Management of immune-related adverse events resulting from immune checkpoint blockade

Introduction: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient’s treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg.

Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs.

Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.     

Correlating digit span performance and event-related potentials to assess working memory.

Event-related brain potentials (ERPs) were recorded during a computerized and modified version of the Digit Span Backwards (DB) task from the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). The modified DB version (ERP-DB task) was divided into two sections of 2, 4, 6 and 8 digits in length (Group 1) and 3, 5 and 7 digits in length (Group 2). Each trial had a study phase and a test phase. For the study phase, a series of digits was presented sequentially and aurally to 20 participants (10 for each group). For the test phase, a second series of digits was also presented sequentially and aurally that either corresponded to the reverse order of the digits in the study phase (correct condition) or had one digit in the sequence replaced by an incorrect digit (incorrect condition). The traditional DB task of the WAIS-III was also administered for comparison purposes. A prolonged positive slow wave (PSW) peaking between 450 and 750 ms was elicited to incorrect condition trials. For each participant, a derived measure was calculated from the ERP differentiation between correct and incorrect conditions. The derived measure was defined as the mean of the t-values obtained from the correct and incorrect waveform comparison, within the temporal interval that encompassed this component. The strongest statistical correlations between the derived measure and the traditional DB test scores were found at the Pz site (Group 1: r=0.79; Group 2: r=0.59). This statistical approach shows that it is possible to adequately relate an individual's performance on a traditional measure of working memory and ERP patterns. Overall, we believe that this kind of ERP approach holds promise as a technique for assessing quantitatively non-communicative patients.     

Amphibian terminal nerve: distribution revealed by LHRH and AChE markers

Immunocytochemical and histochemical studies in the tiger salamander and bullfrog demonstrated the presence of luteinizing hormone-releasing hormone-like immunoreactive (LHRH-ir) material and acetylcholinesterase (AChE) in the terminal nerve (TN). Immunoreactive perikarya and processes were found within the olfactory, vomeronasal and trigeminal nerves and in the nasal epithelium. Central TN projections consisted of fibers terminating in the olfactory bulb and bundles that projected to another group of LHRH-ir perikarya in the preoptic region. Up to 4 weeks following hypophysectomy, the labeling intensity and number of TN-immunoreactive neurons were not altered. Acetylcholinesterase histochemistry in the salamander revealed two distinct groups of neurons associated with the TN: a lightly labeled group of fusiform perikarya was located in the olfactory nerve proper and a more heavily labeled group of larger oval perikarya was found within AChE-positive trigeminal fascicles in the ventral mucosa. This study has demonstrated that the amphibian TN follows olfactory, vomeronasal and trigeminal nerves to reach peripheral targets in the nasal mucosa. The projection of TN fibers to discrete olfactory bulb glomeruli, especially evident in the bullfrog, suggests that the TN functions in odor processing. The TN projection to the preoptic region in both of these amphibians implicates the TN in reproductive processes.     

Effect of a Low-Cost Intervention on Recording Body Mass Index in Patients'' Records

PURPOSE: Evaluate the effectiveness of body mass index (BMI) tables placed in exam rooms as an intervention to encourage providers to calculate and record BMI scores in patients' medical records. DESIGN: In a prospective cohort design, medical record data for 276 adult patients at a federally funded community health center in New England were examined from August 2000 to August 2002 following the intervention. METHODS: Prominent, multicolored, laminated BMI tables were posted in the exam rooms of one of the study site's three primary health care teams. Medical record data collected included documentation of BMI calculation in medical records, documentation of an obesity diagnosis, and inclusion of heights and current weights. Frequency distributions were calculated; chi-square tests were used to identify associations. FINDINGS: In contrast to the comparison teams, patients on the intervention team were more likely to have BMI recorded in the medical record. A statistically significant increase in the diagnosis of obesity was observed throughout the health center after the intervention. CONCLUSIONS: Posting BMI tables in exam rooms contributed to increased BMI documentation in patients' medical records.     

Comparison of salivary calmodulin binding proteins in Sjögren''s syndrome and healthy individuals

Background: Reduction in salivary secretion is the hallmark of Sjögren's syndrome (SS). Calmodulin (CaM) and calmodulin binding proteins (CaMBPs) play a key role in the secretory process of saliva. Recent studies have suggested that SS‐B, an autoantibody associated with SS, is a CaMBP. This finding suggests that CaMBP may contribute to the loss of saliva in SS. To better understand the role(s) of these proteins in SS, the purpose of this study was to compare salivary CaMBPs in Sjögren's patients and controls. Methods: Saliva samples were collected from 20 patients and 20 age‐, race‐, and gender‐matched controls. CaM overlay was used to identify CaMBPs in saliva of patients and controls. Results: Higher number of salivary CaMBPs was observed among patients than controls. Conclusions: The increased number of salivary CaMBPs in SS may suggest a potential role for these proteins in the pathogenesis of the disease.     

