Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Treatment of the Budd-Chiari syndrome with percutaneous transluminal angioplasty. Case report and review of the literature

A patient with the Budd-Chiari syndrome due to membranous obstruction of the right hepatic vein and long segmental obstruction of the inferior vena cava who was successfully treated with percutaneous transluminal angioplasty is described. Review of the literature revealed 14 prior cases of balloon dilatation of the hepatic venous system: 10 of the hepatic portion of the inferior vena cava, three of the right hepatic vein, and one of the left hepatic vein. Follow-up ranged from six months to 37 months. No serious complications were reported. All attempts at dilatation were successful, but reocclusion occurred in six patients, three of whom had occlusion of the hepatic vein. All but one patient with reocclusion, however, underwent repeated angioplasty, which was successful in all cases attempted. Two patients who had repeated angioplasty required no further therapy, but two patients required a total of three angioplasties and two patients required four angioplasties. Successful angioplasty was accompanied by resolution of clinical symptoms in all patients described. It is concluded that percutaneous transluminal angioplasty is a safe and effective mode of therapy in the management of the Budd-Chiari syndrome due to membranous obstruction of the hepatic portion of the inferior vena cava or the hepatic veins.     

Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in human immunodeficiency virus-associated,B-cell non-Hodgkin lymphoma

Four cycles of rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy is as effective as six cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with human immunodeficiency virus-associated DLBCL and high-grade lymphoma treated with four to six cycles of EPOCH plus rituximab based on a response-adapted treatment strategy. One hundred and six evaluable patients with human immunodeficiency virus-associated DLBCL or highgrade CD20⁺ non-Hodgkin lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by an intravenous bolus of cyclophosphamide every 21 days for four to six cycles. Patients received two additional cycles of therapy after documentation of a complete response by computed tomography after cycles 2 and 4. Sixty-four of 106 evaluable patients (60%; 95% confidence interval [95% CI]: 50%-70%) in both treatment arms had a complete response. The 2-year event-free survival rates were similar in the 24 patients with complete response who received four or fewer cycles of EPOCH (78%; 95% CI: 55%-90%) due to having achieved a complete response after two cycles, compared with those who received five or six cycles of EPOCH (85%; 95% CI: 70%-93%) because a complete response was first documented after cycle 4. A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in patients with human immunodeficiency virus-associated lymphoma treated with EPOCH plus rituximab, which merits further evaluation in additional prospective trials. Clinical Trials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00049036","term_id":"NCT00049036"}}NCT00049036.     

Diurnal 18-hydroxy-11-deoxycorticosterone pattern in human stable hypertension.

Diurnal 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) pattern was studied with RIA technique in 33 hypertensive patients in supine position and on normal sodium diet. The compound was evaluated every 2 h from 0800-2000 h. Simultaneously, plasma aldosterone and cortisol were measured. Abnormal 18-OH-DOC behavior was observed in only 2 out of 4 patients with Cushing's disease, while sporadic and slight elevations, synchronous with F, were seen in 5 out of 24 stable essential hypertensive patients [1 with normal plasma renin activity (PRA), 1 with low PRA, and 3 with high PRA]. 18-OH-DOC was normal in 2 cases of hypertension due to renal artery stenosis, in 1 patient with nephrosclerosis, and in 1 patient with horseshoe kidney. From these results, 18-OH-DOC does not seem to play an important pathogenetic role in stable essential hypertension, considering also the low mineralocorticoid activity of the compound.     

Pericarditis and Pericardial Effusion: Management Update

Prompt recognition of the signs and symptoms of pericardial disease is critical so that appropriate treatments can be initiated. Acute pericarditis has a classical presentation, including symptoms, physical examination findings, and electrocardiography abnormalities. Early recognition of acute pericarditis will avoid unnecessary invasive testing and prompt therapies that provide rapid symptom relief. Non-steroidal anti-inflammatory drugs (NSAIDs) remain first-line therapy for uncomplicated acute pericarditis, although colchicine can be used concomitantly with NSAIDS as the first-line approach, particularly in severely symptomatic cases. Colchicine should be used in all refractory cases and as initial therapy in all recurrences. Aspirin should replace NSAIDS in pericarditis complicating acute myocardial infarction. Systemic corticosteroids can be used in refractory cases or in those with immune-mediated etiologies, although generally should be avoided due to a higher risk of recurrence. Pericardial effusions have many etiologies and the approach to diagnosis and therapy depends on clinical presentation. Pericardial tamponade is a life-threatening clinical diagnosis made on physical examination and supported by characteristic findings on diagnostic testing. Prompt diagnosis and management is critical. Treatment consists of urgent pericardial fluid drainage with a pericardial drain left in place for several days to help prevent acute recurrence. Analysis of pericardial fluid should be performed in all cases as it may provide clues to etiology. Consultation of cardiac surgery for pericardial window should be considered in recurrent cases and may be the first-line approach to malignant effusions, although acute relief of hemodynamic compromise must not be delayed. Constrictive pericarditis is associated with symptoms that mimic many other cardiac conditions. Thus, correct diagnosis is critical and involves identification of pericardial thickening or calcification in association with characteristic hemodynamic alterations using noninvasive and invasive diagnostic approaches. Constrictive physiology may occur transiently and resolve with medical therapy. In chronic cases, definitive therapy requires referral to an experienced surgeon for pericardiectomy.     

