Pretreatment resistance mutations and treatment outcomes in adults living with HIV-1: a cohort study in urban Malawi.

BACKGROUND: Pre-treatment drug resistance (PDR) among antiretroviral drug-naïve people living with HIV (PLHIV) represents an important indicator for the risk of treatment failure and the spread of drug resistant HIV variants. We assessed the prevalence of PDR and treatment outcomes among adults living with HIV-1 in Lilongwe, Malawi. METHODS: We selected 200 participants at random from the Lighthouse Tenofovir Cohort Study (LighTen). Serum samples were drawn prior to treatment initiation in 2014 and 2015, frozen, and later analyzed for the presence of HIV-1 drug resistance mutations. Amplicons were sequenced and interpreted by Stanford HIVdb interpretation algorithm 8.4. We assessed treatment outcomes by evaluating clinical outcome and viral suppression at the end of the follow-up period in October 2019. RESULTS: PDR testing was successful in 197 of 200 samples. The overall NNRTI- PDR prevalence was 13.7% (27/197). The prevalence of intermediate or high level NNRTI- PDR was 11.2% (22/197). The most common mutation was K103N (5.6%, 11/197), followed by Y181C (3.6%, 7/197). In one case, we detected an NRTI resistance mutation (M184V), in combination with multiple NNRTI resistance mutations. All HIV-1 isolates analyzed were of subtype C. Of the 27 patients with NNRTI- PDR, 9 were still alive, on ART, and virally suppressed at the end of follow-up. CONCLUSION: The prevalence of NNRTI- PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance. The distribution of drug resistance mutations was similar to that seen in previous studies from the region, and further supports the introduction of integrase inhibitors in first-line treatment in Malawi. Furthermore, our findings underline the need for continued PDR surveillance and pharmacovigilance in Sub-Saharan Africa.

Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target.

Acute myeloid leukemias (AMLs) result from a series of genetic events occurring in a stem or progenitor hematopoietic cell that gives rise to their clonal expansion and an impaired capacity to differentiate. To circumvent the genetic heterogeneity of AML patient cohorts, we have developed a model system, driven by the MLL-AF9 (MA9) oncogene, to generate multiple human leukemias using progenitor cells from a single healthy donor. Through stepwise RNA-sequencing data generated using this model and AML patients, we have identified consistent changes associated with MA9-driven leukemogenesis and demonstrate that no recurrent secondary mutations are required. We identify 39 biomarkers whose high expression level is specific to this genetic subtype of AML and validate that many of these have diagnostic utility. We further examined one biomarker, the receptor tyrosine kinase (RTK) RET, and show through shRNA knockdowns that its expression is essential for in vivo and in vitro growth of MA9-AML. These results highlight the value of novel human models of AML derived from single donors using specific oncogenic fusions to understand their biology and to uncover potential therapeutic targets.

Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC. PATIENTS AND METHODS: Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks, followed by four cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody. RESULTS: Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% [95% CI: 41.1% to 69.5%] according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR. CONCLUSIONS: Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC. CLINICAL TRIAL NUMBER: NCT00933517.

Epigenetic regulation of GATA2 and its impact on normal karyotype acute myeloid leukemia.

The GATA2 gene encodes a zinc-finger transcription factor that acts as a master regulator of normal hematopoiesis. Mutations in GATA2 have been implicated in the development of myelodysplastic syndrome and acute myeloid leukemia (AML). Using RNA sequencing we now report that GATA2 is either mutated with a functional consequence, or expressed at low levels in the majority of normal karyotype AML (NK-AML). We also show that low-GATA2-expressing specimens (GATA2(low)) exhibit allele-specific expression (ASE) (skewing) in more than half of AML patients examined. We demonstrate that the hypermethylation of the silenced allele can be reversed by exposure to demethylating agents, which also restores biallelic expression of GATA2. We show that GATA2(low) AML lack the prototypical R882 mutation in DNMT3A frequently observed in NK-AML patients and that The Cancer Genome Atlas AML specimens with DNMT3A R882 mutations are characterized by CpG hypomethylation of GATA2. Finally, we validate that several known missense single-nucleotide polymorphisms in GATA2 are actually loss-of-function variants, which, when combined with ASE, represent the equivalent of homozygous GATA2 mutations. From a broader perspective, this work suggests for the first time that determinants of ASE likely have a key role in human leukemia.

[Hip fracture in elderly patients: emergency management and indicators]. / Fracture du col du fémur et urgences gériatriques: prise en charge, organisation et indicateurs.

