Abstract
Apoptosis is an indispensable mechanism for eliminating infected cells and activation of executioner caspases is considered to be a point of no return. Streptococcus pneumoniae, the most ...common bacterial pathogen causing community-acquired pneumonia, induces apoptosis via its pore-forming toxin pneumolysin, leading to rapid influxes of mitochondrial calcium Ca2+m as well as fragmentation, and loss of motility and membrane potential, which is accompanied by caspase-3/7 activation. Using machine-learning and quantitative live-cell microscopy, we identified a significant number of alveolar epithelial cells surviving such executioner caspase activation after pneumolysin attack. Precise single-cell analysis revealed the Ca2+m amplitude and efflux rate as decisive parameters for survival and death, which was verified by pharmacological inhibition of Ca2+m efflux shifting the surviving cells towards the dying fraction. Taken together, we identified the regulation of Ca2+m as critical for controlling the cellular fate under pneumolysin attack, which might be useful for therapeutic intervention during pneumococcal infection.
Quantitative live-cell imaging shows that mitochondrial calcium flux is decisive for the recovery of alveolar epithelial cells from apoptotic cell death induced by the pore-forming toxin pneumolysin produced by Streptococcus pneumoniae.
Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the ...immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (
= 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval CI: 40.9-95.2,
= 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2,
= 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease,
status and stage (HR 2.48, 95% CI: 1.03-5.99,
= 0.043, and HR 2.91, 95% CI: 1.11-7.64,
= 0.03, respectively). In the IDS group (
= 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).
Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently ...arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included 46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval PFI was >6 months after the last cycle of prior platinum) median PFI 12.0 months (interquartile range, IQR, 8.8−17.1). Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6−9.2), and median OS (mOS) of 20.6 months (95% CI 13.6−28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 IQR11.2−22.2 and 10.3 IQR 7.4−14.9 months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5−8.6) versus 7.5 months (95% CI 6.5−10.1, p = 0.03), and 16.4 (95% CI 9.3−27.5) versus 24.2 months (95% CI 17.2−NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.
Purpose
The lack of validated surrogate biomarkers is still an unmet clinical need in the management of early breast cancer cases that do not achieve complete pathological response after neoadjuvant ...chemotherapy (NACT). Here, we describe and validate the use of SAMHD1 expression as a prognostic biomarker in residual disease
in vivo
and
in vitro
.
Methods
SAMHD1 expression was evaluated in a clinical cohort of early breast cancer patients with stage II-III treated with NACT. Heterotypic 3D cultures including tumor and immune cells were used to investigate the molecular mechanisms responsible of SAMHD1 depletion through whole transcriptomic profiling, immune infiltration capacity and subsequent delineation of dysregulated immune signaling pathways.
Results
SAMHD1 expression was associated to increased risk of recurrence and higher Ki67 levels in post-NACT tumor biopsies of breast cancer patients with residual disease. Survival analysis showed that SAMHD1-expressing tumors presented shorter time-to-progression and overall survival than SAMHD1 negative cases, suggesting that SAMHD1 expression is a relevant prognostic factor in breast cancer. Whole-transcriptomic profiling of SAMHD1-depleted tumors identified downregulation of IL-12 signaling pathway as the molecular mechanism determining breast cancer prognosis. The reduced interleukin signaling upon SAMHD1 depletion induced changes in immune cell infiltration capacity in 3D heterotypic
in vitro
culture models
,
confirming the role of the SAMHD1 as a regulator of breast cancer prognosis through the induction of changes in immune response and tumor microenvironment.
Conclusion
SAMHD1 expression is a novel prognostic biomarker in early breast cancer that impacts immune-mediated signaling and differentially regulates inflammatory intra-tumoral response.
Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown impressive results in
mutant lung cancer (LC) patients in terms of disease control rate with a ...positive impact on overall survival. Nevertheless, after months of treatment with targeted therapy, progression inevitably occurs. Some patients develop oligoprogression and local treatment is required for optimal disease control while maintaining EGFR-TKIs. This work features a clinical case of a patient harboring an
mutant LC undergoing oligoprogression to EGFR-TKIs, first into the brain and afterward to the primary tumor, requiring local ablative strategies, including primary tumor resection three years after the start of osimertinib. Currently, the patient is still alive and continues with a complete response upon EGFR-TKIs maintenance. Hence, oligoprogression, even in driven oncogenic tumors, represents a distinct biological entity and potential curative disease that deserves particular consideration in multidisciplinary tumor boards. In this case, tumor primary resection after three years of the initial diagnosis represents a paradigm shift in the treatment of
mutant patients.
Zusammenfassung
Hintergrund
Die Sepsis ist eine häufige und lebensbedrohliche Komplikation einer akuten Infektion. In der Notfallmedizin hat sich zum Screening auf Sepsis der Quick ...Sequential-Organ-Failure-Assessment(qSOFA)-Score etabliert. Bereits mit der Einführung des Scores wurde dessen schwache Sensitivität kritisiert. Nun fordern aktuelle Leitlinien, den qSOFA-Score nicht mehr zum Screening auf Sepsis einzusetzen. Als eine Alternative wird der National Early Warning Score 2 (NEWS2) vorgeschlagen.
