Validating lactate dehydrogenase (LDH) as a component of the PLASMIC predictive tool (PLASMIC-LDH).

Background: The PLASMIC score is a convenient tool for predicting ADAMTS13 activity of <10%. Lactate dehydrogenase (LDH) is widely used as a marker of haemolysis in thrombotic thrombocytopenic purpura (TTP) monitoring, and could be used as a replacement marker for lysis. We aimed to validate the PLASMIC score in a multi-centre Asia Pacific region, and to explore whether LDH could be used as a replacement marker for lysis. Methods: Records of patients with thrombotic microangiopathy (TMA) were reviewed. Patients' ADAMTS13 activity levels were obtained, along with clinical/laboratory findings relevant to the PLASMIC score. Both PLASMIC scores and PLASMIC-LDH scores, in which LDH replaced traditional lysis markers, were calculated. We generated a receiver operator characteristics (ROC) curve and compared the area under the curve values (AUC) to determine the predictive ability of each score. Results: 46 patients fulfilled the inclusion criteria, of which 34 had ADAMTS13 activity levels of <10%. When the patients were divided into intermediate-to-high risk (scores 5‒7) and low risk (scores 0‒4), the PLASMIC score showed a sensitivity of 97.1% and specificity of 58.3%, with a positive predictive value (PPV) of 86.8% and negative predictive value (NPV) of 87.5%. The PLASMIC-LDH score had a sensitivity of 97.1% and specificity of 33.3%, with a PPV of 80.5% and NPV of 80.0%. Conclusion: Our study validated the utility of the PLASMIC score, and demonstrated PLASMIC-LDH as a reasonable alternative in the absence of traditional lysis markers, to help identify high-risk patients for treatment via plasma exchange.

Real-world data on the use of emicizumab in patients with haemophilia A with and without inhibitors in Singapore.

Introduction: Emicizumab is a bispecific monoclonal antibody that mimics the function of factor VIII by binding to factor IXa and factor X to achieve haemostasis in haemophilia A. The long half-life and subcutaneous mode of administration makes emicizumab a compelling treatment option for bleeding prophylaxis. There is still limited real-world data on its use and management considerations, especially during surgical procedures. The objective of the study is to describe the real-world experience of emicizumab in a cohort of adult and paediatric haemophilia A patients in Singapore, including its use in the periprocedural setting. Method: This was an observational study conducted at the 2 main haemophilia treatment centres in Singapore. All haemophilia A patients who commenced treatment with emicizumab before 1 July 2022 were recruited. Results: A total of 18 patients with haemophilia A were included in this study. Ten (55.6%) patients had active inhibitors. The median annual bleeding rate for all patients before emicizumab use was 4.5 events (interquartile range [IQR] 2.8-8.3) compared with 0 events (IQR 0-0) after emicizumab was commenced (P=0). There were no adverse events of venous or arterial thrombosis, thrombotic microangiopathy, or death. A total of 6 procedures in 5 patients were performed during the study period with no major bleeding complications. Conclusion: Emicizumab effectively protects against bleeding in haemophilia A patients with and without inhibitors, including in children less than 12 years old. More studies are required to address clinical nuances, such as periprocedural management and the role of immune tolerance in patients with inhibitors on emicizumab.

Impact of the updated 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) gene testing in invasive breast cancers: A single center study.

The study aimed to evaluate the impact of the updated 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) testing in invasive breast cancer compared with previous 2013 guidelines. Between Jan 2014 and May 2020, 3364 consecutive invasive breast carcinomas with concurrent HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) results were retrospectively reviewed for HER2 status. Both 2013 and 2018 testing criteria were applied to establish the HER2 status. The testing algorithms involved testing of invasive breast carcinomas by IHC, with equivocal results being reflexed to FISH assays. Concordance rate improved from 92.7% to 94.1% in the non-equivocal IHC cases with the 2018 guidelines. Comparing 2013 versus 2018 criteria, HER2 non-amplified cases increased significantly from 73.7% (n = 2478) to 76.8% (n = 2585), HER2 amplified cases remained similar from 23.4% (n = 789) to 23.2% (n = 779) while equivocal cases decreased from 2.9% (n = 97) to 0% with the new guidelines. Thus, 107 cases (3.2%) were reclassified from HER2 equivocal (n = 97) and amplified (n = 10) to non-amplified with the updated 2018 guidelines. Under the 2018 criteria, a total of 259 cases (7.7%) belonged to the uncommon categories (groups 2 to 4), with group 3 being the most frequent (4.6%), followed by group 4 (2.9%) and group 2 (0.2%). Implementation of 2018 guidelines resulted in a significant increase in HER2 non-amplified cases, mainly due to the abolishment of the equivocal FISH group. This has helped resolve the clinical practice dilemma by providing a more definitive HER2 gene status.

