A Case Report on Hepatic Extramedullary Hematopoiesis as the Manifestation of Progression to Secondary Myelofibrosis in a Patient with Essential Thrombocytopenia.

Myeloproliferative neoplasms (MPN), which include primary myelofibrosis (PMF) and essential thrombocytopenia (ET), are characterized by the clonal proliferation of mature blood cells as a result of the overactivation of the JAK/STAT pathway. Extramedullary hematopoiesis (EMH), a common complication of PMF, occurs due to the dysregulation of the bone marrow microenvironment. We report an interesting case of a 73-year-old female with a working diagnosis of ET who was found to have EMH in the liver on biopsy after she had newly onset elevated liver enzymes and her ET had progressed to secondary myelofibrosis. We conclude that in patients with MPN who have rising liver enzymes, EMH in the liver should be part of the differential diagnosis. In addition, we believe that EMH is a sign of progression from MPN to secondary myelofibrosis and that it is imperative for performing bone marrow aspiration and biopsy in order to reassess hematopoiesis and to look for bone marrow fibrosis as well as evidence of progression.

Giant vascular spiradenocylindroma of the scalp clinically mimicking a vascular tumor.

We present a giant vascular spiradenocylindroma (GVSC) with a unique presentation. The diagnosis of GVSC can be clinically and radiologically elusive. The differential diagnosis includes angiolipoma, angiosarcoma, and glomus-tumor-like vascular lesions. Dermatologists should consider this variant of spiradenocylindroma in any vascular-like lesion.

Spectrum of lymphoma subtypes based on the latest World Health Organization classification in southern Iran from 2000 to 2011.

Background: Lymphoma, both Hodgkin and non-Hodgkin, is one of the most common malignancies, with a distinct subtype distribution throughout the world. Methods: A total of 453 lymphoma cases, identified retrospectively from January 2000 to October 2011, were studied to identify the subtype distribution of lymphoma in our center, located in southern Iran, according to the latest WHO classification. Results: The most common sites of involvement of all lymphomas were extranodal (59.16%). The highest frequency of extranodal sites in all lymphoid neoplasms were associated with diffuse large B-cell lymphoma (22.95%) and classical Hodgkin lymphoma (10.15%). Of 453 cases, 23 (5.32%) were T and natural killer cell neoplasms, of which the most common subtypes were T-cell large granular lymphocytic leukemia and anaplastic large cell lymphoma. Conclusion: This study indicated that the subtype distribution of lymphoma (except for the higher prevalence of diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and lower rate of follicular lymphoma) in this part of Iran is similar to that in the Middle Eastern countries. Mature B-cell neoplasms are less frequent compared with both western and far east Asian countries.

miR-378-3p Knockdown Recapitulates Many of the Features of Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are clonal neoplasms of the hematopoietic stem cell that result in aberrant differentiation of hematopoietic lineages caused by a wide range of underlying genetic, epigenetic, and other causes. Despite the myriad origins, a recognizable MDS phenotype has been associated with miRNA aberrant expression. A model of aberrant myeloid maturation that mimics MDS was generated using a stable knockdown of miR-378-3p. This model exhibited a transcriptional profile indicating aberrant maturation and function, immunophenotypic and morphologic dysplasia, and aberrant growth that characterizes MDS. Moreover, aberrant signal transduction in response to stimulation specific to the stage of myeloid maturation as indicated by CyTOF mass cytometry was similar to that found in samples from patients with MDS. The aberrant signaling, immunophenotypic changes, cellular growth, and colony formation ability seen in this myeloid model could be reversed with azacytidine, albeit without significant improvement of neutrophil function.

SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization.

