Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Two cases of elevated tryptase in abdominal aortic aneurysm.

INTRODUCTION: From the literature, patients with a history of anaphylaxis to hymenoptera venom and positive specific IgE have shown a correlation between elevated tryptase levels and two clinical situations: systemic mastocytosis and an increased risk of reactions to venom immunotherapy or hymenoptera sting. Other clinical scenarios could explain elevated tryptase levels. MATERIAL AND METHODS: A 67 year old male (P1) and a 77 year old male (P2) were evaluated for previous severe anaphylaxis to hymenoptera sting. They underwent standard diagnostic work-up for hymenoptera venom allergy. Having found elevated tryptase levels, these were followed by a bone marrow biopsy to rule out systemic mastocytosis. RESULTS: P1: specific IgE and skin tests were positive for Vespula species; tryptase 52.8 ng/ml; P2: specific IgE and skin tests were positive for Vespa cabro and tryptase 153 ng/ml. Bone marrow biopsy results were negative for mastocytosis. We carried out magnetic resonance imaging, in P1 to better characterize the severe osteoporosis and in P2 because during physical examination a pulsating mass had been identified in the mesogastrium, and an aneurysm of the abdominal aorta which required surgical intervention in both patients was detected. Eight months after surgery, tryptase levels had diminished significantly (P1: 11.6 ng/ml and P2: 14.5 ng/ml). DISCUSSION: The elevated tryptase levels were correlated to abdominal aneurysm in both patients. In fact, post-surgery tryptase levels dramatically decreased. These two cases demonstrate that high tryptase levels in subjects with a history of hymenoptera venom anaphylaxis can be associated to undiagnosed aneurysmatic disease.

Comparative prognostic value of Ki-67 and MIB-1 proliferation indices in breast cancer.

BACKGROUND: Tumor proliferation index was evaluated in 246 samples of breast carcinoma using Ki-67 and MIB-1 monoclonal antibodies on frozen and paraffin sections, respectively, with the purpose to compare the two proliferation indices from both a quantitative and prognostic point of view. MATERIALS AND METHODS: All determinations were performed with the same immunohistochemical procedure (Avidin-Biotin Complexes). The prognostic relevance of tumor proliferation index, defined by both the antibodies, was investigated in 127 patients. Ki-67 and MIB-1 median values were used to obtain two groups of patients at different risk and life-table analysis (Mantel-Cox) was performed to assess the probabilities of overall survival (OS) and relapse-free survival (RFS). The median time of observation was 61 months. RESULTS: Ki-67 and MIB-1 values were exponentially distributed with overlapping ranges varying from 2% to 90%. Ki-67 mean and median values were 16.7% and 14.0%, respectively, compared to 22.5% and 20% for MIB-1. Ki-67 and MIB-1 mean values were statistically different (t = -4.396; p < 0.001), while no difference was observed for MIB-1 mean values on frozen and paraffin sections (t = 1.35; p = n.s.). Ki-67 and MIB-1 values were statistically correlated (Spearman's coefficient = 0.75; p < 0.0001) and directly associated (agreement rate = 79.3%; p < 0.0001). Patients with tumors having a high proportion of MIB-1 positive cells showed a higher 5-year probability of relapse of disease (43.7% versus 27.6%; p = 0.02) and death (35.4% versus 15.8%; p = 0.007) than those with a low one. In parallels Ki-67 was found to be prognostically relevant for OS (32.2% versus 16.2%; p = 0.02) but not for RFS (40.7% versus 27.9%; p = 0.10). CONCLUSIONS: Such results indicate that the detection of proliferative activity on paraffin sections with MIB-1 monoclonal antibody provides in formation analogous to or even better than that obtained with Ki-67 antibody on frozen ones. Moreover, it represents a valuable tool to obtain kinetic data on "routine" histological samples and, above all, to give prognostic evaluations on the clinical outcome of breast cancer patients.

Proliferation index as a prognostic marker in breast cancer.

BACKGROUND: The proliferative activity of tumors has been extensively investigated with different approaches, among which the use of the monoclonal antibody Ki-67 represents an easy and reliable means of assessing cell proliferation. In this study, the proliferative activity of 129 primary breast cancers was investigated, and the results were related to prognosis. METHODS: Tumor samples, obtained from 129 patients who underwent surgery between January 1987 and December 1988, were processed for staining by an immunohistochemical procedure (avidin-biotin complex). The median time of observation was 42 months (range, 31-55 months). Life-table analysis (Mantel-Cox) was used to assess the probability of disease-free survival (DFS) and overall survival (OS). RESULTS: Tumors with high Ki-67 proliferation indices (> 20%) were associated with a higher 4-year probability of relapse of disease (55.3% versus 79.1%; P = 0.003) and death (71% versus 95.6%; P = 0.00005) when compared with tumors with low Ki-67 values. In addition, this proliferative parameter maintained its prognostic significance when the patients were stratified according to lymph node involvement, menopausal status, and nuclear estrogen receptor content. CONCLUSIONS: Tumor proliferative activity as evaluated by the monoclonal antibody Ki-67 seems to be an effective indicator of prognosis in breast cancer for DFS and OS.

Detection of Ki-67 proliferation rate in breast cancer. Correlation with clinical and pathologic features.

In situ determination of proliferative activity was performed on 203 breast cancers by use of Ki-67 monoclonal antibody and immunohistochemical methods. Tumor proliferation rate was analyzed and correlated to tumor size and nodal status. The relationship between Ki-67 proliferative activity and nuclear estrogen receptor content was also investigated on adjacent tissue sections. Ki-67 values ranged from 1 to 75%, with a median value of 10%. Premenopausal patients had greater Ki-67 values (median value, 14.1%) than postmenopausal ones (median value, 9.8%). The authors observed no correlation with lymph nodal involvement, whereas a statistically significant relationship with tumor size was found (P less than 0.01). An inverse correlation (Spearman's coefficient = -0.56; P less than 0.001) was seen between Ki-67 values and nuclear estrogen receptor content. These results, similar to those reported for other kinetic measurements, suggest that in situ detection of Ki-67 proliferation rate is a useful method for obtaining cell cycle information. Follow-up studies will be needed to assess an eventual prognostic relevance.