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.

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.

[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.

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.

[Macroreticular and butterfly shaped dystrophies of the retinal pigment epithelium (author's transl)]. / Dystrophies en réseau de l'épithélium pigmentaire (dystrophies macroréticulaires et en aile de papillon).

We report the observation of a familiy with 4 cases of macroreticular dystrophy (Mesker) and 1 case of butterfly shaped dystrophy (Deutman) in its ranks. Diagnosis of these conditions is based on ophtalmoscopic and angiographic appearence. Visual loss may be somewhat important in the macroreticular type and it may increase as time passes on. Transmission is autosomal dominant with variable penetrance. The fact that there are anomalies of the retinal pigment epithelium in periphery and around the disk in three of our cases leads us to think that this is a diffuse disease of the retinal pigment epithelium. Macroreticular and butterfly shaped dystrophies are probably similar diseases, they form altogether with the reticular dystrophies (Sjögren) the group of the patterned dystrophies of the retinal pigment epithelium.

[Undergoing retinal detachment and primitive ocular hypertension (author's transl)]. / Décollement de rétine et hypertonie oculaire primitive.

In a survey of 907 patients undergoing retinal detachment surgery, primitive ocular hypertension was found in 3,85%. This ocular hypertension was most often bilateral (85,7%) with open angle (88%) and was found at the time of retinal surgery or on the follow up (54,3%). Retinal detachments in these patients offered no particular character. This percentage of 3,85% is not greater than the percentage of primitive ocular hypertensions in a normal population over 40 years old. However the analysis of our data leads us to think that the presence of ocular hypertension increases the risk of retinal detachment when the patient is aphakic.

[Retinal detachment in the 2d eye. Risk factors]. / Le décollement de rétine du deuxième oeil. Facteurs de risque.

1148 patients underwent retinal detachment (RD) surgery between october 1st 1969 and december 31st 1979 with follow up assured until june 30th 1983 non idiopathic retinal detachments were excluded from this study which was focused on the risk factors concerning detachment of the second eye. With this time criteria the present rate of RD on the second eye is 4,03% : 39 eyes in 970 patients for whom the second eye was present examinable and free of any RD at the time of the first examination. A statistical analysis with the X2 test shows that male patients (p less than 0,025) and heavily myopic eyes (p less than 0,025) are at greater risk; giant tears (70 degrees and more) in the first eye are also an important risk factor. When it comes to preexisting peripheral lesions, the data are more confusing. While the absence of such lesions is not protective against detachment, the contralateral eyes of patients with so-called dangerous lesions may remain detachment-free for a very long time without any treatment. We think that the best prophylactic treatment consists of an equatorial 360 degrees argon laser photocoagulation, with the following indications: giant tear, any break, and peripheral degenerations that lead to a progressive thinning of the inner retina. Care must be taken not to perform heavy photocoagulation therapy on eyes harboring a cellular, densified vitreous.

[Retinal detachment after surgery of the anterior segment using the pars plana approach]. / Décollement de rétine après chirurgie du segment antérieur par la pars plana.

Anterior segment surgery via the pars plana was done on 114 eyes with the Klöti vitreous stripper between January, 1977 and December 31, 1982. In every case the posterior capsule was removed when present and anterior or total vitrectomy was performed. None of the 114 eyes had a history of retinal detachment prior to nor at the time of anterior segment surgery. There were 37 cases of trauma in this series. Follow-up varied from 1 to 66 months with 58% of cases having a follow-up of greater than one year. There was a 10.50% post-operative retinal detachment rate (12/114 eyes). Seven detachments occurred in the 37 traumatized eyes (19.10%) versus 5 detachments in 77 non-traumatized eyes (6.49%). Of the 12 detachments, 7 presented signs of severe proliferative vitreoretinopathy (PVR) while the remaining 5 detachments appeared to be uncomplicated. No detachment was related to an iatrogenic tear and no case of PVR seemed to be related to the sclerotomy site. Successful reattachment was achieved in 3 out of 4 uncomplicated cases and 3 out of 5 cases with PVR. Vitrectomy and posterior capsulectomy are often mandatory in anterior segment problems: pupillary membranes, secondary cataracts, lens ectopiae and dislocations, vitreous wick and vitreocorneal touch. In our opinion other indications for vitrectomy and posterior capsulectomy are congenital, juvenile and post-uveitis cataracts.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

[Outcome of the unaffected eye in retinal detachment. Study of 1148 patients]. / Le devenir de l'oeil adelphe dans le décollement de rétine. Etude sur 1148 patients.

