Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report

Background Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied. Case presentation A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up. Conclusions We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.

The frequency of occult solid malignancy in patients with polymyalgia rheumatica-like symptoms

Aims: We aim to evaluate the clinical usefulness of systematic screening for occult cancer in patients with polymyalgia rheumatic (PMR)-like symptoms in real-life practice. Methods: All patients seen by rheumatologists in Burgundy, France, between March 2016 and December 2018 for new-onset PMR that met the 2012 ACR/EULAR classification criteria were prospectively included. Patients underwent systematic screening including determination of the erythrocyte sedimentation rate, serum C-reactive protein levels, thoracic, abdominal and pelvic computed tomography (CT-TAP) and, in men, serum prostate-specific antigen. The standardized incidence ratio (SIR) for cancers was calculated using 2012 national estimates of cancer incidence. Potential predictive factors for the diagnosis of cancer were then evaluated using univariate and multivariate analyses. Results: Among the 118 patients included, nine cases of cancer were confirmed and diagnosed with CT-TAP: kidney carcinoma ( n = 4), lung cancer ( n = 2), pancreatic, colon, and ampullary carcinoma ( n = 1 each). Among these cancers, five were localized (four kidney, and one ampullary carcinoma) and were treated with complete surgical resection. The expected incidence of cancer in the general population was 1.95, leading to an overall SIR of 4.6 (95% CI 2.4–8.9, p < 0.0001). An additional analysis was performed for the kidney carcinoma, and it showed a highly significant increase in SIR: 80.8 (95% CI 30.3–215.4). In 80% of patients, the PMR-like syndrome regressed during cancer treatment. No other predictive factors for cancer were found. Conclusion: Systematic screening for cancer including CT-TAP in real-life practice revealed occult solid malignancy, mostly early-stage cancer, in a relevant proportion of patients presenting PMR-like symptoms. The high proportion of kidney cancer (40%) is worth highlighting, especially considering that it is not one of the most frequent cancers after 50 years of age.

The Anticancer Activity for the Bumetanide-Based Analogs via Targeting the Tumor-Associated Membrane-Bound Human Carbonic Anhydrase-IX Enzyme

The membrane-bound human carbonic anhydrase (hCA) IX is widely recognized as a marker of tumor hypoxia and a prognostic factor within several human cancers. Being undetected in most normal tissues, hCA-IX implies the pharmacotherapeutic advent of reduced off-target adverse effects. We assessed the potential anticancer activity of bumetanide-based analogues to inhibit the hCA-IX enzymatic activity and cell proliferation of two solid cancer cell lines, namely kidney carcinoma (A-498) and bladder squamous cell carcinoma (SCaBER). Bumetanide analogues efficiently inhibit the target hCA-IX in low nanomolar activity (IC50 = 4.4–23.7 nM) and have an excellent selectivity profile (SI = 14.5–804) relative to the ubiquitous hCA-II isoform. Additionally, molecular docking studies provided insights into the compounds’ structure–activity relationship and preferential binding of small-sized as well as selective bulky ligands towards the hCA-IX pocket. In particular, 2,4-dihydro-1,2,4-triazole-3-thione derivative 9c displayed pronounced hCA-IX inhibitory activity and impressive antiproliferative activity on oncogenic A-498 kidney carcinoma cells and is being considered as a promising anticancer candidate. Future studies will aim to optimize this compound to fine-tune its anticancer activity as well as explore its potential through in-vivo preclinical studies.