68Ga-Fibroblast Activation Protein Inhibitor PET/CT Improves Detection of Intermediate and Low-Grade Sarcomas and Identifies Candidates for Radiopharmaceutical Therapy.

Fibroblast activation protein-α (FAP) is often highly expressed by sarcoma cells and by sarcoma-associated fibroblasts in the tumor microenvironment. This makes it a promising target for imaging and therapy. The level of FAP expression and the diagnostic value of 68Ga-FAP inhibitor (FAPI) PET for sarcoma subtypes are unknown. We assessed the diagnostic performance and accuracy of 68Ga-FAPI PET in various bone and soft-tissue sarcomas. Potential eligibility for FAP-targeted radiopharmaceutical therapy (FAP-RPT) was evaluated. Methods: This prospective observational trial enrolled 200 patients with bone and soft-tissue sarcoma who underwent 68Ga-FAPI PET/CT and 18F-FDG PET/CT (186/200, or 93%) for staging or restaging. The number of lesions detected and the uptake (SUVmax) of the primary tumor, lymph nodes, and visceral and bone metastases were analyzed. The Wilcoxon test was used for semiquantitative assessment. The association of 68Ga-FAPI uptake intensity, histopathologic grade, and FAP expression in sarcoma biopsy samples was analyzed using Spearman r correlation. The impact of 68Ga-FAPI PET on clinical management was investigated using questionnaires before and after PET/CT. Eligibility for FAP-RPT was defined by an SUVmax greater than 10 for all tumor regions. Results: 68Ga-FAPI uptake was heterogeneous among sarcoma subtypes. The 3 sarcoma entities with the highest uptake (mean SUVmax ± SD) were solitary fibrous tumor (24.7 ± 11.9), undifferentiated pleomorphic sarcoma (18.8 ± 13.1), and leiomyosarcoma (15.2 ± 10.2). Uptake of 68Ga-FAPI versus 18F-FDG was significantly higher in low-grade sarcomas (10.4 ± 8.5 vs. 7.0 ± 4.5, P = 0.01) and in potentially malignant intermediate or unpredictable sarcomas without a World Health Organization grade (not applicable [NA]; 22.3 ± 12.5 vs. 8.5 ± 10.0, P = 0.0004), including solitary fibrous tumor. The accuracy, as well as the detection rates, of 68Ga-FAPI was higher than that of 18F-FDG in low-grade sarcomas (accuracy, 92.2 vs. 80.0) and NA sarcomas (accuracy, 96.9 vs. 81.9). 68Ga-FAPI uptake and the histopathologic FAP expression score (n = 89) were moderately correlated (Spearman r = 0.43, P < 0.0002). Of 138 patients, 62 (45%) with metastatic sarcoma were eligible for FAP-RPT. Conclusion: In patients with low-grade and NA sarcomas, 68Ga-FAPI PET demonstrates uptake, detection rates, and accuracy superior to those of 18F-FDG PET. 68Ga-FAPI PET criteria identified eligibility for FAP-RPT in about half of sarcoma patients.

Early Metabolic Response by PET Predicts Sensitivity to Next-Line Targeted Therapy in EGFR-Mutated Lung Cancer with Unknown Mechanism of Acquired Resistance.

Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has established the precision oncology paradigm in lung cancer. Most patients with EGFR-mutated lung cancer respond but eventually acquire resistance. Methods: Patients exhibiting the EGFR p.T790M resistance biomarker benefit from sequenced targeted therapy with osimertinib. We hypothesized that metabolic response as detected by 18F-FDG PET after short-course osimertinib identifies additional patients susceptible to sequenced therapy. Results: Fourteen patients with EGFR-mutated lung cancer and resistance to first- or second-generation EGFR TKI testing negatively for EGFR p.T790M were enrolled in a phase II study. Five patients (36%) achieved a metabolic 18F-FDG PET response and continued osimertinib. In those, the median duration of treatment was not reached (95% CI, 24 mo to not estimable), median progression-free survival was 18.7 mo (95% CI, 14.6 mo to not estimable), and median overall survival was 41.5 mo. Conclusion: Connecting theranostic osimertinib treatment with early metabolic response assessment by PET enables early identification of patients with unknown mechanisms of TKI resistance who derive dramatic clinical benefit from sequenced osimertinib. This defines a novel paradigm for personalization of targeted therapies in patients with lung cancer dependent on a tractable driver oncogene.

Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial.

Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4, administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small-cell lung cancers. When given before curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase 2 study, 60 biomarker-unselected, treatment-naive patients with resectable non-small-cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab) and in 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients, tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 before lung cancer surgery.ClinicalTrials.gov Indentifier: NCT04205552 .

Efficacy of tyrosine kinase inhibitors examined by a combination of Raman micro-spectroscopy and a deep wavelet scattering-based multivariate analysis framework.

HER2 is a crucial therapeutic target in breast cancer, and the survival rate of breast cancer patients has increased because of this receptor's inhibition. However, tumors have shown resistance to this therapeutic strategy due to oncogenic mutations that decrease the binding of several HER2-targeted drugs, including lapatinib, and confer resistance to this drug. Neratinib can overcome this drug resistance and effectively inhibit HER2 signaling and tumor growth. In the present study, we examined the efficacy of lapatinib and neratinib using breast cancer cells by Raman microscopy combined with a deep wavelet scattering-based multivariate analysis framework. This approach discriminated between control cells and drug-treated cells with high accuracy, compared to classical principal component analysis. Both lapatinib and neratinib induced changes in the cellular biochemical composition. Furthermore, the Raman results were compared with the results of several in vitro assays. For instance, drug-treated cells exhibited (i) inhibition of ERK and AKT phosphorylation, (ii) inhibition of cellular proliferation, (iii) cell-cycle arrest, and (iv) apoptosis as indicated by western blotting, real-time cell analysis (RTCA), cell-cycle analysis, and apoptosis assays. Thus, the observed Raman spectral changes are attributed to cell-cycle arrest and apoptosis. The results also indicated that neratinib is more potent than lapatinib. Moreover, the uptake and distribution of lapatinib in cells were visualized through its label-free marker bands in the fingerprint region using Raman spectral imaging. These results show the prospects of Raman microscopy in drug evaluation and presumably in drug discovery.

Long-Term Survival in Patients with Oligometastatic Non-Small Cell Lung Cancer by a Multimodality Treatment-Comparison with Stage III Disease.

Background: In patients with oligometastatic NSCLC, a cT3-cT4 primary tumor or an cN2/cN3 lymph node status was reported to be associated with unfavorable outcome. The aim of this study was to assess the importance of definitive or neoadjuvant thoracic radiochemotherapy for long-term outcome of these patients in order to find more appropriate treatment schedules. Methods: Analysis of the West Cancer Centre (WTZ) institutional database from 08/2016 to 08/2020 was performed. Patients with primary synchronous OMD, all without actionable driver mutations, who received definitive thoracic radiochemotherapy (RCT) or neoadjuvant RCT followed by surgery (trimodality treatment) were included. Survival outcome is compared with stage III NSCLC. Results: Altogether, 272 patients received concurrent radiochemotherapy. Of those, 220 presented with stage III (158 with definitive RCT, 62 with trimodality approach). A total of 52 patients had OMD patients with cT3/cT4 or cN2/cN3 tumors. Overall survival (OS) at five years for OMD patients was 28.3% (95%-CI: 16.4-41.5%), which was not significantly different from OS of patients with stage III NSCLC treated with definitive or neoadjuvant RCT (34.9% (95%-CI: 27.4-42.8%)). However, the PFS of OMD patients at five years or last follow-up was significantly worse than that of stage III patients (13.0% vs. 24.3%, p = 0.0048). The latter was due to a higher cumulative incidence of distant metastases in OMD patients (50.2% vs. 20.4% at 48 months, p < 0.0001) in comparison to stage III patients. A cross-validated classifier that included severe comorbidity, ECOG performance status, gender and pre-treatment serum CRP level as the most important factors in the univariable analysis, was able to divide the OMD patient group into two equally sized groups with a four-year survival rate of 49.4% in the good prognosis group and 9.9% in the poor prognosis group (p = 0.0021). Laboratory chemistry and clinical parameters, in addition to imaging and high-precision therapies, can help to predict and improve prognosis. Conclusions: A multimodality treatment approach and local metastases-directed therapy in addition to chemoimmunotherapy can lead to good long-term survival in patients with cT3/cT4 or cN2/cN3 OMD NSCLC without severe comorbidities and in good performance status and is therefore recommended.

Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

LIONS PREY: A New Logistic Scoring System for the Prediction of Malignant Pulmonary Nodules.

OBJECTIVES: Classifying radiologic pulmonary lesions as malignant is challenging. Scoring systems like the Mayo model lack precision in predicting the probability of malignancy. We developed the logistic scoring system 'LIONS PREY' (Lung lesION Score PREdicts malignancY), which is superior to existing models in its precision in determining the likelihood of malignancy. METHODS: We evaluated all patients that were presented to our multidisciplinary team between January 2013 and December 2020. Availability of pathological results after resection or CT-/EBUS-guided sampling was mandatory for study inclusion. Two groups were formed: Group A (malignant nodule; n = 238) and Group B (benign nodule; n = 148). Initially, 22 potential score parameters were derived from the patients' medical histories. RESULTS: After uni- and multivariate analysis, we identified the following eight parameters that were integrated into a scoring system: (1) age (Group A: 64.5 ± 10.2 years vs. Group B: 61.6 ± 13.8 years; multivariate p-value: 0.054); (2) nodule size (21.8 ± 7.5 mm vs. 18.3 ± 7.9 mm; p = 0.051); (3) spiculation (73.1% vs. 41.9%; p = 0.024); (4) solidity (84.9% vs. 62.8%; p = 0.004); (5) size dynamics (6.4 ± 7.7 mm/3 months vs. 0.2 ± 0.9 mm/3 months; p < 0.0001); (6) smoking history (92.0% vs. 43.9%; p < 0.0001); (7) pack years (35.1 ± 19.1 vs. 21.3 ± 18.8; p = 0.079); and (8) cancer history (34.9% vs. 24.3%; p = 0.052). Our model demonstrated superior precision to that of the Mayo score (p = 0.013) with an overall correct classification of 96.0%, a calibration (observed/expected-ratio) of 1.1, and a discrimination (ROC analysis) of AUC (95% CI) 0.94 (0.92-0.97). CONCLUSIONS: Focusing on essential parameters, LIONS PREY can be easily and reproducibly applied based on computed tomography (CT) scans. Multidisciplinary team members could use it to facilitate decision making. Patients may find it easier to consent to surgery knowing the likelihood of pulmonary malignancy. The LIONS PREY app is available for free on Android and iOS devices.

Comprehensive biomarker diagnostics of unfavorable cancer of unknown primary to identify patients eligible for precision medical therapies.

PURPOSE: Current guidelines recommend combination chemotherapy for treatment of patients with unfavorable cancer of unknown primary (CUP). Biomarker-guided targeted therapies may offer additional benefit. Data on the feasibility and effectiveness of comprehensive genomic biomarker profiling of CUP in a standard clinical practice setting are limited. METHODS: This analysis included 156 patients with confirmed unfavorable CUP diagnosis according to ESMO guidelines, who were treated at the West German Cancer Center, Essen, Germany, from 2015 to 2021. Clinical parameters and outcome data were retrieved from the electronic hospital information system. Genomic biomarker analyses were performed in formalin-fixed paraffin-embedded tumor tissue whenever possible using the QIAseq Multimodal-Pancancer-Panel. RESULTS: Non-squamous histologies, high tumor burden, and age above 60 years associated with poor survival outcome. Tissue availability restricted comprehensive biomarker analyses to 50 patients (32%), reflecting a major limitation in the real-world setting. In those patients a total of 24 potentially actionable alterations were identified in 17 patients (34% of profiled patients, 11% of total population). The most prevalent biomarkers were high tumor mutational burden and BRCA-mutations. CONCLUSION: In a real-world setting precision medicine for patients with CUP is severely restricted by tissue availability, and a limited spectrum of actionable alterations. Progress for patients may require emphasizing the need for sufficient biopsies, and prospective exploration of blood-based biomarker profiling.

Drivers and barriers of patients' acceptance of video consultation in cancer care.