INTRODUCTION: Recent studies have identified subtypes of small cell lung carcinoma (SCLC) defined by the RNA expression of ASCL1, NEUROD1, POU2F3, and YAP1 transcriptional regulators. There are only limited data on the distribution of these markers at the protein level and associated pathologic characteristics in clinical SCLC samples. METHODS: The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was analyzed by immunohistochemistry in 174 patient samples with SCLC. Subtypes defined by these markers were correlated with histologic characteristics, expression of classic neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1), and other SCLC markers, including the neuroendocrine phenotype-associated markers TTF-1 and DLL3. RESULTS: ASCL1 and NEUROD1 expression had the following distribution: (1) 41% ASCL1+/NEUROD1-; (2) 37% ASCL1+/NEUROD1+; (3) 8% ASCL1-/NEUROD1+; and (4) 14% ASCL1-/NEUROD1-. On the basis of their relative expression, 69% of cases were ASCL1-dominant and 17% were NEUROD1-dominant. POU2F3 was expressed in 7% of SCLC and was mutually exclusive of ASCL1 and NEUROD1. YAP1 was expressed at low levels, primarily in combined SCLC, and was not exclusive of other subtypes. Both ASCL1-dominant and NEUROD1-dominant subtypes were associated with neuroendocrine markerhigh/TTF-1high/DLL3high profile, whereas POU2F3 and other ASCL1/NEUROD1 double-negative tumors were neuroendocrine markerlow/TTF-1low/DLL3low. CONCLUSIONS: This is the first comprehensive immunohistochemical and histopathologic analysis of novel SCLC subtypes in patient samples. We confirm that ASCL1/NEUROD1 double-negative tumors represent a distinct neuroendocrine-low subtype of SCLC, which is either uniquely associated with POU2F3 or lacks a known dominant regulator. The expression profiles of these markers appear more heterogeneous in native samples than in experimental models, particularly with regard to the high prevalence of ASCL1/NEUROD1 coexpression. These findings may have prognostic and therapeutic implications and warrant further clinical investigation.

Peripheral Cytotoxic T Cell Lymphoma of the Appendix Presenting as Acute Appendicitis.

INTRODUCTION: Lymphoma of the appendix is a rare cause of acute appendicitis; however, acute appendicitis is a common first manifestation of appendiceal lymphomas. Cytotoxic peripheral T cell lymphoma (PTCL) is a type of aggressive non-Hodgkin lymphoma that portends a generally poor outcome. Cytotoxic PTCL of the appendix is extremely rare with few cases reported in the literature. Case Presentation. This is the report of a 23-year-old man who had experienced lower abdominal pain for three months before presenting to the emergency department with severe right lower abdominal pain, nausea, vomiting, and anorexia since the day prior to admission. The patient was diagnosed with acute appendicitis, and the pathology report confirmed cytotoxic PTCL of the appendix. CONCLUSION: Patients with appendiceal PTCL commonly present with signs and symptoms of acute appendicitis due to luminal obstruction by the tumor. Therefore, appendiceal tumors such as PTCL should be considered in the differential diagnosis of patients presenting as acute appendicitis. In addition, since there is no standard chemotherapy regimen for cytotoxic PTCL, this and other case reports hopefully help in providing the clinical evidence needed for establishing appropriate treatment guidelines.

The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer.

PURPOSE: SMARCA4 mutations are among the most common recurrent alterations in non-small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. EXPERIMENTAL DESIGN: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. RESULTS: In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with class 1 mutations having the best response to ICIs (P = 0.027). CONCLUSIONS: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.

Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib in EGFR-Mutant Lung Cancer.

PURPOSE: Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays, which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements. EXPERIMENTAL DESIGN: To characterize mechanisms of resistance to osimertinib, patients with metastatic EGFR-mutant lung cancers who received osimertinib at Memorial Sloan Kettering Cancer Center and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified. RESULTS: Among 62 patients who met eligibility criteria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of later-line cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 MET amplification, 1 KRAS mutation, 1 RET fusion, and 1 BRAF fusion) whereas 4% (1/27) had an acquired EGFR mutation (EGFR G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired PIK3CA mutation, chromosome 3q amplification, and FGF amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The compound mutation EGFR S768 + V769L and the mutation MET H1094Y were identified and validated as resistance mechanisms with potential treatment options. CONCLUSIONS: Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.See related commentary by Piotrowska and Hata, p. 2441.

Zimmermann-Laband syndrome: Clinical and cytogenetic study in two related patients.

