Uso de mioinositol más Bifidobacterium lactis y Lactobacillus rhamnosus para la prevención de diabetes mellitus gestacional en mujeres mexicanas.

AIM: To compare the incidence of gestational diabetes mellitus (GDM) in women with three or more risk factor to developing GDM supplemented with myo-inositol plus probiotics versus women care without supplementation. METHODS: Retrospective cohort study, group 1, women with supplementation (myo-inositol 2g plus Bifidobacterium lactis and Lactobacillus rhamnosus 5x108 UFC, twice per day, from 12-14 to 28 weeks of gestation; group 2, women with prenatal care without supplementation, matched by age and body mass index (BMI). The primary outcome was the incidence of GDM using the International Association of Diabetes and Pregnancy Study Groups criteria. RESULTS: Group 1 n=48, group 2 n=96. There were no significant baseline differences between groups in age, BMI and number of risk factors. The incidence of GDM in group 1 was n=14 (29.2%), and for group 2 n=46 (47.9%); RR: 0.61 (95% CI: 0.37-0.99; p = 0.03). CONCLUSIONS: Supplementation from 12-14 weeks of gestation with myo-inositol plus probiotics decrease the incidence of GDM in Mexican women.

OBJETIVO: Comparar la incidencia de diabetes mellitus gestacional (DMG) en mujeres con tres o más factores de riesgo para desarrollar DMG suplementadas con mioinositol más probióticos versus mujeres sin suplementación.­. MATERIAL Y ­MÉTODOS: Estudio de cohorte retrospectivo, grupo 1, mujeres con suplementación (mioinositol 2 g más Bifidobacterium lactis y Lactobacillus rhamnosus 5x108unidades formadoras de colonias, dos veces al día, de las 12-14 hasta las 28 semanas de gestación); grupo 2, mujeres con control prenatal habitual sin suplementación, pareadas por edad e índice de masa corporal (IMC). El resultado primario fue la incidencia de DMG utilizando los criterios de la Asociación Internacional de Grupos de Estudio de Diabetes y Embarazo. RESULTADOS: Grupo 1, n = 48, y grupo 2 n = 96. No hubo diferencias significativas en características basales como edad, IMC, y numero de factores de riesgo entre los grupos. La incidencia de DMG en el grupo 1 fue n = 14 (29.2%) y en el grupo 2 n = 46 (47.9%); RR: 0.61 (IC 95%: 0.37-0.99; p = 0.03). CONCLUSIONES: La suplementación desde las 12-14 semanas de gestación con mioinositol más probióticos disminuye la incidencia de DMG en mujeres mexicanas.

Phase I Study of Rapid Alternation of Sunitinib and Regorafenib for the Treatment of Tyrosine Kinase Inhibitor Refractory Gastrointestinal Stromal Tumors.

PURPOSE: Polyclonal emergence of KIT secondary mutations is a main mechanism of imatinib progression in gastrointestinal stromal tumor (GIST). Approved KIT inhibitors sunitinib and regorafenib have complementary activity against KIT resistance mutations. Preclinical evidence suggests that rapid alternation of sunitinib and regorafenib broadens the spectrum of imatinib-resistant subclones targeted. PATIENTS AND METHODS: Phase Ib study investigating continuous treatment with cycles of sunitinib (3 days) followed by regorafenib (4 days) in patients with tyrosine kinase inhibitor (TKI)-refractory GIST. A 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Plasma samples were analyzed for pharmacokinetics and circulating tumor DNA (ctDNA) studies using targeted error correction sequencing (TEC-seq) and droplet digital PCR (ddPCR). RESULTS: Of the 14 patients enrolled, 2 experienced dose-limiting toxicities at dose level 2 (asymptomatic grade 3 hypophosphatemia). Sunitinib 37.5 mg/day and regorafenib 120 mg/day was the RP2D. Treatment was well-tolerated and no unexpected toxicities resulted from the combination. Stable disease was the best response in 4 patients, and median progression-free survival was 1.9 months. Combined assessment of ctDNA with TEC-seq and ddPCR detected plasma mutations in 11 of 12 patients (92%). ctDNA studies showed that KIT secondary mutations remain the main mechanism of resistance in TKI-refractory GIST, revealing effective suppression of KIT-mutant subpopulations in patients benefiting from the combination. CONCLUSIONS: Sunitinib and regorafenib combination is feasible and tolerable. Rapid alternation of TKIs with complementary activity might be effective when combining drugs with favorable pharmacokinetics, potentially allowing active doses while minimizing adverse events. Serial monitoring with ctDNA may guide treatment in patients with GIST.

Correction: Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

The additional information of this manuscript originally stated that the authors declare no competing interests. This statement was incorrect, and should instead have stated the following:M.C.H. has the following competing interests to declare: Equity interest at Molecular MD; Consulting at Molecular MD, Blueprint Medicines, Deciphera Pharmaceuticals; Expert Testimony at Novartis; Licensed patent with royalty payments at Novartis. The remaining authors have no competing interests to declare.The authors apologise for any convenience this may have caused.

Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.