Identifying tumor cells infiltrating normal-appearing brain tissue is critical to achieve a total glioma resection. Raman spectroscopy (RS) is an optical technique with potential for real-time glioma ...detection. Most RS reports are based on formalin-fixed or frozen samples, with only a few studies deployed on fresh untreated tissue. We aimed to probe RS on untreated brain biopsies exploring novel Raman bands useful in distinguishing glioma and normal brain tissue. Sixty-three fresh tissue biopsies were analyzed within few minutes after resection. A total of 3450 spectra were collected, with 1377 labelled as Healthy and 2073 as Tumor. Machine learning methods were used to classify spectra compared to the histo-pathological standard. The algorithms extracted information from 60 different Raman peaks identified as the most representative among 135 peaks screened. We were able to distinguish between tumor and healthy brain tissue with accuracy and precision of 83% and 82%, respectively. We identified 19 new Raman shifts with known biological significance. Raman spectroscopy was effective and accurate in discriminating glioma tissue from healthy brain ex-vivo in fresh samples. This study added new spectroscopic data that can contribute to further develop Raman Spectroscopy as an intraoperative tool for in-vivo glioma detection.
We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer ...treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (
,
,
,
,
,
,
,
) showed a statistically significant negative association with PFS. When we considered PFS < 6 months,
,
,
,
,
, and
were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27
and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.
Abstract
We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit ...from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples
ESR1
and
PI3KCA
mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32–92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while
PI3KCA
mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs,
miR-549a
,
miR-644a, miR-16-5p
were negatively while
let-7c-5p
was positively associated with 18-month PFS. In addition
, miR-520d-3p
and
miR-548g-3p
values were significantly lower while
miR-603, miR-181a-5p
and
miR-199a-miR-199b-3p
values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by
miR-603, miR-181a-5p
and
miR-199a-miR-199b-3p.
Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.
Residual tumor cellularity (RTC) and pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) are prognostic factors associated with improved outcomes in breast cancer (BC). However, ...the majority of patients achieve partial pathologic response (pPR) and no clear correlation between RTC patterns and outcomes was described. Our aims were to define predictive factors for pCR and compare different outcomes of patients with pCR or pPR and with different RTC patterns.
Baseline and post-NAC demographics, clinicopathological characteristics, post-operative data, survival and recurrence status were recorded from our institutional database. A multivariable analysis was performed using a logistic regression model to identify independent predictors of pCR. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) analyses were performed using the Kaplan-Meier method.
Overall, of the 495 patients analyzed, 148 (29.9%) achieved pCR, 347 (70.1%) had pPR, and the median RTC was 40%. Multivariable analysis identified 3 independent factors predictive of pCR: tumor stage before NAC (cT1-2 84.5% versus cT3-4 15.5%), BC sub-type (HER2-positive 54.7% versus triple-negative 29.8% versus luminal-like 15.5%), and vascular invasion (absence 98.0% versus presence 2.0%). We found statistically significant longer DFS, DDFS, and OS in patients with pCR and with RTC <40%; no difference was observed in terms of OS between RTC <40% and RTC ≥40% groups.
Tumor stage before NAC, BC sub-type, and vascular invasion are significant and independent factors associated with pCR. Patients with pCR and with RTC <40% have longer DFS, DDFS, and OS compared with patients with pPR.
•Pathologic complete response and residual tumor cellularity are prognostic factors.•Stage, HER2 and absence of vascular invasion are factors associated with higher pCR.•Patients who achieve pCR have a better prognosis in terms of DFS, DDFS and OS.•Patients with RTC <40% show a statistically significant better DFS and DDFS.
Isocitrate dehydrogenase (IDH) mutational status is pivotal in the management of gliomas. Patients with IDH-mutated (IDH-MUT) tumors have a better prognosis and benefit more from extended surgical ...resection than IDH wild-type (IDH-WT). Raman spectroscopy (RS) is a minimally invasive optical technique with great potential for intraoperative diagnosis. We evaluated the RS’s ability to characterize the IDH mutational status onto unprocessed glioma biopsies. We extracted 2073 Raman spectra from thirty-eight unprocessed samples. The classification performance was assessed using the eXtreme Gradient Boosted trees (XGB) and Support Vector Machine with Radial Basis Function kernel (RBF-SVM). Measured Raman spectra displayed differences between IDH-MUT and IDH-WT tumor tissue. From the 103 Raman shifts screened as input features, the cross-validation loop identified 52 shifts with the highest performance in the distinction of the two groups. Raman analysis showed differences in spectral features of lipids, collagen, DNA and cholesterol/phospholipids. We were able to distinguish between IDH-MUT and IDH-WT tumors with an accuracy and precision of 87%. RS is a valuable and accurate tool for characterizing the mutational status of IDH mutation in unprocessed glioma samples. This study improves RS knowledge for future personalized surgical strategy or in situ target therapies for glioma tumors.
