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Aplastic Anaemia

Anaplastic Anemia is not a cancer. AA is a rare disease in which the bone marrow is unable to produce adequate blood cells; leading to pancytopenia (deficiency of all types of blood cells). AA may occur at any age, but there is a peak in adolescence / early adulthood, and again in old age. Slightly more males than females are diagnosed with AA, also the disease is more common in the Far East. Patients successfully treated for aplastic anemia have a higher risk of developing other diseases later in life, including cancer.

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Fanconi Anaemia

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    MeSH term: Anemia, Aplastic
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Li X, Wu YH, Cai SS, et al.
Early Detection of Myelodysplastic Syndrome/Leukemia-associated Mutations Using NGS Is Critical in Treating Aplastic Anemia.
Curr Med Sci. 2019; 39(2):217-221 [PubMed] Related Publications
Distinguishing between aplastic anemia (AA) and hypoblastic myelodysplastic syndrome (hMDS) with a low percentage of bone marrow (BM) blasts (<5%) can be difficult due to the overlap in clonality and a spectrum of genetic alternations between the two subtypes of diseases. However, due to recent advances in DNA sequencing technology, both spectrum and frequency of mutations can be accurately determined and monitored by next-generation sequencing (NGS) at initial diagnosis and during immunosuppressive therapy (IST) in patients with AA or hMDS. This improvement in acquiring a patient's genetic status and clonal evolution can provide more proper, precise, and on-time information to guide disease management, which is especially helpful in the absence of traditional morphologic/cytogenetic evidence.

Kandula P, Shah KM, Wolverton JE, et al.
Pyoderma gangrenosum: a presenting sign of myelodysplastic syndrome in undiagnosed Fanconi anemia.
Dermatol Online J. 2019; 25(1) [PubMed] Related Publications
A 26-year-old man with a history of congenital bilateral microtia, unilateral renal agenesis, left aural atresia, and right external auditory canal occlusion admitted for right rib cartilage graft harvest and left ear re-construction. Following surgery, an ulceration with violaceous borders and a yellow fibrinous base unresponsive to broad-spectrum antibiotics developed at the harvest site. The wound was expanding and not responsive to systemic broad-spectrum antibiotics. Biopsy revealed a dense dermal infiltrate of neutrophils with negative tissue cultures consistent with pyoderma gangrenosum (PG). He was treated with systemic, intralesional, and topical steroids, as well as doxycycline. Three weeks after the diagnosis of PG, he was found to have persistent anemia and leukopenia. Bone marrow aspiration analysis was consistent with hypocellular myelodysplastic syndrome and genetic testing was consistent with Fanconi anemia. There is a well-known association of PG with hematological disorders. Fanconi anemia is a rare genetic hematologic disorder with congenital defects leading to bone marrow failure and malignancy in long-standing disease. In our patient, we consider his development of PG a paraneoplastic sign associated with the onset of his hypocellular myelodysplastic syndrome.

Toptan T, Brusadelli MG, Turpin B, et al.
Limited detection of human polyomaviruses in Fanconi anemia related squamous cell carcinoma.
PLoS One. 2018; 13(12):e0209235 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia is a rare genome instability disorder with extreme susceptibility to squamous cell carcinoma of the head and neck and anogenital tract. In patients with this inherited disorder, the risk of head and neck cancer is 800-fold higher than in the general population, a finding which might suggest a viral etiology. Here, we analyzed the possible contribution of human polyomaviruses to FA-associated head and neck squamous cell carcinoma (HNSCC) by a pan-polyomavirus immunohistochemistry test which detects the T antigens of all known human polyomaviruses. We observed weak reactivity in 17% of the HNSCC samples suggesting that based on classical criteria, human polyomaviruses are not causally related to squamous cell carcinomas analyzed in this study.

