Congestive heart failure is highly prevalent in the elderly population and left ventricular assist device has been increasingly used in this population. LVAD therapy is more costly than medical treatment but it increases the survival and quality of life of the elderly patients with low disease acuity. Therefore careful selection of candidates and implementation of LVAD therapy earlier in the course of the disease is crucial to improve outcomes. With the technical advances and improvement in clinical management, the financial burden of LVAD therapy in the elderly will become less, making this therapy more economically feasible.
The authors in this manuscript have reported an increase in the number of vascular emergencies seen during the early phase of the COVID-19 pandemic in the Lombardy region of Italy. A significant increase in the number of acute limb ischaemia was seen during this phase along with other vascular emergencies. In this review, we have tried to examine this association between increase in vascular emergencies and COVID-19 infection. We have also described the differences in presentations, prognosis and procedural outcomes following operative interventions in these patients compared to the non-COVID patients. An attempt has been made to assess the role of adjunctive measures like intravenous heparin to improve outcomes.
To the Editor: The interesting and timely paper by Cain et al.1, in press in the Journal of Cardiac Surgery , provides important details concerning the devastating consequences of Mycobacterium chimaera (MC ) infection. In their patient extreme fragility of the mediastinal tissues was observed after repair of an acute aortic dissection; during follow-up multiple reoperations were required to treat recurrent dehiscence of the aortic grafts. Despite repeat explantation of foreign materials infection persisted with mediastinitis and eventual systemic diffusion with fatal outcome.MC infection after open cardiac surgery using cardiopulmonary bypass has been recently reported as a clinical outbreak worldwide and identified as originating by contaminated water in heater-cooler units2. Current experience shows that MC causes a slow-growing and extremely difficult to treat infection with an incubation period which has been recently demonstrated to be as long as >12 years3.We have recently treated a patient, quite similar to that reported by Cain et al.1, who presented with a pseudoaneurysm of the distal suture line twelve years after repair of type A aortic dissection4. At first operation replacement of the ascending aorta and hemiarch using of a Djumbodis®dissection system (Saint Come-Chirurgie, Marseille, France) was performed. At reoperation extremely fragile tissues were noted and, after removing the metallic stent, the aortic arch was replaced with a frozen elephant trunk technique. Cultures of the excised material grewMC . In this case we hypothesized that the stent played an important role in the onset of infection for at least 2 reasons: presence of foreign material in the blood stream and injury to the aortic wall by the edges of the stent. The case described by Cain et al.1 also supports our belief that extreme fragility of the aortic tissues caused by MB was a further important factor in the occurrence of this complication.Interestingly, a delayed diagnosis occurred in both cases; this most likely played a critical role in favouring development of extra‐cardiac manifestations of the disease, in reducing the effectiveness of antibiotic therapy due to immunologic impairment and causing a negative outcome in both patients.MB infection may have different locations ranging from single-organ to systemic manifestations5. When it involves the mediastinum and particularly the major vascular structures often results in life-threatening complications despite proper antimycobacterial treatment. An early diagnosis, even with significantly extended surveillance, appears extremely difficult due to slow-growing and long incubation period of MB .Although no specific guidelines are so far available, intra-operative prevention with improvement of setting and development of heater-cooler units is mandatory and should be based on specific recommendations5.
The well-accepted role of the Heart Team in assessing patients suffering from aortic stenosis is becoming the standard approach in most centers. A tailored approach to individual patients may lead to significant changes in outcomes even though SAVR will continue to play a major rollin the treatment of patients presenting more co-morbidities and anatomical challenges.
