Patient-reported outcomes in relapsed ovarian cancer: Results from a randomized Phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD Alone

ObjectiveTrabectedin in combination with PLD improves progression-free survival (PFS) and overall response rate (ORR) in comparison to PLD alone in patients with relapsed ovarian cancer (J Clin Oncol; 2010 28:3107-14). Here we report the impact of the treatment combination on patient-reported functional status and symptoms.MethodsPatient-reported outcome (PRO) questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit.ResultsOf the 672 patients randomized in this study, 663 treated patients completed at least one of the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Longitudinal data analyses showed no significant differences between the treatment arms for any of the pre-specified scales. Similar analyses of other scales, including Health Index scores and Health State on the Visual Analog Scale, support these findings. Start of subsequent therapy was significantly delayed in the combination arm compared with the monotherapy arm (p = 0.0032).ConclusionsThe addition of trabectedin to PLD led to little or no decrement in patient-reported functional status and symptoms in patients with relapsed ovarian cancer, as compared to treatment with PLD alone. The combination led to manageable and non‐cumulative overall toxicity with a fewer PLD-associated adverse events, and a significant improvement in PFS and ORR compared to single agent.     

Drug Resistance Mutations in HIV-Infected Patients in the Spanish Drug Resistance Database Failing Tipranavir and Darunavir Therapy

The presence of resistance mutations in patients failing tipranavir or darunavir was examined at the national drug resistance database of the Spanish AIDS Research Network. Although mutations emerging during tipranavir and darunavir failures differed considerably, cross-resistance was found in up to half of the patients tested. Interestingly, mutation 54L, which is associated with tipranavir hypersusceptibility, was selected in half of the darunavir failures. Thus, resistance testing seems mandatory to ensure the benefit of the sequential use of these drugs.The protease inhibitors (PI) tipranavir (TPV) and darunavir (DRV) have shown potent antiviral activity against most PI-resistant viruses, reflecting the fact that they display the greatest genetic barrier to resistance within the PI class. The effectiveness of these drugs seems to depend largely on either a unique binding affinity (DRV) or an exclusive nonpeptidomimetic structure (TPV) (5, 9). The RESIST and POWER trials were the first to demonstrate significantly greater reductions in plasma HIV RNA and increases in CD4 counts using TPV and DRV, respectively, over controls using other ritonavir-boosted PIs in HIV-infected patients with extensive PI resistance (3, 7).Early information on TPV resistance derived from the RESIST trials identified 21 mutations located at 16 protease positions associated with a reduced virological response to TPV (2). The presence of more than eight of these changes was associated with a loss of optimal response to TPV. Phenotypic data permitted the splitting out of changes with the most (I47V, I54A, V82T) and least (I13V, K20R, M36I, M46L) impact on TPV susceptibility (10). Subsequently, a TPV weighted score was developed by using the data from the RESIST trials. The mutations I47V, I54A/M/V, Q58E, T74P, V82LT, and N83D had the greatest weights, while the others were considered less important. Interestingly, the mutations L24I, I50L/V, I54L, and L76V were associated with increased TPV susceptibility (hypersusceptibility) and accordingly had negative scores (12). More recently, a new TPV weighted score using additional data from an Italian cohort has been proposed (13).Eleven mutations have been specifically associated with DRV resistance (9). The presence of three or more of these changes was associated with impaired DRV activity in the POWER trials. Although a DRV weighted score is not currently in use, specific changes are known to display the greatest impact (e.g., I50V, I54L, L76V, and I84V), while others show a lesser effect on DRV susceptibility (e.g., V32I, L33F, I47V, V11L, I54M, T74P, and I89V) (6).Information about the selection of drug resistance mutations in patients failing TPV and DRV outside clinical trials is still scarce. Herein, we report results obtained by examining the protease gene in a relatively large group of antiretroviral-experienced HIV-1-infected individuals failing TPV and DRV for whom information was available at the national drug resistance database of the Spanish AIDS Research Network. This is a large clinical database in which viral genotypes derived from more than 3,500 HIV-1-infected patients with a history of prior antiretroviral drug failure outside clinical trials at 12 Spanish clinics have been recorded from 1999 until now (1).TPV resistance-associated mutations (RAMs) were interpreted using the latest TPV weighted score (version 2.1) (14), and DRV RAMs were interpreted using the latest International AIDS Society—USA panel list (December 2009) (8). From a total of 4,813 genotypes derived from 3,299 different HIV-1-infected patients, 105 genotypes belonged to subjects failing TPV (n = 81) or DRV (n = 24).Most of the genotypes examined belonged to highly antiretroviral-experienced patients. Overall, 97.1% had received other PIs. A total of 66.4% had been exposed to three or more PIs before beginning a TPV- or DRV-based regimen, with lopinavir, atazanavir, and fosamprenavir being the most widely used.In TPV failures, the prevalence of TPV RAMs was as follows: L10V, 35.4%; L33F, 60.4%; M36I, 64.6%; K43T, 43.8%; M46L, 29.2%; I47V, 18.8%; I54A, 20.8%; Q58E, 22.9%; V82L, 6.3%; V82T, 45.8%; V84V, 50% (Fig. ​(Fig.1).1). The changes T74P and N83D were not found. The median number of TPV RAMs was 4 (interquartile range, 2 to 6). The most frequent patterns were 33F plus 36I (37.5%), 36I plus 43T (35.4%), 82T plus 36I (29.2%), 82T plus 43T (20.8%), and 82T plus 84V (20.8%).Open in a separate windowFIG. 1.Prevalence of TPV and DRV resistance-associated mutations in 105 HIV-1-infected patients failing antiretroviral therapy with either drug.In DRV failures, the prevalence of DRV RAMs was as follows: V11I, 25%; V32I, 58.3%; L33F, 83.3%; I47V, 33.3%; I54L, 50%; I54M, 16.7%; I84V, 33.3%; L89V, 8.3% (Fig. ​(Fig.1).1). The changes I50V, T74P, and L76V were not found. The median number of DRV RAMs was 3 (interquartile range, 1 to 4). The most frequent resistance patterns were 32I plus 33F (58.3%), 32I plus 54L (50%), 33F plus 46I (50%), and 32I plus 33F plus 43T (50%). Half of the genotypes from DRV failures belonged to patients who had previously failed to fosamprenavir/ritonavir, although I50V was not present in any of them.In agreement with prior observations by others (4, 11, 15), the overlap between protease RAMs in patients failing either TPV or DRV in our study was limited. In fact, only the mutations 33F, 47V, 54M, 74P, and 84V were seen in both groups of patients, with L33F being the most common shared change. It should be noted that this mutation has only minimal impact on TPV or DRV susceptibility. Of the changes considered to produce TPV hypersusceptibility (L24I, I50L, I50V, I54L, and L76V), three (50V, 54L, and 76V) lead to the greatest impairment of DRV susceptibility. Interestingly, only I54L was recognized in patients failing DRV in our study. Overall, cross-resistance between TPV and DRV failures that could preclude their sequential use was recognized in 50% of our patients.The rate of response to DRV as part of salvage therapy in patients who have failed other PIs is relatively high (3, 9), which is in agreement with the robust resistance profile of DRV (9, 15). Our study suggests that in case of DRV failure, TPV-based rescue interventions may be a good option for highly antiretroviral-experienced patients with limited therapeutic options. In fact, only TPV of all of the other PIs might be active in this setting.In summary, although distinct PI resistance-associated mutations emerge in antiretroviral-experienced HIV-1-infected patients failing TPV and DRV, half of these individuals may display cross-resistance. Thus, resistance testing seems warranted to ensure the maximal benefit of the sequential use of these drugs. The frequent selection of the mutation I54L in DRV failures must be highlighted since this change results in TPV hypersusceptibility.     