Hip fracture is a common condition associated with a poor outcome with 20-30% one-year mortality in the elderly. Autonomy and quality of life remains key considerations in this population. Emergency management should consider associated diseases and treatments, as well as fall and fracture. Management should target particular conditions such as pain, anemia and transfusion, time to surgery and occurrence of pressure sores, and should consider these as quality criteria. In this way, a new approach must be evaluated and requires an optimal cooperation between emergency physician, orthopaedic surgeon, anaesthetists and geriatrician. Place and interest of new models of care such as orthogeriatrics unit have to be determined.

[Effects of hypomagnesemia]. / Les effets de l'hypomagnésémie.

INTRODUCTION: The clinical consequences of plasmatic magnesium variations are underecognized in clinical practice. The dosage of plasmatic magnesium is underused and not reliable. Moreover, hypomagnesemia is often associated with other metabolic disorders (hypocalcemia, hypokaliemia), which are responsible for several symptoms. CASE REPORT: We report an 85-year-old man who presented with repeated bronchospasm, confusion, and abdominal and muscular pain, attributed to low magnesium serum level. We then review pathophysiology, various etiologies, clinical features, diagnostic challenge and treatment of low magnesium serum level. CONCLUSION: Hypomagnesemia is poorly known and diagnosed. Therapeutic issues have not been clearly defined.

[Transfusion in elderly patients]. / Transfusion chez les patients âgés.

The frequency of anemia is responsible of a frequent use of transfusion in elderly patients. However, transfusion in elderly patients requires several warnings. First, semiology of elderly patients is characterized with atypical clinical signs, and anemia tolerance is often difficult to appreciate. Second, numerous comorbidities make of elderly patients an heterogeneous population, in which guidelines are poorly applicable. Last, elderly patients are particularly sensitive to iatrogenic events, and the haemodynamic overload related to transfusion has to be carefully managed. All these difficulties raise the need of prospective studies on transfusion in elderly patients to validate clinical practice.

[Ovarian cysts. The respective role of clinical examination, echography, biological markers and cytology]. / Kyste de l'ovaire. Places respectives de l'examen clinique de l'échographie, des marqueurs biologiques et de la cytologie.

The authors assess the value of clinical examinations and para-clinical examinations carried out when an ovarian cyst is discovered. They try to find out whether a diagnosis of the aetiology is possible before the operation and particularly whether the cystic forms of cancer can be detected pre-operatively. The study is concerned with a retrospective assessment of 358 patients. The first line of investigation was seen to be ultrasound which is effective in 91% of cases. When the level of CA-125 is above 35 U/ml that suggests that there may be a malignant neoplasm present. The test is sensitive to about 78.6% and specific at 76%. 96 cysts were considered to be benign using clinical and para-clinical examinations and were punctured under ultrasound control or laparoscopically. The cytology could not be interpreted in 15%. Only one borderline tumour of the ovary was found. 25.3% of cysts that had been aspirated recurred and this is a high figure. Given these figures, the authors suggest a diagnostic and therapeutic program for ovarian cysts.

[Epidemiology, diagnostic approach, prognostic factors of ovarian cystadenocarcinoma]. / Epidémiologie, moyens diagnostiques, facteurs pronostiques des cystadénocarcinomes de l'ovaire.

The number of ovarian cancers is increasing and a parallel increase has been observed in the mortality rate of this disease. Epidemiological surveys have elicited contributing factors such as feeding habits, environmental, individual and familial factors. The ovary being a deep-seated organ, the diagnosis is difficult and rests on physical examination and, chiefly, ultrasonography. The prognosis is poor, with an overall survival rate of about 30 p. 100 at five years.

[Cancer and nipple discharge]. / Cancer et écoulement par le mamelon.

The authors, in a retrospective study, have looked at the clinical and paraclinical parameters that suggest that a cancer may be present when there is a nipple discharge. By using logistic regression on these criteria a model has been able to be constructed with four variables (bloody discharge, and associated palpable tumour, a suspicious mammographic appearance and atypical or proliferating cells in cytology). The probability of a cancer being present varies between three per thousand when none of the four variables are present to 99.1% when all four are present. A first outline of the therapy that can be used is suggested.

[Scarred uterus: management]. / L'utérus cicatriciel: conduite à tenir.

Uterine rupture was seen in a total of 1.1 per cent of 10,012 pregnancies involving scarred uteri. Rupture frequency during pregnancy was estimated as 0.4 per cent, although this is doubtless an underestimate due to the occasionally asymptomatic nature of the condition. Maternal mortality was nil. Fetal mortality related to uterine rupture was also nil, but psychomotor backwardness was seen in one case of uterine rupture after completion of 30 weeks of pregnancy. These results and those of the literature show that maternal and fetal risks linked to uterine rupture are significant during pregnancy and very small during confinement. The indications for systematic prophylactic cesarean section are discussed. An increased frequency of uterine tests could decrease the overall rate of cesarean sections without danger to mother or baby.