Background: Vernal keratoconjunctivitis (VKC) is a rare chronic conjunctivitis characterized by a predominantly eosinophil-mediated inflammatory disorder that could develop critical complications such as blindness. Oxidative stress plays a pivotal role in the pathogenesis of several allergic diseases. The role of oxidative stress has been hypothesized in VKC, but no study explored this issue.Furthermore, cyclosporine A (CsA) exerts an anti-inflammatory and antioxidant action on the conjunctiva. This study aims to assess oxidative stress in VKC patients and controls and to study the effect ofCsA on oxidative stress in these subjects. Methods:Thirty-six consecutive children, including 12 VKC(9 males, 75%; mean age 10,17; SD ± 2.48) patients without treatment,12 VKC treated with CsA(9 males, 75%; mean age 9,08; SD± 2.75) and 12 controls (CT) (7males,58%; mean age8,58; SD ±1,78) were recruited. A cross-sectional study was performed to compare H2O2 in the serum and the tears ofthese children. Results: Compared with CT and VKC children treated with CsA, VKCuntreated children had significantly higher values ofHydrogen peroxide (H2O2) in theserum and the tears.No significant differences were observed between CT and VKC treated with CsA. A significant correlation was found at the linear regression analysis between serum and tear H2O2 levels. Conclusion: This study provides the first report attesting that patients with VKC have high oxidative stress; furthermore, it suggests that CsA could have an anti-inflammatory and antioxidant action that could be useful to prevent the poor VKC outcome.
There is no question that developing new medications in children is fraught with challenges, particularly for rare conditions including pediatric venous thromboembolism (VTE). This is due to both logistical and ethical considerations which are nicely described in a document on the Food & Drug Administration (FDA) website. Furthermore, gaining an approval from the FDA for pediatric use requires a functional partnership between pharmaceutical companies (Pharma), academia, and the regulators/officers at the FDA. When this relationship works well, novel agents can be made available to children that have the assurance of efficacy and safety which is in the best interest of all involved parties, especially patients. The licensure of emicizumab for the prevention of bleeding in hemophilia A patients is one excellent example in which a serious unmet need for a rare disease was addressed in a timely manner (~18 months from the start of a phase 3 trial to approval), and where the labelled indication even includes the word “newborn” with respect to the included age groups. [2,3]Unfortunately, this is not the case with respect to anticoagulants in children, and there is plenty of blame to go around including Pharma, academia (myself included), but also the FDA. I know this all too well as I have had a front seat view having served as an advisor to the FDA on this very topic in 2011 as well as on several other occasions involving specific discussions regarding fondaparinux and rivaroxaban. Although the authors and investigators of this report  are to be commended for the significant effort it took to achieve an FDA-approved indication, one can’t help but feel that with respect at least to injectable anticoagulants that “the ship has sailed.” What do I mean by this? Enoxaparin is the most commonly used low molecular weight heparin (LMWH) and anticoagulant in children with fondaparinux also gaining more use with the prime advantage being that it is a once-a-day option. Despite dalteparin (a less commonly used LMWH) now being licensed for children , I doubt it will ever supersede enoxaparin in prescriptions nor does it have the advantages of fondaparinux, particularly once daily dosing.How did we arrive at such an unenviable situation? Certainly, it is nobody’s fault that enoxaparin does not have a pediatric indication—the author’s clearly explained the fact that enoxaparin came to the market prior to the Pediatric Research Equity Act (PREA), and at this point, despite the sheer volume of data on the pediatric use of enoxaparin, it will likely never be licensed for children. This is not the case, however, for fondaparinux which has been in regulatory limbo with respect to pediatric use for nearly 15 years. This, despite the fact that there is more published data on fondaparinux than dalteparin including a similarly (to dalteparin) designed, prospective, dose-finding, pharmacokinetic, efficacy and safety study [6-8], and the fact that the Pharma companies (the compound has changed hands a few times) have been in discussions with the FDA repeatedly. Unlike with dalteparin, the FDA has placed numerous and pointless hurdles upon the responsible Pharma for capricious reasons succeeding only in potentially putting children at increased risk of harm by, for example, requiring a dose-finding study when the dose of fondaparinux is already well-established. This is the antithesis of what the FDA should be doing. This unending process of which I have played a significant part as an academician has been nothing short of befuddling. While the FDA clearly went to great lengths to work with the sponsor to have dalteparin approved for children, they owe the pediatric