Ioannis Gkiozos

Sarcoidosis-Like Reactions Induced by Checkpoint Inhibitors

ABSTRACT Immune checkpoint inhibitors (ICIs) are a newly developed component of cancer care that expands the treatment possibilities for patients. Their use has been associated with several immune‐related adverse events, including ICI‐induced sarcoidosis‐like reactions. This article reviews the data concerning ICI‐induced sarcoidosis‐like reactions currently available in the medical literature. These reactions have been reported in three classes of ICIs: anti–cytotoxic T‐lymphocyte associated protein 4 antibodies, programmed death 1 inhibitors and programmed death ligand 1 inhibitors. These reactions are indistinguishable from sarcoidosis with a similar histology, pattern of organ involvement, and pattern of clinical manifestations. The most common locations to observe granulomatous inflammation from these reactions is in intrathoracic locations (the lung and/or mediastinal lymph nodes) and the skin. The median time between initiation of an ICI and the development of a sarcoidosis‐like reaction averaged 14 weeks. Clinicians have opted to use corticosteroids and/or discontinue the ICI, or take no action when these reactions have developed. Regardless of whether the clinician performed an intervention or not, these reactions have uniformly improved or resolved after ICI‐treatment, which provides additional temporal evidence supporting the presence of a sarcoidosis‐like reaction as opposed to sarcoidosis. There is even evidence that the development of an ICI‐induced sarcoidosis‐like reaction suggests that the ICI is effective as an anti‐tumor agent and should be continued. As is the case for sarcoidosis, sarcoidosis‐like reactions do not mandate antisarcoidosis therapy, especially if the condition is asymptomatic. When treatment of sarcoidosis‐like reaction is required, it may be prudent to continue ICI therapy and add antisarcoidosis therapy because standard antisarcoidosis regimens seem to be effective. Further research into the mechanisms involved in the development of ICI‐induced sarcoidosis‐like reactions may give insights into the immunopathogenesis of sarcoidosis.

Anaphylaxis during rapid oral desensitization to rifampicin

Rifampicin (also known as rifampin) is one of the most potent first-line antituberculosis drugs and an indispensable treatment option for isoniazid-resistant, rifampicin-sensitive tuberculosis (TB). Hypersensitivity reactions to rifampicin, mainly including fever, flu-like syndrome, rash, thrombocytopenia, acute renal failure, urticaria, and anaphylaxis, are considered rare but may occur among susceptible individuals and lead to premature discontinuation of the drug. Drug desensitization is a well-established procedure that may temporarily modify a patient’s immunologic response to the sensitizing agent, thus allowing for continuation of treatment. Desensitization to rifampicin has been previously described in rare case reports, almost invariably with successful results. We herein report a case of anaphylaxis during rapid oral desensitization to rifampicin in a male patient with active TB and a history of anaphylactic reactions to this agent. To the best of our knowledge, this is the first report in the English literature of a severe immediate-type reaction during desensitization to rifampicin. A 72-year-old man presented to the outpatient pulmonary clinic of “Sotiria” General Hospital, Athens, Greece, with fever, nonproductive cough, and weakness, lasting for 2 weeks. His medical history was significant for adult-onset diabetes mellitus and rheumatoid arthritis, treated with metformin and low-dose prednisone and intravenous infliximab, respectively. The patient was diagnosed with miliary TB and was started on anti-TB treatment with isoniazid (300 mg/day), rifampicin (600 mg/day), pyrazinamide (1500 mg/day), and ethambutol (1200 mg/day). Within 2 weeks after initiation of the above regimen, and 30 minutes after administration of the last dose of rifampicin, the patient developed fever and widespread urticaria; all drugs were subsequently discontinued and gradually reintroduced—after resolution of the cutaneous reaction—to identify the culprit drug. Urticaria, palmoplantar, and oropharyngeal pruritus were noted within 5 minutes after reintroduction of rifampicin and the drug was stopped; rifampicin was thereafter replaced with rifabutin. Ten days after initiation of rifabutin, the patient developed a maculopapular rash that affected the trunk and lower extremities. A skin biopsy was compatible with drug-induced eruption and rifabutin was discontinued. Approximately 3 years after his initial diagnosis of TB, the patient developed recurrent TB and was again started on a multidrug anti-TB regimen comprising isoniazid, rifabutin, pyrazinamide, and ethambutol. Twelve days after initiation of treatment a maculopapular rash appeared on the patient’s upper and lower extremities; rifabutin was again discontinued, followed by gradual resolution of the eruption, and the patient was referred to the Allergy Department of our hospital for further evaluation and management. At the time of the patient’s presentation to our department, skin prick test (SPT) and intradermal (ID) skin testing to rifampicin were performed, based on previous recommendations defining the highest nonirritant intradermal skin concentration of rifampicin (0.002 mg/mL). Histamine and saline were also used as positive and negative controls, respectively. SPT at a concentration of 2 mg/mL was negative, whereas a positive reaction (with a wheal of 15 17 mm and a flare of 42 44 mm) was shown on ID skin testing at a concentration of 0.002 mg/ mL. After obtaining the patient’s informed consent, oral desensitization to rifampicin was carried out in the intensive care unit. Premedication with antihistamines or steroids was not used (prednisone was discontinued for 3 days before the procedure) because these drugs may mask initial symptoms of anaphylaxis during desensitization, as previously emphasized, and the patient was not taking b-blockers or angiotensin-converting enzyme inhibitors. Increasing dosages of rifampicin were administered every 30 minutes, at a starting dose of 0.0002 mg followed by gradual dose escalation (Table I), as described in previously published desensitization protocols. Twenty minutes after administration of the 50 mg rifampicin dose, the patient started complaining of pruritus of the palms, soles, and groin followed by facial and trunk erythema, cough, generalized urticaria, hypotenstion, and sinus tachycardia followed by sinus bradycardia (without other ECG abnormalities). The desensitization procedure was discontinued, and the patient was treated with IV fluids, oxygen and nebulized salbutamol, intramuscular adrenaline, and intravenous methylprednisolone, dimetindene and ranitidine, with gradual recovery. Serum tryptase obtained at 1 hour after the onset of symptoms was 25 mg/L. Repeat serum tryptase, measured 1 week later, was found to be within normal limits (4 mg/L). Given the patient’s anaphylactic reaction during rapid desensitization, anti-IgE treatment and desensitization to rifampicin using slow dose increment over several days were recommended but the patient refused. Hypersensitivity reactions to anti-TB agents are relatively uncommon, encountered in approximately 4%-5% of the treated population, but may as well lead to withdrawal of the culprit drug and switching to an alternative agent. Rifampicin, in particular, is generally considered a well-tolerated drug with a low percentage of adverse events, especially when administered in usual therapeutic doses and outside the context of HIV infection. Delayed reactions, including a variety of cutaneous manifestations, are the commonest adverse reactions induced by rifampicin, whereas severe immediate reactions, such as anaphylaxis, are exceedingly rare.