Is There an Advantage to Repairing Infected Mitral Valves?

Background. The therapy for native mitral valve endocarditis is in evolution. Antibiotics have significantly improved survival rates, but patients with complications of endocarditis may require surgical treatment.

Methods. Between January 1985 and December 1995, 146 patients underwent surgical therapy (repair or replacement) for native mitral valve endocarditis. All patients had documented bacterial endocarditis. Univariate and multivariate analyses were performed to determine predictors of hospital death, long-term event-free survival, and probability of repair. Patients were evaluated in three groups: all patients, patients with acute endocarditis, and patients with chronic endocarditis.

Results. There were ten hospital deaths (6.8%). Patients undergoing repair had a lower hospital mortality rate (p = 0.008) then those having replacement. Event-free survival was improved after mitral valve repair in the overall group (p = 0.02) and in the group with healed (chronic) endocarditis (p = 0.05). Although the acute endocarditis group demonstrated an improved event-free survival rate after mitral valve repair versus replacement (74% versus 20% at 6 years), this did not reach statistical significance.

Conclusions. We conclude that mitral valve repair is preferable to mitral valve replacement when possible, in patients with complications of endocarditis, as repair results in a lower hospital mortality and an improved long-term survival.     

New treatment protocol including lympholytic and antiretroviral drugs to inhibit murine AIDS

Highly active antiretroviral therapy (HAART), although very efficient in reducing viral load to undetectable levels within 2 weeks, does not eradicate HIV-1 infection and after the suspension of therapy, HIV RNA rebounds to pretherapy levels. This limited efficacy is mainly due to the existence of viral reservoirs such as CD4+ T cells, macrophages, and dendritic cells in which the virus can remain latent. Elimination of these latent reservoirs would be a possible solution to this problem and various efforts are now being directed to this end. With this goal in mind, we investigated a lympholytic drug with known activity against lymphoproliferative malignancies, 2-fluoro-ara-AMP (fludarabine). The murine model of AIDS was used to evaluate the efficacy of alternating administration of fludarabine and azidothymidine (AZT). The aim of this experiment was to eliminate infected cells with fludarabine and protect noninfected cells with AZT. LP-BM5-infected mice were treated with two different therapeutic protocols: one group was treated with two alternating 3-week cycles of fludarabine and AZT (treatment A), whereas the other was treated with three alternating 2-week cycles of fludarabine and AZT (treatment B); both treatments lasted 12 weeks and the animals in the two groups received the same amount of drug. At different times of infection, disease-related findings (i.e., splenomegaly, lymphadenopathy, hypergammaglobulinemia, T-cell and B-cell spleen cell proliferative index, and phenotypes of peripheral blood lymphocytes) were analyzed and the content of proviral DNA in the lymph nodes was quantified. The results obtained show that treatment B was more effective in inhibiting disease progression than treatment A. In fact, all parameters investigated were almost within control values. These results were also confirmed by the quantification of proviral DNA content in the lymph nodes, which after 12 weeks of treatment A declined by approximately 50%, whereas treatment B decreased proviral DNA content by approximately 85% with respect to infected/untreated mice. The data obtained suggest that a therapeutic protocol including three cycles rather than two of a lympholytic drug and antiretroviral drugs is more advantageous. The efficacy of the treatment could likely increase if other drugs were used in addition to AZT and more cycles of fludarabine were added. This approach appears to be of potential interest in an HIV-1 eradication protocol.     

Translational repressor bruno plays multiple roles in development and is widely conserved

oskar (osk) mRNA is tightly localized to the posterior pole of the Drosophila oocyte, where the subsequent expression of Osk protein directs abdomen and germ-line formation in the developing embryo. Misplaced expression of Osk protein leads to lethal body patterning defects. The Osk message is translationally repressed before and during the localization process, ensuring that Osk protein is only expressed after the mRNA has reached the posterior. An ovarian protein, Bruno (Bru), has been implicated as a translational repressor of osk mRNA. Here we report the isolation of a cDNA encoding Bru using a novel approach to the expression cloning of an RNA-binding protein, and the identification of previously described mutants in the arrest (aret)-locus as mutants in Bru. The mutant phenotype, along with the binding properties of the protein and its pattern of accumulation within the oocyte, indicate that Bru regulates multiple mRNAs involved in female and male gametogenesis as well as early in embryogenesis. Genetic experiments provide further evidence that Bru functions in the translational repression of osk. Intriguingly, we find that Bru interacts physically with Vasa (Vas), an RNA helicase that is a positive regulator of osk translation. Bru belongs to an evolutionarily conserved family of genes, suggesting that Bru-mediated translational regulation may be widespread. Models for the molecular mechanism of Bru function are discussed.     

Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

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