Angioplasty Guidewire Velocity: A New Simple Method to Calculate Absolute Coronary Blood Velocity and Flow

The Thrombolysis In Myocardial Infarction (TIMI) frame count is a relative index of coronary flow that measures time by counting the number of frames required for dye to travel from the ostium to a standardized coronary landmark in a cineangiogram filmed at a known speed (frames/s). We describe a new method to measure distance along arteries so that absolute velocity (length ÷ time) and absolute flow (area × velocity) may be calculated in patients undergoing percutaneous transluminal coronary angiography (PTCA). After PTCA, the guidewire tip is placed at the coronary landmark and a Kelly clamp is placed on the guidewire where it exits the Y-adapter. The guidewire tip is then withdrawn to the catheter tip and a second Kelly clamp is placed on the wire where it exits the Y-adapter. The distance between the 2 Kelly clamps outside the body is the distance between the catheter tip and the anatomic landmark inside the body. Velocity (cm/s) may be calculated as this distance (cm) ÷ TIMI frame count (frames) × film frame speed (frames/s). Flow (ml/s) may be calculated by multiplying this velocity (cm/s) and the mean cross-sectional lumen area (cm²) along the length of the artery to the TIMI landmark. In 30 patients, velocity increased from 13.9 ± 8.5 cm/s before to 22.8 ± 9.3 cm/s after PTCA (p <0.001). Despite TIMI grade 3 flow both before and after PTCA in 18 patients, velocity actually increased 38%, from 17.0 ± 5.4 to 23.5 ± 9.0 cm/s (p = 0.01). For all 30 patients, flow doubled from 0.6 ± 0.4 ml/s before to 1.2 ± 0.6 ml/s after PTCA (p <0.001). In the 18 patients with TIMI grade 3 flow both before and after PTCA, flow increased 86%, from 0.7 ± 0.3 to 1.3 ± 0.6 ml/s (p = 0.001). Distance along coronary arteries (length) can be simply measured using a PTCA guidewire. This length may be combined with the TIMI frame count to calculate measures of absolute velocity and flow that are sensitive to changes in perfusion. TIMI grade 3 flow is composed of a range of velocities and flows.     

Raloxifene hydrochloride.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. A SERM interacts with estrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of estrogen without the possible stimulatory effects on the breasts or uterus. Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass glucuronidation. Approximately 60% of a dose is absorbed; however, absolute bioavailability is only 2%. The volume of distribution is 2348 L/kg for a single oral dose of 30-150 mg, and the elimination half-life averages 32.5 hours. In clinical trials in postmenopausal women, raloxifene had an estrogen-like effect on bone turnover and increased bone mineral density. It reduced the risk of fractures in women with osteoporosis. Raloxifene also seemed to reduce the risk of breast cancer and positively influenced blood lipid markers of cardiovascular disease. Raloxifene is generally well tolerated; the most common adverse effects are hot flashes and leg cramps. A serious adverse effect is venous thromboembolism. The recommended dosage is 60 mg/day orally without regard to meals. Ultimately, it will be information on cardiovascular or breast cancer benefits that will determine the future role of raloxifene. Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women. More study is needed to verify possible benefits related to heart disease and breast cancer.     

Surgery after intracranial investigation with subdural electrodes in patients with drug-resistant focal epilepsy: outcome and complications

Video-EEG monitoring with intracranial subdural electrodes is a useful assessment tool for the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy. We aimed at assessing the morbidity related to electrode implantation and the surgical outcome in patients who underwent epilepsy surgery after intracranial EEG monitoring. All patients (N?=?58) admitted to our Epilepsy Surgery Centre for drug-resistant focal epilepsy who underwent resective surgery after intracranial monitoring with subdural electrodes and were followed up for at least 2?years were included in the study. Their mean age was 30.4?years (range 8-60?years), 25 (43?%) were female, and 44 (76?%) had a preoperatively detected structural lesion. The mean duration of invasive recording was 2.3?days (range 1-14?days). Extraoperative ECoG allowed the identification of the epileptogenic focus in all cases. The temporal lobe was involved in 21 (36?%) patients, whereas extratemporal foci were identified in 24 (41?%) patients. Thirteen patients (23?%) had multilobar involvement. Functional brain mapping was performed in 15 (26?%) patients. Transient complications related to electrode implantation occurred in three patients. Among patients with evidence of lesion on preoperative MRI, lesionectomy alone was performed in 12 cases (27?%), while it was combined with tailored cortical resection in the remaining cases. Tailored cortical resection was also performed in patients without evidence of lesion on MRI. After resective surgery, transient neurological deficits occurred in five cases, while another patient experienced permanent lateral homonymous hemianopia. At the last follow-up observation, 34 (57?%) patients were seizure-free (Engel class I). This study suggests that invasive EEG recording with subdural electrodes may be useful and fairly safe for many candidates for epilepsy surgery.