Metro-SMHOP 01: Metronomics combination with cyclophosphamide-etoposide and valproic acid for refractory and relapsing pediatric malignancies.

BACKGROUND: In low- and middle-income countries, therapeutic options for advanced, refractory, or relapsing malignancies are limited due to local constraints such as cost of drugs, distance from oncology centers, and lack of availability of new anticancer drugs. Metronomics, which combines metronomic chemotherapy (MC) and drug repositioning, allows for the provision of new therapeutic options for patients in this setting. AIM OF THE STUDY: To evaluate the activity and toxicity of a metronomic regimen in Moroccan pediatric patients with refractory or relapsing malignancies. PATIENTS AND METHODS: From July 2014 to January 2018, patients with refractory/relapsing solid tumors treated in five pediatric oncology centers were consecutively enrolled. The metronomic regimen consisted of 28-day cycles with daily oral administration of cyclophosphamide (30 mg/m2 ) from days 1 to 21, together with oral etoposide (25 mg/m2 ) from days 1 to 21 followed by break of one week and daily valproic acid (20 mg/kg) from days 1 to 28. RESULTS: Ninety-eight children (median age, 8 years) were included. Underlying malignancies were neuroblastoma (24 patients), Ewing sarcoma (18), osteosarcoma (14), rhabdomyosarcoma (14), and miscellaneous tumors (28). A total of 557 cycles were given (median: 6; range, 1-18 cycles). One-year progression-free survival of our patients was 19%, and one-year overall survival was 22%. Complete response was obtained in three cases (3%), partial response in 11 cases (11%), and tumor stabilization for more than six months in 28 cases (28%). CONCLUSION: This three-drug metronomic combination was well tolerated and associated with tumor response and disease stabilization in 42 patients even for a long period.

[Multiple endocrine neoplasia type 1: about a case]. / Néoplasie endocrinienne multiple type 1: à propos d'un cas.

Multiple endocrine neoplasia type 1 (MEN1) is a rare disease, defined as a tumor developing in at least two endocrine glands including the anterior pituitary gland, the parathyroid glands and the duodenopancreatic endocrine tissue. This disorder, inherited in an autosomal dominant pattern, is caused by mutations in the MEN1 gene encoding the tumor suppressor menin and located on chromosome 11q13. However, sporadic cases account for 8-14%. The first endocrine lesion may be solitary in approximately 75% of cases. However, all major alterations can be inaugural. We here report a case of multiple endocrine neoplasia type 1 revealed by aggressive somatoprolactinic pituitary adenoma which didn't respond to conventional treatment. The detection of primary hyperparathyroidism as well as neuroendocrine tumor of the pancreas seven years later make this a very particular case. Therapeutic options are discussed within the multidisciplinary team specialized in endocrine diseases.

The Prevalence of Celiac Disease-Specific Auto-Antibodies in Type 1 Diabetes in a Moroccan Population.

OBJECTIVE: We aimed to determine the prevalence of specific auto-antibodies to celiac disease (CD) in Moroccan type 1 diabetic (T1D) patients and compare the clinical and biological characteristics of seropositive and seronegative cases. PATIENTS AND METHODS: A cross-sectional study was carried out on 276 T1D patients including 109 adults and 167 pediatric cases. The screening for CD was performed by an Elisa IgA anti-tissue transglutaminase antibody (tTGA) testing, combined with IgA quantification by nephelometry. Positive-IgA-tTGA cases were secondly tested for anti-endomysial antibodies (EMA) using an immunofluorescence technique, and the IgA deficiency cases were screened for IgG-tTGA. Patients with low positive tTGA titers underwent HLA-DQ2/DQ8 typing. Sociodemographic and clinical data of the patients were collected using a hetero-administered questionnaire. The comparison of clinical and biological data between seropositive and seronegative diabetics was done using independent T, Mann-Whitney U, chi-squared, and Fisher tests, which were considered significant if p value <0.05. RESULTS: The prevalence of CD-specific auto-antibodies was estimated to be 9.1% (IC = 95%), with 25 positive cases in tTGA and EMA testing. Eight cases displayed low titers of IgA-tTGA, among which 4 were positive for HLA-DQ2, 1 for HLA-DQ8, and 1 for both DQ2 and DQ8. The other 2 cases had a biopsy-proven CD. Compared to seronegative patients, seropositive cases had a higher percentage of associated autoimmune disorders (16% vs. 2.4%, p=0.008), with a significant lower height Z-scores (median: -0.90 (-3.93 to 0.95) vs. -0.51 (-4.54 to 2.18), p=0.029) and a higher HbA1c level (median: 11.30% (7.31 to 16.00) vs. 9.30% (4.40 to17.31), p=0.022). CONCLUSION: The current study gave evidence of a high prevalence of CD specific auto-antibodies in T1D population. The co-existence of these two conditions was associated with a poor glycemic control, a lower height, and other autoimmune diseases. These findings may suggest the necessity of a systematic screening of CD in T1D patients.

