Multiple immune disorders after natalizumab discontinuation: After the CIRIS, the SIRIS?

Natalizumab (NTZ) is an effective treatment for patients with highly active relapsing remitting multiple sclerosis (MS). However, when the therapy must be interrupted, it is important to anticipate the withdrawal to avoid reactivation or disease rebound. Described here is the case of a 35-year-old woman, with a past history of beta thalassemia, bulimia and asthma, who was diagnosed with MS at age 26. She was treated initially with first-line subcutaneous (sc) immunomodulatory treatments. However, due to liver toxicity, interferon beta-1a sc was interrupted and replaced by glatiramer acetate treatment, which was well tolerated and used for several years. Unfortunately, disease progression with numerous relapses and contrast enhancement on brain MRI led to initiation of NTZ treatment. After more than 2 years of treatment, NTZ was interrupted because of pregnancy, and the patient was again put on glatiramer acetate. Eight weeks after interruption of NTZ therapy, the first signs of diabetes were observed, together with an increase in blood levels of hepatic enzymes, skin reactions such as angioedema and giant urticaria, and hypothyroidism requiring hormone supplementation. The patient delivered her baby without complications, and NTZ was reintroduced several months later. At the present time, the patient's hypothyroidism, diabetes and increased blood levels of hepatic enzymes persist, although no new skin reactions have been observed. Withdrawal of NTZ can not only lead to reactivation of the disease or its rebound, but also to autoimmune manifestations within the framework of immune reconstitution inflammatory syndrome (IRIS). This risk needs to be considered when therapy has to be interrupted, especially when a personal and/or familial past history of autoimmune disease is present.

Efficiency of auricular acupuncture in climacteric symptoms after cancer treatments.

OBJECTIVES: This paper aims to highlight the efficiency of auriculotherapy in the treatment of hot flushes, especially in cancer-related menopausal transition. METHODS: We used systematically collected data from patients in 2014 in a medical oncology practice. The treatment was made according to the guidelines of The Inter-University Diploma and the cartography of the World Health Organization; data on satisfaction were collected orally. RESULTS: In 2014, 49 patients, among whom 41 had cancer, were treated for hot flushes. Although it is not recommended to treat several symptoms during the same session, we dealt with 1.7 symptoms per session on average. Sixty-nine percent of the patients were satisfied. We lacked data for nine patients, who did not come to the minimal recommended number of treatments (three). Only one patient among those who did not observe any improvement received three treatments. CONCLUSIONS: Auricular acupuncture is a safe and cheap method to treat hot flushes. It has been effective in numerous and various cases, among which were patients who presented cancer-related menopausal symptoms. It may be applied for a large variety of other symptoms.

[Hematological side effects of natalizumab: Correlation with clinical outcome]. / Anomalies hématologiques du natalizumab et sa signification clinique.

INTRODUCTION: Natalizumab (NTZ) is a monoclonal antibody used in a single-drug regimen to treat active relapsing remitting multiple sclerosis. Safety data collected during the AFFIRM pivotal study and post marketing cohorts reported infusion-related and allergic reactions, with development of persistent anti-NTZ antibodies in 6% of patients. Occurrence of hematological side effects (HSE), such as hyperlymphocytosis (HL) and hypereosinophilia (HEo) have been described. To our knowledge, there is no study assessing neither incidence of HSE, nor their correlation with clinical outcome. The objective is to evaluate prospectively the incidence of HSE of NTZ and to search for correlations with clinical outcome. METHODS: Clinical (EDSS, relapse, tolerance) and biological assessments were performed before the first infusion and every month during the follow-up in all patients treated with NTZ between 2007 and 2010. Before starting NTZ, data were collected on prior history of allergy and previous disease-modifying treatments (DMT). Statistical analysis was performed to search for correlations between the occurrence of HSE and clinical outcome. RESULTS: The series included 66 patients (sex ratio: 1/2.8) followed for up to 17 months. Mean age was 39 (±SD) years. Mean EDSS score was 3.2 (±SD). Fifty-six percent of patients had DMT history with beta interferons (41%), glatiramer acetate (6%) and immunosuppressive drugs (cyclophosphamide, mitoxantrone) (9%). Annualized relapse rate during follow-up was 0.41. Infusion-related reactions were noted in 10% of patients. Two patients had allergic reactions and had stopped their infusions. HL developed in 48% of patients and HEo in 20%. Regarding age and medical or therapeutic history, no predictive factor of HSE occurrence could be identified. Incidence of infusion-related side effects was higher in patients with HEo (38%) in comparison with patients without HEo (3.8%). Relapse rate during NTZ treatment was not significantly different between the different groups. CONCLUSION: This is the first prospective study assessing of HSE during NTZ treatment. There is a higher occurrence of intolerance reactions in patients with HEo.

