Deaths, panic, lockdowns and US equity markets: The case of COVID-19 pandemic.

This study investigates the impact of COVID-19 pandemic on the microstructure of US equity markets. In particular, we explain the liquidity and volatility dynamics via indexes that capture multiple dimensions of the pandemic. Our results suggest that increases in confirmed cases and deaths due to coronavirus are associated with a significant increase in market illiquidity and volatility. Similarly, declining sentiment and the implementations of restrictions and lockdowns contribute to the deterioration of liquidity and stability of markets.

Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma.

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development.

Granzyme B is not required for regulatory T cell-mediated suppression of graft-versus-host disease.

Regulatory T (T(reg)) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses. The mechanisms by which T(reg) cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for T(reg) cell-mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B-deficient T(reg) cells were equally able to suppress effector T (T(eff)) cell proliferation driven by multiple stimuli, including allogeneicantigen-presenting cells. Surprisingly, adoptive transfer of granzyme B-deficient T(reg) cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in T(reg) cell-mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific T(reg) cell-suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses.

Adult T-Cell Leukemia-Lymphoma Presenting Concurrently with Myelopathy.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus. Of the approximate ten to twenty million people currently infected worldwide, 4-9% of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-associated myelopathy/tropical spastic paresis (HAM/TSP) in their lifetime. The current report is based on a patient who presented concurrently with CD30+ lymphoma subtype ATLL and HAM/TSP. The patient's ATLL responded to brentuximab-vedotin-based chemotherapy; however, HAM/TSP did not improve. The patient's peripheral blood mononuclear cells were cultured and injected into immunodeficient mice, and the mice developed massive organ involvement and chronic lymphocytic leukemia-subtype ATLL. This case study is novel in the findings of concurrent development of ATLL and HAM/TSP, the response to brentuximab-vedotin chemotherapy, and the use HTLV-1 helix basic zipper protein-targeted probe for RNAscope for diagnosis.

Use of classic and novel immunohistochemical markers in the diagnosis of cutaneous myeloid sarcoma.

Cutaneous myeloid sarcoma is often challenging to diagnose based solely upon histopathological features. Although immunohistochemistry can aid in its diagnosis, specific markers have not been clearly identified. We evaluated the utility of immunohistochemical markers in 57 cutaneous myeloid sarcoma cases. In addition to classical markers (CD117, CD163, CD34, myeloperoxidase and lysozyme), we used CD33 and CD14, recently described markers in paraffin-embedded tissue samples, and Kruppel-like factor 4 (KLF-4), a novel monocytic marker. Our results show that lysozyme was expressed in 91%, CD33 in 60%, myeloperoxidase in 54%, CD34 in 39% and CD117 in 36% of cases. An antibody panel that included lysozyme, CD117 and CD33 identified all cases. The monocytic markers CD14, KLF-4 and CD163 were expressed in 60, 58 and 40% of all cases, respectively. CD14 and KLF-4 expression was significantly more common in cases with monocytic differentiation. CD14 is the single most sensitive and specific marker for monocytic differentiation (79 and 80%). Although KLF-4 in isolation is relatively insensitive (50 and 87%), it enhances sensitivity in detecting monocytic cutaneous myeloid sarcoma when combined with CD14. Our results indicate that in addition to classical immunohistochemical markers, targeted use of newer antibodies, including CD33, CD14 and KLF-4 is useful in the diagnosis of cutaneous myeloid sarcoma and in the detection of monocytic differentiation.

Bone marrow biopsy in patients with hepatitis C virus infection: spectrum of findings and diagnostic utility.

Patients with hepatitis C virus (HCV) infection develop a number of hematologic disorders, with benign and malignant B-cell proliferations being the most common. HCV-infected patients are also prone to developing peripheral cytopenias, the etiologies of which are multifactorial and include hypersplenism and/or antiviral medications. Some of these patients may undergo bone marrow biopsy but no study has systematically recorded the bone marrow findings in this patient group. Here, we report on the range of bone marrow findings in 47 adult HCV-infected patients. These patients, who lacked concurrent human immunodefiency virus (HIV) infection, most commonly presented for a bone marrow biopsy due to abnormal peripheral cell counts. The bone marrow biopsies displayed a range of findings. Dyserythropoiesis, present in 19% of the cases, was the most common finding. Patients with pancytopenia(n = 6), as defined by current World Health Organization standards, were the most likely to have bone marrow abnormalities; two pancytopenic patients had acute myeloid leukemia, and one patient had a primary myelodysplastic syndrome. There was no correlation in bone marrow findings and antiviral medications, MELD score, cirrhosis or splenomegaly, suggesting that the degree of bone marrow dysfunction is independent of stage of HCV. The results of this study suggest that bone marrow biopsy in HCV-infected patients, even those with features of hypersplenism and/or documented antiviral therapy, can be a valid test for hematologic evaluation, especially for patients with severe pancytopenia and/or sudden alterations in peripheral cell counts.

Uterine extramedullary hematopoiesis: what is the clinical significance?