hematology community an explanation on what has gone so wrong with fondaparinux.So, where does this leave us currently and what would I recommend pediatric hematologists do with the data from this report  and the licensure of dalteparin for children? Importantly, off-label use in the pediatric setting is quite common typically ranging around 50% depending on the setting  so there is no need for any pediatric treater to fret over prescribing anticoagulants as such. Thus, if you are comfortable using enoxaparin or fondaparinux based on the available data, the collective pediatric experience and your personal experience, then I would advocate that you continue to do so until there are better options (more on that later). If, however, you prefer to prescribe medications per the prescribing information (to the extent possible) and you find the data from this study compelling, then certainly you may choose dalteparin as your anticoagulant of choice for your pediatric patients with VTE.Above I discussed the current situation, however on a strongly positive note, there has been outstanding cooperation between Pharma, academicians and the FDA when it comes to the development of the direct oral anticoagulants (DOACs) which without a doubt will dramatically change the management of pediatric VTE. While I have been privy to discussions with the FDA regarding rivaroxaban and have served on the steering committee for the rivaroxaban and edoxaban studies, I am also aware of the productive discussions with respect to dabigatran and apixaban. This trilateral collaboration is the epitome of what PREA is for, and in the coming year or two, it is highly likely that several DOACs will be licensed for use in children and will also lead to the availability of pediatric-friendly formulations.In conclusion, the approval of dalteparin is on the one hand far too little and too late to be of any meaningful clinical use, yet it does set an example of what fruitful pediatric drug development can look like in hematology/oncology (and other specialties as well) particularly for rare diseases. It is incumbent upon the academic community not to request, but in fact to demand that Pharma fund proper studies (not just ones that “check the box”), and that the FDA review data in a fair and reasonable manner such that the future will be filled with more examples like dalteparin and fewer debacles like fondaparinux.Referenceshttps://www.fda.gov/drugs/drug-information-consumers/drug-research-and-children [Accessed September 9, 2020]Young G, Liesner R, Chang , Sidonio R, Oldenburg J, Jimenez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, Mancuso ME. A multicenter, open-label, phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019; 134: 2127-2138.https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf [Accessed September 9, 2020]Merino M, Richardson N, Reaman G, Ande A, Zvada S, Liu C, Hariharan S, De Claro A, Farrell A, Pazdur R. FDA approval summary: Dalteparin for the treatment of venous thromboembolism in pediatric patients. Pediatr Blood Cancer 2020 (in press).https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020287s072lbl.pdf [Accessed September 9, 2020]Young G, Yee DL, O’Brien SH, Khanna R, Barbour A, Nugent DJ. FondaKIDS: A prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer 2011; 57: 1049-1054.Ko RH, Michieli C, Lira JL, Young G. FondaKIDS II: Long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events. Thromb Res 2014; 134: 643-647.Shen X, Wile R, Young G. FondaKIDS III: A long-term retrospective cohort study of fondaparinux for treatment of venous thromboembolism in children. Pediatr Blood Cancer 2020; 67:e28295.Yackey K, Stukus K, Cohen D, Kline D, Zhao S, Stanley R. Off-label prescribing practices in pediatrics: An update. Hosp Pediatr 2019; 9:186-193.
Early and long term Clinical outcome after Minimally Invasive Direct Coronary Bypass Grafting versus off pump Coronary Surgery via Sternotomy In this retrospective study by Cichon Romuald et al (1), 194-patients met the inclusion criteria and were divided into the MIDCAB group (n=111) and OPCAB via median sternotomy group (n=83). The conclusion was that short as well as long-term outcomes of MIDCAB in terms of mortality, myocardial infarction, stroke, and target vessel revascularization were satisfactory, and as safe and effective as OPCAB via sternotomy This retrospective study by Cichon Romuald et al (1), undoubtedly will generate interest for surgeons who want to perform minimally invasive coronary surgery. It is clear that, in order to attract patients to undergo surgery, surgeons must learn to perform minimally invasive coronary surgery. Advantages of minimally invasive coronary surgery include less post-operative discomfort, faster healing times, less risk of infection and avoidance of trauma associated with OPCAB Surgeons must also take the initiative and play an active role in the Hybrid Revascularization Procedures Current surgeons, and those in residency training programs, should learn wire skills and participate in placement of stents. There is a lot to learn from our interventional cardiologists who embrace new technology and procedures. Surgeons will have to adapt to the new reality, and move some of his/her practice outside the operating room.
Is Otsu Thresholding the Answer to Reproducible Quantification of Left Atrial Scar from Late Gadolinium-Enhancement MRI?Suvai Gunasekaran, PhDa, Daniel Kim, PhDa,ba Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, United Statesb Department of Biomedical Engineering, Northwestern University, Evanston, IL, United StatesPlease send correspondence to:Daniel Kim, PhDDepartment of RadiologyNorthwestern University737 N. Michigan Avenue Suite 1600Chicago, IL 60611 email@example.com O:312.926.1733 F:312.926.5991
To the Editor,We read the letter entitled “Acute lymphoblastic leukemia onset in a 3-year-old child with COVID-19 ” by Marcia et al . with great interest and we hereby suggest to start chemotherapy within the same timeline as for non-COVID-19 acute lymphoblastic leukemia (ALL) patients, following our experience managing a 3-year-old boy with concomitant diagnoses of precursor B-ALL and COVID-19. The patient was a previously healthy boy who presented to our hospital with a two-month history of intermittent fevers, night sweats, fatigue and cervical lymphadenopathies. His mother had been tested positive for COVID-19 three months earlier. He had been seen by his family physician by teleconference at the onset of his symptoms, at which point a COVID-19 infection was suspected but not confirmed. The persistence of symptoms and new onset of bone pain led his parents to reconsult at our hospital. At presentation, he had no respiratory symptoms. Physical examination was remarkable for fever, tachycardia and cervical lymphadenopathies. Bloodwork revealed pancytopenia and circulating peripheral blasts. Inflammatory markers were elevated (fibrinogen 7.08 g/L; C-reactive protein 255 mg/L; sedimentation rate 63 mm/h; ferritin 185 ug/L; D-dimers 0.51 ug/ml). Capillary gas, renal function, hepatic function, coagulation studies (INR/aPTT) and cardiac biomarkers (troponin and pro-BNP) were normal. Chest radiograph (CXR) was normal. COVID-19 testing by nasopharyngeal swab was positive. Bone marrow aspiration revealed 80% precursor B lymphoblasts of hyperdiploid subtype.Patient was admitted to a dedicated COVID-19 ward. Given the absence of SARS-CoV-2 infection’s severity criteria, no COVID-19-specific treatment was initiated. Chemotherapy was started promptly once the diagnostic work-up was completed, 6 days following the patient’s confirmed COVID-19 diagnosis. The patient was treated with a three-drug chemotherapy induction based on National Cancer Institute standard-risk criteria consisting of methylprednisolone, vincristine and asparaginase. Supportive treatment consisted of intravenous hydration and allopurinol for tumor lysis prevention, empirical antibiotics, blood transfusions and prophylactic low molecular weight heparin for COVID-19-associated thromboembolic complications. The patient’s clinical course was favorable; fevers, bone pains, peripheral blasts and inflammatory markers resolved quickly following the steroid prophase. Persistent and unexplained tachycardia led to extensive investigations given concerns for COVID-19-related thromboembolic complications. Troponins, pro-BNP, electrocardiogram, echocardiography, CXR and chest CT scan were unremarkable, and the tachycardia improved with packed red blood cell transfusion. The first negative COVID-19 test was obtained on day 4 of induction therapy but came back positive 48 hours later. The patient was discharged on day 13 of induction therapy. Three consecutive nasopharyngeal swabs were negative on days 21, 23 and 38 following COVID-19 diagnosis (Fig.1). End-induction bone marrow aspiration was consistent with morphologic remission and end-induction minimal residual disease by flow cytometry was positive at 0.025%.This case demonstrates the feasibility of treating children with newly diagnosed ALL who tested positive for COVID-19, without chemotherapy delay or modification, nor specific COVID-19 treatments, as done by Marcia et al . The province of Quebec constitutes the COVID-19 epicenter in Canada with half of all Canadian cases; the prevalence of COVID-19-positive cases was 3.3% among children under the age of 10, 5.3% between the age of 10-20 years and 49.2% for people aged 50 years and above.1 Importantly, no death has been reported among children in the province of Quebec, while 97.6% of COVID-related deaths were among individuals over the age of 60 years.1 Children appear to be less affected from COVID-19 infection and exhibit a milder disease course compared to adults, although the impact of COVID-19 infection among pediatric oncology patients remains unknown.2-4 Current published recommendations in the management of pediatric oncology patients during the COVID-19 pandemic