Advantages of non-cryopreserved autologous hematopoietic stem cell transplantation against a cryopreserved strategy.

Autologous stem cell transplantation (auto-HSCT) is an effective treatment strategy for hematological malignancies. The standard mode of handling hematopoietic progenitors for the autologous procedure (CRYO) consists on its collection and freezing with dimethyl sulfoxide (DMSO) and its subsequent thawing and re-infusion. This process is toxic and expensive. Non-cryopreserved (non-CRYO) is a less expensive mode of auto-HSCT. We designed a comparative study between both strategies performed in two different centers to analyze the short-term complications. In total 111 auto-HSCT were performed from January/2015 to October/2016 (42 non-CRYO and 74 CRYO). There were 74 males and 69 (62%) patients had the underlying diagnosis of multiple myeloma. No differences were seen on the characteristics of the apheresis products and their viability. Engraftment was significantly faster in the non-CRYO group (p = 0.001). Febrile neutropenia and severe mucositis were lower in the non-CRYO group (40% vs 92% p = 0.0001 and 11% vs 64%, p = 0.001, respectively). In addition, length of hospitalization was 5 days shorter in the non-CRYO group (p = 0.0001). Overall responses and transplantation outcomes were similar. Our data demonstrate a clear advantage of the non-CRYO over CRYO auto-HSCT with faster engraftment, lower incidence of febrile neutropenia and shorter hospital stay after the transplantation procedure. These data are especially relevant for centers with high transplant activity or with limited resources.

Therapeutic management in ambulatory elderly patients with atrial fibrillation: the S.AGES cohort.

UNLABELLED: Few epidemiologic studies have specifically focused on very old community dwelling population with atrial fibrillation (AF). The objectives of the AF-S.AGES cohort were to describe real-life therapeutic management of non-institutionalized elderly patients with AF according to age groups, i.e., 65-79 and ≥ 80 and to determine the main factors associated with anticoagulant treatment in both groups. METHODS: Observational study (N=1072) aged ≥ 65 years old, recruited by general practitioners. Characteristics of the sample were first evaluated in the overall sample and according to age (< 80 or ≥ 80 years) and to use of anticoagulant treatment at inclusion. Logistic models were used to analyze the determinants of anticoagulant prescription among age groups. RESULTS: Mean age was 78.0 (SD=6.5) years and 42% were ≥ 80 years. Nineteen percent had paroxysmal AF, 15% persistent, 56% permanent and 10% unknown type, 77% were treated with vitamin K antagonists (VKA), 17% with antiplatelet therapy with no differences between age groups. Rate-control drugs were more frequently used than rhythm-control drugs (55% vs. 37%, p < 0.001). VKA use was associated with permanent AF, younger age and cancer in patients ≥ 80 years old and with permanent AF and preserved functional autonomy in patients < 80 years old. Hemorrhagic scores were independently associated with non-use of VKA whereas thromboembolic scores were not associated with VKA use. CONCLUSIONS: In this elderly AF outpatient population, use of anticoagulant therapy was higher even after 80 years than in previous studies suggesting that recent international guidelines are better implemented in the elderly population.

Two dosing regimens of certolizumab pegol in patients with active rheumatoid arthritis.

