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Simple Summary: Despite the heterogeneity of resistance mechanisms to tyrosine kinase inhibitor (TKI)-targeting Epidermal Growth Factor Receptor (EGFR)-activating mutations, many induce the activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. In this study, we characterized nine cases with ARAF amplification resistant to EGFR-TKIs. Overall, these ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, ARAF amplification was predominantly observed in female patients with EGFR exon 19 deletion. We also identified two cases showing a histologic transformation from lung adenocarcinoma to small-cell lung cancer (SCLC). ARAF amplification potentially fosters conditions that promote tumor cell survival and neuroendocrine marker transcription under EGFR-TKIs. Background/Objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. Conclusions: ARAF amplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low‐dose fluconazole (FLCZ) prophylaxis (100 mg/day). Methods: We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low‐dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post‐transplant. Results: Of the 107 patients, 70 received low‐dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection‐related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44–8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02–4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. Conclusion: Low‐dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3‐dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), is an important microenvironmental factor suppressing antitumor immunity. Here, we investigated the clinical impact of aberrant Trp metabolism in patients with multiple myeloma (MM) treated with lenalidomide (Len) and evaluated its effects on T cell immunity ex vivo. Kyn and Trp concentrations were quantified in sera from 72 patients with relapsed or refractory MM prior to the initiation of therapy with Len plus dexamethasone (Ld). Associations of the Kyn/Trp ratio with progression‐free survival (PFS) and overall survival (OS) were analyzed. The expressions of IDO in tumor and stromal cells were evaluated during co‐culture, and the effects of culture medium containing low Trp and high Kyn concentrations on T cells in the presence of Len were investigated. Patients with high serum Kyn/Trp ratios (≥46.0, n = 22) had significantly shorter PFS and OS than those with low ratios (4.9 vs. 12.6 months, and 15.5 vs. 45.7 months, respectively). MM cells promoted IDO expression in stromal cells during co‐culture in both a direct contact and an indirect manner. Incubation in medium with a high Kyn/Trp ratio significantly inhibited T cell cytokine production and upregulated the expression of inhibitory immune receptors. These effects were sustained even in the presence of Len. In conclusion, a high serum Kyn/Trp ratio is associated with poor prognosis in patients with MM. We propose that aberrant Trp metabolism reduces anti‐tumor immunity and the efficacy of Len therapy. [ABSTRACT FROM AUTHOR]