A multicenter review of infusion-related reactions to daratumumab for relapsed multiple myeloma in the real world setting.

BACKGROUND: Daratumumab is used in the treatment of relapsed multiple myeloma. Daratumumab infusion-related reactions can occur with the highest incidence on the first infusion. METHODS: A retrospective review of all daratumumab infusions used as part of the DVd and DRd regimens for relapsed multiple myeloma was undertaken. The review of infusion-related reactions was conducted by reviewing the treatment room nursing note on the days that daratumumab was administered. If the patient experienced an infusion-related reaction, then the data captured included if the full dose was administered. RESULTS: Daratumumab infusion-related reactions occurred most frequently on the first dose. The rates of infusion-related reactions using a split dose approach for daratumumab administration were lower than that reported in clinical trials. All of the infusion-related reactions were managed with appropriate interventions in the outpatient setting. The adoption of rapid infusion daratumumab beginning with cycle 2 of DVd and DRd was well tolerated. CONCLUSIONS: Our experience of daratumumab infusions using a split dose approach was associated with an infusion-related reaction rate in 28% of patients on cycle 1, day 1 of DVd and DRd regimens. All patients were able to complete full doses of daratumumab by utilizing split dose. The rates of daratumumab infusion-related reactions are highest on the first infusion. In addition, our adoption of rapid infusion daratumumab was safe.

Autoimmune heparin-induced thrombocytopenia and venous limb gangrene after aortic dissection repair: in vitro and in vivo effects of intravenous immunoglobulin.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder characterized by heparin-dependent antibodies that activate platelets (PLTs) via PLT FcγIIa receptors. "Autoimmune" HIT (aHIT) indicates a HIT subset where thrombocytopenia progresses or persists despite stopping heparin; aHIT sera activate PLTs strongly even in the absence of heparin (heparin-independent PLT-activating properties). Affected patients are at risk of severe complications, including dual macro- and microvascular thrombosis leading to venous limb gangrene. High-dose intravenous immunoglobulin (IVIG) offers an approach to interrupt heparin-independent PLT-activating effects of aHIT antibodies. CASE REPORT: A 78-year-old male who underwent cardiopulmonary bypass for aortic dissection developed aHIT, disseminated intravascular coagulation, and deep vein thrombosis; progression to venous limb gangrene occurred during partial thromboplastin time (PTT)-adjusted bivalirudin infusion (underdosing from "PTT confounding"). Thrombocytopenia recovered with high-dose IVIG, although the PLT count increase began only after the third dose of a 5-day IVIG regimen (0.4 g/kg/day × 5 days). We reviewed case reports and case series of IVIG for treating HIT, focusing on various IVIG dosing regimens used. RESULTS: Patient serum-induced PLT activation was inhibited in vitro by IVIG in a dose-dependent fashion; inhibition of PLT activation by IVIG was much more marked in the absence of heparin versus the presence of heparin (0.2 U/mL). Our literature review indicated 1 g/kg × 2 IVIG dosing as most common for treating HIT, usually associated with rapid PLT count recovery. CONCLUSION: Our clinical and laboratory observations support dose-dependent efficacy of IVIG for decreasing PLT activation and thus correcting thrombocytopenia in aHIT. Our case experience and literature review suggests dosing of 1 g/kg IVIG × 2 for patients with severe aHIT.

Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.

BACKGROUND: Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. METHODS AND RESULTS: The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. CONCLUSIONS: By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Prevalence and Characteristics of Root Resorption Identified in Cone-Beam Computed Tomography Scans.

