Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.

Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially-resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity (e.g., MDLC with TNBC/basal ductal and ER+/luminal lobular regions), distinct enrichment of senescence/dormancy and oncogenic (ER and MYC) signatures, genetic and epigenetic CDH1 inactivation in lobular, but not ductal regions, and single-cell ductal and lobular sub-populations with unique oncogenic signatures further highlighting intra-regional heterogeneity. Altogether, we demonstrated that the intra-tumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma. Significance: MDLC displays both ductal and lobular tumor regions. Our multi-omic profiling approach revealed that these morphologically distinct tumor regions harbor distinct intrinsic subtypes and oncogenic features that may cause prognostic uncertainty and therapeutic dilemma. Thus histopathological/molecular profiling of individual tumor regions may guide clinical decision making and benefit patients with MDLC, particularly in the advanced setting where there is increased reliance on next generation sequencing.

Recent changes in practice patterns and outcomes in patients with severe traumatic brain injury.

BACKGROUND: Despite recent advances in the management of severe traumatic brain injury, the role of decompressive craniectomy remains unclear. The purpose of this study was to compare practice patterns and patient outcomes between 2 study periods over the past decade. METHODS: This is a retrospective cohort study using the American College of Surgeons Trauma Quality Improvement Project database. We included patients (age ≥18 years) with isolated severe traumatic brain injury. The patients were divided into the early (2013-2014) and late (2017-2018) groups. The primary outcome was the rate of craniectomy, and secondary outcomes included in-hospital mortality and discharge disposition. A subgroup analysis of patients undergoing intracranial pressure monitoring was also performed. A multivariable logistic regression analysis assessed the association between the early/late period and study outcomes. RESULTS: A total of 29,942 patients were included. In the logistic regression analysis, the late period was associated with decreased use of craniectomy (odds ratio: 0.58, P < .001). Although the late period was associated with higher in-hospital mortality (odds ratio: 1.10, P = .013), it was also associated with a higher likelihood of discharge to home/rehab (odds ratio: 1.61, P < .001). Similarly, the subgroup analysis of patients with intracranial pressure monitoring showed that the late period was associated with a lower craniectomy rate (odds ratio: 0.26, P < .001) and a higher likelihood of discharge to home/rehab (odds ratio:1.98, P < .001). CONCLUSION: The use of craniectomy for severe traumatic brain injury has decreased over the study period. Although further studies are warranted, these trends may reflect recent changes in the management of patients with severe traumatic brain injury.