Detection and initial management of gestational diabetes through primary health care services in Morocco: An effectiveness-implementation trial.

BACKGROUND: Gestational Diabetes Mellitus (GDM) testing and management in Morocco is associated with delays resulting in late commencement of treatment. To reduce delays and to increase access of women to GDM care, a country-adapted intervention targeting primary health care providers was designed to test the hypothesis that detection and initial management of GDM at the primary level of care improves newborn outcomes in terms of lower birthweights and less cases of macrosomia and impacts on maternal weight gain, glucose balance and pregnancy outcomes. MATERIALS AND METHODS: We conducted a cluster randomized controlled trial in two districts of Morocco. In each district, 10 health centers were randomly selected to serve either as intervention or control sites. Pregnant women attending antenatal care in the study facilities were eligible to participate. At the intervention sites, women were offered GDM screening by capillary glucose testing following International Association of Diabetes in Pregnancy Study Groups/WHO criteria. Women diagnosed with GDM received counselling on nutrition and exercise and were followed up through their health center whereas at control facilities routine practice was applied. Primary outcome was birthweight and secondary outcomes maternal weight gain, glucose control and pregnancy complications. We further assessed GDM prevalence in the intervention arm. Statistical analysis was performed on 210 recruited women. Continuous variables were reported using means while categorical variables using frequencies with tests of independence applying chi-squared tests. Differences of outcome variables between the two groups were estimated by mixed-effects regression models and effect sizes adjusted for confounders. The trial is registered under NCT02979756 at ClinicalTrials.gov. RESULTS: GDM prevalence reached 23.7% in Marrakech. Birthweight in the intervention group was 147grams lower than in the control group (p = 0.08) as was the proportion of macrosomes (3.5% versus 18.4%; p< 0.001). In the intervention arm, women did two times more follow-ups than at control sites (p = 0.001) and mean follow-up intervals were shorter (11.3 days versus 18.7 days; p < 0.001). Overall, 30% more fasting blood sugar values were balanced (p = 0.005) and mean weekly maternal weight gain 49 grams lower (p = 0.032) in the intervention group. More women from control facilities had a delivery complication whereas more newborn complications were observed in women from intervention facilities. No difference between the two groups existed regarding mode of delivery and mean gestational age at delivery. One of the main limitations of the study was the Hawthorn-effect at control sites that might have led to an underestimation of the effect size. CONCLUSION: A high GDM prevalence in Morocco calls for a context-adapted screening and management approach to enable early interventions. GDM detection and care through antenatal care at primary health facilities may have positively impacted on newborn birthweight but findings are inconclusive. Results of this study will contribute to the decision on a potential upscaling of the intervention in Morocco. Future research could examine long term metabolic changes including diabetes type 2 in the cohort of women and their children.

[Difficulties in managing Graves' disease in children: about a case]. / Difficultés de prise en charge de la maladie de Basedow chez l'enfant: à propos d'un cas.

Adequate management of Graves' disease in children is an area of controversy in pediatric endocrinology, while optimal duration of medical treatment inducing remission in disease as well as indications for therapeutic alternatives still needs to be determined. We report the case of a 11-year old female child with no particular past medical history., presenting with progressive weight loss associated with diarrhea. Her parents brought the child to hospital because neighbours noticed anterior cervical swelling on her. Clinical and paraclinical data helped to retain the diagnosis of Graves' disease. The patient underwent medical treatment with carbimazole. Patient's evolution was marked by the occurrence of thrombocytopenia, suggesting prudent administration of medical treatment. Iratherapy was indicated due to the absence of remission after 4 years of treatment. Although rare, Graves' disease is the first cause of hyperthyroidism in children. Positive diagnosis is easy but its management may pose enormous problems. Medical treatment is based on synthetic antithyroid drugs, but they are not always innocuous, as in the case of our patient. Then subtotal thyroidectomy or radioactive iodine treatment are two therapeutic alternatives. Graves' disease is a rare and severe disease in children posing considerable management difficulties.

[A case of pheochromocytoma discovered during a twin pregnancy: a diagnosis not to be misunderstood and literature review]. / Un cas de phéochromocytome découvert au cours d'une grossesse gémellaire: un diagnostic à ne pas méconnaître et revue de littérature.

The pheochromocytoma is a rare, but potentially serious, which can be revealed by pregnancy. Less than 250 cases described in the literature .The rarity of this association and similarity with pregnancy-induced hypertension explains the frequency of unknown diagnoses during pregnancy. A privileged time of discovery, the prognosis associated with early diagnosis, a multidisciplinary management. Hence the need to explore all arterial hypertension poorly defined or family nature during pregnancy. The certainty diagnosis is conducted by biological tests provided are thought of, a review of localization by ultrasound or magnetic resonance imaging (MRI), a medical preparation can choose according to the term to remove the tumor before or after delivery. We related a case of pheochromocytoma diagnosed during a twin pregnancy of 26 weeks of amenorrhea (SA), bringing us the elements of the clinical and laboratory diagnostic imaging, treatment and maternal and fetal prognosis.

Ewing sarcoma of the adrenal gland: a case report and review of the literature.

BACKGROUND: Ewing sarcoma/primitive neuroectodermal tumor is a family of highly malignant proliferation of neuroectodermal origin, most often skeletal, adrenal localization is extremely rare. Only few cases have been reported in the literature. Classical management includes radical surgery with adjuvant chemotherapy or radiotherapy or both. This case report is the only one where recurrence was surgically removed, and it confirms the importance of adjuvant treatment, and the efficacy of neoadjuvant chemotherapy. CASE PRESENTATION: We report the case of a 23-year-old Moroccan woman presenting with flank pain. An abdominal computed tomography scan showed a large and enhancing left suprarenal mass. After radical nephrectomy, histologic examination revealed a small round cell proliferation. The diagnosis of Ewing sarcoma was confirmed by molecular analysis; time to final diagnosis was 5 months due to financial and coordination issues. Computed tomography (on an asymptomatic patient) revealed a locoregional recurrence, our patient received 12 cycles of the vincristine, doxorubicin and cyclophosphamide/ifosfamide and etoposide protocol used in an alternating schedule, with partial radiologic response (62%) and pathologic complete response, then underwent adjuvant radiotherapy of 45 Gy. The young women is still in remission after 36 months of follow-up. CONCLUSIONS: Our patient had an early recurrence due to absence of adjuvant treatment, but did respond well to neoadjuvant chemotherapy with a pathologic complete response. Management of adrenal Ewing sarcoma could be extrapolated from skeletal one with good outcomes even in locoregional recurrence.

[Epidermoid cyst in the sella turcica: about a case]. / Kyste épidermoide de la selle turcique: à propos d'un cas.

Epidermoid cyst (EC) or cholesteatoma is a benign tumor, often of congenital origin, occurring in the sub-arachnoidian spaces. Its treatment is based on surgery. We report the case of a 38 year-old patient presenting with progressive intracranial hypertension syndrome associated with anterior pituitary insufficiency signs of the corticotropic, thyrotropic, gonadotropic axis occurring 1 year before. Brain MRI showed a craniopharyngioma. Anatomopathologic evaluation of the specimen showed epidermoid cyst.

Short-term effectiveness of a culturally tailored educational intervention on foot self-care among type 2 diabetes patients in Morocco.