INTRODUCTION: Root resorption is a destructive process that compromises tooth structure and can result in tooth loss. Often it remains asymptomatic and is an incidental finding on radiographic examinations. The purpose of this study was to determine prevalence and characteristics of root resorption in patients referred for cone-beam computed tomography (CBCT) imaging for a variety of indications. METHODS: The study included CBCT scans of 1086 consecutive patients referred for CBCT imaging over an 18-month period. A total of 1148 scans were acquired. Data were abstracted from radiology reports, and prevalence estimates of resorption were computed for the aggregate sample and also across specific indications. RESULTS: Resorption was identified in 171 patients (15.7%, 95% CI: 13.6%-17.9%) and in 249 teeth with a prevalence range of 2.6%-92.3% across specific indications. An 18.7% of the patients had 2 resorption sites whereas 8.8% had 3 or more resorption sites. The majority of affected teeth were anteriors (43.8%), followed by molars (40.6%) and premolars (14.5%). The most prevalent resorption types were external (29.3%), cervical (22.5%), infection-induced apical resorption (13.7%), internal (9.6%), and impacted tooth induced (8.8%). The majority of teeth with resorption did not have prior endodontic treatment (73.9%) and had radiographically normal periapex (69.5%). Of 249 teeth with resorption, 31% presented as incidental finding. The prevalence of incidental findings of resorption increased with age, P < .05, and was significantly lower for anterior teeth (20.2%) as compared to premolars (41.7%) and molars (36.6%), (P < .05). CONCLUSION: The high proportion of incidental findings of resorption detected by CBCT suggests that resorption is not recognized/detected by conventional radiography and therefore remains underdiagnosed.

Reprint of: Prevalence and Characteristics of Root Resorption Identified in Cone-Beam Computed Tomography Scans.

INTRODUCTION: Root resorption is a destructive process that compromises tooth structure and can result in tooth loss. Often it remains asymptomatic and is an incidental finding on radiographic examinations. The purpose of this study was to determine prevalence and characteristics of root resorption in patients referred for cone-beam computed tomography (CBCT) imaging for a variety of indications. METHODS: The study included CBCT scans of 1086 consecutive patients referred for CBCT imaging over an 18-month period. A total of 1148 scans were acquired. Data were abstracted from radiology reports, and prevalence estimates of resorption were computed for the aggregate sample and also across specific indications. RESULTS: Resorption was identified in 171 patients (15.7%, 95% CI: 13.6%-17.9%) and in 249 teeth with a prevalence range of 2.6%-92.3% across specific indications. An 18.7% of the patients had 2 resorption sites whereas 8.8% had 3 or more resorption sites. The majority of affected teeth were anteriors (43.8%), followed by molars (40.6%) and premolars (14.5%). The most prevalent resorption types were external (29.3%), cervical (22.5%), infection-induced apical resorption (13.7%), internal (9.6%), and impacted tooth induced (8.8%). The majority of teeth with resorption did not have prior endodontic treatment (73.9%) and had radiographically normal periapex (69.5%). Of 249 teeth with resorption, 31% presented as incidental finding. The prevalence of incidental findings of resorption increased with age, P < .05, and was significantly lower for anterior teeth (20.2%) as compared to premolars (41.7%) and molars (36.6%), (P < .05). CONCLUSION: The high proportion of incidental findings of resorption detected by CBCT suggests that resorption is not recognized/detected by conventional radiography and therefore remains underdiagnosed.

Anticoagulants to prevent placenta-mediated pregnancy complications: a review of current evidence.

PURPOSE OF REVIEW: Placenta-mediated pregnancy complications are relatively common and are associated with significant morbidity and mortality. Although anticoagulants are increasingly being used to prevent these complications, the evidence supporting their use is limited. This article will focus on reviewing the current evidence base for the use of anticoagulants to prevent placenta-mediated pregnancy complications in women with or without identifiable thrombophilia. RECENT FINDINGS: Controversy exists whether inherited or acquired thrombophilias cause placenta-mediated complications. Small randomized studies with methodological limitations suggest that antepartum anticoagulant prophylaxis will reduce pregnancy loss in women with both acquired and inherited thrombophilia and prior pregnancy loss. There are no published randomized controlled trials examining anticoagulant prophylaxis in thrombophilic women with prior preeclampsia, intrauterine growth restriction or placental abruption. More recently, the benefit of antepartum anticoagulant prophylaxis in women without thrombophilia with prior placenta-mediated pregnancy complications has been suggested in a small pilot randomized trial. SUMMARY: Overall, although antepartum anticoagulant prophylaxis has the potential to reduce placenta-mediated pregnancy complications in women with and without identifiable thrombophilia, the data generated by these trials are methodologically limited and inadequate. Hence, we conclude that further trials are required prior to adopting the use of antepartum anticoagulant prophylaxis to prevent placenta-mediated pregnancy complications in routine clinical practice.

