Adjuvant PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) or Gemcitabine Followed by Chemoradiation in Pancreatic Cancer: A Randomized Phase II Trial

Background

Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation.

Methods

Therapy-naive patients, age 18?C75?years, Karnofsky Performance Status (KPS) >60, gross total resection of stage IB?CIII pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1?g/m² weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40?mg/m², day 1; gemcitabine 600?mg/m², days 1, 8; 5-fluorouracil 200?mg/m² daily, days 1?C28) (arm B). Chemotherapy was administered every 4?weeks for 3?months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250?mg/m² daily. Primary endpoint was the probability of being disease-free at 1?year from surgery. Assuming P0?=?35% and P1?=?55%, ???=?.05 and ???=?.10, the study was to enroll 51 patients per arm.

Results

A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60?years; 75% had KPS >80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2?months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35?C63%) and 69.4% (95% CI 56?C83%); median survival 24.8 and 28.9?months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities.

Conclusions

The 4-drug regimen deserves further assessment in resectable pancreatic cancer.     

Partner violence perpetration and victimization and HIV risk behaviors in St. Petersburg, Russia

Whether intimate partner violence (IPV) perpetration and victimization are associated with human immunodeficiency virus (HIV) risk behaviors is seldom investigated in Russia. The present study hypothesized that patients from a sexually transmitted infection center in Russia who perpetrated IPV or were victims of IPV would be more likely to have HIV risk behaviors including injection drug use, multiple partners, and inconsistent condom use than those who were not involved with IPV. We used a self-administered questionnaire to collect information from 381 patients on demographics, health status, injection drug use, sexual behaviors, and violence involving sexual partners between 2008 and 2009. After including sociodemographics, lifetime IPV perpetration was significantly associated with having had multiple sexual partners among male patients (odds ratio [OR] = 2.61, p < .05). IPV victimization was significantly associated with injection drug use among male and female patients (OR = 5.22, p < .05) and with inconsistent condom use among female patients (OR = 8.93, p < .05). IPV perpetration and victimization were common among male and female study participants and were associated with greater HIV risk behaviors. HIV prevention programs in Russia should address the risks associated with IPV among people at risk for HIV.     

On the variability of the McGurk effect: audiovisual integration depends on prestimulus brain states

The McGurk effect demonstrates the influence of visual cues on auditory perception. Mismatching information from both sensory modalities can fuse to a novel percept that matches neither the auditory nor the visual stimulus. This illusion is reported in 60-80% of trials. We were interested in the impact of ongoing brain oscillations-indexed by fluctuating local excitability and interareal synchronization-on upcoming perception of identical stimuli. The perception of the McGurk effect is preceded by high beta activity in parietal, frontal, and temporal areas. Beta activity is pronounced in the left superior temporal gyrus (lSTG), which is considered as a site of multimodal integration. This area is functionally (de)coupled to distributed frontal and temporal regions in illusion trials. The disposition to fuse multisensory information is enhanced as the lSTG is more strongly coupled to frontoparietal regions. Illusory perception is accompanied by a decrease in poststimulus theta-band activity in the cuneus, precuneus, and left superior frontal gyrus. Event-related activity in the left middle temporal gyrus is pronounced during illusory perception. Thus, the McGurk effect depends on fluctuating brain states suggesting that functional connectedness of left STS at a prestimulus stage is crucial for an audiovisual percept.     

Emergency craniotomy for intraparenchymal massive hematoma after embolization of supratentorial arteriovenous malformations