We have found a global bilateral retinal detachments (R.D.) rate of 15,52% over a population of 1148 patients. 60% of these bilateral R.D. have been seen by us for the first time at the moment of the detachment of the second eye. The actual percentage of R.D. on a second eye that was free of any R.D. at the first examination is 3,5% only, and it climbs to 4,45% if we consider only the second eyes harboring dangerous peripheral retinal lesions. This result compares favourably to the 10% to 20% second eye R.D. rate in the absence of preventive treatment; it has been obtained through a systematic prophylaxy of all retinal breaks and almost all lattice, snowflake, and schisis by cryoapplication or xenon photocoagulation or mostly argon laser photocoagulation. In the absence of any peripheral retinal lesion systematic equatorial argon laser circular photocoagulations can be useful.

[Indentation of large retinal tears (author's transl)]. / Indentation des déchirures rétiniennes de grande taille.

According to us large retinal tears are between 20 degrees and 70 degrees in their largest dimension, which excludes true giant tears. Study of the data collected on 42 patients has shown us the following facts:--these retinal tears occur in phakic and often highly myopic eyes;--our global success rate is 73,8%;--tears smaller than 2 to 3 papillary diameters radially are on the whole easy to indent and failures are quite often related to a surgical fault;--tears wider than 3 papillary diameters radially are on the whole difficult to indent and failures are not always related to an obvious surgical fault, fishmouth phenomenon plays an important role;--in every case presence of blood in the vitreous seems to be unfavourable to the prognosis;--use of episcleral pockets solves must of times surgical problems related to fishmouth or tear dimension;--post operative intern limiting membrane retraction is frequent (10% vs 5,7% for all the retinal tears and detachments cured in the same period of time).

[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.

[Retinal detachments treated by argon laser photocoagulation]. / Décollements de rétine traités par photocoagulation au laser à argon.

Twenty-nine rhegmatogenous retinal detachments were treated in 29 patients by argon laser photocoagulation ("damming" technique) between 10-1-77 and 06-30-81. Mean follow up time has been 19.1 months, and retinal detachments have remained perfectly contained in 28 patients without any subsequent macular problem. Eleven cases were asymptomatic retinal detachments, 4 of these occurring after previous argon laser prophylaxis, 16 cases being localized postoperative recurrences or failures after single or repeated surgery. These argon laser "dams" must only be conducted in the absence of major vitreous traction and with strict post-laser control; their indications are therefore limited but they can be useful procedures.

[Retinal detachment and argon laser prophylactic treatment (author's transl)]. / Décollement de rétine et traitement prophylactique par le laser à argon.

We have studied 6 retinal detachments which hapened after a preventive photocoagulation with argon laser in 6 patients who had already had a severe retinal detachment on the other eye (2 anatomical success on 5 operated cases). This preventive photocoagulation was done on eyes which at the term were free of any retinal dehiscence. In this group of 6 we notice 2 giant tears (greater than 70 degrees) or 33% and 3 large tears (between 20 degrees and 70 degrees) or 33%. These high amounts do not correspond to what has been noticed before: - on the non photocoagulated fellow eyes (neither giant nor large tear) - on the whole lot of operated retinal detachments during the same period of time in our unit (2% of giant and 5,7% of large tears). We think that the responsability of laser in the development of these large lesions in predisposed eyes must be thought about. Studies on a larger scale will be necessary to have a more definite idea on this subject.

[Prognosis of the retinal detachment in children (author's transl)]. / Pronostic du décollement de rétine de l'enfant.

Following features seem to characterize retinal detachments in children. High rate of difficult anatomical problems: invisible retinal breaks, macular or paramacular breaks, giant breaks or desinsertions (37% of our cases). High rate of severe traumatic macular lesions. Important delay in treatment with prolonged macular impairment. These facts explain the prognosis. Difficulties in the treatment of retinal breaks explain anatomical results (75% cure rate vs 78,6% for all the retinal detachments treated). In the same way they explain the high rate of multiple operations. Macular impairment and multiple operations explain visual results: 1/3 of the non amblyopic eyes recover a visual acuity comparable to the initial. So, the macular in children does not seem to have a special functional recuperation ability. Two supplementary facts may be mentioned. Delay in treatment has no adverse effect in anatomic prognosis. Non giant "simple" desinsertions expose to a noticeable risk of massive vitreous retraction.