Onishi S, Tajika M, Tanaka T, et al.
Superficial Esophageal Cancer in a Fanconi Anemia Patient That Was Treated Successfully by Endoscopic Submucosal Resection.
Intern Med. 2019; 58(4):529-533 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a disorder of chromosomal fragility characterized by progression to aplastic anemia, myelodysplastic syndrome, and leukemia. FA patients are also predisposed to solid cancers. A case of FA in an adult patient who developed tongue and superficial esophageal cancers following hematopoietic stem cell transplantation is reported. This case was considered significant because it is the first reported case of superficial esophageal cancer in an FA patient that was treated successfully by endoscopic submucosal resection.

Itskoviz D, Tamary H, Krasnov T, et al.
Endoscopic findings and esophageal cancer incidence among Fanconi Anemia patients participating in an endoscopic surveillance program.
Dig Liver Dis. 2019; 51(2):242-246 [PubMed] Related Publications
BACKGROUND AND AIMS: The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers.
METHODS: We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV
RESULTS: Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett's esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV
CONCLUSIONS: FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients.

Mafessoni TP, Mazur CE, Amenábar JM
Salivary lactate dehydrogenase (LDH) as a tool for early diagnosis of oral cancer in individuals with Fanconi anemia.
Med Hypotheses. 2018; 119:29-31 [PubMed] Related Publications
Currently one of the greater challenges is the diagnosis and treatment of cancer. Many studies address the genetic and metabolic aspects to support in early diagnosis and increase the survival of individuals at high risk. Individuals with Fanconi anemia can be included in this high risk group because they have a predisposition to develop head and neck cancer. The use of salivary enzymes as biomarkers to detect the changes in oral tissue at the initial phase seems viable, because saliva is easy to obtain, it moisture oral mucosa and cells metabolic compounds can be found on it. Due to the metabolic characteristics of the cancer cell, an increase in Lactate Dehydrogenase (LDH) may indicate a carcinogenesis process. The hypothesis of this study is to use of salivary LDH as a tool in the early diagnosis of oral cancer on a high risk group such as Fanconi anemia's patients.

McReynolds LJ, Calvo KR, Holland SM
Germline GATA2 Mutation and Bone Marrow Failure.
Hematol Oncol Clin North Am. 2018; 32(4):713-728 [PubMed] Free Access to Full Article Related Publications
GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.

Agarwal S
Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita.
Hematol Oncol Clin North Am. 2018; 32(4):669-685 [PubMed] Related Publications
Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increased awareness and availability of diagnostic tests in recent years. This article summarizes the pathophysiology, evaluation, and management of hematopoietic failure in patients with DC and other TBDs.

Savage SA, Walsh MF
Myelodysplastic Syndrome, Acute Myeloid Leukemia, and Cancer Surveillance in Fanconi Anemia.
Hematol Oncol Clin North Am. 2018; 32(4):657-668 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is a DNA repair disorder associated with a high risk of cancer and bone marrow failure. Patients with FA may present with certain dysmorphic features, such as radial ray abnormalities, short stature, typical facies, bone marrow failure, or certain solid malignancies. Some patients may be recognized due to exquisite sensitivity after exposure to cancer therapy. FA is diagnosed by increased chromosomal breakage after exposure to clastogenic agents. It follows autosomal recessive and X-linked inheritance depending on the underlying genomic alterations. Recognizing patients with FA is important for therapeutic decisions, genetic counseling, and optimal clinical management.

Schaefer EJ, Lindsley RC
Significance of Clonal Mutations in Bone Marrow Failure and Inherited Myelodysplastic Syndrome/Acute Myeloid Leukemia Predisposition Syndromes.
Hematol Oncol Clin North Am. 2018; 32(4):643-655 [PubMed] Free Access to Full Article Related Publications
Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes.

Sieff CA
Introduction to Acquired and Inherited Bone Marrow Failure.
Hematol Oncol Clin North Am. 2018; 32(4):569-580 [PubMed] Related Publications
Acquired aplastic anemia and inherited bone marrow failure syndromes both present with pancytopenia and must be distinguished because they have differences in treatment decisions and continued monitoring requirements. Advances in the genetic interrogation of patient samples have led to identification of inherited germline diseases and appreciation that patients with inherited bone marrow failure disorders may be normal in appearance with few expected clinical clues. Somatic mutations in aplastic anemia may have prognostic value. Hematopoietic stem cells from inherited marrow failure diseases can correct the proliferative defect and may develop further somatic mutations that progress to myelodysplastic syndrome or acute myeloid leukemia.

