Publications by authors named "Nour Ibrahim"

15 Publications

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Gastric outlet obstruction - looking for a syndrome: Bouveret or Mirizzi?

Int J Surg Case Rep 2021 Jul 8;84:106098. Epub 2021 Jun 8.

Department of Digestive Surgery, Sacred Heart Hospital, Beirut, Lebanon.

Introduction And Importance: Gastric outlet obstruction can result from any pathological process that causes intrinsic blockage or extrinsic pressure on the distal stomach and duodenum. Gallstone related gastric outlet obstruction is a well-known entity classically due to a cholecystoenteric fistula formation.

Case Presentation: We present here a case of a 36-year-old man who presented with right upper quadrant abdominal pain associated with marked nausea and vomiting. Abdominal CT scan done in the emergency department revealed a large impacted infundibular gallstone with signs of acute cholecystitis, associated with prominent gastric distention. Gastric outlet obstruction was due to stenosis at the duodenal level from external compression by the large impacted stone with no evidence of fistula. Laparoscopic cholecystectomy was performed with total resolution of symptoms.

Clinical Discussion: Gastric outlet obstruction can be secondary to many etiologies, and notably gallstone disease. Classically this is due to formation of a cholecystoenteric fistula and intrinsic obstruction by the migrated stone. Our case is unique in that a large impacted infundibular gallstone caused gastric outlet obstruction with absence of any fistula or gallstone migration.

Conclusion: Gastric outlet obstruction due to external compression by a non-migrated gallstone is a rare undescribed entity. Surgical treatment should not be delayed to prevent complications and fistula formation.
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http://dx.doi.org/10.1016/j.ijscr.2021.106098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209269PMC
July 2021

[The smartphone as a therapeutic tool in adolescents with type 1 diabetes].

Authors:
Nour Ibrahim

Soins Pediatr Pueric 2021 May-Jun;42(320):16-17. Epub 2021 Mar 26.

Maison de Solenn- Maison des adolescents de l'hôpital Cochin, AP-HP, 97 boulevard de Port-Royal, 75014 Paris, France. Electronic address:

Over the past 15 years, the literature on mobile phone-based interventions for adolescents with type 1 diabetes has increased. While the majority of these interventions focus on therapeutic education of patients, others encourage them to take care of themselves in a broader sense. Young people express great satisfaction with these interventions, but the effectiveness in terms of metabolic control remains to be confirmed.
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http://dx.doi.org/10.1016/j.spp.2021.03.004DOI Listing
June 2021

A systematic review of somatic symptoms in school refusal.

Psychosom Med 2021 May 4. Epub 2021 May 4.

AP-HP, Cochin Hospital, Maison des Adolescents - Maison de Solenn, Integrated Youth Health Care Service, F-75014 Paris, France Faculty of Medicine, Paris-Saclay University, Orsay, France University of Paris, PCPP, F-92100 Boulogne-Billancourt, France Paris-Saclay University, UVSQ, Inserm, CESP, Team DevPsy, F-94807, Villejuif, France Yale University, Yale School of Medicine, New Haven, CT, USA French Clinical Research Group in Adolescent Medicine and Health, France.

Objective: School refusers often display somatic symptoms which are temporally related to school attendance. The aim of this systematic review is to summarize characteristics and causes of somatic symptoms and their management in the context of school refusal. Findings of this review may help clinicians in their daily practice.

Methods: Pubmed and Psycinfo databases were systematically searched (according to PRISMA guidelines) for articles mentioning somatic symptoms in school refusal by May 2020. Among 1,025 identified studies, 148 were included.

Results: Unspecific somatic symptoms were frequently the first complaints in school refusal. Abdominal pain, headache, nausea, vomiting, muscular or joint ache, diarrhea, dizziness, fatigue and palpitation were the most commonly encountered symptoms and were usually not accounted for by an identifiable physical disease. Anxiety was the most recurrent etiology found, but physicians' lack of awareness about psychological comorbidities often delayed psychological/psychiatric referral. Successful therapies consisted of dialectical behavior therapy, anxiety management through relaxation/breathing training and ignoring the somatic symptoms.

Conclusions: Somatic symptoms in school refusal are frequent but poorly understood. Their management could include interventions targeting anxiety, psychotherapies such as emotional awareness and expression therapy, third wave behavioral therapies and psychoeducation. A multidisciplinary approach through strengthened collaboration between school staff, physicians and psychologists/psychiatrists is needed to improve wellbeing in children who experience somatic symptoms as related to school avoidance.
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http://dx.doi.org/10.1097/PSY.0000000000000956DOI Listing
May 2021

Text message reminders for adolescents with poorly controlled type 1 diabetes: A randomized controlled trial.

PLoS One 2021 15;16(3):e0248549. Epub 2021 Mar 15.

Pediatric Endocrinology, Gynecology, and Diabetology Department, Assistance Publique-Hôpitaux de Paris, Necker University Hospital, Paris, France.

Background: Among adolescents with type 1 diabetes, some experience great difficulties with treatment adherence, putting them at high risk of complications. We assessed the effect of text messaging (Short Messaging Service [SMS]) on glycemic control.

Methods: A two-arm open label randomized controlled trial enrolled adolescents with type 1 diabetes aged 12-21 years with baseline HbA1c ≥ 69 mmol/mol (8.5%). The intervention group received daily SMS reminders at self-selected times about insulin injections while the control group received standard of care. The patients allocated to the control group were not aware of the intervention.

Results: 92 patients were randomized, 45 in the SMS arm and 47 in the control arm. After 6 months, median HbA1c level was significantly lower in the intervention arm: 73 mmol/mol (8.8%) in the SMS arm and 83 mmol/mol (9.7%) in the control arm in the intent-to-treat analysis (P = 0.03) but no longer in the per protocol analysis (P = 0.65). When we consider the proportions of patients whose HbA1c level decreased by at least 1% between baseline and 6 months, we find a significant difference among patients whose baseline HbA1c was ≥ 80 mmol/mol (9.5%) (n = 56): 60% in the SMS arm and 30.6% in the control arm had lowered their HbA1c level (P = 0.03) in the intent-to-treat analysis but not in the per-protocol analysis (P = 0.50). Patients in the SMS arm reported high satisfaction with the intervention.

Conclusions: While there is a trend to lower HbA1c in the intervention group, no firm conclusions can yet be drawn. Further studies are needed to address methodological issues as we believe these interventions can support behavior change among adolescents with poorly controlled type 1 diabetes. ClinicalTrials.gov identifier: NCT02230137.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248549PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959392PMC
March 2021

Hyperthyroidism as a Potential Trigger for Benign Recurrent Intrahepatic Cholestasis.

ACG Case Rep J 2020 Jul 16;7(7):e00423. Epub 2020 Jul 16.

Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic disease often causing episodes of jaundice since childhood. Its triggering factors are still unknown. Hyperthyroidism solely is an infrequent cause of jaundice, and it was never described in association with BRIC. In this article, we reported a woman presenting with a new episode of BRIC and was found to have concomitant hyperthyroidism in the absence of any other potential trigger factor. We conclude that hyperthyroidism may trigger cholestasis in patients with BRIC.
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http://dx.doi.org/10.14309/crj.0000000000000423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365710PMC
July 2020

Nasal vestibular body treatment for recalcitrant nasal obstruction.

Int Forum Allergy Rhinol 2020 03 3;10(3):388-394. Epub 2020 Feb 3.

Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA.

Background: The nasal vestibular body (NVB) is a recently reported dynamic swell body present in the inferolateral internal nasal valve. The contribution of NVB presence to persistent nasal obstruction, and effects of NVB treatment, are undefined.

Methods: Thirty-five patients with recalcitrant nasal obstruction and NVB presence were retrospectively reviewed between 2013 and 2019, including 25 patients (48 sides) who had NVBs reduced via radiofrequency ablation (RFA) and 10 patients (20 sides) who had untreated NVBs. Posttreatment healing and complications were reviewed at early (<1 month) and late (mean, 7.3 months) time-points after RFA of the NVB. A subset of the NVB-treatment patients (18 of 25 patients) were compared with 10 NVB-control patients for pre-/posttreatment outcomes using 22-item Sino-Nasal Outcome Test (SNOT-22) and subdomain scoring.

Results: NVBs were successfully reduced in 100% of cases (48 of 48 sides) over both time-points. Early sequelae of NVB treatment, such as local crusting (22 of 23, 95.6%) and bone exposure (4 of 23, 17.3%), resolved by the late time-point, with complete remucosalization (23 of 23, 100%) of all NVB treatment sites. No persistent pain, sensory loss, or pyriform aperture stenosis was noted from any patient/side. Significant reductions between mean pre- and postoperative SNOT-22 (-24, p = 0.001) and individual subdomain (-2, p = 002) scores were seen in the NVB-treatment patients compared to the reductions in NVB-controls (-8 and -1, respectively, both p > 0.001).

Conclusion: NVB treatment using RFA is safe and highly effective, providing complete swell body reduction with only transient local morbidity. NVB presence contributes to persistent/recalcitrant nasal obstruction, with significant improvement in nasal airway function noted after NVB soft tissue reduction.
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http://dx.doi.org/10.1002/alr.22463DOI Listing
March 2020

Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis.

Front Immunol 2019 13;10:2617. Epub 2019 Nov 13.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Granulomatosis with polyangiitis (GPA) is a multi-organ vasculitic syndrome typically associated with neutrophil extracellular trap (NET) formation and aggressive tissue inflammation. Manifestations in head and neck (H&N) GPA include septal perforations, saddle-nose deformities, bony erosions of the orbital and sinus walls, middle ear damage and epiglottitis, indicative of bone, cartilage, and connective tissue destruction. Whether H&N-centric lesions engage disease pathways distinctive from the ischemic tissue damage in the lungs, kidneys, skin, and peripheral nerves is unknown. We have compared inflammatory responses triggered by neutrophilic NETs in patients with H&N GPA and systemic GPA (sGPA). Neutrophils and monocytes were isolated from the peripheral blood of patients with H&N GPA, sGPA, and age/gender matched healthy individuals. Neutrophil NETosis was induced. NETs were isolated and cocultured with monocytes. Gene induction was quantified by RT-PCR, protein upregulation by flow cytometry. Tissue invasiveness of monocytes was measured in a 3D collagen matrix system. Expression of MMP-9 in tissue-residing macrophages was assessed by immunohistochemistry in tissue biopsies. Neutrophils from H&N GPA patients showed more intense NETosis with higher frequencies of netting neutrophils ( < 0.001) and release of higher amounts of NETs ( < 0.001). Isolated NETs from H&N GPA functioned as an inducer of danger-associated molecular patterns in monocytes; specifically, alarmin S100A9. NET-induced upregulation of monocyte S100A9 required recognition of DNA. S100A9 release resulted in the induction of metalloproteinases, including MMP-9, and enabled monocytes to invade into extracellular matrix. Anti-MMP-9 treatment attenuated the tissue invasiveness of monocytes primed with NETs from H&N GPA patients. MMP-9-producing macrophages dominated the tissue infiltrates in naso-sinal biopsies from H&N GPA patients. Distinct disease patterns in GPA are associated with differences in NET formation and NET content. H&N GPA patients with midline cartilaginous and bony lesions are highly efficient in generating NETs. H&N GPA neutrophils trigger the induction of the alarmin S100A9, followed by production of MMP-9, endowing monocytes with tissue-invasive capabilities.
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http://dx.doi.org/10.3389/fimmu.2019.02617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874157PMC
November 2020

Prevention of post-traumatic osteoarthritis after intra-articular knee fractures using hyaluronic acid: a randomized prospective pilot study.

Int Orthop 2019 11 22;43(11):2437-2445. Epub 2019 Jun 22.

Orthopedics and Trauma Department, Cairo University, Cairo, Egypt.

Purpose: Based on the irreversible destruction of hyaline cartilage, post-traumatic osteoarthritis (PTOA) is a notorious sequelae after intra-articular knee fractures. This study evaluates the clinical efficacy and applicability of immediate post-operative intra-articular injection of hyaluronic acid (IA HA) into the knee joint with an intra-articular fracture.

Methods: Prospective randomized case-control study involving 40 patients (20 in each group) with intra-articular knee fracture with an average follow-up of 23 months (range 18-24 months). Twenty patients with intra-articular distal femoral or intra-articular proximal tibial fractures who met our inclusion criteria received three intra-articular hyaluronic acid injections weekly starting immediately after ORIF. Another 20 patients serving as a control group received no injection after ORIF. Patients were assessed functionally with Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) score. Plain X-rays and when indicated CT scans were used to assess radiological union.

Results: The results showed patients treated with intra-articular hyaluronic acid injection after fixation had significantly less pain (KOOS) (p = 0.01). No significant difference was found between both groups in other KOOS-related outcome measures, complications, functional outcome, or quality of life.

Conclusions: These preliminary results support a direct role for hyaluronic acid in the acute phase of the inflammatory process that follows articular injury and provides initial evidence for the efficacy of IA HA.
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http://dx.doi.org/10.1007/s00264-019-04360-8DOI Listing
November 2019

HPV vaccination and sexual health in France: Empowering girls to decide.

Vaccine 2019 03 23;37(13):1792-1798. Epub 2019 Feb 23.

AP-HP, Cochin Hospital, Maison de Solenn, Paris, France; CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, 94805 Villejuif, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address:

Objective: Vaccination coverage against HPV in France is among the lowest in the industrialized world, although the public authorities have recently become aware of this issue. Few studies have looked at teenaged girls' representations of this vaccination, even though they are the most concerned by it. This qualitative study explored the experiences and representations of HPV vaccination by adolescent girls seeing doctors at least occasionally.