[Current aspects of the Vogt-Koyanagi-Harada syndrome. Apropos of 9 cases]. / Les aspects actuels du syndrome de Vogt Koyanagi Harada. A propos de 9 cas.

We have studied 9 cases of the Vogt Koyanagi Harada (VKH) syndrome as defined by the criteria of the American Uveitis Society; all these cases presented evidence of past or present exudative retinal detachment (RD). In 2 cases the RD was shallow and limited to the posterior pole, in 3 cases encephalo-meningeal symptoms were absent, in 2 cases skin and hair symptoms were absent. In all, 5 cases in this series presented as an incomplete, dissociated form of the disease. However the clinical cause of the disease in these "formes frustes" was not simpler or quieter than in the complete forms; incomplete response or drug dependence were encountered with steroid therapy, and immunosuppressive drugs were used in 3 cases. It is to be noted that in one case an extensive RD involving the posterior pole occurred bilaterally: this RD did not respond to maximal steroid and immunosuppressive therapy and reattachment was obtained only after vitrectomy. In another case bilateral optic disc neovascularization was observed in association with severe papillitis despite heavy steroid therapy. A cure was obtained with immunosuppressive drugs.

Properties and requirements for production of a macrophage product which suppresses steroid production by adrenocortical cells.

Lipopolysaccharide-treated murine peritoneal exudate macrophages (PEM) release a factor or factors into the supernatant that suppress adrenocorticotropic hormone-induced steroidogenesis in explanted rabbit adrenocortical cells (J. C. Mathison et al., J. Immunol. 130:2757-2762, 1983). To determine the requirements for suppression, PEM supernatants (30 microliters) were added to explanted rabbit adrenocortical cells in a final volume of 120 microliters with 10 mU of adrenocorticotropic hormone per ml, and after 18 h at 37 degrees C, steroid concentrations were measured by a fluorometric assay. Supernatant from proteose peptone-elicited C3HeB/FeJ PEM (5 X 10(6) PEM per 3.5-cm well, 10 micrograms of Salmonella minnesota Re595 LPS per ml, 18 h) suppressed steroid production ca. 50%, and kinetic studies demonstrated that the appearance of suppressive activity in the supernatant was gradual over 4 to 18 h. Release of suppressive activity was not associated with decreased viability of the PEM (assessed by fluorescein diacetate staining and measurement of lactic dehydrogenase in the supernatant). Suppression was not observed when the PEM supernatant was diluted 10-fold before addition to the adrenocortical cells, whereas supernatant concentrated 20-fold (prepared with a 10,000-molecular-weight-cutoff filter) produced 75 to 80% suppression. The suppressive activity was stable at pH 4, pH 11, or 70 degrees C for 30 min but was inactivated at 100 degrees C (10 min). Suppressive activity was also induced in C3HeB/FeJ PEM by O111:B4 lipopolysaccharide or heat-killed Listeria monocytogenes. In contrast, PEM from C3H/HeJ mice did not produce detectable suppressive activity in response to Re595 lipopolysaccharide or heat-killed L. monocytogenes. Thus, these results provide additional support for the inducible, selective release of a macrophage product that could affect the host response to lipopolysaccharide by regulation of the adrenocortical response to adrenocorticotropic hormone.

[Second-trimester abortion: a difficult, unresolved problem]. / L'avortement du deuxième trimestre: un problème difficile, non résolu.

The authors review the various methods proposed for the late evacuation of the uterus. They report their experience of intra-amniotic injection of prostaglandins and, more recently, the use of extra-amniotic injections. They have found this latter technique to be unsatisfactory. Evacuation following dilatation under local anaesthetic, despite a few complications, appears to be effective... but the problem is far from being resolved.

[Retinal detachments caused by giant tear]. / Les décollements de rétine par déchirure géante.

52 eyes in 50 patients have been treated for a retinal detachment with a giant tear extending over at least 70 degrees. 27 eyes had an inverted posterior retinal flap covering the posterior pole. Conventional extraocular surgery was performed on 20 eyes. There was no success in 6 folded cases and a 42,85% success rate in 14 non-folded retinas. Endocular surgery by vitrectomy plus internal tamponade using air or silicone oil was done on 32 eyes with an 87,50% success rate at the end of surgery. Post-operative retinal retraction reduced the success rates to 45,45% for non-folded cases and 52,38% with folded retinas. There is no question in our mind about the value of endocular surgery for folded retinas. We think that endocular surgery is also the best choice for non folded retinas because of the excellent initial results. Secondary retraction phenomena are caused by endocular cellular proliferation and membrane formation and contraction. We presently try to minimize these by avoiding excess cryopexy, performing a vitrectomy as complete as possible and treating the reattached retina as soon as possible by argon laser photocoagulation. An efficient and safe antiproliferative drug is definitely needed.