Activity of PD-1 blockade with nivolumab among patients with recurrent atypical/anaplastic meningioma: phase II trial results

BackgroundProgrammed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy.MethodsTwenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.ResultsEnrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO.ConclusionNivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.     

Immunohistochemical and clinical evaluation of cathepsin expression in soft tissue sarcomas

Lysosomal proteases are known to enhance the spread of epithelial tumour cells, but little is known of the possible role of proteases in the growth of soft tissue sarcomas (STS). We investigated the expression of cathepsins D, B, S, H, L and procathepsin L in frozen sections of 34 STS from 34 patients by immunohistochemistry (IHC). Cathepsins D, B and H were relatively highly expressed in STS (77–91%). The expression rate of cathepsins S and L and of procathepsin L was lower (40–66%). Cathepsin S and L expression showed a moderate (P = 0.078 andP = 0.019) and procathepsin L a strong (P = 0.00001) correlation with the survival rate of STS patients. Cathepsin S expression is also correlated with the local recurrence rate (P < 0.01). Lysosomal proteases may play a role in STS progression, and cathepsin expression may also have, significance as a prognostic factor in STS.     

Der Nachweis von Heparin in den basophilen Leukocyten

Ohne Zusammenfassung     

Alterations of cancer-related genes in soft tissue sarcomas: hypermethylation of RASSF1A is frequently detected in leiomyosarcoma and associated with poor prognosis in sarcoma

Aberrant methylation is a main mechanism of tumor suppressor gene inactivation in carcinogenesis. In this study, the methylation status of RASSF1A, p16, MLH1, MSH2 and ERalpha was investigated in 84 primary soft tissue sarcomas (STSs), including 22 liposarcomas, 18 malignant fibrous histiocytomas (MFHs), 18 leiomyosarcomas, 6 rhabdomyosarcomas, 6 neurogenic sarcomas and several other sarcoma entities. RASSF1A hypermethylation was detected in 17 of 84 (20%) STSs; however, methylation was more frequent in leiomyosarcomas (39%) compared to MFHs (6%; p < 0.015) and liposarcomas (18%). The p16 CpG island was methylated in 22 out of 82 (27%) cases. In 7 out of 81 (9%) STS samples, the promoter of MLH1 was methylated and in liposarcoma the methylation frequency was higher (14%). For MSH2, no hypermethylation was detected. Methylation of ERalpha was detected in 48 of 63 (76%) STSs, but also in 4 of 8 (50%) normal tissue samples. Furthermore, we analyzed mutational activation of K-ras and BRAF. In 4 out of 84 (5%) of STSs, a substitution at codon 599 of BRAF was found; however, no alteration of K-ras was detected. In an univariate Cox proportional-hazards regression model, we found that the risk of a tumor-related death for STS patients with methylated RASSF1A was significantly increased (RR = 2.9; p = 0.037). In summary, our data indicate that inactivation of RASSF1A is a common event in STS, especially in leiomyosarcoma. Thus, the methylation status of cancer-related genes was distinct in different STS and methylation of RASSF1A promoter can serve as prognostic marker in STSs.     

Cytophotometric studies for evaluating the prognosis in endometrial cancer]

This paper deals with a prospective cytophotometric study of specimens from 48 cases of primary endometrial carcinoma. The tumor material was obtained from the region of tumor invasion immediately after an operation and in 8 cases by fractional curettage after ultrasonographic localisation of the tumor. The specimens were air-dried and Feulgen stained. The cytophotometric examinations were performed with a scanning cytophotometer. A computer-assisted data registration and processing was carried out. The histological diagnosis of the tissue specimen and curettage specimen was established according to standardized criteria. 32 out of the 48 investigated cases of endometrial carcinoma were diploid. Observations conducted over a period of 12 months showed a partially significant correlation (u-test according to Mann and Whitney) between DNA-content and stage of the tumor (FIGO), histological grade of the tumor, relative depth of myometrial invasion as well as the clinical course. A differentiation based on the ploidy and the average relative DNA content (AE) in relation with typing is not possible. It was not possible to state the difference between average nuclear surface (F) and individual morphological variables. The average extinction, as a measure of the chromatin density, was determined for each specimen. A significant increase of the average extinction was established for carcinomas which infiltrated more than 2/3 of the uterine wall. Ploidy, average relative DNA content and average extinction provide an invaluable additional parameter in the assessment of the prognosis, post-operative therapy and aftercare of patients with endometrial carcinoma.     

Human chorionic gonadotropin levels in various compartments in disturbed early pregnancy

The hCG level in the uterine cavity was higher than in peripheral blood in a case of choriocarcinoma and in patients with spontaneous expulsion of the conceptus. In two patients with missed abortion, the hCG concentrations in peripheral blood and in serum from the uterine cavity did not differ. In contrast, the hCG concentrations in PF in these patients were lower than in peripheral blood. The measurement of hCG in these compartments may provide evidence concerning the location of the trophoblast.     

Toxicokinetics of acrylamide in humans after ingestion of a defined dose in a test meal to improve risk assessment for acrylamide carcinogenicity.

High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 +/- 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean +/- SD) 4.4 +/- 1.5%, 50.0 +/- 9.4%, and 5.9 +/- 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 +/- 0.4, 17.4 +/- 3.9, and 25.1 +/- 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 +/- 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment.