Oral mucositis (OM) is a common and dose-limiting side effect of cancer treatment, including 5-fluorouracil (5-FU) and radiotherapy. The efficacy of the therapeutic measures to prevent OM is limited and disease prevention is not fully observable. Amifostine is a cytoprotective agent with a described anti-inflammatory potential. It is clinically used to reduce radiotherapy and chemotherapy-associated xerostomia. This study investigated the protective effect of amifostine on an experimental model of OM. Hamsters were divided into six groups: saline control group (5 mL/kg), mechanical trauma (scratches) of the right cheek pouch; 5-FU (60 and 40 mg/kg, ip , respectively, administered on days 1 and 2); amifostine (12.5, 25, or 50 mg/kg) + 5-FU + scratches. Salivation rate was assessed and the animals were euthanized on day 10 for the analysis of macroscopic and microscopic injury by scores. Tissue samples were harvested for the measurement of neutrophil infiltration and detection of inflammatory markers by ELISA and immunohistochemistry. 5-FU induced pronounced hyposalivation, which was prevented by amifostine (P<0.05). In addition, 5-FU injection caused pronounced tissue injury accompanied by increased neutrophil accumulation, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) tissue levels, and positive immunostaining for TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS). Interestingly, amifostine prevented the inflammatory reaction and consequently improved macroscopic and microscopic damage (P<0.05 vs 5-FU group). Amifostine reduced inflammation and protected against 5-FU-associated oral mucositis and hyposalivation.

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2632 Background: High-TMB was recently approved as an agnostic biomarker for pembrolizumab in advanced cancers. Still, several patients with high-TMB do not respond to ICI, while some patients with low-TMB benefit from immunotherapy. Methods: We collected genomic (MSK-IMPACTassay) and survival data from 1,661 patients and assessed OS (Kaplan-Meier method) according to the mutational status. To better qualify patients with TMB ≥ 10 mut/Mb (TMB-H) (N = 488, 29%) and TMB < 10 mut/Mb (TMB-L) (N = 1,173, 71%) for ICI treatment, we analyzed single gene alterations impacting OS (P < 0.05). For all genes exhibiting a correlation with OS, we conducted a Cox multivariate analysis stratified by median TMB, sex, median age, microsatellite instability (MSI) status, and histology. Results: Survival to ICI increased with higher TMB. Median OS was 42 and 15 months for TMB-H and TMB-L (P < 0.05), respectively. For TMB-H tumors, 5 genes ( STK11, KEAP1, CIC, E2F3, TP53) exhibited reduced OS on ICI, and 22 genes ( NTRK3, TERT, NOTCH3, RNF43, TET1, PTPRD, NCOA3, TENT5C, ZFHX3, RIT1, CCNE1, PPM1D, GATA2, ALK, DNMT1, PTPRT, MET, EPHA7, BCL6, SMO, CDK6, MED12) were associated with better OS, P < 0.05. Cox multivariate analysis confirmed a correlation between mutations in STK11 and E2F3 with worse OS, while mutations in NTRK, PTPRD, RNF43, TENT5C, TET1, and ZFHX3 were associated with better OS (P < 0.05). Histology did not play a relevant role in ICI response except for melanoma (better OS; P < 0.05). MSI status did not significantly affect OS. For TMB-L tumors, 20 genes were related with reduced OS ( TP53, H3C2, DAXX, SMARC4, STK11, SOX17, RB1, PIK3CA, CTNNB1, KMT2D, HLA-A, FBXW7, CDH1, RBM10, KEAP1, IGF1R, H3C11, EGFR, RUNX1, B2M), while 8 genes were associated with better OS ( VHL, SETD2, PBRM1, BRAF, KDM5C, MAP2K1, CSF1R, RET), P < 0.05. Cox multivariate analysis confirmed 15 genes associated with superior ( KDM5C, PBRM1, and VHL) and inferior ( CTNNB1, DAXX, FBXW7, H3C2, H3C1, IGF1R, KMT2D, PIK3CA , RB1, SMARC4, SOX17, TP53) OS (P < 0.05). In the TMB-L context, melanoma histology and MSI status (except among VHL-mutated tumors) were independently associated with better OS. Conclusions: This pan-cancer analysis demonstrates that genomic alterations in single cancer genes can help define outcomes of TMB-H and TMB-L patients treated with ICI. [Table: see text]