Ziel der Arbeit
In einer Subanalyse einer Kohorte von notfallmedizinischen Patient*innen soll die diagnostische Aussagekraft des qSOFA-Scores und des NEWS2 zur Erkennung einer Sepsis verglichen werden. Zusätzlich soll gezeigt werden, inwieweit mithilfe von abweichenden Vitalparametern bereits eine Risikoerhöhung für eine Sepsis ableitbar ist.
Methodik
Mittels AUROC (Area Under Receiver Operating Characteristics) und Odds Ratios wurden die Scores bzw. die Vitalparameter auf ihre Fähigkeit untersucht, septische Patient*innen zu erkennen.
Ergebnisse
Von 312 eingeschlossenen Patient*innen wurde bei 17,9 % eine Sepsis diagnostiziert. Der qSOFA-Score erkannte eine Sepsis mit einer AUROC von 0,77 (NEWS2 0,81). Für qSOFA fand sich eine Sensitivität von 57 % (Spezifität 83 %), für NEWS2 96 % (Spezifität 45 %). Die Analyse der einzelnen Vitalparameter zeigte, dass unter Patient*innen mit einer akuten Infektion eine Vigilanzminderung als deutliches Warnsignal für eine Sepsis zu werten ist.
Diskussion
In der Notfallmedizin sollte qSOFA nicht als alleiniges Tool für das Screening auf Sepsis verwendet werden. Bei Verdacht auf eine akute Infektion sollten grundsätzlich sämtliche Vitalparameter erfasst werden, um das Vorliegen einer akuten Organschädigung und somit einen septischen Krankheitsverlauf frühzeitig zu erkennen.
Graphic abstract
Abstract
Background
Sepsis is a common and life-threatening complication of acute infections. In emergency medicine, the Quick Sequential Organ Failure Assessment (qSOFA)-Score has become an established method of screening for sepsis. However, the low sensitivity of the score has remained under criticism since its introduction. As such, current guidelines now recommend against the use of qSOFA as a sepsis screening tool, suggesting the National Early Warning Score 2 (NEWS2) instead.
Objectives
To compare the diagnostic accuracy of qSOFA and NEWS2 for identifying sepsis in a secondary analysis of an emergency department cohort of patients with suspected infections. Furthermore, to show to what extent changes in different vital signs reflect an increased risk of sepsis.
Materials and methods
Patients in a prospective cohort were assessed to identify cases of sepsis. The scores and vital signs were assessed using the area under receiver operating characteristics (AUROCs) and odds ratios.
Results
Of the 312 enrolled patients, 17.9% were assessed as having sepsis. qSOFA identified sepsis with an AUROC of 0.77 (NEWS2 0.81). Using established thresholds, qSOFA had a sensitivity of 57% and specificity of 83%, compared to 96% and 45%, respectively, for NEWS2. The vital sign analysis showed that among patients with acute infections, altered mental status should be treated as a key warning sign of sepsis.
Conclusion
In emergency medicine, qSOFA should not be used as a single tool for sepsis screening. In cases of suspected acute infections, all vital signs should be assessed to identify acute organ dysfunction and, thereby, sepsis as early as possible.
Abstract Background Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor prognosis. It is known that the activation of STAT3 signaling pathways promotes the ...development and progression of this neoplasia and it has been described the role of PTPRT as a negative regulator of STAT3. Then, we have evaluated the impact of them as biomarkers of outcome in a series of patients with recurrent and/or metastatic SCCHN treated with weekly paclitaxel‐plus‐cetuximab (ERBITAX) regimen. Patients and methods Between 2008 and 2017, 52 patients with recurrent/metastatic SCCHN were treated with ERBITAX at our center, 34 of whom had available tumor samples. Phosphorylated STAT3 (pSTAT3) protein expression was analyzed by immunohistochemistry, STAT3 mRNA expression by qPCR, and PTPRT promoter methylation by methylation‐specific PCR. Molecular results were correlated with response rate (RR), progression‐free survival (PFS), and overall survival (OS). Results pSTAT3 overexpression was detected in 67% and PTPRT promoter hypermethylation in 41% of tumor samples. PTPRT promoter hypermethylation showed a trend towards an association with lower RR (21% vs. 60%; p = 0.06). A lower RR was also observed in patients with pSTAT3 overexpression (36% vs. 54%) and in those with high STAT3 mRNA levels (43% vs. 64%), but these differences did not reach statistical significance. PTPRT promoter hypermethylation correlated with pSTAT3 overexpression ( p = 0.009) but not with STAT3 mRNA overexpression. OS and PFS was shorter in patients with activated STAT3, but the difference did not reach statistical significance. Conclusions Although this was a relatively small retrospective study, it provides preliminary indications of the potential role of the STAT3 pathway on outcome in SCCHN and confirms that PTPRT acts as a negative regulator of STAT3. Our findings warrant investigation in a larger patient cohort to determine if inactivating this pathway through specific targeted treatments could improve outcomes in recurrent/metastatic SCCHN patients.
T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in ...HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice.
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