Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers.

BACKGROUND: Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. METHODS: We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. RESULTS: In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA, AKT1, BRAF, and FGFR4. CONCLUSION: The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

Fasciolosis due to Fasciola hepatica in ruminants in abattoirs and its economic impact in two regions in Algeria.

and February 2009. The aim of the study was to determine the prevalence of infected livers with fascioliasis and to evaluate the economic loss due to the condemnation of livers infected with fascioliasis. A total of 3,457 cattle, 6,161 sheep and 5,764 goats were slaughtered and examined in El Tarf abattoir, north Algeria (humid climate), and 2,151 cattle, 5,724 sheep, 351 goats and 582 camels in Ouargla abattoir, south Algeria (saharan climate). In El Tarf region, the prevalence of fascioliasis infection was 26.7±2.5%, 6.5±0.4% and 2.5±0.2% in cattle, sheep and goats, respectively (P< 0.001). In Ouargla region, fascioliasis is reported for the first time in cattle (1.7±0.7%). Sheep, goats and camels were not infected. The overall economic loss due to hepatic condemnations as a result of fascioliasis was estimated at 60,000 euros in El Tarf region and 4,000 euros in Ouargla region. According to this study, it can be concluded that fascioliasis is endemic in the northern Algeria in ruminants and, the disease should be considered seriously as a great threat to ruminant health and profitability.

Serological and molecular evidence of Q fever among small ruminant flocks in Algeria.

Q fever, a commonly reported zoonosis worldwide, is caused by infection with Coxiella burnetii, an obligate intracellular bacterium. The infection is often asymptomatic in ruminants, but it can lead to reproductive disorders with bacterial shedding into the environment. Between 2011 and 2013, a study was undertaken in small ruminant flocks in different regions of Algeria. A total of 35 flocks were visited and 227 sera and 267 genital swabs were collected from females after abortions or the lambing period to investigate Q fever infection. Indirect ELISA was used to detect specific antibodies against C. burnetii and real-time PCR for detecting bacterial DNA. Our survey indicated that 58% (95% CI=40-76%) of flocks had at least one positive animal (17 seropositive flocks) and individual seroprevalence was estimated at 14.1% (95% CI=11.8-16.4%) (32 seropositive animals). Bacterial excretion was observed in 21 flocks (60%), and 57 females showed evidence of C. burnetii shedding (21.3%). These results suggest that C. burnetii distribution is high at the flock level and that seropositive and infected (shedder) animals can be found all over the country. Further studies are needed in other regions and on different animal species to better understand the distribution and incidence of Q fever, as well as human exposure, and to develop an adequate prophylaxis program.

Sarcoidosis-related hypercalcemia in 3 chronic hemodialysis patients.

Hypercalcemia is a frequent complication in chronic hemodialysis (CHD) patients. A rare cause of this condition is sarcoidosis, and has only been reported 6 times in CHD. Herein, we report on 3 cases of sarcoidosis-related hypercalcemia in CHD patients: an overt case, a probable case, and a recurrence of pre-dialysis sarcoidosis. Hypercalcemia is a frequent complication in chronic hemodialysis patients: it is often related to uncontrollable secondary hyperparathyroidism or to the inappropriate use of calcium phosphate binders, 1alpha-hydroxylated vitamin D metabolites, high dialysate calcium concentrations, or to aluminium-related bone disease [Uach and Bover 1996]. However, other rare causes should also be considered, such as multiple myeloma, non-Hodgkin lymphoma [Uach and Bover 1996], vitamin A intoxication [Fishbane et al. 1995], or granulomatous diseases such as sarcoidosis. The latter has only been described in a total of 6 hemodialysis patient reports [Barbour et al. 1981, Barnard et al. 2002, Herrero et al. 1998, Kalantar-Zadeh et al. 1994, Kuwae et al. 2003, Naito et al. 1999]. In the present paper, we report on 3 cases of sarcoidosis-related hypercalcemia in chronic hemodialysis patients with 3 different patterns, i.e. overt sarcoidosis, probable sarcoidosis, and recurrence of pre-dialysis sarcoidosis.