Filler-induced blindness "seen" by ophthalmologists: Case presentation and treatment algorithm.

PURPOSE: Filler-induced blindness (FIB) is the most threatening complication following periocular injection. To date, no standard of care has been established. The goal of this study is to report a new case of FIB with partial visual recovery and present our personalized algorithm for treatment based on fluorescein angiography findings. MATERIALS AND METHODS: Case report with 24 months follow-up and treatment algorithm. RESULTS: Our patient experienced complete vision loss to no light perception following forehead lipofilling. Retinal angiography identified a posterior ciliary artery occlusion. Antiplatelet medication, steroids and intraocular pressure lowering medications were administrated, followed by hyperbaric oxygen treatment (HBOT). Visual acuity improved to +0.8 logMar. The HBOT treatment was monitored by fluorescein angiogram. Based on this case and on the ophthalmic literature on retinal and ciliary artery occlusion, we established a personalized FIB protocol guided by fluorescein angiography. CONCLUSION: Although prevention remains the best treatment, all physicians should be prepared to manage FIB. Prompt management at the office guided by written protocols, as well as emergency kits, are essential. In referral centers, personalized treatment should be undertaken based on fluorescein angiography findings.

[L-carnitine treatment and fish odor syndrome: an unwaited adverse effect]. / Traitement par L-carnitine et mauvaise odeur corporelle: un effet secondaire à connaître.

INTRODUCTION: Levocarnitine treatment is usually well tolerated, with essentially dose-dependent diarrhea as the main induced adverse effect. CASE REPORT: We report a case of fish odor syndrome during levocarnitine treatment which resolved after levocarnitine discontinuation. CONCLUSION: This adverse effect seems to be correlated with excedent carnitine intake and might be expressed when the elimination pathway becomes saturated or in a situation of deficiency enzymatic metabolism.

Eye amputation following lifitegrast treatment for ocular graft-versus-host disease: First case report.

Graft-versus-host disease (GVHD) is a common complication in patients undergoing allogeneic stem cell transplantation for acute myeloblastic leukemia that could be very difficult to treat. Lifitegrast 5% (Xiidra@, Novartis), a new immunosuppressive eye drop, was recently approved by the FDA for the treatment of severe dry eye and is currently under review by the European Medicines Agency. In France, lifitegrast has been approved by the French authorities for temporary use in refractory dry eye syndrome resistant to tear substitutes and topical cyclosporine. To date, serious complications have been reported only exceptionally. In this article, we report the case of a 65-year-old patient with a medical history of acute myeloid leukemia (AML) diagnosed in 2015 who received a first matched related donor transplant. In 2019, this patient developed chronic GVH involving the skin, oral mucosa and eye. Despite taking topical and systemic medications for 3 months, the patient did not report relief of ocular symptoms. Therefore, lifitegrast was prescribed. To our knowledge, we report the first case of corneal perforation in which evisceration was required following treatment with topical lifitegrast for chronic GVH. In the case presented here, it can be assumed that the underlying mechanisms leading to corneal perforation are multifactorial. Using drug accountability criteria, lifitegrast appears to be strongly associated with the development of bacterial keratitis and corneal perforation.

[Natalizumab (Tysabri) prescription practices of neurologists in southern France]. / Enquête auprès des neurologues sur les prescriptions de natalizumab en région Provence-Alpes-Côte-d'Azur.