emphasize on the importance of pursuing protocol-prescribed chemotherapy regimens based on the curable nature of most pediatric malignancies and the milder COVID-19 disease course observed in the pediatric population.4 However, case reports of severe COVID-19 disease in pediatric oncology patients start to emerge,5 and management of concomitant COVID-19 infection and newly diagnosed ALL can be challenging. First, our patient presented with a multisystem inflammatory syndrome which made it difficult to discern whether he was symptomatic from the COVID-19 infection versus the leukemia itself. Furthermore, we questioned whether the positive COVID-19 test by polymerase chain reaction (PCR) amplification in our patient truly reflects active infection since there was a nearly 3-month period between the first positive test in his family and when our patient was first tested positive. The positive PCR test could result from prolonged viral shedding in an immunocompromised patient affected by his leukemia onset. Alternatively, a positive test does not necessarily indicate the presence of viable virus as Wolfel and colleagues demonstrated that virus could not be grown from samples obtained from hospitalized patients beyond the eighth day of illness.6 Therefore, the general approach to await a negative result prior to begin chemotherapy might cause significant therapy delay and adversely impact outcomes in newly diagnosed ALL patients during the COVID-19 pandemic. Indeed, our patient took over 23 days to have 2 consecutive negative PCR tests 48 hours apart. Furthermore, the use of COVID-19-specific antiviral treatment in non-critically ill children is controversial given the lack of efficacy in this population.7Antiviral treatment may have significant drug interactions with chemotherapy and contribute to additive gastrointestinal and myelosuppressive toxicities. Nevertheless, the benefit of dexamethasone in COVID-19-positive patients requiring respiratory support in reducing early mortality8 and the exquisite sensitivity of lymphoblasts to corticosteroids could be an effective early strategy to safely initiate therapy in newly diagnosed ALL patients affected with COVID-19, particularly for those presenting with oncologic emergencies such as hyperleukocytosis or mediastinal mass. As the COVID-19 pandemic continues to evolve, pediatric oncologists will be confronted with the ongoing challenge to manage newly diagnosed cancer patients with concomitant COVID-19 infection. International COVID-19 registries in pediatric oncology are actively collecting clinical data to comprehensively assess the impact of COVID-19 within this patient population and to develop standardized management guidelines.9 As for now, an assessment of risks and benefits to initiate or delay cancer therapy will need to be carefully balanced on a case-by-case basis according to the patient’s clinical symptoms, type of malignancy, evidence-based treatment options, and emerging knowledge of COVID-19’s impact in our young cancer patients.CONFLICT OF INTEREST: The authors declare no conflict of interest.REFERENCES1. INSPQ. Données COVID-190 au Québec. 2020.2. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663-1665.3. Cruz AT, Zeichner SL. COVID-19 in Children: Initial Characterization of the Pediatric Disease. Pediatrics. 2020;145(6).4. Bouffet E, Challinor J, Sullivan M, Biondi A, Rodriguez-Galindo C, Pritchard-Jones K. Early advice on managing children with cancer during the COVID-19 pandemic and a call for sharing experiences. Pediatr Blood Cancer. 2020;67(7):e28327.5. Stokes CL, Patel PA, Sabnis HS, Mitchell SG, Yildirim IB, Pauly MG. Severe COVID-19 disease in two pediatric oncology patients.Pediatr Blood Cancer. 2020;67(9):e28432.6. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature.2020;581(7809):465-469.7. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020.8. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.9. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. The COVID-19 pandemic: A rapid global response for children with cancer from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St Jude Global.Pediatr Blood Cancer. 2020;67(7):e28409.Figure 1. Variation of C-reactive protein (CRP) throughout the hospitalization course (blue line). COVID-19 test results are identified in green when positive and red when negative. The day of ALL diagnosis, the day of chemotherapy start (black arrows), the duration of hospitalization (red box) and the duration of symptoms (green box) are indicated. Induction chemotherapy includes: Methylprednisone/prednisone (Day 1-32), Vincristine (Day 4, 11, 18, 25), PEG-Asparaginase (Day 7) and intrathecal cytarabine (Day 1 & 18).
