Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.

BACKGROUND: Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure. CASE PRESENTATION: We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20. CONCLUSIONS: This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.

Anti-amyloid ß autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid ß (Aß) autoantibodies in the acute and remission phases of CAA-ri. METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aß autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aß40, Aß42, tau, P-181 tau, and APOE genotype were also investigated. RESULTS: During the acute phase of CAA-ri, anti-Aß autoantibodies were specifically increased and directly correlated with Aß mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aß and axonal degeneration markers decreased in parallel. INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aß, directly related to autoantibody concentration and soluble Aß. The CSF dosage of anti-Aß autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aß autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

Chemotherapy-induced peripheral neurotoxicity can be misdiagnosed by the National Cancer Institute Common Toxicity scale.

The assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) is still uncertain as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. The aim of this study was to compare the assessment of CIPN using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale and a formal neurological assessment scored with the Total Neuropathy Score (TNS, i.e., a composite scale designed to grade the impairment in neuropathy patients) to identify possible discrepancies in the diagnosis. In this prospective study, 155 patients treated with cisplatin/carboplatin or with paclitaxel/docetaxel and CIPN were examined in a collaborative oncological/neurological multi-center trial using the NCI-CTC scale and the TNS; the results were then extensively compared. We evidenced that the TNS allows possible misdiagnosed neuropathies to be revealed. In fact, the NCI-CTC evaluation performed by experienced examiners overestimated the occurrence of motor neuropathy, possibly because of the presence of confounding factors (e.g., fatigue, depression, cachexia), which might be difficult to be ruled out without a formal neurological examination. This study strongly indicates that a more formal neurological assessment of patients with CIPN than that achievable with the common toxicity scales (e.g., NCI-CTC) is advisable.

Chemotherapy-Induced Peripheral Neurotoxicity assessment: a critical revision of the currently available tools.

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a frequent, potentially severe and dose-limiting side-effect of cancer treatment. Despite its clinical relevance that limits the use of several antineoplastic agents and even the future development of new anticancer drugs, several crucial aspects of CIPN remain unsolved, one of which is how to assess its occurrence and severity in the most effective and reliable way. CIPN severity is generally assessed using Common Toxicity Criteria (CTC) scales, although it is well known that significant inter-observer disagreement exists using these scales. Moreover, most CTC scores mix impairment, disability and quality of life measures, which could lead to misinterpretation of the results and unpredictable under- or overestimation of the effect. This uncertainty may lead to different interpretations of the results of the same clinical trials by clinicians and also by regulatory agencies. The use of other types of scale based on clinical and instrumental examinations, or the use of self-administered questionnaires for patients, has not yet really improved the accuracy of CIPN assessment, although some of these tools are promising and deserve to be further validated. As a result, there is a general recognition that CIPN has still not been properly assessed and that improvements should be made. In this review, the available data regarding the different tools used to assess CIPN will be revised and their features will be critically examined, with a special focus on their reliability and reproducibility across examiners and, when available, through direct comparison.

Role of a pre-existing neuropathy on the course of bortezomib-induced peripheral neurotoxicity.

We investigated a series of bortezomib-treated patients and correlated the course of bortezomib-induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty-eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty-three patients had a baseline TNSr = 0-2, and 25 patients had a baseline TNSr >2 (median = 6, range 3-13). The course of bortezomib-induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib-induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.

The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI-CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.

Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy in rats.

The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compared, since no animal models of docetaxel peripheral neurotoxicity have yet been reported. In this experiment, we examined the effect of the chronic administration of these two taxanes in the Wistar rat using neurophysiological, neuropathological and morphometrical methods. Our results showed that both paclitaxel and docetaxel induced a significant, equally severe and dose-dependent reduction in nerve conduction velocity. On the contrary, the morphometric examination demonstrated that the effect on the nerve fibres was more severe after paclitaxel administration when the same schedule was used. However, the overall severity of the pathological changes was milder than expected on the basis of the neurophysiological results. Our results support the hypothesis that taxanes (and particularly docetaxel) may exert their neurotoxic effect not only on the microtubular system of the peripheral nerves, but also on other less obvious targets.