Study Design: We used a written essay question to explore this issue among 101 adolescent girls at six urban medical centers and a semi-structured interview to discuss it in further depth with five of them. The analysis was lexicometric (ALCESTE®) and phenomenological (Interpretative Phenomenological Analysis).

Results: These results are organized around four superordinate themes: the teenage girls' factual knowledge about this vaccine, their motives for and obstacles to vaccination, their involvement in this decision, and finally the need for information about and solutions to this issue.

Conclusions: Teenage girls know little about this vaccine and are more sensitive to the emotional discourse that surrounds it than to rational knowledge about it. The requirement for parental authorization for this vaccine reinforces the girls' lack of investment. Vaccination programs should integrate the HPV vaccine more thoroughly into general prevention concerning sexual health and should send a strong signal by offering minors anonymous vaccination free of charge, as is already the case in France for requests for contraception, the morning-after pill, elective abortion, and screening and treatment of sexually transmitted infections.
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http://dx.doi.org/10.1016/j.vaccine.2019.02.020DOI Listing
March 2019

[Temporalities of care for obese teenagers].

Soins Pediatr Pueric 2018 Nov - Dec;39(305):12-14

Maison des adolescents de l'Hôpital Cochin-Maison de Solenn, AP-HP, 97, boulevard de Port-Royal, 75014 Paris, France; Centre de recherche en épidémiologie et santé des populations, Faculté de médecine, Université Paris-Sud-Université Versailles-Saint-Quentin, Inserm, Université Paris-Saclay, 94805 Villejuif, France; Université Paris Descartes, Faculté de médecine, Sorbonne Paris Cité, 15, rue de l'École de Médecine, 75006 Paris, France.

Obesity in adolescents is a common reason for consulting a physician for angst associated with a need to lose weight. The multidisciplinary treatment takes into account the teenager's temporality. The duration of the initial treatment must be optimised in order to construct, with the teenager, a project which corresponds to his or her particular difficulties.
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http://dx.doi.org/10.1016/j.spp.2018.09.002DOI Listing
February 2019

Comparison of the Quality of Pediatric Randomized Controlled Trials Published in Both Nursing and Medical Journals: Adherence to the CONSORT Statement.

Worldviews Evid Based Nurs 2018 Dec 15;15(6):447-454. Epub 2018 Oct 15.

Pharmacology and Drug Evaluation in Children and Pregnant Women, Paris Descartes University, Sorbonne Paris Cité, France.

Background: Nursing care should be based on scientific evidence. However, studies must be performed rigorously with accurate reporting for their findings to be applicable to practice. Since the body of scientific nursing literature is broad, the quality and validity of its findings should be regularly controlled and verified to ensure their application and their practical impact.

Purpose: To compare reporting quality of pediatric randomized controlled trial (RCT) articles in nursing and medical journals.

Methods: Randomly selected articles were reviewed and scored to assess the number of CONSORT items that were adequately reported, generating a CONSORT score. The CONSORT scores for 28 items were compared between the two journal types.

Results And Discussion: The CONSORT scores by journal type were not significantly different: (19.2 [16.2; 22] for medical journals and 19.5 [16.1; 21.5] for nursing journals, p = .77). The reporting of CONSORT items was poor for both journal types. However, there were two significant differences: item 19 (Declaration of all important harm or unintended effects, p = .0006) and item 23 (Registration number of the study, p = .0003), were reported more often in medical journals. The adherence of journals to the CONSORT statement and large sample size was associated with better quality of the reporting of studies.

Conclusions: Based on reporting quality, nursing studies have the same scientific credibility and rigor as medical studies in the pediatric field.

Linking Evidence To Action: The findings of this study could help researchers improve the reporting of their studies and highlight the importance of reporting quality for future knowledge transfer and practical use. The quality of research and its reporting is necessary to improve knowledge transfer into practice.
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http://dx.doi.org/10.1111/wvn.12329DOI Listing
December 2018

Virtual simulation to personalize student learning in a required pharmacy course.

Curr Pharm Teach Learn 2018 06 6;10(6):750-756. Epub 2018 Apr 6.

University of Michigan College of Pharmacy, Ann Arbor, MI, United States. Electronic address:

Background And Purpose: Virtual simulation is used to provide a realistic and safe environment for student pharmacists to learn and practice a variety of skills in the didactic and experiential settings.