Dear Editor, First we would like to thank Dr Lopez de la Cruz for her comments and interest about our recently published article “the odyssey of suturing cardiac wounds: lessons from the past”. We highly appreciated and agree with the complements she made especially about Larrey and Milton role in this field. One should also note Theodore Tuffier’s attempt at cardiac resuscitation in 1898 in a young man dying on the wards at La Pitié Hospital (Paris)¹. Although this act was performed on an unwounded heart it adds information about the history of surgical approach in such dramatic condition. We do recognize left anterolateral thoracotomy as the gold standard in an emergency room to treat a penetrating cardiac injury. However a median longitudinal sternotomy may be discussed in our opinion if the patient arrived directly in a cardiac surgery operating theater. The patent presented in our paper was directly brought in our operative theater of cardiac surgery and managed immediately by cardiac surgeons and cardiac anesthesiologists, with a cardiopulmonary bypass ready, dedicated scrub nurses and perfusionist. In such specific conditions a sternotomy may be discussed, depending on the context and the anatomical suspected lesions (it was the option retained in the presented case and the surgical procedure was safely performed with good outcome). Clearly, in a peripheral hospital or at the emergency room sternotomy is not an option to be considered and we agree with Dr Lopez de la Cruz.
Jones et al. have given us an excellent guide for the management of symptomatic osteonecrosis in children and young adults with ALL. (1) I would like to present our 10 year retrospective concurrent control evaluation of pamidronate for reducing the incidence of symptomatic osteonecrosis which may be of interest.Patients aged 10-28 years at time of ALL diagnosis were given intravenous pamidronate (1 mg/kg IV over 2 hours) monthly for one year at the discretion of the primary oncologist, starting as early as possible after diagnosis.Concurrent controls age 10-28 did not receive pamidronate. All were treated according to the concurrent COG protocols with intermittent dexamethasone during delayed intensification.(2) Imaging was performed if osteonecrosis was suspected based on symptoms. Patients with BCR-ABL ALL were excluded, as dasatinib may increase the risk of osteonecrosis. (3,4)Patients were diagnosed between January 2010 and March 2018. They were censored at relapse (n=4; 2 controls) bone marrow transplant (n=4; 3 controls) or at last follow up. Data was analyzed 6/1/2020. The median follow up is 3.3 years from diagnosis to event or censoring. This retrospective study was approved by Children’s Minnesota IRB. Data was entered into excel and transferred to SPSS version 23 for analysis.There were 65 patients, 38 males, 27 females, of which 49 had B-lineage and 16 T-lineage ALL. Pamidronate was started during induction in 63% of patients, and before delayed intensification in 85%. The mean, median and interquartile range for the number of pamidronate doses was 11.6, 12, 10.8 to 12. Pamidronate was used in 26 patients, with four subsequently developing symptomatic osteonecrosis. There were 39 concurrent controls who did not receive pamidronate with 14 developing osteonecrosis. Five from this group have since received joint replacements. There were no short or long term side-effects from pamidronate infusions including osteonecrosis of the jaw or hypocalcemia.The incidence of symptomatic osteonecrosis by Kaplan-Meier analysis with was 16% with pamidronate vs. 39% in controls (figure 1). P-value is significant at 0.043 (Breslow Generalized Wilcoxan). There was no significant difference in the leukemia lineage, gender distribution or Body Mass Index (BMI) at diagnosis between groups. For all patients the mean, median, and interquartile range for BMI was 25.8; 22.0; 14.2 to 28.8 Kg/m2.The age at diagnosis was significantly greater in the pamidronate group with a mean, median and Interquartile range 18.4; 18.6; 13.8 to 23.4 years for pamidronate patients vs. 15.6; 15.7; 11.5 to 19.9 in concurrent controls (independent means t-test p = 0.01). Age was not significant for osteonecrosis in Cox Proportional Hazard analysis (p=0.10).Study limitations include small numbers of patients from a single institution and lack of a randomized control group. Strengths of the study are the long duration of followup, as most of the patients are beyond the peak risk time for osteonecrosis. We hope these results even with its limitations would spark interest in a randomized trial of pamidronate in patients at high risk of symptomatic osteonecrosis.Author Contributions and Disclosures: Bruce Bostrom was the sole contributor to this submission and has no conflict-of-interest to disclose. Jack Knutson assisted with data collection as part of a high school senior mentor connection project. Char Bostrom provided invaluable editorial assistance.Figure 1 legend : Incidence of symptomatic osteonecrosis from time of ALL diagnosis in patients who received prophylactic pamidronate and concurrent controls.