BACKGROUND: Zimmermann-Laband Syndrome (ZLS) is an extremely rare autosomal dominant congenital disorder. It is a craniofacial malformation syndrome with predominant intraoral involvement consisting of gingival fibromatosis diffusion in early development. The molecular basis of ZLS is still unknown. Although familial aggregation with different inheritance patterns is detected in ZLS patients, most of the cases are sporadic. MATERIAL AND METHODS: We report on two sibling patients with clinical manifestations of ZLS. Blood samples of both patients were obtained in EDTA-tubes followed by performing cytogenetic study using Cyto2.7M array. Analysis of the copy number was performed using the Chromosome Analysis Suite Software (version 1.0.1, annotation file na 30, Affymetrix) and interpreted with recourse to the UCSC genome browser (http://genome.ucsc.edu/; Human Mar. 2006NCBI Build 36.1/hg18 assembly). RESULTS: The array analysis revealed overlapping regions of chromosomal aberrations in both patients. We detected a 258-kb deletion at 3q13.13, a 89-kb duplication at 1q25.2 as well as two 67-kb duplications at 1p12 and 19q12. These altered regions do not contain any known genes and protein-coding sequences. CONCLUSIONS: In conclusion, the findings of this report revealed new chromosomal aberrations, including a deletion at 3q13.13 and duplications at 1q25.2, 1p12 and 19q12, in the two patients with ZLS. Such findings indicate that whole genome screening for genomic rearrangements is fruitful in typical and atypical patients with ZLS. Key words:Zimmermann-Laband syndrome, cytogenetic array, whole genome screening, chromosomal aberration, gingival fibromatosis.

Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes.

INTRODUCTION: EGFR-mutant lung cancers are clinically and genomically heterogeneous with concurrent RB transcriptional corepressor 1 (RB1)/tumor protein p53 (TP53) alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown. METHODS: Patients with EGFR/RB1/TP53-mutant lung cancers, identified by next-generation sequencing from 2014 to 2018, were compared to patients with untreated, metastatic EGFR-mutant lung cancers without both RB1 and TP53 alterations. Time to EGFR-tyrosine kinase inhibitor discontinuation, overall survival, SCLC transformation rate, and genomic alterations were evaluated. RESULTS: Patients with EGFR/RB1/TP53-mutant lung cancers represented 5% (43 of 863) of EGFR-mutant lung cancers but were uniquely at risk for transformation (7 of 39, 18%), with no transformations in EGFR-mutant lung cancers without baseline TP53 and RB1 alterations. Irrespective of transformation, patients with EGFR/TP53/RB1-mutant lung cancers had a shorter time to discontinuation than EGFR/TP53- and EGFR-mutant -only cancers (9.5 versus 12.3 versus 36.6 months, respectively, p = 2 × 10-9). The triple-mutant population had a higher incidence of whole-genome doubling compared to NSCLC and SCLC at large (80% versus 34%, p < 5 × 10-9 versus 51%, p < 0.002, respectively) and further enrichment in triple-mutant cancers with eventual small cell histology (seven of seven pre-transformed plus four of four baseline SCLC versus 23 of 32 never transformed, respectively, p = 0.05). Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutation signature was also enriched in triple-mutant lung cancers that transformed (false discovery rate = 0.03). CONCLUSIONS: EGFR/TP53/RB1-mutant lung cancers are at unique risk of histologic transformation, with 25% presenting with de novo SCLC or eventual small cell transformation. Triple-mutant lung cancers are enriched in whole-genome doubling and Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like hypermutation which may represent early genomic determinants of lineage plasticity.

Prognostic Significance of Complex Karyotypes in Acute Myeloid Leukemia.

OPINION STATEMENT: Acute myeloid leukemia (AML) patients with a complex karyotype (CK-AML) show at least 3 unrelated clonal cytogenetic abnormalities with notoriously poor outcome. Such cases fall into either AML with myelodysplasia-related changes or therapy-related AML in the current World Health Organization classification of AML. Allogeneic stem cell transplantation is one of the only treatment modalities that can provide a long-term survival benefit and is recommended as a consolidative treatment in patients who are able to achieve complete remission. Unfortunately, transplantation is also associated with a higher relapse rate and more than half of CK-AML patients relapse from disease within the first 2 years. The probability of achieving remission with traditional induction using cytarabine and daunorubicin or idarubicin ("7 + 3") is so small that investigational therapies should be considered up front in these patients. Less intensive therapeutic backbones, typically using one of the hypomethylating agents, azacitidine or decitabine, minimize toxicity and show a trend toward the improved overall survival. CPX 351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin and this encapsulation leads to prolonged exposure to the two drugs. This drug is approved for AML patients with MDS-related changes and therapy-related AML, both of which are frequently associated with complex karyotype. Such patients show improved outcome in trials using this combination. Combination therapy that includes venetoclax (BCL2 inhibitor) with hypomethylating agents may also be appropriate for such patients.

