Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer

[BACKGROUND] Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody–drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.[METHODS] We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.[RESULTS] A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).[CONCLUSIONS] Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.)Peer reviewe

High grade, advanced, serous ovarian cancer with low serum CA125 levels

This study compares characteristics of advanced stage, high grade serous ovarian cancer, presenting with high or low serum CA125 level. This was a retrospective cohort of 118 patients with high grade serous ovarian, fallopian tube or primary peritoneal cancer, stages IIIC–IV diagnosed from January 1 1997 through January 9 2017. Patient demographics, tumour characteristics, surgical findings, chemotherapy protocols and clinical outcomes were collected. Three groups were evaluated: group A: 21 patients with CA125 serum level ≤152 U/ml, group B: 97 patients with CA125 serum level >152 U/ml, group C: 43 patients from group B with CA125 serum level >500 U/ml and <1000 U/ml. No significant difference was found between groups regarding age, stage at diagnosis, extent of residual disease or disease volume. More group A patients had surgery as primary treatment compared to groups B and C (p=.003, p=.022, respectively). CA125 level at recurrence was lower in group A as compared to the other groups (162.2 vs. 851.7 and 603.4, p=.003, p=.006). Overall survival and progression-free survival did not differ based on CA125 levels. We conclude that patients with advanced stage, high grade, serous ovarian cancer with low CA125 serum levels had the same clinical outcome as patients with higher levels.Impact Statement What is already known on this subject? It is known that CA125 level is a prognostic and predictive factor for epithelial ovarian cancer (EOC) outcome. It is elevated in 80% of the patients and within normal range in only 10% of women with advanced stage EOC. Various studies had addressed the patients with advanced stage serous EOC who had high serum CA125 levels at time of diagnosis. But, no study has addressed the 10% of patients with advanced stage who had low serum CA125 levels at time of diagnosis. What the results of this study add? To the best of our knowledge, this is the first study addressing patients with advanced stage EOC who had low serum CA125 levels at time of diagnosis. According to the results of this study, patients with advanced stage, high grade serous EOC presenting with low serum CA125 levels have similar clinical outcomes as do patients with high serum CA125 levels. What the implications are of these findings for clinical practice and/or further research? Further translational research is encouraged for this group of tumours to identify specific molecular markers that might lead to better understanding and treatment for the disease

Influence of crystallization kinetics and flow behavior on structural inhomogeneities in 3D printed parts made from semi-crystalline polymers

We report the results of a study focusing on the influence of crystallization kinetics and the flow behavior on structural inhomogeneities in 3D printed parts made from polyamide 12 (PA12) and poly (lactic acid) (PLA) by Dynamic Mechanical Analysis (DMA), Differential Scanning Calorimetry (DSC), Fast Scanning Calorimetry (FSC) and Wide-Angle X-ray Diffraction (WAXD). Temperature-dependent WAXD measurements on the neat PLA filament reveal that PLA forms a single orthorhombic α phase during slow cooling and subsequent 2nd heating. The PA12 filament shows a well pronounced polymorphism with a reversible solid-solid phase transition between the (pseudo)hexagonal γ phase near room temperature and the monoclinic α′ phase above the Brill transition temperature TB = 140 °C. The influence of the print bed temperature Tb on structure formation, polymorphic state, and the degree of crystallinity χc of the 3D printed parts is investigated by height and depth dependent WAXD scans and compared with that of 3D printed single layers, used as a reference. It is found that the heat transferred from successive layers has a strong influence on the polymorphic state of PA12 since a superimposed mixture of γ and α phase is present in the 3D printed parts. In case of PLA a single α phase is formed. The print bed temperature has, in comparison to PA12, a major influence on the degree of crystallinity χc and thus the homogeneity of the 3D printed parts, especially close to the print bed. By comparing the obtained results from WAXD, DMA, DSC and FSC measurements with relevant printing times, guidelines for 3D printed parts with a homogeneous structure are derived

Численное моделирование наплавленного осаждения для производства деталей с высокой геометрической точностью и механическим качеством

With increasing usage of additive manufacturing methods for mechanical parts the need for precise and reliable simulations of the manufacturing process increases as well. In this paper various com- putations suited for simulating the fused deposition modeling process are considered in two dimensions. In fused deposition modeling a molten polymer is laid down on a prescribed path before the cooling of the melt begins. The occuring flows are treated as multiphase flows. To model the deposition of the filament, methods of computational fluid dynamics are used in ANSYS-Fluent, namely the volume of fluid method (VOF). Different numerical experiments are simulatedС увеличением использования аддитивных методов производства механических деталей также возрастает потребность в точном и надежном моделировании производственного процесса. В этой статье различные расчеты, пригодные для моделирования процесса наплавленного осаждения, рассматриваются в двух измерениях. При моделировании наплавленного осаждения расплавленный полимер укладывается по заданной траектории до начала охлаждения расплава. Возникающие потоки рассматриваются как многофазные. Для моделирования отложения нити в Ansys Fluent используются методы вычислительной гидродинамики, а именно метод объема жидкости (VOF). Проведено моделирование различных численных эксперименто

Morphology of Porous Hosts Directs Preferred Polymorph Formation and Influences Kinetics of Solid/Solid Transitions of Confined Pharmaceuticals

The pore morphology of a porous host may determine which polymorph a crystallizable guest preferentially forms and may influence the kinetics of solid/solid transitions. Slow cooling of the drug acetaminophen (ACE) inside the straight cylindrical pores of anodic aluminum oxide (AAO, tortuosity = 1) in contact with a bulk ACE surface film preferentially yields uniformly oriented form II and/or form III crystals. The occurring orientations of form II and form III crystals are characterized by high structural registry along the AAO pores. The uniformly oriented form III crystals inside the AAO pores were readily converted into likewise uniformly oriented form II crystals by a solid/solid transition. Thus, we obtained uniformly oriented form II crystals in AAO at high yields. We suggest that sporadic heterogeneous nucleation at bulk crystals formed in the bulk surface film on top of the AAO coupled with kinetic selection of crystal orientations results in fast growth of properly oriented crystals along the 100 μm deep AAO pores. This mechanism is suppressed in controlled porous glass (CPG) having isotropic spongelike pores (tortuosity > 1.5) with free growth paths on the order of 100 nm, where form I formed instead. Moreover, the transition from form III to form II is suppressed in CPG. Possible reasons may include impingement of the propagation front of the solid/solid transition on the CPG pore walls after short propagation paths and inevitable formation of form II grains with different orientations separated by energetically disadvantageous grain boundaries. The results reported here are relevant to mesoscopic crystal engineering aimed at controlled drug release from nanoscale delivery systems. Polymorphs not accessible otherwise in nanoscale containers may be produced at high yields. The principles reported here may be transferred to areas such as nanowire-based organic electronics