•Intimal sarcomas affect great vessels and the heart, commonly the pulmonary artery.•MDM2 and PDGFRA amplifications confirm the histopathological diagnosis.•Early aggressive surgery with complete ...resection and clear margins is standard.•Doxorubicin-based chemotherapy remains the most effective strategy in advanced STS.
Only a few hundred cases of intimal sarcomas of pulmonary artery (ISPA) were reported on the literature. Diagnosis of this rare entity is a challenging dilemma with the need for a high expertise in the radiological and pathological identification of ISPA. Treatment strategies rely initially on an early aggressive surgery aiming for complete surgical resection with clear margins while no clear recommendations guiding the choice for additional drug therapy or radiotherapy exist. In this article, we perform an extensive review of the literature on ISPA with details on the clinical presentation, diagnosis and management strategies. An additional goal of this paper is to make practicing oncologists aware of this rare entity with clear idea on the initial management.
The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes "POLE mutated," "microsatellite ...unstable," "TP53 mutated," and "no specific molecular profile." We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous "no specific molecular profile" and "TP53 mutated" subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (δ-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the "no specific molecular profile" subset, δ-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among "TP53 mutated," a DNA-pk+/FANCD2- profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 "POLE mutated/Microsatellite unstable" > group2 "no specific molecular profile with no DNA damage" > group3 "TP53 mutated/Non Homologous End-Joining negative" > group4 "no specific molecular profile with high DNA damage" > group5 "TP53 mutated/Non Homologous End-Joining positive"; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.
Aims
The aim of this multicentre study was to harmonize programmed death‐ligand 1 (PD‐L1) immunohistochemistry (IHC) and melanoma scoring. To provide a reference for PD‐L1 expression independently of ...the IHC protocol, PD‐L1 mRNA expression was compared with IHC.
Methods and results
Standardized PD‐L1 assays (22C3, 28–8, SP142, SP263) and laboratory‐developed tests (QR1, 22C3) were evaluated on three IHC platforms with a training set (seven cases). mRNA expression was determined by RNAscope (CD274/PD‐L1 probe) and analysed with image analysis. PD‐L1 IHC findings were scored by seven blinded pathologists using the tumour proportion score (TPS), the combined positive score (CPS), and the MELscore. This method was validated by three blinded pathologists on 40 metastatic melanomas. Concordances among various antibody/platforms were high across antibodies intraclass correlation coefficient (ICC) >0.80 for the CPS, except for SP142. Two levels of immunostaining intensity were observed: high (QR1 and SP263) and low (28–8, 22C3, and SP142). Reproducibilities across pathologists were higher for QR1 and SP263 (ICC ≥0.87 and ICC ≥0.85 for the TPS and the CPS, respectively). QR1, SP263 and 28–8 showed the highest concordance with mRNA expression. We developed a standardized method for PD‐L1 immunodetection and scoring, tested on 40 metastatic melanomas. Concordances among antibodies were excellent for all criteria, and concordances among pathologists were better for the MELscore than for other scores.
Conclusion
Harmonization of PD‐L1 staining and scoring in melanomas with good concordance is achievable with the PD‐L1 IHC protocols applied to other cancers; this reproducible approach can simplify daily practice.
Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are ...poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0-300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1-/RAD51+, hazard ratio (HR) 3.13,
= 0.009 and HR 2.78,
= 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89,
= 0.05 and HR 2.38,
= 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79,
= 0.038 and HR 2.04,
= 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi).
The use of immunohistochemistry for the determination of pulmonary carcinoma biomarkers is a well-established and powerful technique. Immunohistochemisty is readily available in pathology ...laboratories, is relatively easy to perform and assess, can provide clinically meaningful results very quickly, and is relatively inexpensive. Pulmonary predictive biomarkers provide results essential for timely and accurate therapeutic decision making; for patients with metastatic non-small cell lung cancer, predictive immunohistochemistry includes ALK and programmed death ligand-1 (PD-L1) (ROS1, EGFR in Europe) testing. Handling along proper methodologic lines is needed to ensure patients receive the most accurate and representative test outcomes.
Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms ...of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I-deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I-proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint-inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer.
Von Hippel-Lindau
(
) is a rare hereditary syndrome due to mutations of the
tumor suppressor gene. Patients harboring the R167Q mutation of the
gene have a high risk of developing ccRCCs. We asked ...whether the R167Q mutation with critical aspects of pseudo-hypoxia interferes with tumor plasticity. For this purpose, we used wild-type
(WT-VHL) and VHL-R167Q reconstituted cells. We showed that WT-VHL and VHL-R167Q expression had a similar effect on cell morphology and colony formation. However, cells transfected with VHL-R167Q display an intermediate, HIF2-dependent, epithelial-mesenchymal phenotype. Using RNA sequencing, we showed that this mutation upregulates the expression of genes involved in the hypoxia pathway, indicating that such mutation is conferring an enhanced pseudo-hypoxic state. Importantly, this hypoxic state correlates with the induction of genes belonging to epithelial-mesenchymal transition (EMT) and stemness pathways, as revealed by GSEA TCGA analysis. Moreover, among these deregulated genes, we identified nine genes specifically associated with a poor patient survival in the TCGA KIRC dataset. Together, these observations support the hypothesis that a discrete VHL point mutation interferes with tumor plasticity and may impact cell behavior by exacerbating phenotypic switching. A better understanding of the role of this mutation might guide the search for more effective treatments to combat ccRCCs.
Background
Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of ...anthracycline‐based regimens, gemcitabine‐based regimens, and pazopanib in patients with InS.
Methods
Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2‐positive InS who were treated with anthracycline‐based regimens, gemcitabine‐based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence‐free survival (RFS), progression‐free survival (PFS) and overall survival were computed by Kaplan‐Meier method.
Results
Seventy‐two patients were included (66 anthracycline‐based regimens; 26 gemcitabine‐based regimens; 12 pazopanib). In the anthracycline‐based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real‐world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline‐related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively.
Conclusion
This retrospective series shows the activity of anthracycline‐based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.
Anthracycline‐based regimens are a potentially effective medical option in intimal sarcoma. Of note, anthracyclines were used to treat primary cardiac tumors, with no significant cardiac toxicity reported. The value of gemcitabine and pazopanib is limited, but these agents could nonetheless be used as further‐line therapy or in patients unfit for anthracyclines.
Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single‐agent in a larger series of patients with ...advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single‐agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI‐CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1–6.5), and median OS was 9.9 months (95%CI: 6.6–13.4). Single‐agent gemcitabine has clinically meaningful activity in advanced, heavily pre‐treated angiosarcoma.
We aimed to evaluate the activity of single‐agent gemcitabine in the largest series of 42 patients with advanced angiosarcoma. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%), median PFS was 5.4 months, and median OS was 9.9 months. Single‐agent gemcitabine has clinically meaningful activity in advanced, heavily pre‐treated angiosarcoma.
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