The European Medicines Agency review of sacituzumab govitecan for the treatment of triple-negative breast cancer.

Sacituzumab govitecan (SG) is an antineoplastic agent which combines a humanized monoclonal antibody binding to trophoblast cell surface antigen-2 (Trop-2)-expressing cancer cells, linked with cytotoxic moiety SN-38 (govitecan) with topoisomerase I inhibitor action. On 22 November 2021, a marketing authorization valid through the European Union (EU) was issued under the European Medicines Agency (EMA)'s accelerated assessment program for SG as monotherapy for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, including at least one of them for advanced disease. The assessment was based on results from an open-label, randomized, phase III trial to evaluate the safety, tolerability, pharmacokinetics and efficacy of SG versus treatment of physician's choice (TPC) in patients with mTNBC who received at least two prior treatments including at least one of them for advanced disease. The efficacy results in the overall population, based on mature data, showed a statistically significant improvement of SG over TPC in progression-free survival (PFS) and overall survival (OS). The median PFS was 4.8 months versus 1.7 months [hazard ratio (HR) = 0.43, n = 529; 95% CI 0.35-0.54; P < 0.0001] and the median OS was 11.8 months versus 6.9 months (HR = 0.51, n = 529; 95% CI 0.41-0.62; P < 0.0001). The most common (>30%) side effects of SG were diarrhea, neutropenia, nausea, fatigue, alopecia, anemia, constipation and vomiting. The aim of this manuscript is to summarize the scientific review of the application leading to regulatory approval in the EU.

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer.

On 21 January 2021, the European Commission amended the marketing authorisation granted for pembrolizumab to include the first-line treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) in adults. The recommended dose of pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion. Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints. Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving pembrolizumab were diarrhoea, fatigue, pruritus, nausea, increased aspartate aminotransferase, rash, arthralgia, and hypothyroidism. Having reviewed the data submitted, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit-risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.

The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome.

The Rab6 GTPase regulates intracellular transport at the level of the Golgi apparatus, probably in a retrograde direction. Here, we report the identification and characterization of a novel human Rab6-interacting protein named human GAPCenA (for 'GAP and centrosome-associated'). Primary sequence analysis indicates that GAPCenA displays similarities, within a central 200 amino acids domain, to both the yeast Rab GTPase activating proteins (GAPs) and to the spindle checkpoint proteins Saccharomyces cerevisiae Bub2p and Schizosaccharomyces pombe Cdc16p. We demonstrate that GAPCenA is indeed a GAP, specifically active in vitro on Rab6 and, to a lesser extent, on Rab4 and Rab2 proteins. Immunofluorescence and cell fractionation experiments showed that GAPCenA is mainly cytosolic but that a minor pool is associated with the centrosome. Moreover, GAPCenA was found to form complexes with cytosolic gamma-tubulin and to play a role in microtubule nucleation. Therefore, GAPCenA may be involved in the coordination of microtubule and Golgi dynamics during the cell cycle.

[A combination of conventional single contrast arthrography with arthro-CT of the shoulder--an evaluation of 78 cases]. / Kombination von konventioneller Einfachkontrastarthrographie mit Arthro-CT der Schulter--Auswertung von 78 Untersuchungen.

For the diagnosis of traumatic shoulder lesions, 78 patients have been examined by conventional single contrast arthrography with subsequent CT. For 26 patients, it was possible to compare the radiological diagnosis with the arthroscopic or surgical findings. The combination of both diagnostic methods provided a high sensitivity (94%) and specificity (100%) for lesions of the ventral or dorsal limbus. Ruptures of the rotator cuff showed a sensitivity of 60% and a specificity of 89%. An unsatisfying sensitivity (60%) with high specificity (95.6%) was observed in the diagnosis of the ventral capsula. A retrospective screening of the roentgenography showed a good detectable leak of contrast medium, which was misinterpreted as being an artefact. All in all, the combination of conventional arthrography in mono-contrast and CT in daily routine should be recommended the diagnosis of traumatic shoulder lesions since it is easy to use, is of low inconvenience for the patient, and provides a high level of information.