INTRODUCTION: Tysabri is indicated as single-drug disease-modifying therapy in patients with highly active relapsing remitting multiple sclerosis (RRMS). Potential risk for opportunistic infection and especially for progressive multifocal leucoencephalopathy has implied specific guidelines for use. The purpose of this study was to ascertain the prescription practices of neurologists in southern France and to learn more about how the drug is used in clinical practice compared with management guidelines stated in the product's characteristics and national recommendations. METHODS: We developed a questionnaire which was sent to all neurologists practicing in our region, whether they had multiple sclerosis patients or not. Questions regarded demographic data (geography, practice in hospital or private office), current knowledge on natalizumab (mechanism of action, indications), monitoring of treated patients (pre-therapeutic and therapeutic check-up), rescue decisions and overall experience with using natalizumab. RESULTS: Two hundred fifty neurologists, practicing in eight administrative districts in our region, were contacted. Demographic data showed that most of them were prescribing Tysabri. Patients treated with Tysabri were mostly followed in teaching hospitals (79%). Concerning knowledge about natalizumab, neurologists applied the recommended check-up (73%) but most of them preferred prescribing Tysabri as a second line of treatment after IFN failure (66%). Inefficacy was mainly evaluated on clinical parameters (one or two relapses under treatment with sequels or EDSS progression in each answer); MRI was only useful to confirm clinical conclusions, but for the neurologists, gadolinium enhancement was required to confirm lack of efficacy. DISCUSSION: Results tended to show that, in clinical practice, despite some deviation from national guidelines, the recommended precautions are applied for the use of Tysabri. Neurologists considered that Tysabri is other immunosuppressant drugs used in RRMS. Further medical information might be useful to improve compliance with all of the recommended indications and standard practices for patient follow-up. CONCLUSION: This survey enabled an assessment of current knowledge about Tysabri as a treatment for RRMS patients and to learn more about how it was used in real life practice during its first year of marketing in France.

[Bilateral optic neuropathy with loss of vision after an influenza vaccination in a patient suffering from mixed connective tissue disease]. / Névrite optique rétrobulbaire bilatérale cécitante après vaccination contre la grippe saisonnière chez une patiente présentant un syndrome de Sharp.

BACKGROUND: Optic neuropathy is a rare adverse reaction to vaccination. CASE REPORT: A 62-year-old-woman was hospitalized for bilateral optic neuropathy with loss of vision. The symptoms occurred 15 days after a seasonal influenza vaccination. Her past medical history included a mixed connective tissue disease with no immunosuppressive treatment for several years. Investigations did not reveal any obvious cause and the hypothesis of post-influenza vaccination bilateral optic neuropathy was retained although a complication of the connective tissue disease complication could not be ruled out. The patient was given intravenous methylprednisolone 1g daily. At a cumulative dose of 8 g, oral steroids were given and tapered off. DISCUSSION: Few similar case reports have been described in literature. The causal link between vaccination and optic neuropathy thus remains to be confirmed. Clinicians should however consider this etiology.

[Coordination of health vigilances: for a global management of hospital risks]. / La coordination des vigilances sanitaires : pour une gestion plus globale des risques hospitaliers.

The sanitary vigilances represent a permanent sanitary surveillance. They signal, enregister, treat and investigate the adverse events occurring through the use of health products. They assure the traceability of these health products and the management of the sanitary alerts. The sanitary vigilances are part of the sanitary security. They are optimized when coordinated and integrated to the global risk management process of the health care establishments.

[A severe side effect of antitubercular therapy: pyrazinamide induced thrombocytopenia]. / Un effet indésirable grave du traitement antituberculeux: la thrombopénie au pyrazinamide.

The haematological side effects of antitubercular drugs are not well known. We report the observation of a patient who received Rifater for the treatment of pulmonary tuberculosis. After one month of treatment, he developed an acute pulmonary infection, with neutropenia (1218/microl) and thrombocytopenia (109,000/microl), requiring suspension of his antitubercular drugs. After the reintroduction of he again developed thrombocytopenia (6,000/microl) associated with bleeding and required treatment with intravenous immunoglobulin. The introduction of a combination of moxifloxacin, isoniazid, pyrazinamide, and ethambutol was followed by a new relapse of the thrombocytopenia. Responsibility of pyrazinamide was then suspected and later confirmed by the evolution of platelet levels after stopping and reintroducing this antibiotic. This is the third reported case of pyrazinamide induced thrombocytopenia, whose frequency is probably underestimated because of the use of compound treatment.

Prevalence of burnout, depression and job satisfaction among French senior and resident radiation oncologists.