Background: Due to digitization in the medical sector, many healthcare interactions are switched to online services. This study assessed the acceptance of video consultations (VCs) in cancer care, and determined drivers and barriers of acceptance. Methods: A cross-sectional online-based survey study was conducted in Germany from February 2022 to February 2023. Recruitment took place at oncology outpatient clinics, general practitioners, oncology practices and via cancer-related social media channels. Inclusion criteria were a cancer diagnosis, cancer treatment and internet access. Sociodemographic, medical data, eHealth-related data were acquired via an online assessment. The Unified Theory of Acceptance and Use of Technology (UTAUT) model was used to determine the acceptance of VC and its predictors. Results: Of N = 350 cancer patients, 56.0% (n = 196) reported high acceptance of VC, 28.0% (n = 98) stated moderate acceptance and 16.0% (n = 56) indicated low acceptance. Factors influencing acceptance were younger age (ß = -.28, p < .001), female gender (ß = .35, p = .005), stage of disease (ß = .11, p = .032), high digital confidence (ß = .14, p = .010), low internet anxiety (ß = -.21, p = .001), high digital overload (ß = -.12, p = .022), high eHealth literacy (ß = .14, p = .028), personal trust (ß = -.25, p < .001), internet use (ß = .17, p = .002), and the UTAUT predictors: performance expectancy (ß = .24, p < .001), effort expectancy (ß = .26, p < .001), and social influence (ß = .34, p < .001). Conclusions: Patients' acceptance of VC in cancer care is high. Drivers and barriers to acceptance identified should be considered for personalized applications. Considering the growing demand for cancer care establishing digital healthcare solutions is justified.

Postoperative Tobacco Cessation Improves Quality of Life, Lung Function and Long-Term Survival in Non-Small-Cell Lung Cancer Patients.

OBJECTIVES: About 90% of all non-small cell lung cancer (NSCLC) cases are associated with inhalative tabacco smoking. Half of patients continue smoking during lung cancer therapy. We examined the effects of postoperative smoking cessation on lung function, quality of life (QOL) and long-term survival. MATERIALS AND METHODS: In total, 641 patients, who underwent lobectomy between 2012 and 2019, were identified from our single institutional data base. Postoperatively, patients that actively smoked at the time of operation were offered a structured 'smoking cessation' program. For this retrospective analysis, two patient groups (total n = 90) were selected by pair matching. Group A (n = 60) had no postoperative tobacco smoking. Group B (n = 30) involved postoperative continued smoking. Lung function (FEV1, DLCO) and QOL ('SF-36' questionnaire) were measured 12 months postoperatively. We compared long-term outcomes using Kaplan-Meier curves. RESULTS: The mean age in group A was 62.6 ± 12.5 years and that in group B was 64.3 ± 9.7 years (p = 0.82); 64% and 62%, respectively, were male (p = 0.46). Preoperative smoking habits were similar ('pack years': group A, 47 ± 31; group B, 49 ± 27; p = 0.87). All relevant baseline characteristics we collected were similar (p > 0.05). One year after lobectomy, FEV1 was reduced by 15% in both groups (p = 0.98). Smoking cessation was significantly associated with improved DLCO (group A: 11 ± 16%; group B: -5 ± 14%; p <0.001) and QOL (vitality (VT): +10 vs. -10, p = 0.017; physical role function (RP): +8 vs. -17, p = 0.012; general health perceptions (GH): +12 vs. -5, p = 0.024). Patients who stopped smoking postoperatively had a significantly superior overall survival (median survival: 89.8 ± 6.8 [95% CI: 76.6-103.1] months vs. 73.9 ± 3.6 [95% CI: 66.9-80.9] months, p = 0.034; 3-year OS rate: 96.2% vs. 81.0%, p = 0.02; 5-year OS rate: 80.0% vs. 64.0%, p = 0.016). The hazard ratio (HR) was 2.31 [95% CI: 1.04-5.13] for postoperative smoking versus tobacco cessation. CONCLUSION: Postoperative smoking cessation is associated with improved quality of life and lung function testing. Notably, a significant increase in long-term survival rates among non-smoking NSCLC patients was observed. These findings could serve as motivation for patients to successfully complete a non-smoking program.

Fibroblast Activation Protein α-Directed Imaging and Therapy of Solitary Fibrous Tumor.