胎儿和新生儿同种异体免疫性血小板减少症:进展与持续性争议

胎儿和新生儿同种异体免疫性血小板减少症(AIT)是引起胎儿和新生儿严重血小板减少的最常见原因.母亲针对源自父亲的胎儿血小板抗原的IgG抗体,在妊娠早期就可通过胎盘,通常导致胎儿严重血小板减少.由于一些血小板减少症临界值(50、100或150×109/L)的不同,他们的发生率亦各不相同.但在多数未经选择的人群中,AIT影响1/1 000到1/2 000活产数.在新生儿病房,临床确诊的重症AIT很罕见,可能只有1:10 000分娩数.     

Comparison between anatomical polyester (Parietex) mesh and polypropylene (Prolene) mesh with fixation in total extraperitoneal repair for inguinal hernia

Introduction: Laparoscopic inguinal hernia surgery has been gaining in worldwide popularity, with the total extraperitoneal (TEP) repair gaining greater acceptance than the transabdominal pre‐peritoneal repair. Most techniques using TEP advocate some form of fixation of the prosthesis, but newer meshes avoid the use of fixation. Methods: We compared the use of the polyester mesh (Parietex; Tyco, Princeton, USA) without fixation and polypropylene (Prolene; Ethicon, USA) mesh with fixation using either ProTack (Tyco, USA) or EndoAnchor (Ethicon, Cincinnati, USA) in a consecutive series of patients who underwent total TEP endoscopic inguinal hernia repair. Results: Of 127 patients who underwent TEP repairs, 60 had Parietex mesh while 67 had Prolene mesh with fixation. The mean age was 50 years old and 97% were men. There was no difference in patient demographics or complication rate. The most common complication was small seroma or hematoma formation in 14% of patients and none required re‐operation. There was no hernia recurrence in either group with a mean follow‐up period of 13 months. Conclusion: This study shows that in laparoscopic TEP inguinal hernia repair, early results indicate comparable results between the use of polyester (Parietex) mesh without fixation and polypropylene (Prolene) mesh with fixation.     