PURPOSE: Cancer caregivers are at high risk of burn-out, with potential severe consequences on professionals' health and on patients' care. We have investigated the prevalence of burn-out and its impact in terms of psychological morbidity among French radiation oncologists. METHODS AND MATERIALS: An anonymous online questionnaire was advertised in all French senior radiation oncologists and residents, including demographical data, job-related stress factors, drug use, the Maslach Burn-out Inventory (MBI) and the General Health Questionnaire (GHQ-12). RESULTS: The response rates were 37% (76 out of 204) for radiation oncologists and 22% (166 out of 751) for residents. Sixty-four (84%) radiation oncology residents and 104 (63%) radiation oncologists met criteria for moderate/severe burn-out (odd ratio 2.1 [95% confidence interval 1.0-4.8], P=0.03). Radiation oncology residents were more prone to depersonalization (P<0.001) and lower personal accomplishment (P<0.001). Burn-out was more frequent in radiation oncologists working for public facilities. Symptoms of depression (GHQ-12≥4) were reported by 42% of residents and 36% of radiation oncologists (P=0.40). Psychological morbidity, suicidal ideation and anxiolytic consumption were more frequent in burnt out responders. CONCLUSION: Our figures are in the highest range of published data. Active screening and prevention of burn-out should be implemented and particularly aimed at radiation oncology residents.

Prognostic factors in chordoma: role of postoperative radiotherapy.

We have investigated prognostic factors for survival in a series of 26 patients with chordoma treated in Lyon, France, between 1979 and 1993. In this series, the median progression-free (PFS) and overall survival (OS) were 10 and 90 months, respectively. In univariate analysis, PFS, but not OS, was found significantly longer in males as compared to females (median: 19 versus 7 months, P = 0.05); and patients under 60 years of age had a longer PFS (median: 18 versus 6 months; P = 0.06) and OS (median: 108 versus 47+, P = 0.05) than older patients. A favourable prognostic subgroup including male patients under 60 years and a poor prognostic group including female patients and male over 60 years were thus defined (median PFS: 36 versus 6 months, P = 0.001; median OS: 108 versus 55+, P = 0.15). Primary treatment combining surgery and postoperative radiotherapy was associated with a longer PFS than surgery only (median: 36 versus 7 months, P = 0.002) in the whole series and in both prognostic subgroups.

Intraoperative radiation therapy combined with limited lymph node resection in gastric cancer: an alternative to extended dissection?

PURPOSE: To describe the results of a series of 63 Western patients presenting with gastric adenocarcinoma and treated with surgery and intraoperative radiation therapy (IORT) over a 8-year period and to discuss the role of IORT when combined with limited lymph node dissection. METHODS AND MATERIALS: From 1986 to 1993, 63 patients with gastric adenocarcinoma have been operated in the department of radiation oncology of the Hospices Civils de Lyon. The stage was: I in 17, II in 11, IIIA in 9, IIIB in 20, and IV in 6. The lymph node dissection was considered to be limited in 56 patients and extended in 7. The IORT dose ranged from 12 to 23 Gy (median: 15). Thirty patients also underwent a postoperative external beam irradiation with a standard dose of 44-46 Gy. RESULTS: The postoperative mortality rate was 4.8%. The 5-year overall survival in the entire series was 47% and was 82, 55, 78, 20, and 0% in Stages I, II, IIIA, IIIB, and IV, respectively. Loco-regional relapse occurred in 15 of 63 patients and metastases in 15 of 63. CONCLUSION: In Western patients treated by gastrectomy for adenocarcinoma of the stomach, IORT combined with limited lymph node dissection may provide overall survival similar to that observed after gastrectomy with extended lymph node dissection but with less postoperative mortality.

Endocavitary irradiation for early rectal carcinomas T1 (T2). A series of 101 patients treated with the Papillon's technique.

PURPOSE: This work is a retrospective analysis of a series of patients treated with endocavitary irradiation stressing the role of transrectal ultrasound (TRUS), which has been used routinely in the staging since 1987. METHODS AND MATERIALS: Between 1977 and 1993, 101 patients with infiltrating adenocarcinomas were treated. Clinical staging was 65 T1 N0 and 36 T2 N0. TRUS used in 36 patients showed: 22 UT1 N0, 10 UT2 N0, and 3 UT2 N1. Contact x-ray was delivered with a 50 kV radiotherapy unit. The median dose was 92 Gy (60-125) in five fractions, 55 days. In 28 patients a boost was given with 192Ir implant delivering a median dose of 25 Gy/21 h. RESULTS: Complete response was observed in all patients at the completion of treatment. Loco-regional failures were seen in 14 patients (local in 7 patients, nodal pararectal in 6 patients, and local + nodal in 1 patient). A curative salvage treatment was attempted in 13 patients and resulted in an ultimate pelvic control rate of 99 patients. Rectal preservation was possible in 92 patients. Overall and specific 5-year survival was 83.3% and 94.4%. No serious complication was observed. TRUS was more sensitive than digital rectal examination to detect involvement of pararectal metastatic nodes (N1). No loco- regional relapse was observed out of 22 UT1 N0. CONCLUSION: Endocavitary irradiation can cure early adenocarcinoma of the rectum without complication. TRUS appears as a significant improvement in the selection of patients amenable to this treatment. If restricted to UT1 N0 tumors, endocavitary irradiation should control locally more than 90% of these patients. Any UN1 is a contraindication for endocavitary irradiation alone.