Teratogenic Effects of Intravitreal Injection of Bevacizumab in a Pregnant Rat Model.

In this research study, to investigate teratogenic effect of intravitreal injection of bevacizumab in pregnant rat model, twenty seven female Wistar rats were inseminated. Pregnant rats were divided into 6 groups (three groups as case and three as control groups). Each case and control groups were divided according to the day of intravitreal injections (day 2, 10 and 18). Rats in the case groups received 4 µL intravitreal injection of bevacizumab and the control groups received the same volume of distilled water. The tail and umbilical cord length in case groups 1, 2, and 3 did not display any significant differences compared to their control groups. The fetal weight was significantly lower in the case groups 1 (p>0.001) and 2 (p>0.001) compared to their control groups. Furthermore, the placental weight was only lower in the case group 1 (p>0.001). Case group 2 had a shorter crown rump length in comparison with its control group (p=0.029). Morphological investigations showed two abnormal cases of gastroschisis in group 1 and a case of a cleft in the skull in one of the rats in case group 2. The results show that intravitreal bevacizumab has developmental effect when administered in the early stages of pregnancy; but it is safe when administered in the last week of pregnancy in rats.

Adenoid Cystic Carcinoma of the Larynx Presenting as a Thyroid Mass and Brief Literature Review.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the larynx and trachea is very rare. CASE: A 45-year-old man with ACC of the larynx presenting as a thyroid mass is reported in this study. Physical examination revealed a large solid thyroid nodule in the left lobe without any lymphadenopathy. A technetium thyroid scan showed multinodular goiter with cold nodules in the left lobe, isthmus, and functioning nodules in the right lobe. A large thyroid mass originating from the left side of the larynx, mostly the left vocal cord and the infraglottic part, was seen using enhanced magnetic resonance imaging after rupture of the thyroid cartilage on the left side. Ultrasound-guided fine needle aspiration smears and cell blocks of the thyroid nodule showed highly cellular smears composed of large tissue fragments, three-dimensional clusters, and sheets of neoplastic cells with slightly enlarged round and hyperchromatic nuclei. Immunohistochemical study showed that the cell block expressed C-kit and CK 7 on the cribriform growth pattern of the tumoral cells. However, protein expression of thyroglobulin and thyroid transcription factor-1 was not detectable. CONCLUSION: To approach a thyroid nodule, direct invasion or metastatic tumors of other organs must be borne in mind.

mir-126 rs4636297 and TGFßRI rs334348 functional gene variants are associated with susceptibility to endometriosis and its severity.

microRNAs (miRNAs) are negative regulators in a variety of cellular processes that occur in endometriosis. Therefore, functional polymorphisms in miRNA and miRNA binding sites may affect gene expression and contribute to susceptibility of endometriosis. In this study, we evaluated the association of two miRNA related polymorphisms, mir-126 rs4636297 and TGFßRI rs334348, with endometriosis risk and its severity. This case-control study was done on 157 endometriosis patients and 252 healthy women as a control group. Tetra amplification refractory mutation system-polymerase chain reaction (tetra-ARMS PCR) was designed to determine the polymorphisms. Our finding showed significant differences in genotype frequency of mir-126 rs4636297 between the groups (χ2 = 6.26, p = 0.044). A significant protection against endometriosis was found for mir-126 rs4636297 in allele (G versus A allele: OR = 0.695, 95% CI = 0.519-0.931, p = 0.015) and genotype (GG versus AA genotype: OR = 0.451, 95%CI = 0.233-0.873, p = 0.018). Significant association was also observed between the A allele and severity of endometriosis (OR = 0.478, 95%CI = 0.297-0.768, p = 0.002). Moreover, we found a significant association between AA genotype with the risk of endometriosis (OR = 0.493, 95%CI = 0.250-0.970, p = 0.041) and its severity (OR = 0.240, 95%CI = 0.065-0.883, p = 0.032) regarding TGFßRI rs334348 polymorphism. These finding suggest that, for the first time, mir-126 rs4636297 and TGFßRI rs334348 polymorphisms may influence individual's susceptibility to endometriosis and its severity.