Purpose: Solid tumors harboring tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb) received agnostic approval for pembrolizumab. This work aims to analyze the somatic mutational profile’s influence on the outcomes of patients with TMB-high tumors treated with immune checkpoint inhibitors (ICIs). Methods: This post-hoc analysis evaluated clinical and molecular features of patients with solid tumors treated with ICIs that could be either monoclonal antibody directed against programmed cell death protein-1 or monoclonal antibody directed against programmed cell death ligand 1 (anti-PD-1/anti-PD-L1), monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen (anti-CTLA-4) or a combined treatment regimen including one anti-PD-1/anti-PD-L1 and one anti-CTLA-4 (ICIs combination). We performed OS analysis for TMB thresholds of ≥10, ≥20, and <10 mut/Mb. We assessed OS according to the mutational profile for a TMB ≥ 10 mut/Mb cutoff. For genes correlated with OS at the univariate assessment, we conducted a Cox multivariate analysis adjusted by median TMB, sex, age, microsatellite instability (MSI), and histology. Results: A total of 1661 patients were investigated; 488 with a TMB ≥10 mut/Mb (29.4%). The median OS was 42 months for TMB ≥10 or 20 mut/Mb, and 15 months for TMB <10 mut/Mb (p < 0.005). Among TMB ≥10 mut/Mb patients, mutations in E2F3 or STK11 correlated with worse OS, and mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1, or ZFHX3 with better OS. These associations were confirmed with univariate and multivariate analyses (p < 0.05). Melanoma histology and TMB above the median endowed patients with better OS (p < 0.05), while MSI status, age, and gender did not have a statistically significant effect on OS. Conclusion: Combining TMB and mutation profiles in key cancer genes can better qualify patients for ICI treatment and predict their OS.

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Werner’s syndrome is caused by the inactivation of both WRN alleles and is characterized by premature aging and increased risk of neoplasms, especially those of mesenchymal origins, such as sarcomas. Given the characteristic genomic instability, patients with this syndrome are more susceptible to develop toxicities when exposed to cytotoxic agents, such as alkylators and anthracyclines. The impact of the monoallelic WRN mutation on treatment-associated toxicities is poorly understood. Here, we report a patient with locally advanced dedifferentiated liposarcoma of the retroperitoneum harboring a heterozygous germline inactivation mutation in the WRN gene, who was treated with a classic regimen of ifosfamide and doxorubicin and developed exacerbated and prolonged hematological and renal toxicities.

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the spine and pelvic bones was carried out with a GE Signa Profile system without contrast enhancement 100 days after auto-HSCT. The nature of the lesions was determined and the bone marrow infiltration lesions (≥ 5 mm) counted. Statistical analysis was done using Statistica 10. Results: After auto-HSCT, the following antitumour response rates were observed: CR in 10 (72%), VGPR in 2 (14%) and PR in 2 subjects (14%). At 100 days after auto-HSCT all patients achieved strict CR (MRD-negativity according to flow cytometry). Focal changes in the bone marrow by MRI after auto-HSCT were detected in 12 patients: the minimum number of lesions was 1, the maximum was 40 (average 6). The distribution of patients according to the number of lesions after auto-HSCT was as follows: 0 -1 in 7 (50%) patients, 2 -40 in 7 (50%) cases. After auto-HSCT patients did not receive maintenance therapy they were monitored until the disease recurred. With a median follow-up of 21 months, relapse was documented among 8 patients. At the same time, in 3 of them, the results of MRI performed on the 100th day after auto-HSCT showed minimal bone marrow damage (less than 1 focus) and in 5 cases more than 1 lesion of the bone marrow was detected. 3-year PFS in the group of patients with minimal bone marrow damage on MR-tomograms (less than 1 lesion) was significantly (p < 0.05) higher and amounted to 52% versus 18% in the group of patients with more than 1 lesion detected in the bone marrow by MRI data (Figure 1). Summary/Conclusion: Differences in PFS suggest that in patients with MRD-negativity after auto-HSCT, a whole-body MRI reveals focal lesions in the bone marrow. Flow cytometry examines only local bone marrow damage from a biopsy. MRI of the bone marrow can reduce the false-negative results of the determination of MRD after auto-HSCT.