Radiation therapy in the conservative treatment of carcinoma of the anal canal.

PURPOSE: Radiotherapy is the standard treatment of anal canal carcinoma. We retrospectively analyzed our experience with 108 patients. Special attention was given in evaluating 51 patients who received concomitant chemotherapy with 5-FU-CDDP. METHODS AND MATERIALS: From January 1980 to December 1989, 108 patients with anal canal carcinoma were treated with exclusive radiotherapy at the Centre Hospitalier Lyon Sud. There were 11 men and 97 women, mean age was 65 years (30-86). Histologic types were 94 epidermoid carcinomas, 13 basaloid carcinomas, and one adenocarcinoma. The TNM classification (UICC 87) was: 16 T1 (14.8%), 53 T2 (49%), 33 T3 (39.5%), six T4 (5.5%), 77 N0 (71.3%), 20 N1 (18.5%), nine N2 (8.3%) and two N3 (1.8%). Papillon's radiotherapy technique with a Cobalt direct perineal field was used in 82 patients. Ninety-six patients were treated with an interstitial 192Ir implant with a mean delay of 55 days after the end of the radiotherapy. In 59 patients at least one course of either 5-FU-mitomycin (8) or 5-FU-CDDP was added with at least one course concomitantly to the radiotherapy in 53 patients. RESULTS: A complete response in 104/108 patients (96%) was obtained 2 months after the brachytherapy. A locoregional relapse (local and/or pelvic failure) was seen in 18 patients (16.6%) and inguinal node relapse in nine (8.3%). Eight patients with locoregional recurrence and five with inguinal relapse were salvaged. A systemic failure occurred in six (5.5%) patients. Twenty-nine patients died, 16 of progressive disease. One patient died of treatment related toxicity. The overall 5-year survival was 64% +/- 6 and specific survival 72% +/- 8. None of the patient parameters was found to be statistically significant but there was a trend toward longer 5-year survival in T1-T2 patients and in those with well or moderately differentiated tumors. Noteworthy are the same survival rates for N0 and N1-N3 patients (65 vs. 62%). The objective response and the locoregional failure rates were similar in the patients treated with or without chemotherapy. The difference did not reach statistical significance though it was important for the following parameters: overall survival rates for T1-T2 with and without chemotherapy (94 vs. 61%) and for N1-3 patients (73% vs. 27%). The main prognostic factors in this series were differentiation (5-year overall survival with chemotherapy 95% vs. 27% without chemotherapy p = 0.02) and the response at 3 months after treatment initiation, before brachytherapy implant (5-year overall survival for complete responders and "very good responders" 71% vs. 34% in partial responders p = 0.002). The complications rate was acceptable (Grade III 9%, Grade II 14%). Anal preservation was possible in 85% of the patients (92/108). Nine abdominoperineal resection were performed for recurrence and seven for severe necrosis. The T3-T4 group abdomino perineal resection was 23% while it was 9.2% of the T1-T2 group. CONCLUSION: We confirm that exclusive radiotherapy is the treatment of choice for epidermoid carcinomas of the anal canal. The role of chemotherapy is still unclear.

Stereotactic radiosurgery for arteriovenous malformations of the brain using a standard linear accelerator: the Lyon experience.

Radiosurgery (RS) was initiated in Lyon in October 1989. The technique was adapted from that described by Lutz and Saunders in Boston (BRW stereotactic frame). Irradiation is delivered with 18-MV photons produced by a LINAC. From December 1989 to December 1992, 41 patients with arteriovenous malformations were treated by RS; the median age was 33 years. The largest lesion diameter was 11.2-38.5 mm. Fifteen to 20 Gy were delivered on the 70% isodose line. Angiography was performed at 2 years post-treatment in 32 patients demonstrating an overall complete thrombosis rate of 81.3%. This incidence was significantly correlated with the Spetzler and Martin grade before RS (P = 0.0055). Two patients (4.9%) experienced haemorrhage after radiosurgical treatment and one died from an intracerebral-intraventricular haemorrhage. Four patients (9.7%) experienced permanent radiation-induced neurological complications.