Assessment of transient changes in oxygen diffusion of single red blood cells using a microfluidic analytical platform.

Red blood cells (RBCs) capability to deliver oxygen (O2) has been routinely measured by P50. Although this defines the ability of RBCs to carry O2 under equilibrium states, it cannot determine the efficacy of O2 delivery in dynamic blood flow. Here, we developed a microfluidic analytical platform (MAP) that isolates single RBCs for assessing transient changes in their O2 release rate. We found that in vivo (biological) and in vitro (blood storage) aging of RBC could lead to an increase in the O2 release rate, despite a decrease in P50. Rejuvenation of stored RBCs (Day 42), though increased the P50, failed to restore the O2 release rate to basal level (Day 0). The temporal dimension provided at the single-cell level by MAP could shed new insights into the dynamics of O2 delivery in both physiological and pathological conditions.

Implementation of cytogenomic microarray with plasma cell enrichment enables better abnormality detection and risk stratification in patients with plasma cell neoplasia than conventional cytogenetics and fluorescence in situ hybridization.

The detection of chromosomal abnormalities is important in the diagnosis, prognosis and disease monitoring in plasma cell neoplasia (PCN). However, the gold standard diagnostic techniques of conventional cytogenetics (CC) and fluorescence in situ hybridization (FISH) are hampered by culture difficulties and probe availability. Cytogenomic microarray (CMA), however, is able to surmount such limitations and generate a comprehensive genomic profile with the implementation of plasma cell (PC) enrichment. In this study, we examined 89 bone marrow specimens with CC and FISH without PC enrichment, 35 of which were examined with CMA after PC enrichment. Results revealed that after PC enrichment, CMA was able to detect chromosomal abnormalities in 34 of 35 specimens tested (97.1%), compared to 21 and 32 specimens (60% and 91.4%, respectively) achieved by CC and FISH, respectively, which were similar to the abnormality detection rates among all 89 specimens (59.5% by CC and 92.1% by FISH). In addition, as the only technique capable of detecting copy neutral loss of heterozygosity (CN-LOH) and chromothripsis, CMA appears to be the most powerful tool in risk stratification as it successfully re-stratified 9 (25.7%) and 12 (34.3%) specimens from standard risk (determined by CC and FISH, respectively) to high risk. Based on the encouraging data presented by our study and others, we conclude that implementation of CMA with PC enrichment is of great value in routine clinical workup in achieving a more complete genetic profile of patients with PCN.

Chromosomal microarray analysis is superior in identifying cryptic aberrations in patients with acute lymphoblastic leukemia at diagnosis/relapse as a single assay.

INTRODUCTION: Conventional cytogenetics (CC) is important in diagnosis, therapy, monitoring of post-transplant bone marrow, and prognosis assessment of acute lymphoblastic leukemia (ALL). However, due to the nature of ALL, CC often encounters difficulties of complex karyotype, poor chromosome morphology, low mitotic index, or normal cells dividing only. In contrast, chromosomal microarray analysis (CMA) showed a specificity >99% and a sensitivity of 100% in chronic lymphocytic leukemia (CLL) patients. Here, we report our experience with CMA on adult ALL patients. METHODS: Thirty-three bone marrow/blood samples from ALL patients (aged 18-79 years, median 44) at diagnosis/relapse, analyzed by CC and/or fluorescence in situ hybridization (FISH), were recruited. Chromosomal microarray analysis results were compared with CC. Fluorescence in situ hybridization analysis, if available, was applied when there was a discrepancy. RESULTS: Copy-neutral loss-of-heterozygosity (CN-LOH) was found in 8 cases (24.2%). Only CN-LOH at 9p was recurrent (3 cases, 9.1%). Copy number alterations (CNAs) were detected in 6 of 9 cases (66.7%) with normal karyotypes, in 3 of 5 cases (60.0%) with sole "balanced" translocations, and in 18 of 19 cases (94.7%) with complex karyotypes. Common CNAs involved CDKN2A/2B (30.3%), IKZF1 (27.3%), PAX5 (9.1%), RB1 (9.1%), BTG1 (6.7%), and ETV6 (6.7%), which regulate cell cycle, B lymphopoiesis, or act as tumor suppressors in ALL. Copy number alteration detection rate by CMA was 81.8% (27 of 33 cases) as compared to 57.6% (19 of 33 cases) by CC. CONCLUSION: Incorporation of CMA as a routine clinical test at the time of diagnosis/relapse, in conjunction with CC and/or FISH, is highly recommended.

Symmetry recovery of cell-free layer after bifurcations of small arterioles in reduced flow conditions: effect of RBC aggregation.

Heterogeneous distribution of red blood cells (RBCs) in downstream vessels of arteriolar bifurcations can be promoted by an asymmetric formation of cell-free layer (CFL) in upstream vessels. Consequently, the CFL widths in subsequent downstream vessels become an important determinant for tissue oxygenation (O2) and vascular tone change by varying nitric oxide (NO) availability. To extend our previous understanding on the formation of CFL in arteriolar bifurcations, this study investigated the formation of CFL widths from 2 to 6 vessel-diameter (2D-6D) downstream of arteriolar bifurcations in the rat cremaster muscle (D = 51.5 ± 1.3 µm). As the CFL widths are highly influenced by RBC aggregation, the degree of aggregation was adjusted to simulate levels seen during physiological and pathological states. Our in vivo experimental results showed that the asymmetry of CFL widths persists along downstream vessels up to 6D from the bifurcating point. Moreover, elevated levels of RBC aggregation appeared to retard the recovery of CFL width symmetry. The required length of complete symmetry recovery was estimated to be greater than 11D under reduced flow conditions, which is relatively longer than interbifurcation distances of arterioles for vessel diameter of ∼50 µm. In addition, our numerical prediction showed that the persistent asymmetry of CFL widths could potentially result in a heterogeneous vasoactivity over the entire arteriolar network in such abnormal flow conditions.

Implications of the Updated 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations on Human Epidermal Growth Factor Receptor 2 Gene Testing Using Immunohistochemistry and Fluorescence In Situ Hybridization for Breast Cancer.

CONTEXT: Human epidermal growth factor receptor 2 (HER2/neu) amplification is used as a predictive marker for trastuzumab treatment in breast cancer. Both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) testing algorithms have been based on the 2007 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. In late 2013, the guidelines were updated with new scoring criteria. OBJECTIVE: To assess the impact of the revised ASCO/CAP recommendations on both IHC and FISH results by using the dual-color HER2/neu and centromeric FISH probes. DESIGN: Retrospective analysis of 590 invasive carcinomas with concurrent IHC and dual-color HER2/neu and centromeric 17 (CEP17) FISH results, based on 2007 ASCO/CAP guidelines, was conducted from July 2011 to June 2013. With the revised guidelines, patients were recategorized and concordance rates between the 2 assays were recalculated. RESULTS: Overall concordance rates for FISH and IHC decreased from 94.9% to 93.8% with reclassification. Negative FISH cases decreased from 79.1% to 69.3%. However, equivocal FISH cases were significantly increased from 0.7% to 9.5%, leading to more retesting. Both positive IHC and FISH cases were also noted to be increased, leading to more patients being eligible for trastuzumab treatment, especially those patients with concurrent HER2/neu and CEP17 polysomy. Approximately 1% of patients with initial FISH negative results were reclassified as having positive results when both the ratios and average copy number of HER2/neu were considered under the revised guidelines. CONCLUSIONS: The revised 2013 ASCO/CAP guidelines can potentially lead to more patients being eligible for trastuzumab therapy but additional retesting is to be expected owing to an increased number of equivocal FISH cases.

Amplification of 1q21 and other abnormalities in multiple myeloma patients from a tertiary hospital in singapore.

Much effort has been made to stratify multiple myeloma patients for targeted therapy. However, responses have been varied and improved patient stratifications are needed. Forty-five diagnostic samples from multiple myeloma patients (median age 65 years) were stratified cytogenetically as 15 having non-hyperdiploidy, 20 having hyperdiploidy and 10 having a normal karyotype. Fluorescence in situ hybridization (FISH) assays with FGFR3/IGH, CCND1/IGH, IGH/MAF, RB1 and TP53 probes on bone marrow samples showed that IGH rearrangements were the most common abnormality in the non-hyperdiploid group but these were also found among hyperdiploid patients and patients with normal cytogenetics. Of these, FGFR3/IGH rearrangements were most frequent. Deletion of RB1/monosomy 13 was the most common genetic abnormality across the three groups and was significantly higher among non-hyperdiploid compared to hyperdiploid patients. On the other hand, the study recorded a low incidence of TP53 deletion/monosomy 17. The FGFR3/IGH fusion was frequently seen with RB1 deletion/monosomy 13. FISH with 1p36/1q21 and 6q21/15q22 probes showed that amplification of 15q22 was seen in all of the hyperdiploid patients while amplification of 1q21, Amp(1q21), characterized non-hyperdiploid patients. In contrast, deletions of 1p36 and 6q21 were very rare events. Amp(1q21), FGFR3/IGH fusion, RB1 deletion/monosomy 13, and even TP53 deletion/monosomy 17 were seen in some hyperdiploid patients, suggesting that they have a less than favorable prognosis and require closer monitoring.

CpG Oligonucleotide and Interleukin 2 stimulation enables higher cytogenetic abnormality detection rates than 12-o-tetradecanolyphorbol-13-acetate in Asian patients with B-cell chronic lymphocytic leukemia (B-CLL).

The present study was designed to compare abnormality detection rates using DSP30 + IL2 and 12-O-Tetradecanoylphorbol-13-acetate (TPA) in Asian patients with B-CLL. Hematological specimens from 47 patients (29 newly diagnosed, 18 relapsed) were established as 72 h-DSP30 + IL2 and TPA cultures. Standard methods were employed to identify clonal aberrations by conventional cytogenetics (CC). The B-CLL fluorescence in situ hybridization (FISH) panel comprised ATM, CEP12, D13S25, and TP53 probes. DSP30 + IL2 cultures had a higher chromosomal abnormality detection rate (67 %) compared to TPA (44 %, p < 0.001). The mean number of analyzable metaphases and abnormal metaphases per slide was also higher (p < 0.005, p < 0.001, respectively). Culture success rate, percentage of complex karyotype, and percentage of non-clonal abnormal cell were not significantly different (p > 0.05). Thirteen cases with abnormalities were found exclusively in DSP30 + IL2 cultures compared to one found solely in TPA cultures. DSP30 + IL2 cultures were comparable to the FISH panel in detecting 11q-, +12 and 17p- but not 13q-. It also has a predilection for 11q- bearing leukemic cells compared to TPA. FISH had a higher abnormality detection rate (84.1 %) compared to CC (66.0 %) with borderline significance (p = 0.051), albeit limited by its coverage. In conclusion, DSP30 + IL2 showed a higher abnormality detection rate. However, FISH is indispensable to circumvent low mitotic indices and detect subtle abnormalities.

The road to memory: an early rest for the long journey.

Central memory T lymphocytes were reported to develop after acute but not chronic infection, which prompted this feasibility study on generating long-term CD8 T cells ex vivo, by applying a culture condition that simulates an acute infection. During 35 d of culture, naive T cells (CD45RA(+), CD127(+), CCR7(+), CD62L(+), CXCR3(+)) first developed into effector T cells (CD45RA(+/-), CD127(+/-), CCR7(+/-), CD62L(+), CXCR3(+)), followed by three intermediate stages: intermediate T cells 1 (CD45RO(+), CD127(+/-), CCR7(+), CD62L(+), CXCR3(+)), intermediate T cells 2 (CD45RO(+), CD127(-), CCR7(-), CD62L(+), CXCR3(+)), and intermediate T cells 3 (CD45RO(+/-), CD127(+), CCR7(+), CD62L(-), CXCR3(+)) before reverting to stable CD45RA(+) central memory T cells (CD45RA(+), CD127(+), CCR7(+), CD62L(+), CXCR3(+)). If both anti-CD3 and the inflammatory milieu persisted beyond day 10, intermediate T cells 2 gradually developed into effector memory T cells (CD45RO(+), CD127(-), CCR7(-), CD62L(-), CXCR3(+)). Furthermore, intermediate T cells 2 or effector memory T cells, when cultured in persistent inflammatory cytokines devoid of anti-CD3, were converted to central memory T cells (CD45RO(+), CCR7(+), CD62L(+)). Overall, these results support ex vivo memory-like T lymphocyte production and favor a developmental pathway including both divergent and linear relationships.

Cytogenetic and molecular aberrations of multiple myeloma patients: a single-center study in Singapore.

BACKGROUND: Much is known about the cytogenetic lesions that characterize multiple myeloma (MM) patients from the USA, Europe, and East Asia. However, little has been published about the disease among Southeast Asians. The aim of this study was to determine the chromosomal abnormalities of MM patients in our Singapore population. METHODS: Forty-five newly-diagnosed, morphologically confirmed patients comprising 18 males and 27 females, aged 46 - 84 years (median 65 years) were investigated by karyotyping and fluorescence in situ hybridization (FISH). FISH employing standard panel probes and 1p36/1q21 and 6q21/15q22 probes was performed on diagnostic bone marrow samples. RESULTS: Thirty-four cases (75.6%) had karyotypic abnormalities. Including FISH, a total detection rate of 91.1% was attained. Numerical and complex structural aberrations were common to both hyperdiploid and non-hyperdiploid patients. Numerical gains of several recurring chromosomes were frequent among hyperdiploid patients while structural rearrangements of several chromosomes including 8q24.1 and 14q32 characterized non-hyperdiploid patients. With FISH, immunoglobulin heavy chain (IGH) gene rearrangements, especially fibroblast growth factor receptor 3 (FGFR3)/IGH and RB1 deletion/monosomy 13 were the most common abnormalities (43.4%). Amplification 1q21 was 10 times more frequent (42.5%) than del(1p36) and del(6q21). CONCLUSIONS: We have successfully reported the comprehensive cytogenetic profiling of a cohort of newly-diagnosed myeloma patients in our population. This study indicates that the genetic and cytogenetic abnormalities, and their frequencies, in our study group are generally similar to other populations.

Differential outcomes in an extended family with constitutional t(11;22)(q23.3;q11.2).

The t(11;22) rearrangement is the most common recurrent familial reciprocal translocation in man. Heterozygote carriers are phenotypically normal but are at risk of subfertility in the male, miscarriages, and producing chromosomally unbalanced offspring. The unbalanced progeny usually results from an extra der(22) chromosome resulting from a 3:1 malsegregation. We present here a family with t(11;22). Of six siblings, three were found to be carriers following prenatal diagnosis of the proband fetus. Neither of the two married carrier siblings have a live born child. In keeping with the prevailing knowledge of the pregnancy outcomes of heterozygote carriers, between the siblings they had recurrent miscarriages, a fetus with a +der(22) chromosome, and other subfertility issues resulting in multiple failed in vitro fertilization cycles with preimplantation genetic diagnosis. However, unlike the siblings, their extended family comprising their heterozygote translocation mother, married aunts and an uncle had normal fertility and a lack of a history of miscarriages or an abnormal child. The differing outcomes may be related to the male partners having additional semen anomalies which may further exacerbate problems associated with the t(11;22). Because the t(11;22) rearrangement tends to run in families, it is recommended that chromosome studies are offered to family members of an affected relative as an option, and provide them with appropriate genetic counseling so that they will have the necessary information with regard to their risk for subfertility, miscarriages, and production of viable unbalanced offspring. Follow-up prenatal diagnosis should also be offered to affected expectant family members, especially after preimplantation genetic diagnosis.

HER2/neu revisited: quality and interpretive issues.

BACKGROUND: Immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) are the only tests currently approved by the US Food and Drug Administration for classifying which patients will benefit from trastuzumab therapy. The accuracy of these two testing methods can be adversely affected by a variety of pre-analytical, analytical and post-analytical factors. According to the latest published recommendations of the panel of the Joint Committee of the American Society of Clinical Oncology and College of American Pathologists for HER2/neu testing, laboratories performing IHC and FISH for HER2/neu status in breast cancer are now required to have a high concordance of at least 95% between IHC and FISH, significantly higher than that in the published literature. AIM: To perform a retrospective analysis of the concordance of IHC and FISH analysis for HER2/neu at Singapore General Hospital and review potential causes of disparity between these two methods. METHOD: A retrospective review of a total of 106 invasive ductal carcinomas evaluated for HER2/neu at the Department of Pathology, Singapore General Hospital between 2007 and 2008 were included in the study. The initial HER2/neu immunostained slides were reviewed independently without knowledge of FISH results, and concordance between IHC and FISH was determined. RESULTS: Concordance between IHC and FISH assay was excellent and within the published range (104/106=98.1%). The discordant cases represent a well-recognised subset of genetic heterogeneity in HER2/neu, which is known to contribute to positive IHC and negative FISH tests.

Bone marrow cytogenetics workup: Application of lean management system to determine if additional cell workup is helpful and necessary to analysis.