Fibroblast activation protein α (FAPα) is expressed at high levels in several types of tumors. Here, we report the expression pattern of FAPα in solitary fibrous tumor (SFT) and its potential use as a radiotheranostic target. Methods: We analyzed FAPα messenger RNA and protein expression in biopsy samples from SFT patients using immunohistochemistry and multiplexed immunofluorescence. Tracer uptake and detection efficacy were assessed in patients undergoing clinical 68Ga-FAPα inhibitor (FAPI)-46 PET,18F-FDG PET, and contrast-enhanced CT. 90Y-FAPI-46 radioligand therapy was offered to eligible patients with progressive SFT. Results: Among 813 patients and 126 tumor entities analyzed from the prospective observational MASTER program of the German Cancer Consortium, SFT (n = 34) had the highest median FAPα messenger RNA expression. Protein expression was confirmed in tumor biopsies from 29 of 38 SFT patients (76%) in an independent cohort. Most cases showed intermediate to high FAPα expression by immunohistochemistry (24/38 samples, 63%), which was located primarily on the tumor cell surface. Nineteen patients who underwent 68Ga-FAPI-46 PET imaging demonstrated significantly increased tumor uptake, with an SUVmax of 13.2 (interquartile range [IQR], 10.2), and an improved mean detection efficacy of 94.5% (SEM, 4.2%), as compared with 18F-FDG PET (SUVmax, 3.2 [IQR, 3.1]; detection efficacy, 77.3% [SEM, 5.5%]). Eleven patients received a total of 34 cycles (median, 3 cycles [IQR, 2 cycles]) of 90Y-FAPI-46 radioligand therapy, which resulted in disease control in 9 patients (82%). Median progression-free survival was 227 d (IQR, 220 d). Conclusion: FAPα is highly expressed by SFT and may serve as a target for imaging and therapy. Further studies are warranted to define the role of FAPα-directed theranostics in the care of SFT patients.

Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Background: Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385.

Efficacy, safety, and prognosis prediction in patients treated with ribociclib in combination with letrozole: Final results of phase 3b RIBECCA study in hormone receptor positive, human epidermal growth factor receptor-2 negative, locally advanced or metastatic breast cancer.

BACKGROUND: In MONALEESA-2, addition of ribociclib to letrozole resulted in significantly longer progression-free survival (PFS) in postmenopausal women with HR+HER2- advanced breast cancer (ABC). RIBociclib for the treatment of advanCed breast CAncer (RIBECCA) study investigated ribociclib plus letrozole in a patient population reflecting routine clinical practice. PATIENTS AND METHODS: In this multicenter, open-label, single-arm, phase 3b study, patients with HR+HER2- ABC not amenable to curative therapy and ECOG performance status ≤ 2 received ribociclib plus letrozole (cohort A: postmenopausal women and men in first-line; cohort B: pre-/perimenopausal women in first-line [B1], patients pretreated for advanced disease [B2]). The primary endpoint was clinical benefit rate (CBR) by week 24; secondary endpoints included overall response rate (ORR), PFS, overall survival (OS), and safety. Association of patient and tumor characteristics with PFS was analyzed by multivariable Cox regression analysis. RESULTS: Overall, 487 patients were evaluable for efficacy, 502 for safety. By week 24, CBR was 60.8 % (95 % CI, 56.3-65.1), ORR was 19.3 % (95 % CI, 15.9-23.1). Median PFS was 21.8 months (95 % CI, 13.9-25.3) in first-line postmenopausal patients and 11.0 months (95 % CI, 8.2-16.4) in premenopausal and pretreated patients. Median OS was not reached. Higher baseline ECOG performance status, higher histological grade, and negative progesterone receptor status showed an unfavorable effect on PFS. Most common adverse events were neutropenia (50.0 %), nausea (42.0 %), and fatigue (39.2 %). CONCLUSION: In this broad population of patients with HR+HER2- ABC, efficacy and safety results of ribociclib plus letrozole were similar to those observed in pivotal trials.

HPV-associated head and neck cancer is characterized by distinct profiles of CD8+ T cells and myeloid-derived suppressor cells.