Yang HD, Xia MT, Shao YF, Ying P
Recurrent ovarian hemorrhage in a patient with aplastic anemia: A case report.
Medicine (Baltimore). 2018; 97(27):e11409 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Recurrent ovarian hemorrhage resulting in ovarian infarction may lead to a life-threatening intraperitoneal hemorrhage in women with bleeding disorders such as aplastic anemia (AA). Moreover, it is seen as ovarian tumors in the diagnosis. The authors report a clinical case with the aim of sharing our experiences and exploring the ways to diagnose, treat, and avoid ovarian hemorrhage.
PATIENTS CONCERNS: A 48-year-old woman with AA had suffered from a serious abdominal distension for the past 24 hours, which had occurred intermittently for the past 15 years.
DIAGNOSES: Pelvic ultrasonography had revealed a large anechoic area of fluid in the abdomen without any sign of primary hemorrhage each time she had experienced an episode over the past 15 years. The volume of pelvic fluid had decreased after anti-inflammatory and hemostatic treatment. At presentation, the abdominal computed tomography suggested an ovarian tumor with a massive hemoperitoneum (a right ovarian mass, 5.7 × 5.0 × 5.0 cm in size, with a large amount of abdominal and pelvic fluid).
INTERVENTIONS: Surgery was performed with respect to the bilateral uterine adnexa. On laparotomy, there were blood clots of approximately 6.0 × 6.0 × 5.0 cm surrounding the right ovary and approximately 400 mL bloody fluid in the abdomen.
OUTCOMES: The patient recovered without incident and was transferred to a hematology ward 1 week later. Postoperative pathology confirmed hemorrhagic infarction of the right ovary.
LESSONS: In conclusion, continuous ovarian bleeding can cause ovarian infarction to women with bleeding disorders and it may be confused with an ovarian tumor. Moreover, an earlier ovariectomy procedure under stable conditions or treatment with gonadotropin-releasing hormone that prevent bleeding via ovulation suppression may be effective for such cases.

Feben C, Wainstein T, Kromberg J, et al.
Fanconi anaemia in South Africa: Past, present and future.
S Afr Med J. 2018; 108(5):393-398 [PubMed] Related Publications
Fanconi anaemia (FA) is an inherited genetic disorder characterised by somatic anomalies, bone marrow failure and an increased predisposition to solid tumours and haematological malignancies. South African (SA) black and Afrikaner individuals are at higher than average risk for this condition owing to genetic founder mutations in certain Fanconi-associated genes. This review explores the epidemiology, clinical presentation, diagnostic modalities and recommended care of affected patients, focusing on the founder population groups in SA. The early diagnosis of FA is important and provides improved opportunities for early intervention, but remains challenging.

Arian SE, Flyckt RL, Herman R, et al.
Fertility preservation in pediatric female cancer patients.
Fertil Steril. 2018; 109(5):941 [PubMed] Related Publications
OBJECTIVE: To describe and demonstrate ovarian tissue cryopreservation (OTC) as an emerging fertility preservation technique DESIGN: Video presentation.
SETTING: University hospital.
PATIENT(S): A 6 year-old female patient diagnosed with aplastic anemia with plan for bone marrow transplantation underwent laparoscopic unilateral oophorectomy in conjunction with surgical procedure for port placement by the pediatric surgeon, followed by cryopreservation of ovarian tissue.
INTERVENTION(S): Laparoscopic unilateral oophorectomy followed by ovarian decortication in the operating room, and ovarian tissue freezing prior to undergoing bone marrow transplantation.
MAIN OUTCOME MEASURE(S): To present principle surgical techniques of ovarian tissue harvesting prior to OTC in pediatric patients, and different surgical techniques for ovarian auto-transplantation of cryobanked ovarian tissue after completion of gonadotoxic treatment and when the patient is ready to conceive.
RESULT(S): This video demonstrates the detailed surgical technique for ovarian tissue harvesting. This harvesting can be performed laparoscopically or via mini-laparotomy and can involve a complete oophorectomy versus removing a portion of the ovary (a procedure also known as ovarian decortication).
CONCLUSION(S): In the prepubertal child, due to the small size of the ovaries, we recommend oophorectomy rather than decortication owing to the small size of prepubertal gonadal tissue. Many young cancer patients can be offered the option of ovarian tissue freezing. This tissue contains immature primordial follicles that can be stored. OTC requires surgical ovarian harvesting followed by cryopreservation of strips of ovarian tissue. The increased number of eggs in prepubertal children underscores the fact that smaller ovarian size in this population does not preclude OTC. At this time, ovarian auto-transplantation is the only option to utilize this stored tissue for fertility preservation. OTC is a relatively new procedure within the area of ART. The overall data from OTC is reassuring and further suggests that cryopreservation of ovarian tissue has the potential to become an established fertility preservation method in the near future.