OBJECTIVE: To investigate clinical efficacy and safety of 2 certolizumab pegol (CZP) maintenance dosing regimens plus methotrexate (MTX) in active rheumatoid arthritis (RA) patients achieving the American College of Rheumatology 20% improvement criteria (ACR20) after the CZP 200 mg every 2 weeks open-label run-in period. METHODS: DOSEFLEX (dosing flexibility) was a double-blind, placebo-controlled randomized study with an open-label run-in phase. During the run-in phase, all patients received CZP 400 mg (weeks 0, 2, and 4) and 200 mg every 2 weeks to week 16. Week 16 ACR20 responders were randomized 1:1:1 at week 18 to CZP 200 mg every 2 weeks, 400 mg every 4 weeks, or placebo. RESULTS: A total of 209 (of 333) patients were randomized at week 18 (CZP: 200 mg, n = 70; 400 mg, n = 70; placebo, n = 69). Groups had similar baseline characteristics (week 0). Week 34 ACR20 response rates were comparable between the CZP 200 mg every 2 weeks and the 400 mg every 4 weeks groups (67.1% versus 65.2%), which was significantly higher than placebo (44.9%; P = 0.009 and P = 0.017). ACR50/70 and remission criteria were met more frequently in CZP groups than placebo at week 34, with similar responses between anti-tumor necrosis factor-experienced and naive patients. Improvements from baseline Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and Health Assessment Questionnaire disability index scores were maintained in CZP groups from week 16 to 34 while worsening on placebo. Adverse event (AE) rates in the double-blind phase were 62.9% versus 60.9% versus 62.3%; serious AE rates were 7.1% versus 2.9% versus 0.0% (CZP 200 mg, 400 mg, and placebo groups). CONCLUSION: In active RA patients with an incomplete MTX response, CZP 200 mg every 2 weeks and 400 mg every 4 weeks were comparable and better than placebo for maintaining clinical response to week 4 following a 16-week, open-label run-in phase.

Umbilical cord blood transplantation in hematologic diseases in patients over 15 years old: long-term experience at the Pontificia Universidad Católica de Chile.

Most patients who require a sibling stem cell transplantation do not have a matched donor. In our experience, only 1/3 patients have a matched unrelated donor (MUD); therefore, the majority of the patients will require umbilical cord blood (UCB). Patients treated for hematologic diseases with UCB transplants were included. UCB selection and conditioning regimens were performed according to the Minnesota group. Graft-versus-host disease (GVHD) prophylaxis, infection prevention, and patient care were performed according to institutional guidelines. We analyzed patients and graft demography, neutrophil and platelet recovery, chimerism kinetics, GVHD incidence, overall (OS), progression-free survival (PFS) and transplant-related mortality (TRM). We included 29 patients with a median age of 34.8 years (range 15-55). Eighteen were male and the median weight was 72.6 kg (range 54-100). Nineteen patients had acute leukemia. Myeloablative (MA) conditioning was used in 27 patients. Seventeen received double UCB (DUCB) grafts. Median total nucleated cell (10(7)/kg) was 4.2 (range 3.9-4.9) and 4.4 (range 2.8-6.3) for single UCB (SUCB) and DUCB transplants, respectively. Median time for neutrophil engraftment was 24.7 (range 14-43) and 25.8 days (range 14-52) after SUCB and DUCB transplants, respectively. Median time for platelet engraftment was 147 (range 30-516) and 81 days (range 37-200) after SUCB and DUCB transplants, respectively. All the patients receiving MA conditioning had >95% chimerism shortly after transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD was 41% and 20%, respectively. Localized chronic GVHD was seen in 14% of the patients. Median follow-up was 16.7 months (range 1-63). Five-year OS and PFS were 38% and 39%, respectively. One-year TRM was 42%. UCB transplantation is associated with potential cure of hematologic malignancies and our results are similar to other series. Studies are needed to decrease mortality and improve immune reconstitution.

The therapeutic management of chronic pain in ambulatory care patients aged 65 and over in France: the S.AGES Cohort. Baseline data.

OBJECTIVE: The main objective of the S.AGES (Elderly Subjects) cohort study is to describe the current therapeutic strategy for chronic pain in non-institutionalised elderly patients in France. METHODS: In this prospective cohort study, non-institutionalised patients aged 65 years and over with chronic pain were recruited by general practitioners (GP) across France. All medicinal and non- medicinal prescriptions were recorded at inclusion and will be followed up over 3 years via an eCRF. Data recorded at baseline are presented in this paper. RESULTS: Two hundred and sixty GPs enrolled 1379 evaluable patients between June 3rd, 2009 and June 3rd, 2011. Pain was mainly of a mechanical nature, due to osteoarthritis or common back pain. 80% of the patients had moderate or severe pain. More than a third of patients were treated with a step 1 analgesic (mainly paracetamol), and approximately 30% received a step 2 analgesic (23% dextropropoxyphene and 40.3% tramadol/paracetamol combination). Only 3% received step 3 analgesics; this rate remained low even in patients with severe pain. The proportion of patients treated with an antiepileptic was higher in case of neuropathic pain. More than 25% of patients did not receive any analgesic medication. CONCLUSION: The baseline S.AGES study results exhibit a well-balanced therapeutic management of chronic pain by GPs for ambulatory elderly patients. Clinicaltrials.org NCT01065909.