The American obstetrician, Joseph DeLee, ‘father of modern obstetrics’, founded the Chicago Lying-in Hospital in 1931 with his vision for womens’ health captured in a set of five stone plaques at the top of the cloister of the hospital’s building. Four of the five stone plaques are engraved with the names of pioneering clinicians whose contributions to the field of obstetrics and gynaecology have been seminal: Jan Palfyn (1650-1730), for introducing the obstetric forceps in the 1720s, Hendrik Van Deventer (1651-1724), for discovering obstetric anatomical disorders, William Smellie (1697-1763), for improving the design of the forceps, and Eduardo Porro (1842 –1902), for introducing hysterectomy to stop postpartum haemorrhage. The fifth stone plaque, in the centre, which is still blank today, is reserved for the physician/scientist who discovers the cause and cure of preeclampsia according to legend.That clusters of preeclamsia occur in family units prompted the question whether preecclampsia is an inherited disorder, and if so, what is the mode of inheritance? Familial clustering opened the possibility of deploying genome wide association studies (GWAS) for the identification of candidate genes and susceptibility loci for the development of preeclampsia and researchers have focused on this question since the discovery of DNA. However, till date, there has been no clearly defined causal relationship between a preeclampsia genotype and phenotype except for heterozygous women who are pregnant with long-chain hydroxyacyl-CoA dehydrogenase deficient fetus who have nearly 80% chance of developing HELLP syndrome or acute fatty liver of pregnancy. Defining the genetics and mode of inheritance of preeclampsia is challenged in part by the involvement of two genomes (maternal and fetal), and a wide spectrum of women who meet the diagnostic criteria according to the International Society for the Study of Hypertension in Pregnancy.There is persuasive literature that coexisting maternal medical disorders such as diabetes, chronic hypertension, renal disease, autoimmune disease, antiphospholipid antibody syndrome and other maternal-fetal risk factors including obesity, dyslipidemia, nulliparity, previous/family history of preeclampsia, and multifetal gestation, increase the risk of preeclampsia. In this issue of the Journal, Gray and colleagues (BJOG 2020 xxxx) used single nucleotide polymorphisms (SNPs) for 21 distinct clinical traits for increased risk of preeclampsia within 7 categories (cardiovascular, inflammatory/ autoimmune, insulin resistance, liver, obesity, renal, and thrombophilia) from the European GWAS to test the hypothesis that women with genetic predisposition to these disorders would have increased risk of preeclampsia in a case/control sample of data from the largest known US preeclampsia GWAS. The authors’ findings that; a) risk alleles for raised diastolic blood pressure and increased BMI were strongly associated with preeclampsia risk (more so for the early-onset disease variant), b) risk alleles for raised alkaline phosphatase levels, increased HDL, GFR, and venous thromboembolism were protective, and c) no significant associations for the other traits examined, are consistent with the current status of preeclampsia and HELLP as highly complex disorders with variable clinical presentations depending on pre-pregnancy maternal conditions, fetal/placental genotypes, and maternal adaptation to the challenge of pregnancy.So, preeclampsia is far from a Mendelian inherited type of genetic disease and the search for its cause and cure continues 90 years after DeLee’s vision!Conflict of interest: None. A completed disclosure of interest form is available to view online as supporting information.
Title: The Time May Soon Be At HandRunning Head: Time May Soon Be At HandAuthors: Saqib Masroor, MD1 and Donald B. Glower MD21. University of Toledo College of Medicine and Life Sciences, Department of Surgery, Division of Cardiothoracic Surgery2. Duke University Medical Center, Department of Surgery, Division of Cardiothoracic SurgeryMeeting Presentation: NoneDisclosure: NoneWord Count: 1213