Toret E, Demirag B, Köker SA, et al.
Aplastic Anemia as an Immune-mediated Complication of Thymoma: A Case Report.
J Pediatr Hematol Oncol. 2018; 40(7):e464-e466 [PubMed] Related Publications
Thymomas are the most common masses located in the anterior mediastinum, and they are often associated with autoimmune disorders including myasthenia gravis, polymyositis, and aplastic anemia (AA). Autoreactive T-cell clones generated by the thymoma may lead to autoimmune disorders. We report the case of a 14-year-old boy who was examined for AA, and the underlying cause was determined to be an immune-mediated complication of thymoma. He had no matched sibling donors. He underwent thymectomy, and 3 months later he was treated with immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A. The duration of the IST was determined to be a period of 12 months. He has recently been in complete response condition for 6 months since IST stopped. IST is a successful treatment choice for thymomas associated with AA in childhood.

Furquim CP, Pivovar A, Amenábar JM, et al.
Oral cancer in Fanconi anemia: Review of 121 cases.
Crit Rev Oncol Hematol. 2018; 125:35-40 [PubMed] Related Publications
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by aplastic anemia, progressive pancytopenia, congenital anomalies, and increased risk of cancer development. After hematopoietic stem cell transplant (HSCT), patients have an estimated 500-fold increase in the risk of developing head and neck cancer compared to a non-affected, and the oral cavity is affected in one-third of cases. Thus, this study aimed to better understand the natural history of oral cavity cancer in patients affected by FA. After conducting a keyword search on MEDLINE, we found 121 cases of oral cavity cancer in patients who had been affected by FA. In conclusion, HSCT may increase the risks of oral cancer development, especially after 5 years after the transplant. In the normal population, the tongue is the most affected area. FA patients should be informed of the risks of oral malignant transformation and encouraged to be undergo medical surveillance.

Fiz F, Sahbai S, Campi C, et al.
Tumor Burden and Intraosseous Metabolic Activity as Predictors of Bone Marrow Failure during Radioisotope Therapy in Metastasized Prostate Cancer Patients.
Biomed Res Int. 2017; 2017:3905216 [PubMed] Free Access to Full Article Related Publications
Rationale: Radium-223-Dichloride (Ra-223) is an alpha-emitter, used to treat bone metastases. Patients with high metastatic burden and/or with increased trabecular bone uptake could present a higher incidence of hematologic toxicity. We hypothesized that these two factors are predictors of bone marrow failure.
Material and Methods: A computer algorithm discriminated between trabecular bone (