[Drainage of subretinal fluid: technic and results]. / Le drainage du liquide sous-rétinien : techniques et résultats.

The drainage of subretinal fluid (S.R.F.) after choroidal diathermy offers a distinct advantage: important reduction of massive haemorrhages from the drainage site (4% vs 48% in the non diathermy group in our series). According to us it is not a decisive factor for the anatomical prognosis because complications of drainage in themselves seem to be a quite infrequent cause of anatomical failure. On the other hand we think that visual outcome is better in the diathermy group because of a diminution of macular haemorrhages.

[Effects of flunitrazepam on intraocular pressure (author's transl)]. / Effets du flunitrazépam sur la pression intra-oculaire.

Though ophthalmologists operate upon patients that are in a debilitated state, a general anesthesia has to be employed with increasing frequency. Flunitrazepam, known to possess good cardiovascular tolerance, was studied to evaluate its effects on intraocular pressure in 34 unselected patients undergoing 41 operations under general anesthesia, usually 41 operations under general anesthesia, usually for retinal detachment or cataract. Ocular pressure was normal in all cases before surgery, but a history of chronic respiratory insufficiency was obtained in 8 cases and of cardiovascular disease in 18. After premedication with 0.02 mg . kg-1 of flunitrazepam and 0.01 mg . kg-1 of atropine, anesthesia was induced by 0.04 mg . kg-1 i.v. of flunitrazepam alone. No marked alterations in cardiac of respiratory functions were observed. Intraocular pressure was measured with a Schiötz tonometer, just before and 5 minutes after the i.v. injection of flunitrazepam. Results showed -- before: 1.61 +/- 0.51 kPa (12.1 +/- 3.8 mmHg); after: 1.09 +/- 0.36 kPa (8.2 +/- 2.7 mmHg) -- a statistically reduction of 32 p.cent. The precise mechanism of action of flunitrazepam on intraocular pressure is not known, but cannot be related to the reduction in aqueous humor secretory flow or the marked diminution in arterial or venous pressure. A probable explanation is the lowering of resistance to aqueous humor flow exterior to the ocular globe as a result of the muscle relaxant properties of the product. Flunitrazepam appears to be a narcohypnotic of choice in ophthalmological surgery on these inherently debilitated patients.

[Retinal detachment recurrences. 1. Frequency and risk factors (author's transl)]. / Les récidives de décollement de rétine. 1. Fréquence et facteurs de risque.

Retinal detachment recurrence is defined the reappearance of a detachment after an initial complete success, whatever the delay between surgery and recurrence. This eliminates immediate failures due to inadequate buckles or major complications during surgery, exsudative retinal detachments that reattach spontaneously within a few days and cases where it is not sure that the retina had been completely reattached initially (cloudy media). Employing these criteria, a retrospective study demonstrated 130 eyes with recurrences out of a total of 1237 eyes operated between 1-10-69 and 31-12-79 (10,5 per cent rate); recurrences occurred in this series between 3 days and 7 years after initial surgery, 53,5 per cent of them within an interval of less than 3 months. The most important recurrence risk factors appear to be: detachment due to a retinal tear and not a hole, bullous detachment, abnormal vitreous but not full blown, massive vitreo-retinal retraction and massive intraocular bleeding during subretinal fluid drainage.

[Pars plana lensectomy II - Short- and long-term complications]. / Broutage du cristallin par la pars plana II. Complications à court et moyen terme.

Pars plana lensectomies or membranulectomies were performed on 67 eyes with posterior capsule removal in every case, with follow-up of 60 eyes for more than 3 months (mean: 18 months). No peroperative or early postoperative complication was specifically related to the procedure employed. Irvine's syndromes and retinal detachments were the two most severe late complications. Four of the 5 Irvine's syndromes occurred after a membranulectomy and this encouraged systematic removal of the posterior capsule, knowing the risk of postoperative opacification; 3 of these 5 eyes, in fact, had a final visual acuity better than 6/10. Four of the 5 retinal detachments occurred after traumatic cataract removal, 2 of them associated with intraocular foreign body and 1 with penetrating injury. Retinal detachment prophylaxis in these high risk eyes should be based above all on systematic vitrectomy at the end of the lensectomy, and therefore the pars plana approach must be used. The pars plana approach for cataracts and membranules is effective and reasonably safe at the present time.