Influence of tumor stenosis on the accuracy of endosonography in preoperative T staging of esophageal cancer.

The T stage is an important criterion for determining prognosis in esophageal carcinoma. Endosonography, although established as a highly accurate method in preoperative determination of the T stage, may be less reliable in non-traversable tumor stenoses. In a comparative prospective study, 41 patients with carcinoma of the esophagus were investigated to determine the role of tumor stenosis on the accuracy of endosonography in preoperative T staging. The results were correlated with the histology of the resected specimen. The overall accuracy in T staging with endosonography was 76%, compared with 49% in computed tomography. T staging results of endosonography were good in easily and non-traversable stenoses (92%, 87% respectively), but lower accuracy was obtained in stenoses which could be traversed only with difficulty (46%). Computed tomography was inferior to endosonography in all three groups of patients. The high accuracy of endosonography in non-traversable stenoses might be due to the fact that all tumors were in an advanced stage (T3 or T4). When passage of the echoendoscope proves difficult, the low focal distance between the ultrasonic transducer and tumor may hamper clear visualisation of the wall layers and tumor penetration depth. These limitations of endosonography should stimulate further efforts in improving ultrasonic resolution in these cases.

The human endothelin-1 gene (EDN1) encoding a peptide with potent vasoactive properties maps distal to HLA on chromosome arm 6p in close linkage to D6S89.

We determined the precise genetic location of the human endothelin-1 gene (EDN1), which encodes a peptide with extremely potent vasoactive properties and is apparently involved in a spectrum of diseases ranging from hypertension to asthma. Analyzing the segregation of a four-allele EDN1 polymorphism in 40 CEPH families including 480 individuals, we detected significant linkage of EDN1 to DNA markers spanning the telomeric half of chromosome arm 6p. EDN1 was closest to the highly polymorphic nucleotide-repeat marker D6S89 at a theta = 0.06 with the highest pairwise LOD score Zmax = 31.2. Subsequent multipoint analysis placed EDN1 at 8 cM distal to D6S89; EDN1 was flanked at its telomeric site at a 13-cM distance by the gene encoding the A subunit of blood clotting factor XIII (F13A1). Furthermore, EDN1 was located at approximately 34-36 cM distal to the HLA region defined by HLA-A, -B, and -DRB1, and 31 cM proximal to the most telomeric marker D6S7. This location of EDN1 on the primary genetic map is strongly supported with odds of 2.7 x 10(12):1 against the next best alternative.

Effect of periodontal trauma upon intrabony pockets.

Conflicting results have been reported regarding the effect of periodontal trauma upon progression of periodontitis. In these studies, different initial pocket morphologies were present. This study investigated the effect of trauma superimposed upon existing intrabony pockets. Localized intrabony pockets were produced adjacent to the mesial and distal surfaces of the mandibular third bicuspids in 10 squirrel monkeys. Two animals were killed after 10 weeks of periodontitis. In four (experimental) of the remaining eight animals, mesio-distal jiggling of the third bicuspid was begun 10 weeks after induction of periodontitis, and continued for another 10 weeks. The other four animals (control) were killed 20 weeks after initiation of periodontitis. Step-serial histologic sections were selected from experimental and control specimens and analyzed for loss of connective tissue attachment, loss of crestal alveolar bone and percentage of bone in the coronal interproximal periodontium. When corresponding dimensions from experimental and control surfaces were compared statistically, there were no differences in loss of connective tissue attachment but a greater loss of bone had occurred in specimens with the combination of periodontitis and trauma. In addition, there was a marked difference in osseous morphology between the experimental and control specimens. It was concluded that trauma superimposed upon existing intrabony pockets increased loss of alveolar bone and altered osseous morphology, but did not affect the loss of connective tissue attachment.

Osseous repair in the presence of active tooth hypermobility.