Opioid rotation in the treatment of joint pain. A review of 67 cases.

OBJECTIVE: To determine that opioid rotation can be useful for establishing a more advantageous analgesia/toxicity relationship in rheumatologic pain. METHODS: Among patients treated with opioids for rheumatologic non-malignant pain, 67 patients with opioid rotation were enrolled retrospectively. In all cases, the other analgesics had failed. The opioids used were: oral morphine, oral hydromorphone, oral buprenorphine and transdermal fentanyl. The reasons for rotation were noted and the improvement of pain was assessed by comparing baseline and post-treatment visual analog scales (VAS in mm). RESULTS: The 67 patients suffered from low back pain with sciatica in 27 cases, inflammatory arthritis in 14 cases, brachial neuralgia in six cases, osteoarthritis in eight cases and miscellaneous in 12 cases. The opioid rotations were the substitution of morphine by transdermal fentanyl, by oral hydromorphone in most of the cases. The principal reason for opioid rotation was failure of the first treatment. The mean of VAS improvement was 30 mm (P < 0.001). CONCLUSION: In rheumatologic non-malignant pain, the opioid rotation might allow the physician to bypass side effects or failure to alleviate pain in most cases.

[Preventive therapy for nausea and vomiting in patients on opioid therapy for non-malignant pain in rheumatology]. / Intérêt de la prévention des nausées et vomissements chez des patients traités par morphine pour des douleurs bénignes d'origine rhumatologique.

OBJECTIVE: To determine if systematic use of metoclopramide associated with opioids (Morphine sulfate SR) decreases the incidence of nausea and vomiting (N&V), established adverse effects of opioids. METHOD: Open randomised study with 132 patients treated for non malignant pain (71 women, 61 men, mean age 53.4 years). One group (n = 76) was treated with morphine alone; the other (n = 56) with morphine plus metoclopramide. Mean duration of therapy: 6 days; mean dosage: 60 mg/d RESULTS: In the 2 groups, N&V were present in the first 72 hours. The frequency of N&V in the morphine group was 38.1% (conform with the literature). The systematic use of metoclopramide decreases the frequency of N&V: p < 0.005. However the use of morphine > 60 mg/d decreases N&V: p = 0.036. High dosages of morphine can have an antiemetic effect by interaction with the mu receptors in the antiemetic center and not in the trigger zone which has an emetic effect. CONCLUSION: The systematic use of metoclopramide with opioid therapy for non malignant pain in rheumatology decreases the risk of nausea and vomiting.

Aromatase in synovial cells from postmenopausal women.

Peripheral aromatization of androgens exerts estrogenic actions in many tissues. In this study, osteoarthritis synoviocytes were examined to clarify the possible action of adrenal androgen on synovial cell. Synoviocytes from postmenopausal women are able to express aromatase mRNA. By sequence analysis, the PCR fragment (485 bp) was determined to be 100% identical to that of human placental aromatase cDNA. Moreover, this study demonstrates that adrenal androgen, androstenedione, is converted to estrone (E(1)) and estradiol (E(2)) in synoviocytes by aromatase which is positively regulated by glucocorticoids such as dexamethasone. E(2) production reduced significantly IL-6 secretion. These data provide preliminary evidence that in situ estrogen production by synoviocytes may have a role in OA susceptibility. However the role of E(2) in OA is not clear and remains to be determined.

Efficacy of dideoxynucleosides against human foamy virus and relationship to its reverse transcriptase amino acid sequence and structure.