Dental management in renal failure: patients on dialysis

Chronic renal failure is an important health care problem throughout the world, with an incidence of 337, 90, 107 and 95 new cases per million inhabitants/year in the United States, Australia, New Zealand and the United Kingdom, respectively. These figures moreover invariably tend to increase. During the progression of renal damage, clinical manifestations are noted in practically all body organs and systems, and 90% of all affected patients experience oral symptoms. The existing management options range from simple measures based on changes in diet and life style, to different forms of dialysis (hemodialysis and peritoneal dialysis), and also kidney transplantation. Given the multiple oral manifestations of chronic renal failure, and the different repercussions of its treatment upon the oral cavity, these patients require special considerations and precautions in the face of dental treatment. Consultation with the nephrologist is essential before any dental treatment is carried out, in order to determine the condition of the patient, define the best moment for dental treatment, introduce the necessary pharmacological adjustments, or to establish other important aspects for preventing complications in the dental clinic. The present study reviews the characteristics of the disease, the existing therapeutic options, and the considerations of relevance for the dental professional.     

Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates

Osteonecrosis of the jaws (ONJ) is an important possible late adverse effect of bisphosphonates. Serum C-terminal cross-linking telopeptide of type I collagen (CTX) can determine bone turnover and can act as a biological marker of bone resorption. We studied this biological marker in 15 patients (Group 1) with bisphosphonate-induced ONJ comparing with a control group of 10 healthy people matched by age and gender. We found no statistically significant relationships in Group 1 either between the serum CTX and the number of areas of exposed bone nor with the size of the osteonecrotic area.     

Rapid assessment of phenotypic resistance to protease inhibitors in human immunodeficiency virus type 1 group O

A bacteriophage lambda-based method was used to investigate the development of resistance to protease inhibitors (PI) in one subject infected with human immunodeficiency virus (HIV) type 1 group O who underwent multiple treatment regimens over a period of 4 years. A reduction in the susceptibility to indinavir of 6-fold and a reduction in the susceptibility to saquinavir of 24-fold were recognized after long exposure to these drugs with respect to baseline. The emergence of PI resistance corresponded to the selection of amino acid changes L10V, G48M, F53L, I54V, and L90M at the protease. The results were concordant with those obtained by a drug susceptibility assay with primary HIV isolates.     

Spinal abnormalities in pediatric patients: MR imaging findings compared with clinical, myelographic, and surgical findings

Eighty-one pediatric patients with a variety of spinal disorders, including suspected dysrhaphism, scoliosis, neoplasia, and neurofibromatosis, underwent magnetic resonance (MR) imaging. The results were retrospectively compared with those of myelography followed by computed tomography (CT) and surgery. In patients with dysrhaphism, most abnormalities, including hydromyelia, inclusion tumors, and sites of cord tether, were demonstrated with MR imaging. Diastematomyelia and small hydromyelic cavities were indistinguishable on routine coronal and sagittal T1-weighted images; axial images with T2 weighting were optimal for this differentiation. MR imaging did not enable direct visualization of a thickened filum or evaluation of tethering with a thin, dorsally positioned neural placode. Congenital or severe scoliosis required lengthy studies with multiple planes of imaging or myelography and CT. Milder curvatures were readily evaluated with MR imaging, and neoplastic lesions, with the exception of intrathecal tumor seeding, were adequately defined.     

Maintenance treatment of adults with chronic refractory immune thrombocytopenic purpura using repeated intravenous infusions of gammaglobulin [see comments]

Intravenous infusion of gammaglobulin (IVGG) has been extensively used in the treatment of immune thrombocytopenic purpura (ITP) in adults to acutely raise the platelet count but not as a maintenance therapy. This report describes the maintenance treatment of adults with chronic ITP using repeated infusions of 800 to 1,000 mg/kg of IVGG. Sixteen of 40 patients were able to discontinue all therapy after receiving between one and 15 infusions. Five patients achieved remission and 11 other patients became stable without therapy (SWT) maintaining a platelet count greater than 20,000/microL without bleeding. The average quantity of gammaglobulin received for all patients was 606 g per patient. Of the 30 patients who underwent but did not respond to splenectomy, 11 (37%) were able to discontinue all therapy by either achieving remission (5) or becoming SWT (6). None of the five patients who achieved remission did so after only the initial therapy; all first received between one and 12 maintenance infusions. The ten splenectomized patients who were unresponsive to IVGG also failed to subsequently respond to conventional therapy including immunosuppressive agents and androgens. No toxicity of IVGG was seen except for postinfusion headaches. IVGG is an effective although expensive maintenance therapy for adults with ITP and is useful in patients who have not responded to splenectomy.