Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study.

BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %)  + 1.3  × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. PATIENTS AND METHODS: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. RESULTS: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. CONCLUSIONS: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.

Meningitis y responsabilidad profesional médica en pediatría: ¿en qué podemos mejorar? / Meningitis and professional medical liability in pediatrics: How can we improve?

Introducción: La meningitis es un problema de salud pública con repercusiones en materia de responsabilidad profesional médica (RPM), de especial interés en pediatría. El estudio de las reclamaciones permite guiar las posibles mejoras en seguridad clínica. Metodología: Se analizaron las características clínicas, microbiológicas y jurídicas de las reclamaciones relacionadas con la meningitis, interpuestas ante el Consejo de Colegios de Médicos de Cataluña entre 1988 y 2014, junto con el estudio descriptivo y analítico de los casos. Resultados: Se analizaron 53 casos (1,96 casos/año) con una tasa de RPM del 24,53%. Los casos implicaron con frecuencia a menores (54,7%), con un diagnóstico inicial de síndrome febril inespecífico (45,5%). La tasa de RPM fue significativamente mayor en los casos relacionados con la cirugía, si no se producía el fallecimiento del paciente y si existía defecto de asepsia. Los microorganismos más comunes fueron Neisseria meningitidis y Streptococcus pneumoniae. Conclusiones: La asistencia a la meningitis es un campo que requiere mejoras en seguridad clínica en pediatría, si bien resulta especialmente evidente la necesidad de revisar ciertos aspectos, como la asepsia en la anestesia y la cirugía

Introduction: Meningitis is a public health problem with implications for medical professional liability (MPL) of special interest for pediatricians. The study of claims potentially guides improvements in clinical safety. Methods: We analyzed the clinical, microbiological and legal characteristics of the complaints related to meningitis filed against the Council of Physicians' Colleges of Catalonia between 1988 and 2014, with a descriptive and analytical study of the cases.Results: We analyzed 53 cases (1.96 cases per year) with a MPL rate of 24.53%. The cases frequently involved minors (54.7%), with an initial diagnosis of non-specific febrile syndrome (45.5%). The MPL rate was significantly higher in cases related to surgery, when death did not occur and when asepsis defect existed. The most common microorganisms were Neisseria meningitidis and Streptococcus pneumoniae. Conclusions: Pediatric care of meningitis needs improvements in clinical safety, but results highlight the risk of other areas such as those related to asepsis in anesthesia and surgery

Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients.

BACKGROUND: The validation of KRAS mutations as a negative marker of response to anti-epidermal growth factor receptor (EGFR) antibodies has meant a seminal advance towards treatment individualisation of colorectal cancer (CRC) patients. However, as a KRAS wild-type status does not guarantee a response to anti-EGFR antibodies, a current challenge is the identification of other biomarkers of response. On the basis of pre-clinical evidence, we hypothesised that mitogen-activated protein kinase phosphatase-1 (MKP-1), a phosphatase that inactivates MAPKs, could be a mediator of resistance to anti-EGFR antibodies. METHODS: Tumour specimens from 48 metastatic CRC patients treated with cetuximab-based chemotherapy were evaluated for KRAS and BRAF mutational status and MKP-1 expression as assessed by immunohistochemistry. RESULTS: As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. Mitogen-activated protein kinase phosphatase-1 was overexpressed in 16 patients (33%) and was not associated with patient baseline clinicopathological characteristics and KRAS mutational status. All patients with BRAF mutations (n=3) had MKP-1 overexpression. Among KRAS wild-type patients, MKP-1 overexpressors had a 7% response rate (RR), whereas patients not overexpressing MKP-1 had a 44% RR (P=0.03). Moreover, median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs 13 weeks, P=0.009). CONCLUSION: These results support the concept of MKP-1 as a promising negative marker of response to cetuximab-based treatment in CRC patients with wild-type KRAS.

Genetic changes in small cell lung carcinoma

Small cell lung carcinoma (SCLC) accounts for approximately 15% of all lung cancer cases. Despite a frequently good response to first-line treatment with chemotherapy and/or radiotherapy, early relapse occurs in the majority of patients and 5-year survival is only about 5%. Therefore, there is a need to develop novel treatments to improve the outcome of patients with SCLC. To fulfil this need, it is critical to gain further understanding on the molecular basis of SCLC and specifically to identify novel therapeutic targets. Clinical trials with molecularly targeted agents have been performed with little success in the past, but recently many promising oncogenic pathways have been discovered and novel targeted therapies are under evaluation. In this review, we summarise the most relevant genetic and signalling pathway alterations reported to date in SCLC and discuss the potential therapeutic implications of such events (AU)

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Renal malakoplakia: report of a case with multifocal involvement.

The authors report the light microscopic and ultrastructural features in one case of malakoplakia involving the kidney, the urinary bladder, and the skin. The kidney was excised. Lesions of the urinary bladder and the skin regressed after topical treatment with cholinergic agonists and antimicrobial drugs. This case illustrates the pathogenesis of malakoplakia and the possibility that early lesions can be cured with medical therapy before extensive tissue destruction has taken place.