Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors.

The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2-12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon.

Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses.

BACKGROUND: Tecemotide is a MUC1-antigen-specific cancer immunotherapy. The phase III START study did not meet its primary end point but reported notable survival benefit with tecemotide versus placebo in an exploratory analysis of the predefined patient subgroup treated with concurrent chemoradiotherapy. Here, we attempted to gain further insight into the effects of tecemotide in START. PATIENTS AND METHODS: START recruited patients who did not progress following frontline chemoradiotherapy for unresectable stage III non-small-cell lung cancer. We present updated overall survival (OS) data and exploratory analyses of OS for baseline biomarkers: soluble MUC1 (sMUC1), antinuclear antibodies (ANA), neutrophil/lymphocyte ratio (NLR), lymphocyte count, and HLA type. RESULTS: Updated OS data are consistent with the primary analysis: median 25.8 months (tecemotide) versus 22.4 months (placebo) (HR 0.89, 95% CI 0.77-1.03, P = 0.111), with ∼20 months additional median follow-up time compared with the primary analysis. Exploratory analysis of the predefined subgroup treated with concurrent chemoradiotherapy revealed clinically relevant prolonged OS with tecemotide versus placebo (29.4 versus 20.8 months; HR 0.81, 95% CI 0.68-0.98, P = 0.026). No improvement was seen with sequential chemoradiotherapy. High sMUC1 and ANA correlated with a possible survival benefit with tecemotide (interaction P = 0.0085 and 0.0022) and might have future value as biomarkers. Interactions between lymphocyte count, NLR, or prespecified HLA alleles and treatment effect were not observed. CONCLUSION: Updated OS data support potential treatment benefit with tecemotide in patients treated with concurrent chemoradiotherapy. Exploratory biomarker analyses suggest that elevated sMUC1 or ANA levels correlate with tecemotide benefit. CLINICALTRIALSGOV NUMBER: NCT00409188.

Anemia before and during concurrent chemoradiotherapy in patients with cervical carcinoma: Effect on progression-free survival.

To determine the impact of anemia before and during chemoradiation in patients with cervical cancer, we collected data on hemoglobin (Hb) levels before and during treatment from 60 unselected patients with cervical carcinoma. All patients had FIGO stage IB to IVA disease and were treated with concurrent chemoradiation for the aim of cure. Patients with an Hb value below or equal to the lower 25th quartile were considered anemic. Progression-free survival (PFS) was evaluated by univariate and multivariate analyses. After a median follow-up of 26.3 months, 20 patients developed disease progression. The lowest Hb during chemoradiation (nadir Hb), the stage of disease, and parametrial involvement were correlated significantly with PFS. On multivariate analysis, the nadir Hb (relative risk [RR] 0.29) and tumor stage (RR 3.4) remained the only prognostically relevant factors predicting PFS. At 60 months the PFS was 39.1% for anemic patients and 48.0% for nonanemic patients (P < 0.0002). In patients undergoing chemoradiation for cervical carcinoma, a low nadir Hb is highly predictive of shortened PFS, whereas the Hb before treatment is prognostically not significant.

Impact of hemoglobin levels before and during concurrent chemoradiotherapy on the response of treatment in patients with cervical carcinoma: preliminary results.

BACKGROUND: In patients undergoing radiation for cervical carcinoma, there is evidence that anemia is associated with an impaired outcome. For patients undergoing chemoradiation, there are no data available. The objective of this retrospective study was to examine the impact of anemia before and during chemoradiation in patients with cervical carcinoma. METHODS: The authors collected data on hemoglobin (Hb) levels before and during treatment from 57 patients with cervical carcinoma. The stage of disease ranged between Stage IB and Stage IVA. All patients were treated with concurrent chemoradiation. Response to chemoradiation was evaluated by univariate and multivariate analyses. RESULTS: The mean Hb level at the time of presentation was 12.9 +/- 1.6 g/dL in patients with a complete clinical response (CCR) and 12.1 +/- 1.4 g/dL in those with persistent disease (P = 0.126). In patients with a CCR, the mean nadir Hb level was 11.1 +/- 1.3 g/dL, and in patients with treatment failure, it was 9.8 +/- 1.8 g/dL (P = 0.008). A univariate logistic regression model demonstrated that the nadir Hb level was the most predictive factor for treatment failure (relative risk, 1.92; P = 0.015) followed by disease stage (relative risk, 0.51; P = 0.074). In a multivariate model, the nadir Hb level remained the only prognostically relevant factor predicting the response to chemoradiation. Only patients with nadir Hb values > 11 g/dL throughout chemoradiation had a more than 90% chance of achieving a CCR. CONCLUSIONS: In patients undergoing chemoradiation for cervical carcinoma, the nadir Hb level is highly predictive of response to treatment, whereas the Hb level at the time of presentation is prognostically not significant.

Effects of exercise during head-down bed rest on postural control.

BACKGROUND: The effects of exercise on postural control during walking were evaluated following exposure to head-down bed rest (BR). METHODS: Two groups of male subjects (N = 18, mean age = 21.4 yr +/- SE 1.0) were exposed to 5 d of 6 degrees head-down bed rest. The experimental group (E) exercised 90 min.d-1 (n = 12 subjects) during the BR while the control group received no intervention (n = 6). The exercise treatment consisted of a combination of isotonic and isokinetic lower extremity exercise training. Electromyographic (EMG) activity in the tibialis anterior, gastrocnemius, vastus lateralis, and biceps femoris was measured during walking before and after BR. RESULTS: Following BR, EMG activity increased in both test subject groups for all muscles (p < 0.05). However, there were no significant differences in EMG activity between the C and E groups either before or after BR. CONCLUSIONS: These data suggest that the ability of the postural control system to adjust to the gravitational environment was compromised as a result of BR. In addition, we conclude that the exercise protocol used was not an effective countermeasure to the alterations in the postural control system.

Marital adjustment among housestaff and new attorneys.

Previous reports have suggested that physicians' marriages may be adversely affected by the stresses of the profession. Some social scientists, however, question the view that demanding careers are the primary cause of poor marital adjustment and suggest instead that such careers may actually invigorate a marriage. This study, involving 116 housestaff physicians, 106 new attorneys, and the spouses of both groups, identified the factors that significantly affected their marital adjustments. No difference in marital adjustments was found between housestaff and attorneys or between the two spouse groups. In general, the spouses had higher marital adjustment scores than did the professionals, and the women professionals had higher scores than did the men professionals. The two most important factors associated with adjustment were the perceived level of emotional support received from one's spouse for one's career and the level of such support given to one's spouse for his or her career. The results suggest that housestaff and new attorneys are as satisfied with their marriages as are the other populations in which the same marital inventory has been used.