Ling T, Crispino JD, Zingariello M, et al.
GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy.
Expert Rev Hematol. 2018; 11(3):169-184 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: GATA1, the founding member of a family of transcription factors, plays important roles in the development of hematopoietic cells of several lineages. Although loss of GATA1 has been known to impair hematopoiesis in animal models for nearly 25 years, the link between GATA1 defects and human blood diseases has only recently been realized. Areas covered: Here the current understanding of the functions of GATA1 in normal hematopoiesis and how it is altered in disease is reviewed. GATA1 is indispensable mainly for erythroid and megakaryocyte differentiation. In erythroid cells, GATA1 regulates early stages of differentiation, and its deficiency results in apoptosis. In megakaryocytes, GATA1 controls terminal maturation and its deficiency induces proliferation. GATA1 alterations are often found in diseases involving these two lineages, such as congenital erythroid and/or megakaryocyte deficiencies, including Diamond Blackfan Anemia (DBA), and acquired neoplasms, such as acute megakaryocytic leukemia (AMKL) and the myeloproliferative neoplasms (MPNs). Expert commentary: Since the first discovery of GATA1 mutations in AMKL, the number of diseases that are associated with impaired GATA1 function has increased to include DBA and MPNs. With respect to the latter, we are only just now appreciating the link between enhanced JAK/STAT signaling, GATA1 deficiency and disease pathogenesis.

Nalepa G, Clapp DW
Fanconi anaemia and cancer: an intricate relationship.
Nat Rev Cancer. 2018; 18(3):168-185 [PubMed] Related Publications
Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2-FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.

Khoury R, Sauter S, Butsch Kovacic M, et al.
Risk of Human Papillomavirus Infection in Cancer-Prone Individuals: What We Know.
Viruses. 2018; 10(1) [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have been intensely studied in laboratory models and humans. What remains largely unknown are host tissue and immune-related factors that determine an individual's susceptibility to infection and/or carcinogenesis. Such susceptibility factors could serve to identify those at greatest risk and spark individually tailored HPV and SCC prevention efforts. Fanconi anemia (FA) is an inherited DNA repair disorder that is in part characterized by extreme susceptibility to SCCs. An increased prevalence of HPV has been reported in affected individuals, and molecular and functional connections between FA, SCC, and HPV were established in laboratory models. However, the presence of HPV in some human FA tumors is controversial, and the extent of the etiological connections remains to be established. Herein, we discuss cellular, immunological, and phenotypic features of FA, placed into the context of HPV pathogenesis. The goal is to highlight this orphan disease as a unique model system to uncover host genetic and molecular HPV features, as well as SCC susceptibility factors.

Marsh JCW, Gutierrez-Rodrigues F, Cooper J, et al.
Blood Adv. 2018; 2(1):36-48 [PubMed] Free Access to Full Article Related Publications
Biallelic germline mutations in

Vicenzi EB, Calore E, Decembrino N, et al.
Posaconazole oral dose and plasma levels in pediatric hematology-oncology patients.
Eur J Haematol. 2018; 100(3):315-322 [PubMed] Related Publications
BACKGROUND: Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level.
METHODS: A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included.
RESULTS: Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 μg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 μg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04.
CONCLUSIONS: Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics.

Aljasem HA, Messner HA, Lipton JH, et al.
Outcome following second allogeneic hematopoietic cell transplantation: A single-center experience.
Eur J Haematol. 2018; 100(3):308-314 [PubMed] Related Publications
OBJECTIVE: Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single-center study sought to investigate parameters that influence post-second allogeneic HCT survival.
METHOD: We investigated 92 patients who underwent second allogeneic HCT between 1980 and 2016 for relapse or graft failure following first HCT. Median age at second HCT was 41 years (range 16-68), performed for relapse in 59 patients (64%) and for graft failure in 33 patients (36%).
RESULTS: On univariate analysis, 3-year OS of the entire cohort was 35% (95% CI=25-45). Eastern Cooperative Oncology Group (ECOG) score (3-year OS 48% for ECOG 0-1, 18% for ECOG 2-3, P=.0006), second HCT indication (3-year OS 43% for relapse, 20% for graft failure, P=.02), time from first HCT to relapse/graft failure (3-year OS for <12months 21%, for ≥12months 46%, P=.009), and conditioning intensity (3-year OS for MA 42% vs other regimens 23%, P=.08) significantly influenced OS. Multivariable analysis confirmed ECOG score (HR=2.15 for ECOG 2-3, 95% CI=1.32-3.51, P=.002) and second HCT indication (HR=1.67 for graft failure, 95% CI=1.02-2.75, P=.04) to independently influence survival.
CONCLUSION: Second HCT may offer long-term survival particularly to patients with good performance status who relapse post-first HCT.