INTRODUCTION: High workload volumes in a Cytogenetics laboratory can lead to long result turn-around times (TAT). This study aimed to improve laboratory efficiency by adopting Lean Management System initiatives to increase productivity through the elimination of wastes. This study examined if the prerequisite 20-cell analysis was sufficient for a conclusive result or if additional cell workup was necessary to ascertain the presence of a previous chromosome abnormality among cases on follow-up, or when a single abnormal cell was encountered during the analysis to determine the presence of a clone. MATERIALS AND METHODS: The karyotype results of cases that had additional workup were retrieved from among 8040 bone marrow cases of various haematological disorders performed between June 2003 and June 2008. RESULTS: Of 8040 cases analysed, 2915 cases (36.3%) had additional cell workup. Only 49 cases (1.7%) led to the establishment of a clone. The majority of these cases could have been resolved without the additional workup, especially if fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR)-based assays had been utilised. CONCLUSION: This study shows that the additional workup procedure is redundant. The time saved by discontinuing the workup procedure can be used to analyse other cases, leading to increased laboratory efficiency and a faster TAT without compromise to patient care. The practice of additional workup over and above the 20- cell analysis should be dispensed with as little benefit was derived for the amount of additional manpower expended. FISH or PCR-based assays should be utilised to elucidate a case further.

Synovial sarcoma of the kidney: a report of 4 cases with pathologic appraisal and differential diagnostic review.

BACKGROUND: Synovial sarcoma of the kidney is rare. It is clinicoradiologically indistinguishable from the more frequently encountered renal cell carcinoma. Histologically it needs to be differentiated from other spindle cell lesions occurring within the kidney, including a spectrum of benign to malignant tumors. Among malignant spindle cell tumors of the kidney, mimics of synovial sarcoma are sarcomatoid renal cell carcinoma, sarcomatoid urothelial carcinoma and other primary sarcomas, such as leiomyosarcoma and malignant fibrous histiocytoma. CASES: Four cases of synovial sarcoma originated in the kidney, with this report focusing on clinicopathologic and differential diagnostic features. CONCLUSION: The correct diagnosis of synovial sarcoma requires support by an immunohistochemical panel as well as adjunctive investigations like polymerase chain reaction and fluorescence in situ hybridization to determine the presence of the SYT-SSX fusion gene and translocation (X,18), respectively.

Occurrence of trisomy 12, t(14;18)(q32;q21), and t(8;14)(q24.1;q11.2) in a patient with B-cell chronic lymphocytic leukemia.

Trisomy 12, t(14;18)(q32;q21), and t(8;14)(q24.1;q11.2) were found in a 59-year-old man with B-cell chronic lymphocytic leukemia (CLL). While trisomy 12 is one of the most common cytogenetic abnormalities in chronic lymphocytic leukemia, the t(14;18) rearrangement has a strong association with follicular lymphoma and the t(8;14) is associated with T-cell neoplasia. Occurrence of these three abnormalities in CLL are rare, and the significance of this finding is unclear. Further studies of similar cases may shed additional insight into this finding.

Holoprosencephaly: an antenatally-diagnosed case series and subject review.

INTRODUCTION: Holoprosencephaly (HPE) is an uncommon congenital failure of forebrain development. Although the aetiology is heterogeneous, chromosomal abnormalities or a monogenic defect are the major causes, accounting for about 40% to 50% of HPE cases. At least 7 genes have been positively implicated, including SHH, ZIC2, SIX3, TGIF, PTCH1, GLI2, and TDGF1. CLINICAL PICTURE: Twelve antenatally- and 1 postnatally-diagnosed cases are presented in this study. These comprised 6 amniotic fluid, 3 chorionic villus, 2 fetal blood, 1 peripheral blood, and 1 product of conception. OUTCOME: The total chromosome abnormality rate was 92.3%, comprising predominantly trisomy 13 (66.7%). There was 1 case of trisomy 18, and 3 cases of structural abnormalities, including del13q, del18p, and add4q. CONCLUSION: Despite the poor outcome of an antenatally-diagnosed HPE and the likely decision by parents to opt for a termination of pregnancy, karyotyping and/or genetic studies should be performed to determine if a specific familial genetic or chromosomal abnormality is the cause. At the very least, a detailed chromosome analysis should be carried out on the affected individual. If the result of high resolution karyotyping is normal, Fluorescence in situ hybridisation (FISH) and/or syndrome-specific testing or isolated holoprosencephaly genetic testing may be performed. This information can be useful in making a prognosis and predicting the risk of recurrence.