underwent a surgical procedure with the application of horse pericardium as a dural prosthesis. RESULTS: The follow-up controls of the patients included a neurosurgical visit and advanced diagnostic imaging (CT or MR). In the first 3 cases, an accumulation of CSF occurred under the surgical edge. Lumbar 7-days drainage was required in just one case. The use of Zero 5 suture seems to have obviated this problem, as it was never observed again in subsequent cases. The diagnostic imaging showed no alterated images and no clinical-neurological sequelae regarding the prosthesis in question were recorded. CONCLUSIONS: The Audiomesh Neuro prosthesis has all the characteristics of reabsorbable membranes: they are free from antigenic effects and do not produce any toxic catabolites. The membrane proved to be resistant to surgical suture, impermeable to CSF and is transparent. Yet the suture must be carried out carefully through a small non-traumatic needle. Audiomesh Neuro does not adhere to the underlying cerebral cortex and does not cause any clinical evidence or radiological artifacts.

Cervical anterior hyperostosis: a rare cause of dysphagia. Report of 3 cases.

Disorders of the cervical spine rarely cause dysphagia and/or dysphonia. Exuberant osteophytosis, secondary to diffuse idiopathic skeletal hyperostosis, also referred to as Forestier's disease, seems to be the predominant cause. Forestier's disease is a non inflammatory enthesopathy, of unknown etiology, ossifying the anterior longitudinal ligament of the spine, sparing the discs, and usually affecting older men. We describe the successful surgical treatment of 3 cases, over the course of 26 years, observed in our Neurosurgical Unit.

Ultrasound guided brachial arterial angioplasty during the creation of a radio-cephalic arteriovenous fistula: a case report.

UNLABELLED: To prevent arteriovenous fistula (AVF) early failure, due to radial or brachial artery stenosis, ultrasound guided angioplasty performed while surgically creating the AVF could be an effective procedure. CASE REPORT: A 76-year-old diabetic male patient, on hemodialysis (HD) for 15 months, presented extensive thrombosis of the radio-cephalic AVF at the right arm, which had lasted for about 10 days. Ultrasound examination showed a 40% brachial artery stenosis with eccentric calcified plaque. The stenosis was localized about 1.5 cm before the artery bifurcation. The brachial artery diameter was 0.45 cm before and 0.26 cm at the level of the stenosis, the latter being 0.45 cm long. At the left wrist, under local anesthesia, the radial artery and the cephalic vein were exposed; the radial artery was then longitudinally incised for 7-8 mm in the area selected to create the AVF. A 6 Fr introducer, a metallic guide wire and a catheter for angioplasty were inserted one after the other in the radial artery. When the correct position of the angioplasty catheter in the stenotic area was established by ultrasound examination, the balloon was blown up to 13 atm for 35 sec, reducing the stenosis from 40-20%. Finally, a side-to-side radio-cephalic fistula was created, legating the distal vein. The AVF was used for HD after 3 weeks. The follow-up at 6 months demonstrated fair access performance and it was used without problems. Our satisfactory experience suggests that ultrasound guided angioplasty of brachial artery stenosis, performed simultaneously with surgical AVF creation, is possibly a successful procedure. This technique reduces the risk of early AVF failure and also allows, when required, stent implantation.

Analysis of diltiazem and its related substances by HPLC and HPLC/MS.

Diltiazem (DTZ) is an optically active calcium channel blocker having a benzodiazepine structure. The drug used in therapy is (+)-cis-diltiazem with configuration (2S,3S). To describe the analytical profile of DTZ different stationary phases (RP-18, RP-8, monolithic support) were tested. The best separation of DTZ from A, B, E and F was obtained using as stationary phase a RP-8 or a monolithic RP-18. The characterization of impurities was carried out using two analytical systems, HPLC and HPLC/MS.

Cauda equina melanoma presenting with subarachnoid hemorrhage. A case report.

The case of a 57-year-old woman with a primary melanoma of the cauda equina is reported. The peculiarity of the case is the very rare clinical presentation mimicking a subarachnoid hemorrhage. The patient underwent surgical excision of the mass. The clinicopathological and neuroradiological features are summarized.

The microsurgical approach to extraforaminal lumbar disc herniations. An analysis of 15 cases.

AIM: Extraforaminal lumbar disc herniations are uncommon, but thanks to recent progress in imaging procedures, they may be easily diagnosed. Several surgical approaches have been described and employed to remove these herniations. The aim of this study is to evaluate the clinical, radiological and surgical features which differentiate the treatment of this type of hernia from the more common surgical approaches to other types of lumbar disc hernias. METHODS: The authors report the results of the surgical treatment of 15 cases of extraforaminal lumbar disc herniation through an extracanalicular, intertransverse microsurgical approach and describe the technique employed. RESULTS: All cases experienced a prompt recovery from the preoperative symptoms with no complications, which notably reduced the time necessary for postoperative care. No instability was documented and none of the cases observed presented the neuropathic pain sometimes reported with this method of approach to these herniations. CONCLUSION: This particular site of disc herniation can be approached effectively through the extracanalicular route. The procedure, however, requires an extremely accurate preoperative anatomical evaluation and a good microsurgical experience.

Favourable effects of bicarbonate dialysis on the body pool of phosphate.

An intravenous infusion of 3,430mg of PO4- has been given to 11 patients on acetate and to 11 patients on bicarbonate haemodialysis. The 'phosphate spaces' and dialytic removal were determined. The bicarbonate dialysis causes lower values of phosphate pool, total phosphate space, cellular space and phosphate cellular clearance. There is also a greater phosphate removal during bicarbonate dialysis. The better correction of metabolic acidosis and the absence of acetate metabolism are two factors which may be responsible for these phenomena.

The prevention of nasal liquorrhea caused by transphenoidal surgery for pituitary adenomas. Technical note.

The Authors report their experience in the surgical treatment of nasal liquorrhea in transphenoidal surgery. They suggest the use of clotting substances like the adhesive Tissucol in order to prevent this complication.

Muzolimine in advanced chronic renal failure.

27 patients with creatinine clearances ranging from 20 to 2 ml/min were treated daily with 6.9 mg/kg of muzolimine, for 10 to 25 days. The hyperhydration state with oedema decreased gradually in all patients without hypotensive phenomena. Muzolimine benefited hypertension in patients with expansion of the extracellular space and it also strengthened the effect of clonidine or minoxidil. Important diuretic and natriuretic effects were obtained. Metabolic acidosis improved. No subjective adverse reactions to the drug or side effects were noted. High-dose muzolimine appears to be efficacious and safe for short-term treatment in patients with severe chronic renal failure.

Surgical treatment of acute cervical fracture-dislocation.

The authors describe their experience in the surgical treatment of acute cervical fracture-dislocation by reporting the results obtained after the observation and follow-up examination of 53 cases. The surgical procedure adopted, after realignment of bone segments was obtained, depended on type of fracture. Posterior fixation with wire or wire and acrylic was performed in 31 cases. The anterior route was chosen in 19 cases, performing a ventral subtotal resection of the vertebral body with the use of acrylic. Three patients were treated by both procedures (anterior plus posterior approach). The authors describe the surgical technique and recommend the rapid mobilization of the patient, so as to avoid complications which could impede his recovery.