Human foamy virus (HFV), a retrovirus of simian origin which occasionally infects humans, is the basis of retroviral vectors in development for gene therapy. Clinical considerations of how to treat patients developing an uncontrolled infection by either HFV or HFV-based vectors need to be raised. We determined the susceptibility of the HFV to dideoxynucleosides and found that only zidovudine was equally efficient against the replication of human immunodeficiency virus type 1 (HIV-1) and HFV. By contrast, zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), and didanosine (ddI) were 3-, 3-, 30-, and 46-fold less efficient against HFV than against HIV-1, respectively. Some amino acid residues known to be involved in HIV-1 resistance to ddC, 3TC, d4T, and ddI were found at homologous positions of HFV reverse transcriptase (RT). These critical amino acids are located at the same positions in the three-dimensional structure of HIV-1 and HFV RT, suggesting that both enzymes share common patterns of inhibition.

[Strong opioids for chronic non-cancer pain]. / Les opioïdes forts dans les douleurs chroniques non cancéreuses.

A CHALLENGING SITUATION: A number of patients experiencing chronic noncancer pain are unsatisfied with standard treatment modalities. This raises the question of whether there may be a place for strong opioids in the management of these patients. Randomised placebo-controlled trials of strong opioids generated rather disappointing results in this type of pain. Observational studies have indicated that strong opioids may improve comfort and function in some patients with intractable nociceptive or neuropathic pain. However, opioids may be ineffective in others and intolerable side effects, heightened pain and functional impairment as well as drug addiction may also occur. A PROMISING SOLUTION: Finally, strong opioids do not appear to be the issue to all intractable chronic nonmalignant pain states, but they may be a possible issue to a subset of selected and informed patients who agree on the goals of the treatment and accept regular monitoring.

The pharmacological management of drug-induced rheumatic disorders.

Many drugs can induce adverse effects such as rheumatoid disorders, which we need to be aware of in order to best detect and manage them. New drugs are constantly entering the marketplace and can cause an increasing number of disorders. Through this article, we review the prevention and pharmacological management of drug-induced rheumatic disorders. These include articular and peri-articular manifestations induced by fluoroquinolones, retinoids, cyclosporin, drug-induced disorders of bone metabolism such as corticosteroid-induced osteoporosis and drug-induced osteomalacia, and multisystemic manifestations including drug-induced lupus and arthritis induced by vaccinations and cytokines.

Drug-induced rheumatic disorders: incidence, prevention and management.

The purpose of this article is to review the causes, the clinical manifestations and the management of the more frequent drug-induced rheumatic disorders. These include: (i) articular and periarticular manifestations induced by fluoroquinolones, nonsteroidal anti-inflammatory drugs, injections of corticosteroids, and retinoids; (ii) multisystemic manifestations such as drug-induced lupus and arthritis induced by vaccination, Bacillus Calmette-Guerin therapy and cytokines; (iii) drug-induced disorders of bone metabolism (corticosteroid-induced osteoporosis, drug-induced osteomalacia and osteonecrosis); and (iv) iatrogenic complex regional pain syndromes. Disorders caused by nonpharmacological and rarely used treatments have been deliberately excluded. Knowledge of these drug-induced clinical symptoms or syndromes allows an earlier diagnosis and treatment, and earlier drug withdrawal if necessary. With the introduction of new medications such as the recombinant cytokines and antiretroviral treatments, the number of drug-induced rheumatic disorders is likely to increase.

Current use of analgesics for rheumatological pain.

Rheumatological pain is the most frequent pain doctors have to deal with. Faced with a patient experiencing pain, the clinician must work towards global management of the patient, including the prescription of analgesics. The results of a European survey amongst 722 general practitioners, rheumatologists, orthopaedic surgeons and internal specialists showed that about half of all patients treated for moderate-to-severe pain suffered from musculoskeletal pain. Despite this high treatment frequency, the management of rheumatological pain was generally perceived as problematic by the respondents. The drugs prescribed to treat rheumatological pain differed from country to country, but NSAIDs were generally the most-prescribed substances. Important reasons given for selecting analgesics included efficacy and tolerability, but also tolerance and addiction potential. NSAIDs are common first-line drugs, but their adverse reactions and interactions have led to paracetamol being recommended more often in this role. However, it has been recently demonstrated that the efficacy of paracetamol is often inadequate. On the other hand, the reduced risk of GI toxicity of the new COX-2 selective inhibitors could assure them a major role in mild-to-moderate rheumatological pain treatment. When any of these drugs are no longer effective, or when a patient cannot tolerate their adverse reactions, weak opioids should be considered. Tramadol is one such drug, which is gaining popularity for the treatment of moderate-to-severe rheumatological pain. Finally, strong opioids should be used in selected patients when all other options have been exhausted.