BACKGROUND: Self-management education (SME) is an important yet unacknowledged aspect of diabetes care. Despite the raise of diabetes and its complications with significant burden in developing countries, research on SME interventions in Morocco is lacking. AIMS: To assess the effectiveness of a culturally tailored SME intervention on foot-care self-management practices among type 2 diabetes patients and to identify factors associated with practices variation. METHODS: We designed a pre-post prospective quasi-experimental study and recruited patients with type 2 diabetes aged 30 years old or above. The intervention consisted of an interactive group discussion using different materials: a narrative video, a PowerPoint presentation and a printed guide. Foot-care practices were assessed prior to the session and one month later using 2 items from the Summary of Diabetes Self-Care Activities (SDSCA). Binary logistic regression was performed to identify factors associated with a favorable variation, defined as an increase in the mean frequency score of foot-care by a minimum of 1 day/week. RESULTS: A total of 199 participants were recruited and 133 completed the second assessment. Mean age was 55.2 ± 11.2 years old. Women represented 67% and 72% of participants was illiterate. The foot-care score mean increased from 3.5 ± 2.9 days to 5.9 ± 1.8 days one month after the intervention (mean variation was 2.4 ± 3.1 days; p < 0.001). A favorable variation was found among 75 (37.7%) participants. In multivariate analysis, literacy was associated with higher likelihood of a favorable variation of foot-care practices (OR = 2.82; 95%CI: 1.09-7.31) while previous education about diabetic foot was associated with lower likelihood of a favorable variation (OR = 0.26; 95%CI: 0.08-0.78). CONCLUSIONS: There was a general improvement in foot-care practices after the intervention. Our findings suggest the role of literacy and previous patient education in shaping the observed variation. Culturally tailored interventions targeting other disease management domains are needed in our context.

Improving detection and initial management of gestational diabetes through the primary level of care in Morocco: protocol for a cluster randomized controlled trial.

BACKGROUND: Morocco is facing a growing prevalence of diabetes and according to latest figures of the World Health Organization, already 12.4% of the population are affected. A similar prevalence has been reported for gestational diabetes (GDM) and although it is not yet high on the national agenda, immediate and long-term complications threaten the health of mothers and future generations. A situational analysis on GDM conducted in 2015 revealed difficulties in access to screening and delays in receiving appropriate care. This implementation study has as objective to evaluate a decentralized GDM detection and management approach through the primary level of care and assess its potential for scaling up. METHODS: We will conduct a hybrid effectiveness-implementation research using a cluster randomized controlled trial design in two districts of Morocco. Using the health center as unit of randomization we randomly selected 20 health centers with 10 serving as intervention and 10 as control facilities. In the intervention arm, providers will screen pregnant women attending antenatal care for GDM by capillary glucose testing during antenatal care. Women tested positive will receive nutritional counselling and will be followed up through the health center. In the control facilities, screening and initial management of GDM will follow standard practice. Primary outcome will be birthweight with weight gain during pregnancy, average glucose levels and pregnancy outcomes including mode of delivery, presence or absence of obstetric or newborn complications and the prevalence of GDM at health center level as secondary outcomes. Furthermore we will assess the quality of life /care experienced by the women in both arms. Qualitative methods will be applied to evaluate the feasibility of the intervention at primary level and its adoption by the health care providers. DISCUSSION: In Morocco, gestational diabetes screening and its initial management is fragmented and coupled with difficulties in access and treatment delays. Implementation of a strategy that enables detection, management and follow-up of affected women at primary health care level is expected to positively impact on access to care and medical outcomes. TRIAL REGISTRATION: The trial has been registered on clininicaltrials.gov ; identifier NCT02979756 ; retrospectively registered 22 November 2016.

Moderate-to-Severe Iodine Deficiency in the "First 1000 Days" Causes More Thyroid Hypofunction in Infants Than in Pregnant or Lactating Women.

Background: Iodine deficiency early in the life cycle-the "first 1000 days"-can cause hypothyroidism and irreversibly impair neuromotor development. However, the relative vulnerability among women and infants during this critical period is unclear, making it difficult for country-based programs with limited resources to prioritize their iodine interventions.Objective: Our aim was to determine the prevalence of thyroid hypofunction in women and infants living in an area of moderate-to-severe iodine deficiency.Methods: In a cross-sectional survey in Morocco, we measured urinary iodine concentrations (UICs) and concentrations of thyroid-stimulating hormone (TSH) and total or free thyroxine (TT4 or fT4, respectively) in women of reproductive age (n = 156), pregnant women (n = 245), and lactating women (n = 239) and their young infants (n = 239). We calculated daily iodine intakes and measured iodine concentrations in breast milk and household salt. We compared the incidence of hypothyroidism between the 3 groups of women and with the infants.Results: Women of reproductive age, pregnant women, and lactating women had median (IQR) UICs of 41 (29-63), 32 (17-58), and 35 (19-62) µg/L; and estimated iodine intakes were ∼60%, 22%, and 26% of Recommended Nutrient Intakes (RNIs). The infants' median UIC was 73 (28-157) µg/L, which was greater than for all 3 groups of women (P < 0.001), and their dietary intakes were 27% of the RNI. The prevalence of hypothyroidism was not significantly different between the 4 groups, whereas the prevalence of hypothyroxinemia was higher in infants (40%) than in the 3 groups of women (11-14%) (P < 0.001). The median breast-milk iodine concentration was 42 (26-81) µg/L. Only 6% of salt samples were adequately iodized to a concentration of ≥15 ppm; 54% were inadequately iodized and 40% contained no measurable iodine.Conclusions: In an area of moderate-to-severe iodine deficiency, the prevalence of thyroid hypofunction is ∼4-fold higher in young infants compared with the 3 groups of women, suggesting that, in the "first 1000 days," infants are more vulnerable than their mothers and that programs should prioritize iodine prophylaxis for this group.

Association of newly diagnosed type 1 diabetes and autoimmune pancreatitis.

Autoimmune pancreatitis is a new nosological entity in which a lymphocytic infiltration of the exocrine pancreas is involved. The concomitant onset of autoimmune pancreatitis and type 1 diabetes has been recently described suggesting a unique immune disturbance that compromises the pancreatic endocrine and exocrine functions. We report a case of type1 diabetes onset associated with an autoimmune pancreatitis in a young patient who seemed to present a type 2 autoimmune polyglandular syndrome. This rare association offers the opportunity to better understand pancreatic autoimmune disorders in type 1 diabetes. LEARNING POINTS: The case makes it possible to understand the possibility of a simultaneous disturbance of the endocrine and exocrine function of the same organ by one autoimmune process.The diagnosis of type 1 diabetes should make practitioner seek other autoimmune diseases. It is recommended to screen for autoimmune thyroiditis and celiac diseases. We draw attention to consider the autoimmune origin of a pancreatitis associated to type1 diabetes.Autoimmune pancreatitis is a novel rare entity that should be known as it is part of the IgG4-related disease spectrum.

[Hyperprolactinemia: unusual association between peripheral hypothyroidism and microprolactinoma]. / Hyperprolactinémie: coexistence rare d'une hypothyroïdie périphérique et d'un microprolactinome.

We report a rare case of hyperprolactinemia revealing the association between peripheral hypothyroidism and prolactin pituitary macroadenomas. The patient was a 43-year old woman, presenting with spontaneous bilateral galactorrhea over a period of 1 year. Hyperprolactinemia was confirmed and etiologic investigation revealed peripheral hypothyroidism secondary to autoimmune thyroiditis. Therapy consisted of administration of thyroid hormone, with clinical stabilization and hormonal normalization three months later. The evolution was marked by the persistence of hyperprolactinemia and galactorrhea. The diagnosis of microprolactinoma was objectified by pituitary MRI which showed microadenoma, justifying the administration of antidopaminergic therapy Six months later, the evolution was marked by normalization of prolactin levels and disappearance of pituitary microadenoma image.

Management of diabetes in Morocco: results of the International Diabetes Management Practices Study (IDMPS) - wave 5.

