Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study.

PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC

Crustal strain in central Greece from repeated GPS measurements in the interval 1989-1997

A 66-station GPS network spanning central Greece, first observed in 1989, has been occupied fully on three occasions: June 1989, October 1991 and May 1993. Subsets of this network bounding the Gulf of Korinthos have also been occupied in June 1995, October 1995, May 1996 and September/October 1997. The first three occupations were processed using fiducial GPS methodology, whereas later surveys were processed using CODE precise orbits. Combination of data from different surveys to yield smooth site velocities requires global network translations at each epoch to compensate for errors in the realization of the reference frame. This method provides a posteriori estimates of the relative coordinate errors and reference frame noise. Only one earthquake, the 1995 June 15 Egion event, has caused significant local coseismic displacement, and its effects on the interseismic velocity field are removed using an elastic dislocation model. We constrain the orientation of the 100 yr triangulation-GPS velocity estimates of Davis et al. (1997) using 14 sites common to the two networks. The goodness of fit of this transformation indicates that the short-term and 100 yr geodetic estimates of deformation are highly compatible. We infer that short-term geoetic studies are capable of determining longer-term deformation rates provided that transient, local effects can be modelled. From the combined velocity field, we estimate principal strains and rigid-body rotation rates at points on a regular grid using data form neighbouring sites. Strain rates are high within the Gulf of Korinthos and much lower elsewhere. The extension rate with historial and recent rates of seismic release of strain reveals significant medium-term seismic hazard in the western Gulf of Korinthos, and may also indicate long-term aseismic strain

Inventaire des moustiques (Diptera : Culicidae) des îles du sud-ouest de l’océan Indien, Madagascar excepté — Une revue critique

International audienceInventory of the mosquitoes (Diptera: Culicidae) of the islands of southwestern Indian Ocean, Madagascar excluded-A Critical Review. The biodiversity of mosquitoes in the islands of southwestern Indian Ocean is the concern of numerous publications. Here, we propose a synthetic inventory and the analysis of the mosquito diversity, based on the available literature. A comprehensive annotated checklist of mosquito species has been recently published on Madagascar; this is the reason why this land is excluded from our work. Studied area encompasses 28 tropical islands in the southern hemisphere: 4 islands in the Comoros archipelago, 5 Scattered Islands (îles Éparses), 5 in Mascarene, 11 in the Seychelles and 3 in the Chagos archipelago. In total, the mosquito list presents 73 valid species, of which 10 are Anophelinae and 63 Culicinae. The number of species that are distributed in these islands only is 19, i.e. 26%, which is a remarkable level for endemism. The richness in mosquito species in these islands is analysed through several aspects including geography, local speciation and natural or human dissemination. This updated inventory increases by 33% the number of known species by regard to the previous inventory published by Julvez & Mouchet in 1994. The historical responsibility of humans in the introduction of new mosquito species in these islands is strongly documented. For instance, the species with the highest distribution among islands are Aedes aegypti, Ae. albopictus and Culex quinquefasciatus. The islands belong to the afrotropical biogeographic area and, logically, the majority (63%) of mosquito species present phylogenetic affinities with continental Africa and/or Madagascar; interestingly, the number of species present in these islands and in Madagascar but absent in continental Africa is higher than the number of species present in these islands and in continental Africa but absent in Madagascar (respectively 12 and 2 species). Thanks to valuable increase in the sampling effort, our knowledge of the culicidian fauna is increasing in these islands that constitute indisputably hotspots of biodiversity.Résumé. La biodiversité des moustiques dans les îles du sud-ouest de l'océan Indien a fait l'objet de nombreuses publications. Nous proposons ici un inventaire des espèces et une analyse des peuplements, en se basant sur les données disponibles dans la littérature. Madagascar est exclu de cette étude car un inventaire des espèces de moustiques vient d'y être réalisé. La présente étude retient 28 îles tropicales de l'hémisphère sud : 4 îles dans l'archipel des Comores, 5 îles Éparses, 5 aux Mascareignes, 11 aux Seychelles et 3 dans l'archipel des Chagos. Au total, 73 espèces valides de moustiques ont été recensées, dont 10 Anophelinae et 63 Culicinae. Le nombre d'espèces exclusivement présentes dans ces îles est de 19, soit un remarquable endémisme concernant 26 % des espèces. La richesse spécifique est analysée sous plusieurs aspects incluant la géographie, la spéciation sur place, la dissémination des populations par des voies naturelles ou humaines. Le présent inventaire accroit de 33 % le nombre d'espèces connues par rapport à l'inventaire précédemment publié par Julvez & Mouchet en 1994

Striatal Dopamine D-2/3 Receptor Availability in Treatment Resistant Depression

Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D-2/3 receptor (D2/3R) binding has not been investigated in TRD subjects. We used [I-123] IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p <0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs