Microsurgical Head and Neck Reconstruction in Patients With Fanconi Anemia.

ABSTRACT: Patients with Fanconi anemia (FA) are at increased risk for head and neck cancers that often necessitate extensive reconstructions. Such patients have multiple comorbidities including anemia and thrombocytopenia frequently requiring bone marrow transplant, and they are at an increased risk of cancer recurrence and need for further extirpation. in the present study, charts from 3 patients with FA who underwent microvascular free tissue transfer by the senior author were retrospectively reviewed for pertinent pre- and peri-operative details in addition to functional and cosmetic outcomes. Two of these patients ultimately required metachronous free flap reconstructions for recurrence. All patients had acceptable functional and cosmetic outcomes following each instance of free flap reconstruction, thereby demonstrating the utility of microvas- cular free tissue transfer in patients with FA. The authors herein present each patient's clinical history in addition to a discussion of the current literature and an outline of our approach to these challenging cases.

Squamous cell carcinoma development in Fanconi anemia patients who underwent hematopoietic stem cell transplantation.

We examined SCC development of 24 FA patients, who received HSCT from HLA-matched relatives. In our BMT center, we applied low-dose CY + LFI + ATG (n:13) as conditioning regimen for FA patients between 1992 and 1999, and CY + BU + ATG (n:11) between 1999 and 2002. The aim of this study was to investigate SCC development after HSCT and examine features of the follow-up patients. The 10-year overall survival (OS) of the group with LFI + regimen was 43%, whereas the group without LFI regimen was 60%. There was a statistically significant relationship between infections (viral/bacterial) and overall survival (Fisher's Exact test P < .001). Five out of 13 long-term (>1 year) surviving patients developed SCC in the HNSCC (n:4) and esophagus (n:2) region (a patient with oral SCC developed a second primary esophageal SCC). The SCC rate in our FA patients was 38%, four of the SCC patients were transplanted with irradiation used conditioning regimens, three of them had acuteGvHD (Grade II-III), only one developed chronic GvHD. The interval between HSCT and SCC diagnosis was median 13 (range 6-18) years, the age for the development of cancer was median 21 (range 15-32) years. Survival after SCC was low, median 6 months (range 6-12), due to delayed SCC diagnosis, tumor progression under therapy and treatment-related toxicities of the usually reduced RT and/or CT.

[Fungemia and septic arthritis caused by Saprochaete capitata in a patient with fanconi aplastic anemia: a case report]. / Fanconi aplastik anemili bir hastada Saprochaete capitata'nin neden oldugu fungemi ve septik artrit: bir olgu sunumu.

Saprochaete capitata (formerly known as Blastoschizomyces capitatus, Trichosporon capitatum, Geotrichum capitatum) is a rare but emerging yeast-like fungus. It is commonly found in environmental sources and can be isolated from skin, gastrointestinal system and respiratory tract of healthy individuals as well. It mainly infects patients with hematological malignancies such as acute myeloid leukemia (AML), especially in the presence of neutropenia; and mortality rates are high in those patients. Although the data about the in vitro antifungal susceptibility are limited, it is being reported that amphotericin B and voriconazole are more effective on S.capitata isolates whereas caspofungin had no activity. Here, we report a case of fungemia and septic arthritis due to S.capitata in a patient with Fanconi aplastic anemia. A 22-year-old male patient with Fanconi aplastic anemia was hospitalized in our hematology department for bone marrow transplantation. Two days after the hospitalization, neutropenic fever developed and multiple nodules similar to candidiasis were detected in his liver with the whole abdomen magnetic resonance imaging (MRI). Caspofungin treatment (single 70 mg/kg loading dose, followed by 1 x 50 mg/kg/day) was started. The patient remained febrile, and his blood culture yielded S.capitata. The treatment regimen was changed to a combination of liposomal amphotericin B (3 mg/kg/day) and voriconazole (2 x 4 mg/kg/day). A few days later, pain and swelling came out on patient's left knee and he underwent a surgical process with the prediagnosis of septic arthritis. Culture of synovial fluid was also positive for S.capitata. On the 26th day of the hospitalization, the patient died due to sepsis and multiple organ failure. Patient's blood and synovial fluid samples were incubated in BacT/Alert automated blood culture system (bioMérieux, France). After receiving the growth signal, yeast cells were seen in Gram staining and cream-coloured, wrinkled, yeast-like colonies that were able to grow at 45oC and resistant to cycloheximide were detected on Sabouraud dextrose agar (SDA). Urease test was negative, and according to API 20C AUX (bioMérieux, France) system, none of the carbonhydrates were utilized except glucose. The isolates that were able to produce annelloconidia in corn meal-Tween 80 agar slide culture were identified as S.capitata. The identification was further confirmed by DNA sequence analysis. Minimal inhibitory concentrations (MICs) of amphotericin B, fluconazole, voriconazole, and caspofungin were found to be 0.5 µg/ml, 1.5 µg/ml, 0.032 µg/ml, and > 16 µg/ml respectively. Repetitive sequence based PCR (rep-PCR) (DiversiLab system, bioMérieux, France) was used to determine clonal relatedness of the isolates from blood and synovial fluid samples. The isolates were indistinguishable (similarity coefficient > 97%) according to rep-PCR. In conclusion, S.capitata infections should be taken into consideration in the presence of fungemia and septic arthritis in hematological patients who receive caspofungin therapy.

Successful Outcome With Fludarabine-Based Conditioning Regimen for Hematopoietic Stem Cell Transplantation From Related Donor in Fanconi Anemia: A Single Center Experience From Turkey.

BACKGROUND: Fanconi anemia (FA) is a heterogeneous autosomal recessive (and rarely X linked) disorder, which is characterized by congenital malformations, progressive bone marrow failure, and predisposition to malignancies. Hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for the hematological manifestations in FA. PROCEDURE: Twenty-seven patients with FA underwent HSCT using fludarabine (Flu) based regimen at our center between April 2004 and May 2014. One patient who developed acute leukemia before HSCT was excluded from the study. The remaining 26 patients were included. The median age of the patients at the time of transplantation was 9.6 years (range 5.6-17.0 years) and male/female ratio was 19/7. Donors were Human leukocyte antigen (HLA)-identical sibling in 18 patients, HLA-identical other relatives in six patients, and HLA 1-antigen mismatched sibling in two patients. Conditioning regimen consisted of Flu, cyclophosphamide, and antithymocyte globulin. RESULTS: All patients engrafted but one developed poor graft function and underwent second HSCT. Acute graft versus host disease (GVHD) (≥grade 2) occurred in two patients (7.6%) and chronic GVHD in one patient (3.9%). Three patients developed venoocclusive disease (11.5%). Survival rate was 96.2% (25/26) at a median follow-up of 54 months (10-131 months) and all patients who survived were in good clinical condition. None of the patients developed secondary malignancy during the follow-up period. CONCLUSIONS: The present study from Turkey, a middle-income country, shows successful transplant outcome with low toxicity using Flu-based conditioning in patients with FA who underwent HSCT from HLA-related donors.

Sequential renal and bone marrow transplants in a child with Fanconi anemia.

FA is an autosomal recessive disorder characterized by small stature and renal abnormalities. FA can lead to progressive bone marrow failure, myelodysplastic syndrome, or acute leukemia. Using a multidisciplinary team approach, we managed a 3-yr-old boy with FA who simultaneously developed renal and hematopoietic failure. Because renal function was insufficient to support the conditioning regimen for HCT, we performed a deceased donor renal transplant in December 2012 prior to HCT with the known risk of graft-versus-graft rejection of the donor kidney. Seven months later he underwent allogeneic HCT. He obtained myeloid engraftment on day +11 and peripheral blood chimerism demonstrated all donor by day +21. He developed asymptomatic CMV reactivation and despite antirejection medications, mild skin graft-versus-host disease. He has maintained excellent renal function and remains transfusion independent with full hematopoietic recovery. He has not experienced any renal rejection episodes nor developed donor-specific antibodies toward his renal donor. Peripheral blood chimerism remains completely HCT donor. He is clinically well, now greater than two and a half yr after renal transplant and two yr after HCT. The continuing close collaboration between the Pediatric Nephrology and Bone Marrow Transplant teams is a major factor in this successful outcome.

Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia.

Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre-transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen-matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft-versus-host disease was 19%. 5-year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups.

Primary intracranial leiomyosarcoma of the torcular Herophili associated with Fanconi anemia and allogenic stem cell transplantation.

PURPOSE: Fanconi anemia is associated with a high risk for developing malignant tumors. The occurrence of primary intracranial leiomyosarcoma, however, which in general has a poor prognosis, has not been described thus far. The purpose of this study is to report on management and outcome of leiomyosarcoma of the torcular Herophili associated with Fanconi anemia in a pediatric patient. CASE REPORT: A 12-year-old girl with Fanconi anemia presented with a primary intracranial leiomyosarcoma arising from the torcular Herophili and infiltrating the adjacent venous sinuses after previous allogenic hematopoietic stem cell transplantation. Radical tumor resection followed by radiotherapy resulted in tumor-free survival and good outcome at a 2-year follow-up. CONCLUSION: Despite occurrence of leiomyosarcoma in a site thought unfavorable for surgery, combined tumor resection and radiosurgery may yield excellent outcome.

More than 10 years after the first 'savior siblings': parental experiences surrounding preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) to create a healthy donor for a sibling's hematopoetic stem cell transplantation for a child with Fanconi Anemia (FA) was first reported in 2001. Yet we know little about the experiences of parents who have encountered decision making surrounding PGD and human leukocyte antigen (HLA)-typing. The first aim of this study was to understand parents' awareness, perceptions and beliefs about reproductive decision-making including emotional, cognitive, moral dimensions as well as regret surrounding the use of this technology. The second aim was to describe the experiences and rationale of parents of children with a single gene disorder regarding the factors that influenced their decision making surrounding the use of natural pregnancy and/or PGD and HLA-typing. Parents from two national FA support networks in the US and Canada responded to an emailed survey about reproductive decision making and outcomes surrounding natural pregnancy and PGD and HLA-typing. Descriptive statistics and Pearson's Chi-Square tests were used to describe and compare data. Our results indicate that the most important factors in the PGD decision making process were the health of the child and cognitive appraisals followed by emotional responses and then moral judgments. A significant difference was noted in parents considering natural pregnancy before and after 2001 (p = 0.01). Unexpected findings were that less than 35 % of parents were offered PGD by any health care professional and only 70 % were aware PGD with HLA-typing was a reproductive option. Our research suggests that the option of PGD and HLA-typing may influence parents' reproductive decision making choices.

Oral Premalignant and Malignant Lesions in Fanconi Anemia Patients.

OBJECTIVE: There is a lack of data supporting cancer surveillance in pediatric Fanconi Anemia patients. We sought to describe the rates of upper aerodigestive lesions and malignancy in this population to augment current management guidelines. METHODS: A retrospective cohort study of patients with Fanconi Anemia from a quaternary referral center between 2007-2021 was completed for head and neck cancer risk. RESULTS: One hundred and five FA patients were reviewed. Average age at presentation was 11.3 years old and 90.5% of patients underwent hematopoietic stem cell transplant (HSCT). A total of 8.6% of patients had leukoplakia or erythroplakia and 3.8% developed malignancy. The standardized incidence ratio of head and neck malignancy was 483.8. Patients presented with leukoplakia and malignancy at an average age of 14.6 and 25.1 years old, respectively. Malignancies were aggressive and marked by recurrence. There were no premalignant or malignant lesions found on flexible laryngoscopy. This series represents the largest longitudinal series of pediatric FA head and neck lesions. CONCLUSIONS: Fanconi Anemia patients should begin screening for head and neck cancer at age 10 or after HSCT. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 133:1745-1748, 2023.

Matched sibling donor stem cell transplantation for Fanconi anemia patients with T-cell somatic mosaicism.

SCT from HLA-identical sibling donors is generally associated with an excellent survival in FA patients if performed prior to the development of MDS or leukemia. However, the optimal conditioning regimen has not been defined. We report here our experience with 15 Japanese FA patients who underwent HLA-matched sibling donor SCT. The aim of this study is to compare radiation-based conditioning to Flu-based conditioning for FA patients in a Japanese population where the T-cell somatic mosaicism is higher than in the Caucasian population. Eight patients (a-group) received a radiation-based conditioning (500-600 cGy of thoracoabdominal/TBI) with CY dose modification (20-120 mg/kg), and ATG; two patients exhibited rejection. Seven patients (b-group) received CY (40 mg/kg), 150-180 mg/m(2) of Flu, and ATG. Durable engraftment was demonstrated in all patients. In FA patients, Flu-based conditioning may allow stable engraftment in matched sibling donor transplantation without radiation, even in patients with T-cell somatic mosaicism.

Post-hematopoietic stem cell transplant squamous cell carcinoma in patients with Fanconi anemia: a dreadful enemy.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with Fanconi anemia (FA) and hematological manifestations but it does not prevent solid tumors, especially squamous cell carcinomas (SCC). METHODS: Retrospective study in 22 FA patients who had received HSCT and had been followed up beyond 2 years after HSCT. RESULTS: The median follow-up was 15 years. Six patients developed head-and-neck SCC after transplantation. The cumulative incidence of SCC at 15 and 30 years from the HSCT was 14.2% and 71.2%, respectively. One patient was diagnosed in stage IV and the rest, who were being followed up in cancer screening programs, in stage I. Treatment of SCC consisted of surgery in all patients; radiotherapy and chemotherapy were used in two patients and were poorly tolerated. CONCLUSION: FA patients have high risk of head-and-neck SCC. Multi-disciplinary programs for early cancer detection are of special relevance in these patients.

On how Rac controls hematopoietic stem cell activity.

Rac GTPases form part of the family of Rho small GTPases. Rac GTPases, like other Rho family GTPases, are key molecular switches controlling the transduction of external signals to cytoplasmic and nuclear effectors. The development of genetic and pharmacological tools has allowed a more precise definition of the specific roles of Rac GTPases in hematopoietic stem cells (HSCs). Our current knowledge has enabled dissection of their specific and redundant roles. Rac GTPases are now known to be crucial in the response of HSCs to the hematopoietic microenvironment cues. This review will briefly summarize the known HSC functions that are regulated by Rac GTPases, focusing on adhesion, migration, retention, proliferation, and survival, and how Rac relates to the physiological functions of HSC. The development of small molecule inhibitors with the ability to interfere with Rac GTPase activation offers new therapeutic strategies to manipulate the function of HSC in vivo and ex vivo.

Allogeneic hematopoietic stem cell transplantation of patients with FA and high risk features using fludarabine without radiation.

Several factors unique to Fanconi anemia (FA) limit the success of allogeneic hematopoietic stem cell transplantation (HSCT) in this population. In this report, we describe a multi-center pilot study of five consecutive FA patients with high-risk features for transplant prepared with fludarabine, without radiation. Four patients engrafted quickly, experienced minimal toxicity and are well at 43-65 months post-transplant. One patient had a C-mismatched unrelated donor transplant and had unsustained engraftment. This fludarabine based regimen without radiation was safe and effective for four high-risk patients, suggesting that eliminating radiation should be further studied as an approach to HSCT in children with FA.

Related donor hematopoietic stem cell transplantation for Fanconi anemia without radiation: a single center experience in Turkey.

Eight children with FA underwent allogeneic HSCT without using irradiation for the conditioning regimen. Patients received two different conditioning regimens: first two patients received BU 1.5 mg/kg/day for four days and CY 10 mg/kg/day for four days and the other regimen was: Flu 30 mg/m(2)/day for five days, CY 10 mg/kg/day for two days, and ATG-Fresenius 9-10 mg/kg/day for four days. GVHD prophylaxis consisted of CsA + MTX for the first two patients and only CsA for the others. All patients received HLA-identical stem cells from related donors. Primary engraftment was demonstrated in all patients. No patient developed acute GVHD and one patient had chronic GVHD. Only one patient who received BU based regimen died because of VOD. Overall, seven patients (87.5%) are alive with stable full donor chimerism at a median follow-up time of 2.5 yr (range: 1.7-8.9 yr). None of the patients developed secondary malignancy. Based on our data, we conclude that Flu-based, non-irradiation conditioning regimen was safe with low organ toxicity and stable engraftment in FA patients undergoing HSCT from matched related donors.

An unusual pattern of B-cell immunological reconstitution after allogeneic stem cell transplantation: a possible correlation with CMV reactivation?

IR after HSCT is a slow process that involves several components of the immune response, and, in allogeneic setting, it can be delayed by GvHD and immuno-suppressive therapy. Our study on IR post-HSCT included a child with FA who underwent MUD transplantation. To evaluate B, T and NK cell reconstitution and to investigate the differentiation of B lymphocyte repertoire, this patient was carefully monitored at various time points by IgHCDR3 (third complementarity determining region of the immunoglobulin heavy chain) fingerprinting and by FACS analysis. IgHCDR3 fingerprinting showed a strong oligoclonality of IgM and IgG profiles from day +60 to +180 post-transplant. CMV reactivation was present at the same time points and overlapped the clonal pattern shown in IgHCDR3 fingerprinting. Immunophenotype analysis showed early repopulation of T and NK cells following HSCT, whereas B cells increased first at one yr post-transplant. The overlapping of virus reactivation and B-cell clonal expansion seems to suggest that B lymphocytes may be involved in the CMV immunological response, at least in the early time points after HSCT when the immune repertoire is still reconstituting.

AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice.

Fanconi anemia (FA) is a heterogeneous inherited disorder characterized by a progressive bone marrow (BM) failure and susceptibility to myeloid leukemia. Genetic correction using gene-transfer technology is one potential therapy. A major hurdle in applying this technology in FA patients is the inability of granulocyte colony-stimulating factor (G-CSF) to mobilize sufficient numbers of hematopoietic stem (HSC)/progenitor cells (HPC) from the BM to the peripheral blood. Whether the low number of CD34(+) cells is a result of BM hypoplasia or an inability of G-CSF to adequately mobilize FA HSC/HPC remains incompletely understood. Here we use competitive repopulation of lethally irradiated primary and secondary recipients to show that in two murine models of FA, AMD3100 synergizes with G-CSF resulting in a mobilization of HSC, whereas G-CSF alone fails to mobilize stem cells even in the absence of hypoplasia.

Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry.

BACKGROUND: Fanconi anemia is an inherited genomic instability syndrome associated with progressive bone marrow failure leading to death or the requirement for hematopoietic stem cell transplantation, acute myeloid leukemia, and solid tumors. Prior epidemiological studies have quantified the risks of bone marrow failure, acute myeloid leukemia and solid tumors, but these estimates have not been replicated. DESIGN AND METHODS: We assembled a cohort of 181 patients with Fanconi anemia mostly from Germany. We calculated the ratio of observed to expected cancers, and the risks of bone marrow failure, acute myeloid leukemia, and solid tumors by age. RESULTS: The first adverse event was bone marrow failure in 66 patients, acute meyloid leukemia in 14 patients and solid tumors in 10 patients. The ratio of observed to expected cancers was 44 for all cancers, 26 for all solid tumors, and 868 for acute myeloid leukemia; these increased risks were statistically significant. Significantly elevated ratios of observed to expected cancers were observed for esophageal (6281), vulvar (2411), head and neck (240), breast (34) and brain (23) tumors. Absent or abnormal radii, and a five-item congenital abnormality score, were significant risk factors for bone marrow failure. The cumulative incidence of bone marrow failure by the age of 10 years varied from 12.6% in the lowest bone marrow failure risk group to 84% in the highest. The relative hazard of bone marrow failure was significantly higher in complementation group G versus A (relative hazard=2.2) and in C versus A (relative hazard=5.4). CONCLUSIONS: Findings from the German Fanconi Anemia Registry cohort validate prior risk estimates, and strongly support the concept that Fanconi anemia is a highly penetrant cancer susceptibility syndrome with early onset of acute myeloid leukemia and slightly later onset of specific solid tumors.

The outcome of children with Fanconi anemia given hematopoietic stem cell transplantation and the influence of fludarabine in the conditioning regimen: a report from the Italian pediatric group.

BACKGROUND AND OBJECTIVES: Hematopoietic stem cell transplantation (HSCT) still represents the only treatment potentially able to prevent/rescue the development of marrow failure and myeloid malignancies in patients with Fanconi anemia (FA). While in the past HSCT from an HLA-identical sibling was proven to cure many patients, a higher incidence of treatment failure has been reported in recipients of an unrelated donor (UD) or HLA-partially matched related allograft. DESIGN AND METHODS: We analyzed the outcome of 64 FA patients (age range, 2-20 years) who underwent HSCT between January 1989 and December 2005. Patients were transplanted from either an HLA-identical sibling (n=31), an UD (n=26), or an HLA-partially matched relative (n=7). T-cell depletion of the graft was performed in patients transplanted from an HLA-disparate relative. RESULTS: The 8-year estimate of overall survival (OS) for the whole cohort was 67%; it was 87%, 40% and 69% when the donor was an HLA-identical sibling, an UD and a mismatched relative, respectively (p<0.01). The outcome of recipients of grafts from an UD improved over time, the probability of survival being 10% and 72% for patients transplanted before and after 1998, respectively (p<0.05). The OS probability of children who did or did not receive fludarabine in preparation for the allograft was 86% and 59%, respectively (p<0.05). INTERPRETATION AND CONCLUSIONS: These data, useful for counselling, provide support to the concept that a relevant proportion of FA patients undergoing HSCT can now be successfully cured, even in the absence of an HLA-identical sibling, especially if the conditioning regimen includes fludarabine.