Education Activity And Setting: The simulation program, MyDispense, that is used to teach medication dispensing in the outpatient setting was incorporated into a 2-credit hour required first-year pharmacy practice skills course. A total of 30 optional and 16 required exercises were completed by students.

Findings: There was a total of 2,457 attempts (mean = 28.9 attempts per student) at optional practice exercises and students completed an average of 16.6 ± 7.9 (range 1-30). While variation in the number of optional practice exercises completed was observed between students with varying levels of pharmacy experience, the difference was not statistically significant. A component of the final exam utilized the virtual simulation program and all students passed this portion of the exam based on a minimum requirement of 70.0% (mean 92.9%, range 74.5-100%).

Discussion: Students generally identified that the use of virtual simulation was an effective tool to learn medication dispensing skills in a classroom setting. Furthermore, this created an opportunity for pharmacy practice residents to develop teaching skills. The biggest barrier to implementation was the amount of time required to create and test each exercise.

Summary: The virtual simulation program allowed students to self-identify the amount of practice they thought was necessary in order to gain specific skills related to medication dispensing.
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http://dx.doi.org/10.1016/j.cptl.2018.03.017DOI Listing
June 2018

Clinical criteria for CT scan evaluation of upper digestive tract fishbone.

Laryngoscope 2018 11 15;128(11):2467-2472. Epub 2018 Feb 15.

Department of Otolaryngology-Head and Neck Surgery, Galilee Medical Center, affiliated with Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.

Objectives: To establish clinical criteria for performing computed tomography scan for suspected upper digestive tract fishbone.

Methods: This is a prospective study of all adult patients referred to the otolaryngology emergency department at our medical center for suspected fishbone in the upper digestive tract after no fishbone was seen on physical examination. The patients were divided into two groups: 1) The first was a high clinical suspicion group, which included patients with at least one of the following criteria: drooling, accumulation of saliva in the sinus piriformis, fever, referral 24 hours after the ingestion with worsening/continuing symptoms, and readmission. These patients underwent nonenhanced CT scan (NECT) of the neck. 2) The second was a low clinical suspicion group, which included patients discharged with no NECT performed. These patients were followed at 1 week and 3 months.

Results: One hundred and fourteen patients were included in the study; the median age was 41 years. Half of the patients arrived at the emergency department within 7 hours. There were no false negatives. The negative predictive value and sensitivity were 100%. Positive predictive value and specificity were 28.5% and 65%, respectively. Referral to the emergency department 24 hours after the ingestion with continuing symptoms had the highest false positive rate.

Conclusions: Our clinical criteria score for excluding foreign body fishbone in the upper aerodigestive tract was established. According to this score, a NECT can be spared in about 75% of all cases, thus reducing unnecessary ionizing radiation, stay at the emergency department, and costs with a very high NPV of almost 99%.

Level Of Evidence: 4. Laryngoscope, 2467-2472, 2018.
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http://dx.doi.org/10.1002/lary.27125DOI Listing
November 2018

Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK).

Rev Neurosci 2018 Jun;29(4):387-415

Triplex Consulting, 54 Firethorn Lane, Northampton, MA 01060, USA.

Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences from in vitro and in vivo disease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.
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http://dx.doi.org/10.1515/revneuro-2017-0071DOI Listing
June 2018

Vulvar cancer in the north of Israel.

Rambam Maimonides Med J 2014 Jul 25;5(3):e0022. Epub 2014 Jul 25.

Division of Oncology, Rambam Health Care Campus, Haifa, Israel and.

Purpose: This is a population study of patients who were treated for vulvar cancer in a tertiary center in northern Israel, aimed to report clinical findings, treatment, and outcome.

Methods: A retrospective chart review of all medical records of consecutive patients who were treated for vulvar cancer in the years 1993-2012 was conducted. Data extracted from the medical records included demographics, histology, size of lesion, stage of disease at diagnosis, type of treatment, radiation dose, follow-up, recurrence, and survival.

Results: The study included 44 patients with a median age of 69.8 years (range, 42-93 years). Thirty-five (79.5%) of the patients were of Jewish descent, five were Arabic, and four were of other descent. The most common histology type was squamous cell carcinoma in 35 (79.5%) patients. Most patients were staged FIGO II-III at time of diagnosis. Surgery was the most common primary treatment modality (54.2%). Twenty-three (52.2%) patients had recurrent disease. Older age and more advanced stage at diagnosis were associated with increased mortality.

Conclusion: Vulvar cancer is common among elderly women with co-morbidities who present in advanced disease stage; all these factors are significant for survival.
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http://dx.doi.org/10.5041/RMMJ.10156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128593PMC
July 2014
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