The present investigation was undertaken to evaluate the periodontal response after resolution of inflammation in a situation of established marginal periodontitis, but in the presence of active, continued tooth hypermobility. Periodontitis was induced unilaterally around mandibular second and third bicuspids in 4 squirrel monkeys by tying plaque retentive silk ligatures at the gingival margins. Jiggling trauma to the periodontium between these bicuspids was begun 5 weeks later and continued for the remaining 20 weeks. Ligatures were removed 15 weeks after placement, whereupon regular oral hygiene was begun and continued. Periodontitis and trauma were produced around the corresponding contralateral teeth (control) so that the interproximal area represented the situation immediately prior to ligature removal. Infiltrated connective tissue, loss of connective tissue attachment and alveolar bone, and percentage of bone were determined histometrically for each coronal interproximal periodontium. In control specimens, 58% of the supracrestal tissue was infiltrated with inflammatory cells compared to 19% in experimental specimens. There were no differences in levels of connective tissue attachment or crestal alveolar bone. However, bone repair occurred in the experimental specimens which increased bone volume from 11 to 18% (P less than 0.05). It was concluded that osseous repair occurred in the presence of active, continued tooth hypermobility after resolution of inflammation.

Association of human leucocyte low responsiveness to inducers of interferon alpha with HLA-DR 2.

The influence of antigens of the major histocompatibility complex (MHC) on the production of interferon (IFN) alpha or IFN gamma by human peripheral blood leucocytes (PBL) in vitro has been studied. Synthesis of IFN gamma by PBL stimulated with purified phytohaemagglutinin (PHA-P) or protein A of Staphylococcus aureus (SpA) appeared not to be controlled by MHC antigens. The production of IFN alpha, however, was influenced by the HLA type of the donor. Low responsiveness of PBL to inducers of IFN alpha (influenza virus, Molt 4 cells) was associated with HLA-DR 2. Implications of these observations for studies of IFN production and natural killer (NK) cell activity are discussed.

Genetic influence on natural cytotoxicity and interferon production in multiple sclerosis studies in monozygotic discordant twins.

A dysfunction in natural killer (NK) cell activity has been assumed to play a substantial role in the pathogenesis of multiple sclerosis (MS). To investigate whether such a defect is genetically determined and thus in combination with a certain HLA status may represent an additional risk factor for contracting MS, spontaneous and interferon (IFN) induced NK cells activity against the K562 target cell were analyzed in nine pairs of monozygotic twins discordant for MS. In addition, IFN production was tested in nonadherent lymphocytes stimulated with PHA, influenza virus or leukemia cells. When compared to healthy controls, NK function appeared to be normal in healthy twins, whereas some MS patient displayed decreased activity. No difference in IFN induced NK cell activity and IFN production could be detected between normal controls, healthy twins, and MS patients. These data argue against a genetically determined dysfunction within the NK-IFN system in patients with MS.

Multiple sclerosis: immunogenetic analyses of sib-pair double case families. II. Studies on the association of multiple sclerosis with C2, C4, BF, C3, C6, and GLO polymorphisms.

The complement component polymorphisms of C2, C4, BF, C3, C6, and the enzyme polymorphism GLO were studied in 13 sib-pair double case families with multiple sclerosis. A significant association was seen between MS patients and the C4 haplotype A4,B2 as compared with their healthy siblings. This finding seems to parallel reports on C2 hypocomplementemia in MS patients since C4 A4,B2 in normal individuals was also seen to be in linkage disequilibrium with the C2 deficiency allele (C2QO) by other investigators.

Interproximal and buccal cell populations apical to the sulcus before and during experimental periodontitis in squirrel monkeys.

The purpose of this investigation was to study inflammatory cell populations apical to the buccal and interproximal gingival sulcus during destructive experimental marginal periodontitis in squirrel monkeys. Specimens were obtained of the clinically healthy periodontium, and (after 2 and 10 weeks) of experimental periodontitis induced by the placement of plaque-retentive silk ligatures at the gingival margin. Cell populations were characterized and quantitated in a standard area of connective tissue immediately subjacent to the most apical cells of the junctional epithelium in buccal and interproximal locations. Comparisons of periodontitis cell populations showed there were no differences between the regions in relation to either total numbers of cells, or in the percentages of inflammatory cell types. The inflammatory cells consisted primarily of granulocytes and macrophages, with only small percentages of lymphoid and plasma cells. Mechanisms and consequences of these cell types relative to periodontal tissue destruction are discussed.