Patients with HPV--localized head and neck cancer (HNC) show inferior outcomes after surgery and radiochemotherapy compared to HPV-associated cancers. The underlying mechanisms remain elusive, but differences in immune status and immune activity may be implicated. In this study, we analyzed immune profiles of CD8+ T cells and myeloid-derived suppressor cells (MDSC) in HPV+ versus HPV- disease.The overall frequency of CD8+ T cells was reduced in HNC versus healthy donors but substantially increased after curative therapy (surgery and/or radiochemotherapy). In HPV+ patients, this increase was associated with significant induction of peripheral blood CD8+/CD45RA-/CD62L- effector memory cells. The frequency of HPV-antigen-specific CD8+ cells was low even in patients with virally associated tumors and dropped to background levels after curative therapy. Pre-therapeutic counts of circulating monocytic MDSC, but not PMN-MDSC, were increased in patients with HPV- disease. This increase was accompanied by reduced fractions of terminally differentiated CD8+ effector cells. HPV- tumors showed reduced infiltrates of CD8+ and CD45RO+ immune cells compared with HPV+ tumors. Importantly, frequencies of tumor tissue-infiltrating PMN-MDSC were increased, while percentages of Granzyme B+ and Ki-67+ CD8 T cells were reduced in patients with HPV- disease.We report differences in frequencies and relative ratios of MDSC and effector T cells in HPV- HNC compared with more immunogenic HPV-associated disease. Our data provide new insight into the immunological profiles of these two tumor entities and may be utilized for more tailored immunotherapeutic approaches in the future.

Pneumonectomy for Primary Lung Tumors and Pulmonary Metastases: A Comprehensive Study of Postoperative Morbidity, Early Mortality, and Preoperative Clinical Prognostic Factors.

BACKGROUND: Pneumonectomy is a major surgical resection that still remains a high-risk operation. The current study aims to investigate perioperative risk factors for postoperative morbidity and early mortality after pneumonectomy for thoracic malignancies. METHODS: We retrospectively analyzed all patients who underwent pneumonectomy for thoracic malignancies at our institution between 2014 and 2022. Complications were assessed up to 30 days after the operation. Mortality for any reason was recorded after 30 days and 90 days. RESULTS: A total of 145 out of 169 patients undergoing pneumonectomy were included in this study. The postoperative 30-day complication rate was 41.4%. The 30-day-mortality was 8.3%, and 90-day-mortality 17.2%. The presence of cardiovascular comorbidities was a risk factor for major cardiopulmonary complications (54.2% vs. 13.2%, p < 0.01). Postoperative bronchus stump insufficiency (OR: 11.883, 95% CI: 1.288-109.591, p = 0.029) and American Society of Anesthesiologists (ASA) score 4 (OR: 3.023, 95% CI: 1.028-8.892, p = 0.044) were independent factors for early mortality. CONCLUSION: Pneumonectomy for thoracic malignancies remains a high-risk major lung resection with significant postoperative morbidity and mortality. Attention should be paid to the preoperative selection of patients.

Molecular Imaging Biomarkers in Cardiooncology: A View on Established Technologies and Future Perspectives.

Novel therapeutic options have significantly improved survival and long-term outcomes in many cancer entities. Unfortunately, this improvement in outcome is often accompanied by new and increasingly relevant therapy-related cardiovascular toxicity. In this context, cardiooncology has emerged as a new field of interdisciplinary individual patient care. Important tasks are pretherapeutic risk stratification and early detection and treatment of cardiotoxicity, which comprises cardiac damage in relation to cardiovascular comorbidities, the tumor disease, and cancer treatment. Clinical manifestations can cover a broad spectrum, ranging from subtle and usually asymptomatic abnormalities to serious acute or chronic complications. Typical manifestations include acute and chronic heart failure, myo- and pericarditis, arrythmias, ischemia, and endothelial damage. They can be related to almost all current cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, hormonal therapy, and radiotherapy. Molecular imaging biomarkers can aid in pretherapeutic cardiooncologic assessment for primary prevention and personalized surveillance, detection, and differential diagnosis of cardiotoxic complications. Potential advantages over conventional diagnostics are the higher detection sensitivity for subtle changes in cardiac homeostasis, higher reproducibility, and better observer independence. Hybrid imaging with highly sensitive PET/MRI may be particularly suited for early diagnosis. Important technologies that are encouraged in current multidisciplinary guidelines are equilibrium radionuclide angiography for evaluation of ventricular function and chamber morphology, as well as myocardial perfusion imaging for additional detection of ischemia. Novel modalities that may detect even earlier signs of cardiotoxicity comprise 123I-metaiodobenzylguanidine SPECT to visualize sympathetic innervation, 18F-FDG and somatostatin receptor (68Ga-DOTATOC/DOTATATE) PET to indicate a metabolic shift and inflammation, and 68Ga-fibroblast activation protein inhibitor PET to monitor cardiac remodeling. In addition, PET imaging of mitochondrial function has recently been introduced in preclinical models and will potentially broaden the field of application through higher sensitivity and specificity and by enabling higher individualization of diagnostic concepts.

New Prognostic Score (Essen Score) to Predict Postoperative Morbidity after Resection of Lung Metastases.

BACKGROUND: Pulmonary metastasectomy (PM) is a widely accepted surgical procedure. This study aims to investigate postoperative morbidity and mortality after PM and develop a score to predict high-risk patients. METHODS: We retrospectively investigated all patients undergoing a PM in our institution from November 2012 to January 2023. Complications were defined as the diagnosis of any new disease after the PM up to 30 days after the operation. RESULTS: 1284 patients were identified. At least one complication occurred in 145 patients (11.29%). Only one patient died during the hospital stay. Preoperative cardiovascular comorbidities (OR: 2.99, 95% CI: 1.412-3.744, p = 0.01), major lung resections (OR: 2.727, 95% CI: 1.678-4.431, p < 0.01), repeated pulmonary metastasectomy (OR: 1.759, 95% CI: 1.040-2.976, p = 0.03) and open thoracotomy (OR: 0.621, 95% CI: 0.415-0.930, p = 0.02) were identified as independent factors for postoperative complications. Based on the above independent factors for postoperative morbidity, the Essen score was developed (overall correct classification: 94.6%, ROC-Analysis: 0.828, 95% CI: 0.795-0.903). CONCLUSION: PM is a safe surgical procedure with acceptable morbidity and low mortality. The aim of the Essen score is to identify patients that are associated with risk for postoperative complications after PM.

Krebs von den Lungen 6 (KL-6) is a novel diagnostic and prognostic biomarker in pleural mesothelioma.

OBJECTIVES: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM. MATERIALS AND METHODS: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro. RESULTS: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort. CONCLUSION: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM.

Elucidation of the Bovine Intramammary Bacteriome and Resistome from healthy cows of Swiss dairy farms in the Canton Tessin.

Healthy, untreated cows of nine dairy herds from the Swiss Canton Tessin were analyzed three times within one year to identify the most abundant species of the intramammary bacteriome. Aseptically collected milk samples were cultured and bacteria identified using MALDI-TOF. Of 256 cows analyzed, 96% were bacteriologically positive and 80% of the 1,024 quarters were positive for at least one bacterial species. 84.5% of the quarters were healthy with somatic cell counts (SCC) < 200,000 cells/mL, whereas 15.5% of the quarters showed a subclinical mastitis (SCC ≥ 200,000 cells/mL). We could assign 1,288 isolates to 104 different bacterial species including 23 predominant species. Non-aureus staphylococci and mammaliicocci (NASM) were most prevalent (14 different species; 73.5% quarters). Staphylococcus xylosus and Mammaliicoccus sciuri accounted for 74.7% of all NASM isolates. To describe the intramammary resistome, 350 isolates of the predominant species were selected and subjected to short-read whole genome sequencing (WGS) and phenotypic antibiotic resistance profiling. While complete genomes of eight type strains were available, the remaining 15 were de novo assembled with long reads as a resource for the community. The 23 complete genomes served for reference-based assembly of the Illumina WGS data. Both chromosomes and mobile genetic elements were examined for antibiotic resistance genes (ARGs) using in-house and online software tools. ARGs were then correlated with phenotypic antibiotic resistance data from minimum inhibitory concentration (MIC). Phenotypic and genomic antimicrobial resistance was isolate-specific. Resistance to clindamycin and oxacillin was most frequently observed (65 and 30%) in Staphylococcus xylosus but could not be linked to chromosomal or plasmid-borne ARGs. However, in several cases, the observed antimicrobial resistance could be explained by the presence of mobile genetic elements like tetK carried on small plasmids. This represents a possible mechanism of transfer between non-pathogenic bacteria and pathogens of the mammary gland within and between herds. The-to our knowledge-most extensive bacteriome reported and the first attempt to link it with the resistome promise to profoundly affect veterinary bacteriology in the future and are highly relevant in a One Health context, in particular for mastitis, the treatment of which still heavily relies on antibiotics.