OBJECTIVES: The International Diabetes Mellitus Practice Study (IDMPS) is a 5-year survey documenting changes in diabetes treatment practices in developing countries. The primary objective of this survey was to assess the therapeutic management of type 2 diabetes mellitus (T2DM) in real-life medical practice. The secondary objectives were to evaluate the clinical management of type 1 diabetes mellitus (T1DM) and to assess the proportion of all diabetic patients failing to reach the glycated haemoglobin (HbA1c) <7% target. METHODS: Data were analysed for 738 patients (240 with T1DM and 498 with T2DM) included in wave 5 of the IDMPS in Morocco in 2011. RESULTS: Nearly two-thirds (61%) of T2DM patients were treated with oral glucose-lowering drugs (OGLDs) alone, 13.1% were treated with insulin alone and 23.3% were treated with OGLDs plus insulin. Insulin use was less frequent, was initiated later and involved a greater use of premixes versus basal/prandial schedules compared to other populations evaluated in the IDMPS. The majority (92.5%) of T1DM patients were treated with insulin alone and the remainder received insulin plus an OGLD. Insulin protocols included basal + prandial dosing (37.5%) and premix preparations (41.3%). The recommended target of HbA1c <7% was achieved by only 22.2% of T1DM patients and 26.8% of T2DM patients. More macrovascular but fewer microvascular complications were reported in T2DM compared to T1DM patients. Late complications increased with disease duration so that 20 years after diagnosis, 75.7% of T2DM patients were found to have at least one late complication. CONCLUSIONS: The clinical burden of diabetes is high in Morocco and the majority of patients do not achieve the recommended glycaemia target, suggesting that there is a huge gap between evidence-based diabetic management and real-life practice. Better education of patients and improved compliance with international recommendations are necessary to deliver a better quality of diabetic care.

[Etiology of endocrine arterial hypertensions: about a series of cases]. / Etiologies des hypertensions artérielles endocrines: à propos d'une série de cas.

Arterial hypertensions (HTA) of endocrine origin are a rare cause of hypertension; HTA overall prevalence don't exceed 4% of hypertensive patients. Research interest in endocrine HTA is due to the severity of some life-threatening, potentially curable and reversible forms of HTA. The aim of our study was to determine the clinical, paraclinical, etiological and therapeutic profile of secondary HTA of endocrine origin in patients treated in endocrinology department at the University Hospital Mohamed VI in Marrakech. We conducted a prospective, descriptive study spanned 4 years, enrolling 45 patients with endocrine HTA. The average age was 44.89 years, with a clear predominance of women (sex ratio 0.49). Etiology of endocrine HTA was dominated by pheochromocytoma (17 cases), hypercorticism (11 cases) and acromegaly (8 cases). HTA were paroxysmal in 24.4%. HTA were immediately classified as grade 3 severe in 40% of cases. HTA were complicated by heart disease in 24% of cases and by renal disease in 20% of cases. Curative treatment cleared up HTA in 60% of cases (27 cases). The diagnosis of secondary endocrine HTA is sometimes difficult because of the lack of clinical specificity. It is not unusual for HTA to be the only manifestation of the disease. In our study we noted the paroxysmal and severe nature of HTA. The potentially curable nature of HTA in more than two thirds of cases, demostrates the importance of early diagnosis of each severe HTA resistant to treatment or in the presence of suggestive clinical, biological or radiological signs.

Jaw tumor in primary hyperparathyroidism is not always a brown tumor.

Primary hyperparthyrodism (PHPT) is a common endocrine disease. It results from an inappropriate parathyroid hormone (PTH) secretion relative to serum ionized calcium level. Clinical manifestation of severe PHPT include bone disease called osteitis fibrosa cystica which reflects an increase osteoclastic resorption and osteoblastic activity. This high bone turnover is responsible of the occurrence of osteoclastomas, also named "brown tumors" (1). Rarely, PHPT may occur in inherited forms with association to fibrous jaw tumor that are unrelated to hyperparathyroidism. In this uncommon disease: hyperparathyroidism-jaw tumor (HPT-JT) syndrome, parathyroid tumor is frequently malignant and usually associated with nonendocrine malignancies (2). We report a case of a HPT-JT syndrome to focus on the differential diagnosis with brown tumors.