Vlachos A
Acquired ribosomopathies in leukemia and solid tumors.
Hematology Am Soc Hematol Educ Program. 2017; 2017(1):716-719 [PubMed] Free Access to Full Article Related Publications
A mutation in the gene encoding the small subunit-associated ribosomal protein RPS19, leading to RPS19 haploinsufficiency, is one of the ribosomal protein gene defects responsible for the rare inherited bone marrow failure syndrome Diamond Blackfan anemia (DBA). Additional inherited and acquired defects in ribosomal proteins (RPs) continue to be identified and are the basis for a new class of diseases called the ribosomopathies. Acquired RPS14 haploinsufficiency has been found to be causative of the bone marrow failure found in 5q- myelodysplastic syndromes. Both under- and overexpression of RPs have also been implicated in several malignancies. This review will describe the somatic ribosomopathies that have been found to be associated with a variety of solid tumors as well as leukemia and will review cancers in which over- or underexpression of these proteins seem to be associated with outcome.

Nepal M, Che R, Zhang J, et al.
Fanconi Anemia Signaling and Cancer.
Trends Cancer. 2017; 3(12):840-856 [PubMed] Free Access to Full Article Related Publications
The extremely high cancer incidence associated with patients suffering from a rare human genetic disease, Fanconi anemia (FA), demonstrates the importance of FA genes. Over the course of human tumor development, FA genes perform critical tumor-suppression roles. In doing so, FA provides researchers with a unique genetic model system to study cancer etiology. Here, we review how aberrant function of the 22 FA genes and their signaling network contributes to malignancy. From this perspective, we will also discuss how the knowledge discovered from FA research serves basic and translational cancer research.

Singh T, Andi K
Fanconi anaemia and oral squamous cell carcinoma: management considerations.
N Z Med J. 2017; 130(1466):92-95 [PubMed] Related Publications
Fanconi anaemia (FA) is a rare multi-system genetic disorder where patients are susceptible to the development of oral malignancies. Clinicians involved in their management should be vigilant in detecting lesions early, and an individualised treatment plan should then be formulated. Although surgery forms the mainstay of oncological treatment, adjuvant therapy can be instituted with care. Unfortunately, prognosis is poor, and close long-term follow-up is required. This short report describes pertinent management considerations in relation to a case of oral squamous cell carcinoma.

Chao MM, Thomay K, Goehring G, et al.
Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms.
Klin Padiatr. 2017; 229(6):329-334 [PubMed] Related Publications
Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in

Bierings M, Bonfim C, Peffault De Latour R, et al.
Transplant results in adults with Fanconi anaemia.
Br J Haematol. 2018; 180(1):100-109 [PubMed] Related Publications
The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76-87%), acute graft-versus-host disease (GvHD) grade II-IV in 22% (95% CI 16-28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.

Alter BP, Giri N, Savage SA, Rosenberg PS
Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
Haematologica. 2018; 103(1):30-39 [PubMed] Free Access to Full Article Related Publications
The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers.

Cooper JN, Young NS
Clonality in context: hematopoietic clones in their marrow environment.
Blood. 2017; 130(22):2363-2372 [PubMed] Free Access to Full Article Related Publications
Clonal hematopoiesis occurs normally, especially with aging, and in the setting of disease, not only in myeloid cancers but in bone marrow failure as well. In cancer, malignant clones are characterized by recurrent somatic mutations in specific sets of genes, but the direct relationship of such mutations to leukemogenesis, when they occur in cells of an apparently healthy older individual or after recovery from immune aplastic anemia, is uncertain. Here we emphasize a view of clonal evolution that stresses natural selection over deterministic ontogeny, and we stress the selective role of the environment of the marrow and organism. Clonal hematopoieses after chemotherapy, in marrow failure, and with aging serve as models. We caution against the overinterpretation of clinical results of genomic testing in the absence of a better understanding of clonal selection and evolution.

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