OBJECTIVE: We sought to evaluate the efficacy of emergency craniotomy for patients with massive hematoma secondary to endovascular embolization of supratentorial arteriovenous malformations (AVMs) and to investigate relevant factors affecting outcome. METHODS: Within the past 15 years, 605 patients with intracranial AVMs have undergone 1066 endovascular embolizations at our institution. Of these, 24 patients experienced intracranial hemorrhage during or after the procedure. Fourteen patients were demonstrated to have massive intraparenchymal hematomas and deteriorated to a comatose state (Glasgow Come Scale score < or =6). Twelve patients underwent craniotomy within 170 minutes of being diagnosed with intraparenchymal hemorrhage. The surgical procedures performed were hematoma evacuation with total (6 patients) or partial (2 patients) resection of the AVM or hematoma evacuation only (4 patients). The clinical records of these 12 patients were analyzed retrospectively. RESULTS: Nine patients recovered to a favorable condition (good recovery, four patients; moderately disabled, five patients), one patient remained in a persistent vegetative state, and two patients died. The interval between hemorrhage and emergency craniotomy was significantly shorter in patients with favorable outcomes than in those with poor clinical outcomes. Advanced age and a larger volume of intraoperative blood loss were the factors relevant to poor outcome. Temporal lobe location of the AVM and incomplete embolization tended to correlate to poor clinical outcome, but this correlation was not statistically significant. The sizes of the AVM and the hematoma did not correlate to patient outcome. There was no difference in outcomes with regard to the surgical procedure performed. CONCLUSION: In patients with massive postembolization hematomas, emergency craniotomy should be performed as soon as possible to achieve a favorable outcome. Cooperation among interventional neuroradiologists, intensive care physicians, and neurosurgeons is essential to manage AVM patients with critical postembolization hemorrhage. There is no need to persist in performing simultaneous total resection of the AVM at the emergency craniotomy.     

Impact of cyclosporine 2-h level and mycophenolate mofetil dose on clinical outcomes in de novo heart transplant patients receiving anti-thymocyte globulin induction

BACKGROUND: Cyclosporine (CsA) 2-h post-dose level (C2) correlates better than trough levels (C0) with the area under the curve. We evaluated the clinical impact of C2 and mycophenolate mofetil (MMF) dose in adult heart transplant patients receiving anti-thymocyte globulin (ATG) induction. METHODS: Two immunosuppressive strategies were sequentially evaluated. In Group 1 (13 patients), simultaneous C0/C2 (ng/mL) were analyzed. CsA dose monitoring was initially based on C0 : <3 months: 200-300, 4-6 months: 150-250, 6-9 months: 100-200, and on C2 thereafter (as in Group 2). In Group 2 (nine patients), C2 monitoring was implemented: <3 months: 600-800, 4-6 months: 500-700, >6 months: 400-600. All patients received ATG induction, corticosteroids, and MMF (1.0 g b.i.d. in Group 1 and 1.5 g b.i.d. in Group 2). RESULTS: Patients in Group 2 received higher MMF doses during the first trimester. C2 at 1, 3, 6, 12, 24, and 36 months was, respectively, 1199 +/- 476, 1202 +/- 587, 999 +/- 467, 664 +/- 203, 593 +/- 208, and 561 +/- 147 in Group 1, and 809 +/- 160 (p = 0.02), 644 +/- 178 (p = 0.003), 664 +/- 169 (p = 0.02), 616 +/- 221, 464 +/- 234, and 451 +/- 165 in Group 2. The incidence of acute rejection (grade > or =3A) at 6, 12, 24, and 36 months was, respectively, 38.5, 38.5, 46, and 54% in Group 1, and 11, 44, 56, and 56% in Group 2 (p = NS). At 3 months, the creatinine clearance was 25% lower in Group 1. Thereafter, renal function remained stable in both groups. CONCLUSION: Our results suggest that heart transplant patients receiving ATG induction may experience similar outcomes with either a higher C2 and a lower MMF dose or a lower C2 and a higher MMF dose. These results could be considered to design prospective studies to optimize C2 monitoring, to reduce the incidence of acute rejection without increasing the risk of renal dysfunction.     

Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials

BACKGROUND AND OBJECTIVES: Clonidine is added to intrathecal local anesthetics to improve intraoperative analgesia and to increase the duration of sensory and motor block. The aim of this systematic review is to quantify beneficial and harmful effects of clonidine when used as an adjuvant to intrathecal local anesthetics for surgery. METHODS: We included data from 22 randomized trials (1,445 patients) testing a large variety of doses of clonidine, added to intrathecal bupivacaine, mepivacaine, prilocaine, or tetracaine. RESULTS: Clonidine 15 to 150 microg prolonged in a linear, dose-dependent manner, the time to 2 segment regression (range of means, 14 to 75 minutes) and the time to regression to L2 (range of means, 11 to 128 minutes). The time to first analgesic request (median 101 minutes, range 35 to 310) and of motor block (median 47 minutes, range 6 to 131) was prolonged without evidence of dose-responsiveness. Time to achieve complete sensory or motor block, and extent of cephalic spread remained unchanged. There were fewer episodes of intraoperative pain with clonidine (relative risk, 0.24; 95% confidence interval [CI], 0.09-0.64; number needed to treat, 13) but more episodes of arterial hypotension (relative risk, 1.81; 95% CI 1.44-2.28; number needed to harm, 8) without evidence of dose-responsiveness. The risk of bradycardia was unchanged. CONCLUSIONS: This study may serve as a rational basis to help clinicians decide whether or not to combine clonidine with an intrathecal local anesthetic for surgery. The optimal dose of clonidine, however, remains unknown.     

Chronic renal failure in Kuwaiti children: an eight-year experience

Over an 8-year period (January 1996 to December 2003), a total of 171 patients below the age of 15 years were diagnosed with chronic renal failure. The mean incidence rate of CRF in Kuwaiti children was found to be 38.2 per million children per year, with a peak incidence of 55 per million children per year. While the mean age at diagnosis was 33±12 months (range: 1 month to 15 years), the male:female ratio was 2.7:1. Etiological factors for chronic renal failure included congenital urological malformation (61.9%), chronic glomerulopathies (5.2%), hereditary nephropathies (21%), multi-system disease (0.5%), chronic pyelonephritis (without VUR) (4.6%), tumors (0.6%), ischemic renal disease (1.1%) and unknown etiology (1.7%). Thirty percent of patients reached end-stage renal disease within a mean of 18 months following diagnosis. The overall mortality before reaching ESRD was reported to be 4%. Kuwait has one of the highest incidence and prevalence rates of CRF in children. It is likely that genetic and hereditary factors are the cause of these high rates.     

Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion

BACKGROUND: Ischemia/reperfusion (I/R) injury after organ transplantation is a major cause of delayed graft function. Following I/R, locally produced CXC chemokines attract and activate granulocytes, which in turn promote graft damage. METHODS: We examined the involvement of granulocyte recruitment via the CXCR2 pathway in a rat model of 4 hours cold ischemia followed by kidney transplantation. Serum creatinine and intragraft granulocyte infiltration were monitored in the early phase posttransplant. A CXCR2 inhibitor, repertaxin, was given to recipients before transplantation (at -24 hours or -8 hours or -2 hours), immediately before reperfusion and 2 hours later. RESULTS: An increase of granulocyte chemoattractant CINC-1/interleukin-8 (IL-8) mRNA expression after I/R both in syngeneic and allogeneic transplantation was associated with a marked infiltration of granulocytes in renal tissue. In syngeneic transplantation, Lewis rats given 15 mg/kg repertaxin 24 hours before surgery had granulocyte graft infiltration and serum creatinine levels significantly reduced in respect to vehicle-treated animals. Intermediate effects were observed with 5 mg/kg, whereas the dose of 30 mg/kg had toxic effects. We found that reducing the pretreatment time to 8 hours before surgery was still effective. Prevention of granulocyte infiltration and serum creatinine increase was also obtained in allogeneic transplantation, when Brown Norway recipients of Lewis kidneys were given 15 mg/kg repertaxin starting 8 hours before surgery. CONCLUSION: Repertaxin treatment of the recipient animal was effective in preventing granulocyte infiltration and renal function impairment both in syngeneic and in allogeneic settings. The possibility to modulate I/R injury in this rat model opens new perspectives for preventing posttransplant delayed graft function in humans.