Erlotinib-Associated Rash in Advanced Non-Small Cell Lung Cancer: Relation to Clinicopathological Characteristics, Treatment Response, and Survival

Systematic treatment of advanced non-small cell lung cancer (NSCLC) includes targeted treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The development of skin rash and its intensity have been associated with EGFR TKIs efficacy. The main purpose of this study was to further investigate the potential value of erlotinib-associated rash as a predictor of prognosis and treatment response in a real-world cohort of patients with advanced NSCLC. The medical records of all NSCLC patients treated with erlotinib at the Oncology Unit of GPP, Sotiria Athens General Hospital between January 1, 2014 and August 31, 2016 were retrospectively reviewed. Seventy-nine patient medical records fulfilled the criteria and were included in the study. Development of erlotinib-associated rash was correlated with clinicopathological characteristics of patients, treatment response, and overall survival (OS) using univariate and multivariate Cox regression analysis. The number of patients with rash was greater in the responders group (90% vs. 46.4%, p = 0.015). In univariate analysis, there was a statistically significant association between rash development and time to progression (TTP) [HR: 0.32 (0.17-0.57), p < 0.001]. With multivariate Cox regression analysis, it was found that PS ≥ 2 (HR: 2.01, 95% CI: 1.12-3.60, p = 0.018) and rash (HR: 0.34, 95% CI: 0.18-0.63, p = 0.001) were independently associated with TTP and also that the duration of treatment with erlotinib (HR: 0.58, 95% CI: 0.42-0.80, p = 0.001) and rash (HR: 0.10, 95% CI: 0.20-0.48, p = 0.004) was an independent predictor of survival. Our results suggest that erlotinib-associated rash may represent a clinically valuable biomarker for the prediction of treatment response and OS in patients with advanced NSCLC.

PET/CT and brain MRI role in staging NSCLC: prospective assessment of the accuracy, reliability and cost–effectiveness

Aim: To determine whether PET/CT and brain MRI used in staging NSCLC can be accurate, reliable and cost-effective tools. NSCLC represents 80–85% of lung cancer and adequate information on the initial tumor staging is critical for planning an optimal therapeutic strategy. Patients & methods: Data from 30 newly diagnosed NSCLC patients in Greece were collected and prospectively recorded. Patients with potential resectable disease were evaluated to ensure that there are no detectable metastases that would rule out the possibility of a curative surgery. Results: Divergence occurred in 50% of cases of staging with CT or PET/CT alone, while metastases undetectable by the CT were revealed using PET/CT. Unnecessary thoracotomies were avoided by 10% of patients and another 10% was operated on after chemotherapy with a better prognosis. Conclusion: PET/CT and brain MRI combined are reliable for correct staging, reducing avoidable thoracotomies, morbidity rates and costs.

The prognostic value of serum and bronchoalveolar lavage levels of adiponectin in advanced non-small-cell lung cancer

Aim We aimed to explore the prognostic implications of adiponectin (APN) levels in the serum and bronchoalveolar lavage (BAL) of patients with advanced NSCLC. Materials & methods 29 newly diagnosed patients with stage IV NSCLC were prospectively enrolled. Baseline serum and BAL levels of APN were assayed by ELISA and correlated with various clinicopathological parameters, including overall survival. Results No statistically significant correlations were observed between the serum or BAL levels of APN and the clinicopathological parameters evaluated. The only prognostic factor identified, both by univariate and multivariate survival analyses, was performance status. Conclusion The results of our cohort failed to reveal any prognostic significance of serum and BAL levels of APN in stage IV NSCLC.