Treatment of the postenucleation socket syndrome with a new hydroxyapatite tricalcium phosphate ceramic implant.

PURPOSE: Surgical correction of the postenucleation socket syndrome (PESS) is challenging. Various biomaterials are used for reconstruction of the anophthalmic orbit, often with unsatisfactory long-term results. Implants have been placed between the periorbital and the orbital floor. The authors describe a new material composed of hydroxyapatite tricalcium phosphate (HA-TCP) in the form of ceramic blocks, to be placed into the orbital fat as a new surgical site. METHODS: Ten patients with PESS underwent surgery to compensate the volume deficit of the anophthalmic orbit. Blocks of HA-TCP were created by fragmentation of a larger piece, tailored as needed, and implanted in the orbital fat. The patients were monitored regularly with clinical and radiologic examinations to evaluate the behavior of the implants. RESULTS: The volume of the HA-TCP was measured in 5 cases (mean, 2.95 +/- 1.08 ml). A significant reduction of enophthalmos was obtained: mean Hertel exophthalmometry measured 12.7 +/- 2.5 mm preoperatively and 14 +/- 2.4 mm postoperatively (p < 0.05). The average prosthesis volume was significantly reduced in the cases measured: 2.7 ml +/- 0.94 ml preoperatively and 1.8 +/- 0.7 ml postoperatively (p < 0.02). There was a negative correlation between the HA-TCP implant volume and postoperative prosthesis volume (correlation coefficient = -0.925; p < 0.05). According to photographic evaluation, correction of the enophthalmos and of the superior sulcus depression were obtained in 70% and 90% of cases, respectively. Magnetic resonance imaging seems to demonstrate that the blocks become well integrated into the surrounding orbital tissue. CONCLUSION: The HA-TCP blocks correct some anomalies of PESS. Placement of the blocks directly into the orbital fat is a promising alternative to the traditional subperiosteal location.

[Secondary reconstruction of anophthalmic orbits by intraorbital biomaterial implantation]. / Reconstruction secondaire des orbites anophtalmes par implantation intra-orbitaire d'un biomatériau.

Poor cosmetic symptoms related to enucleation or evisceration, lead to the post enucleation socket syndrome. A surgical technique is described, with implantation of hydroxyapatite tricalcium phosphate ceramic blocks in the intraorbital fat.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE): a form of paraneoplastic polyarthritis?

OBJECTIVE: To describe the clinical and laboratory features and outcome of 6 patients presenting with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) revealing a solid tumor. METHODS: Patients with RS3PE who presented with a solid tumor and who had been seen between January 1, 1994, and December 31, 1996, were included in a retrospective multicenter analysis. These patients fulfilled McCarty's description of RS3PE and the following criteria: (1) bilateral pitting edema of both hands, (2) sudden onset of polyarthritis, (3) age >50 years, and (4) absence of rheumatoid factor (RF). RESULTS: Six male patients with RS3PE are described, of mean age 74 years (range 72-78), presenting prostatic (n = 4), gastric (n = 1), and colic (n = 1) adenocarcinomas. The clini cal picture was characterized by the classical form of RS3PE syndrome and by a deterioration in general condition, sometimes with fever. All patients were negative for RF and antinuclear antibodies. In 2 cases of prostatic adenocarcinoma serum levels of interleukin 6 (IL-6) were high, but decreased with treatment. In these 6 patients, the articular manifestations regressed totally or partially in response to corticosteroids, sometimes at low doses, associated in most cases with specific antitumoral therapy. None displayed erosion or distal bone destruction. The mean survival following discovery of RS3PE was 11 months (range 6-18), 5 patients dying of metastatic dissemination of their cancer and the 6th of myocardial infarction. CONCLUSION: RS3PE is a heterogeneous syndrome that can reveal a solid tumor, notably an adenocarcinoma. There exist no specific criteria to define its forms, but this syndrome should be kept in mind in the face of a deterioration in general health. Although the pathogenic mechanism is unknown, this could involve a type of paraneoplastic polyarthritis linked to the synthesis of a factor such as IL-6.