Cytotoxicity of enantiomers of gossypol Schiff's bases and optical stability of gossypolone.

Optical Schiff's bases of gossypol were prepared with chiral gossypol and ethylamine. As has been similarly observed among the gossypol enantiomers, the (-)-gossypol ethylimine was more active than either the (+)-gossypol ethylimine or the racemic gossypol ethylimine against KB and MCF7 cells. Gossypolone was also observed to be more toxic than gossypol against both cell lines. All of the gossypol products tested showed comparable toxicity toward MCF7/ADR (adriblastine-resistant) cells. Attempts at producing chiral gossypolone from chiral gossypol failed because of rapid racemization. In addition, the Schiff's base derivatives of gossypolone formed with R-(+)-2-amino-3-phenyl-1-propanol could only be separated at reduced temperature, indicating that gossypolone Schiff's bases are less optical stable than gossypol Schiff's bases.

Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies.

Patients with cancer-associated venous thromboembolism (VTE) should be treated with low molecular weight heparin. The ideal duration of anticoagulation in this population is unknown. It is important to evaluate whether there is variation in susceptibility for recurrent VTE according to malignancy characteristics. In this systematic review we sought to evaluate cancer characteristics that may influence the risk for VTE recurrence and the success of anticoagulation in patients with cancer-associated VTE. A systematic literature search strategy identified potential studies on MEDLINE, Embase, the Cochrane Register of Controlled Trials, MEDLINE In-Process and other nonindexed citations using the Ovid interface. There was no restriction to study design or language. No randomized controlled trials fulfilled our inclusion criteria. We included four retrospective and six prospective studies. VTE recurrence rate according to tumour stage suggested an increased risk for patients with metastatic malignancy compared with patients with localized disease (relative risk 1.36; 95% confidence interval 1.06-1.74, P = 0.01). We were unable to pool data to evaluate VTE recurrence according to tumour site and histology. The isolated evaluation of the included studies suggested that younger patients with adenocarcinoma, lung or gastrointestinal malignancy have the highest risk. There is paucity of data regarding detailed malignancy characteristics in patients with cancer-associated VTE. It appears that metastatic malignancy, or adenocarcinoma, or lung malignancy confers a higher risk of VTE recurrence than patients with localized malignancy, nonadenocarcinoma or breast cancer.

Dynamic changes in Rap1 activity are required for cell retraction and spreading during mitosis.

At the onset of mitosis, most adherent cells undergo cell retraction characterised by the disassembly of focal adhesions and actin stress fibres. Mitosis takes place in rounded cells, and the two daughter cells spread again after cytokinesis. Because of the well-documented ability of the small GTPase Rap1 to stimulate integrin-dependent adhesion and spreading, we assessed its role during mitosis. We show that Rap1 activity is regulated during this process. Changes in Rap1 activity play an essential role in regulating cell retraction and spreading, respectively, before and after mitosis of HeLa cells. Indeed, endogenous Rap1 is inhibited at the onset of mitosis; conversely, constitutive activation of Rap1 inhibits the disassembly of premitotic focal adhesions and of the actin cytoskeleton, leading to delayed mitosis and to cytokinesis defects. Rap1 activity slowly increases after mitosis ends; inhibition of Rap1 activation by the ectopic expression of the dominant-negative Rap1[S17A] mutant prevents the rounded cells from spreading after mitosis. For the first time, we provide evidence for the direct regulation of adhesion processes during mitosis via the activity of the Rap1 GTPase.

New thioderivatives of gossypol and gossypolone, as prodrugs of cytotoxic agents.

New dithiane or dithiolane derivatives of gossypol and gossypolone were synthesized with dithiolethane or dithiolpropane in the presence of BF(3)/Et(2)O. These thioderivatives exhibited low toxicity on KB cells (human epidermoid carcinoma cells of the mouth). They react easily with electrophiles in aprotic solvents to regenerate gossypolone or to form dehydrogossypoldithianes and dehydrogossypoldithiolanes, which display higher toxicity on KB cells. In addition, the low toxicity of gossypol thioderivatives was reversed by nitric oxide donors in physiological media. These experiments suggest that gossypol and gossypolone dithianes and dithiolanes can be used as prodrugs that target tumor cells surrounded by high concentrations of nitric oxide.