The majority of breast cancer (BC) patients treated with neo-adjuvant chemotherapy (NAC) achieves a pathologic partial response with different patterns of residual disease. No clear correlation ...between these patterns and oncological results was described. Our aims were to define the predictive factors for different patterns of residual disease and compare the outcomes between the scattered versus the circumscribed pattern.
We reviewed 219 postoperative surgical specimens. Patients were divided into two groups: scattered versus circumscribed. Disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were analyzed.
The scattered and circumscribed patterns were assessed in 111 (50.7%) and 108 (49.3%) patients. Two independent predictive factors for the circumscribed pattern were identified: discontinuation of NAC cycles (
= 0.011), and tumor size post-NAC >18 mm (
= 0.022). No difference was observed in terms of DFS and DDFS. Patients with the scattered pattern exhibited a statistically significant better OS. Discontinuation of NAC cycles, tumor size >18 mm, triple-negative BC, and ypN+ were associated with increased recurrence and poorer survival.
Discontinuation of NAC cycles and tumor size are independent factors associated with patterns of residual disease. The scattered pattern presents better survival. Understanding the relationship between NAC, the residual pattern, and differences in survival outcomes offers the potential to optimize the therapeutic approaches.
Introduction
Intracranial aneurysms occur in 3%–5% of the general population. While the precise biological mechanisms underlying the formation, growth, and sudden rupture of intracranial aneurysms ...remain partially unknown, recent research has shed light on the potential role of inflammation in aneurysm development and rupture. In addition, there are ongoing investigations exploring the feasibility of employing new drug therapies for controlling the risk factors associated with aneurysms. CD68, a glycosylated glycoprotein and the human homolog of macrosialin, is prominently expressed in monocyte/macrophages within inflamed tissues and has shown potential application in oncology. An observational study was conducted with the aim of comparing the histological characteristics of aneurysm walls with preoperative MRI scans, specifically focusing on CD68 activity.
Method
An observational pilot study was conducted to investigate the histological characteristics of the aneurysm wall that could be potentially associated with aneurysm growth and rupture. A total of 22 patients diagnosed with ruptured and unruptured intracranial aneurysms who had undergone conventional clipping between January 2017 and December 2022 were included in the study.
Results
A histopathological analysis of the aneurysm wall was performed in all patients, particularly focusing on the presence of CD68. A preoperative MRI with gadolinium was conducted in 10 patients with unruptured aneurysms and six patients with ruptured aneurysms. An emergency clipping was performed in the remaining six patients. The results showed that CD68 positivity and wall enhancement were significantly associated with intracranial aneurysm wall degeneration, growth, and rupture.
Conclusion
The histological and radiological inflammatory findings observed in the wall of cerebral aneurysms, as well as the CD68 positivity, are significantly associated with the risk of intracranial aneurysm growth and rupture. This study highlights the crucial importance of considering clinical and medical data when making treatment decisions for intracranial aneurysms. Furthermore, it emphasizes the relevance of evaluating wall enhancement in MRI scans as part of the diagnostic and prognostic process.
Abstract
Luminal-like breast cancer (BC) constitutes the majority of BC subtypes, but, differently from highly aggressive triple negative BC, is poorly infiltrated by the immune system. The quality ...of the immune infiltrate in luminal-like BCs has been poorly studied, thereby limiting further investigation of immunotherapeutic strategies. By using high-dimensional single-cell technologies, we identify heterogeneous behavior within the tissue-resident memory CD8+ T (Trm) cells infiltrating luminal-like tumors. A subset of CD127− CD39
hi
Trm cells, preferentially present in the tumor compared to the adjacent normal breast tissue or peripheral blood, retains enhanced degranulation capacity compared to the CD127+ CD39
lo
Trm counterpart ex vivo, and is specifically associated with positive prognosis. Nevertheless, such prognostic benefit is lost in the presence of highly-suppressive CCR8
hi
ICOS
hi
IRF4+ effector Tregs. Thus, combinatorial strategies aiming at boosting Trm function and infiltration while relieving from Treg-mediated immunosuppression should be investigated to achieve proper tumor control in luminal-like BCs.
(1) Background: We investigated the role of 11C-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical ...resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18–70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and 11C-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of 11C-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on 11C-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. 11C-methionine uptake changed RT volume in 11% of patients. The presence of 11C-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: 11C-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.
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