Pesquisa de cepas de enterococcus sp. con altos níveles de resistencia a los aminoglicósidos / Search of enterococcus sp. strains with high level of aminoglycoside resistance

En las últimas décadas ha habido un aumento en la frecuencia de infecciones producidas por enterococcus sp., situándose entre los patógenos nosocomiales más comúnmente reportados. En forma simultánea se está reportando una mayor resistencia a los antimicrobianos, en especial a altos niveles de aminoglicósidos y a vancomicina. Entre marzo y julio de 1998 se recolectó en la ciudad de Valdivia, 34 cepas de enterococcus sp, aisladas de muestras clínica provenientes del Laboratorio Central del Hospital Clínico Regional de Valdivia y de un laboratorio privado, para determinarles altos niveles de resistencia a los aminoglicósidos (ANRA) por el método de dilución en agar y sensibilidad a vancomicina por el método de difusión en agar. El 23,8 por ciento de las cepas hospitalarias y el 7,7 por ciento de las extrahospitalarias presentaron ANR a estreptomicina. Para gentamicina se obtuvo un 4,8 por ciento de cepas de origen hospitalario con ANR, en cambio no se encontró cepas de origen extrahospitalario resistentes a este antibiótico. Todas fueron sensibles a vancomicina

[Value of delayed botulinum toxin injection in esotropia in the child as first line treatment]. / Intérêt de l'injection tardive de toxine botulique dans l'ésotropie de l'enfant en première intention.

PURPOSE: Evaluation of botulinum toxin to treat esotropia in children over 3 years old. MATERIAL AND METHODS: Eight children (6 boys and 2 girls), aged from 3 to 6 years (mean 4), underwent bilateral injection of 1.25 UI botulinum toxin Botox in medial rectus muscles, under general anesthesia. Preoperative diagnosis was infantile esotropia in 7 cases, and decompensated esophoria in 1 case. Six children had alternating isoacuity before injection, and two had amblyopia. Mean follow-up was 1.8 months (6 to 24 months). RESULTS: One transient exotropia, and one transient ptosis were reported. Lasting orthotropia was achieved in four children (including one who presented again spasms in near vision), and lasting angle reduction in another child. Another child had late recurrence at 18 months. The injection was a failure for the two amblyopic children. DISCUSSION: Botulinum therapy allowed to avoid surgery in three cases, and to perform a more limited operation in one case. CONCLUSION: Botulinum toxin injection in extraocular muscles is of interest in infantile esotropia as a first treatment, even in children over 3 years. The success relies principally on the absence of deep amblyopia, and muscular elongation troubles. However, the use of botulinum is limited, because it requires general anesthesia, and because of its price.

[Male osteoporosis]. / L'ostéoporose masculine.

AN UPCOMING PUBLIC HEALTH PROBLEM: There has been a considerable focus on osteoporosis in men recently. Bone mass is high in men who have larger bones than women. The frequency of fractures is also higher due to post-trauma lesions. Femoral neck fractures have also increased over the last few years although the F/M ratio remains about 2.8. Overall, there is a trend towards an increased incidence of masculine osteoporosis (and vertebral fractures) due to population aging. FAVORING FACTORS IN MEN: The most important factors are hypoandrogenism, hypoestrogenism (pre or post-puberty), the alcohol-smoking association, malnutrition, lack of sun exposure and chronic liver disease. Other causes of osteoporosis (hyperthyroidism, Cushing's disease, hemochromatosis, gastrectomy, inflammatory rheumatic disease, tubulopathy, hypercalciuria and iatrogenic causes) should also be taken into consideration. PRETHERAPY WORK-UP: All the different possible etiologies should be investigated. Therapeutic protocols should provide hormone replacement when required, withdrawal of causal drugs, better nutrition and reduced alcohol and tobacco use.