Extramedullary hematopoiesis (EMH) represents abnormal development and growth of hematopoietic tissue outside the bone marrow. Recent studies have shown its association with myelofibrosis and myeloid metaplasia, chronic myeloproliferative disorders, and other hematologic malignancies in up to two-thirds of the cases. Eleven cases of uterine EMH (UEMH) have been reported earlier; of these half had a concurrent, or subsequently developed a clinically significant hematologic disorder. We studied a larger group of patients with UEMH to understand the relationship with hematologic disorders. Cases diagnosed as UEMH between 1995 and 2007 were retrieved from our files (n=20). UEMH was confirmed in all 20 cases. Eighteen cases were located in the fundus including 5 in endometrial polyps and 5 in leiomyomas. Two foci were located within the cervix. The erythroid lineage was present in all foci; 35% also had myeloid precursors, and 2% had megakaryocytes. Twelve of 20 patients had underlying anemia (mean Hgb of 11 mg/dL, range: 5.5 to 15.7 mg/dL). No preexisting hematologic malignancy was identified in any of the patients. Follow-up information was available on 17 patients (mean: 2.88 yr; range: 0.2 to 9 yr). None of the patients developed a significant hematologic disorder other than anemia during follow-up. On the basis of our study, UEMH is frequently associated with chronic anemia. In comparison with existing literature suggesting a strong link between UEMH and hematopoietic disorders, our findings suggest that UEMH is rarely associated with serious underlying hematologic conditions and therefore does not warrant extensive hematologic workup.

Bone Marrow Biopsy Needle Type Affects Core Biopsy Specimen Length and Quality and Aspirate Hemodilution.

Objectives: Bone marrow biopsies are essential for evaluating patients with suspected or confirmed hematopoietic disorders or malignancies, but little is known about how biopsy needle type affects biopsy length and/or quality. We sought to compare bone marrow biopsy quality in specimens obtained with two different needles. Methods: A retrospective analysis was performed on bone marrow specimens obtained with manual single-bevel (n = 114) or triple-bevel (n = 166) needles. The lengths of evaluable marrow, core quality, and aspirate quality were assessed by blinded hematopathologists. Results: The triple-bevel needle produced 1.33-mm shorter lengths of evaluable marrow than the single-bevel needle and was five times less likely to produce a specimen rated as "adequate" and 4.2 times more likely to produce crush artifact. The triple-bevel needle was also 2.4 times more likely to produce hemodilute aspirates. Conclusions: Bone marrow biopsy needle type affects the length of evaluable marrow and quality of core and aspirate specimens.

The spectrum of adult B-lymphoid leukemias with BCR-ABL: molecular diagnostic, cytogenetic, and clinical laboratory perspectives.

The Philadelphia (Ph) chromosome is characteristic of chronic myelogenous leukemia (CML), but it is also the most frequent cytogenetic abnormality in precursor B-lymphoblastic leukemia (ALL) of adults. The vast majority of CML patients have a BCR-ABL translocation that yields a 210 kD (p210) oncoprotein, whereas adult Ph-positive ALL cases can present with either a p190 or a p210 oncoprotein, or both. Considering that 30% of the patients with CML that progress to blast crisis will have a lymphoblastic presentation, adults presenting with a p210 ALL may have either a de novo ALL or CML presenting for the first time in lymphoblastic phase. To identify the distinguishing features, cases of p190-ALL, p210-ALL, and lymphoblastic CML were compared. In spite of significant overlap between the three entities, a number of features were found to aid in their differentiation. p210-ALL patients present at a younger age with blasts that frequently show loss of expression of CD34, whereas p190-ALL patients present with marked increase in peripheral blast percentage. Interestingly, bone marrow findings characteristic of a myeloproliferative disorder are specific, but are not sensitive for lymphoblastic CML. This study suggests that despite the similarities between these leukemias, p190-ALL, p210-ALL, and lymphoblastic phase CML likely represent three distinct diseases.

Immunophenotypic Variations in Mantle Cell Lymphoma and Their Impact on Clinical Behavior and Outcome.

CONTEXT.­: Immunophenotypic variations in mantle cell lymphoma (MCL) from the classic CD5+/CD10-/CD23-/FMC-7+ immunophenotype have been reported in the literature, but correlation with clinical behavior and outcome has not been fully studied. OBJECTIVE.­: To investigate clinicopathologic and prognostic differences between immunophenotypically aberrant MCL and immunophenotypically typical MCL. DESIGN.­: We evaluated differences in clinical presentation, laboratory parameters, prognostic indices, response to initial treatment, and progression-free and overall survival between patients with aberrant MCL and patients with immunophenotypically typical MCL. RESULTS.­: There were 158 patients with newly diagnosed cyclin D1 or t(11;14)(q13;q32)+ MCL identified in the original search, of which, 29 patients (18%) showed immunophenotypic aberrancies, with CD23 coexpression being the most common. When compared with 33 randomly selected patients with immunophenotypically typical MCL, statistically significant differences were seen in white blood cell counts ( P = .02), in the presence of absolute lymphocytosis ( P = .03), in the MCL International Prognostic Index score ( P = .02), and in response to initial treatment ( P = .04). The "immunophenotypic status" of the MCL was the only independent factor associated with response to treatment ( P = .05), but not with the MCL International Prognostic Index score, absolute lymphocytosis, or white blood cell count. No significant differences were seen for progression-free or overall survival. CONCLUSIONS.­: Immunophenotypic variations in MCL are associated with differences in clinical presentation and response to therapy when compared with immunophenotypically typical MCL. However, with current intensive frontline immunochemotherapy, immunophenotypic aberrations do not appear to affect progression-free or overall survival.

Role of Weight-Bearing Exercises in the Treatment of Post-Menopausal Osteoporosis.

OBJECTIVE: To determine the change in T-score of post-menopausal osteoporosis patients with weight-bearing exercises. STUDY DESIGN: A quasi-experimental study. PLACE AND DURATION OF STUDY: Physiotherapy Department and Orthopedic Unit I, Mayo Hospital, Lahore, from May to October 2014. METHODOLOGY: Two hundred and seventy-four patients were randomly divided into two groups according to inclusion and exclusion criteria using non-probability purposive sampling technique. The group 1 was treated by medication and weightbearing exercises and group 2 was given medication alone. The dual energy X-ray absorptiometry (DEXA)scan was used tofind the T-score before and after treatment and improvement was compared. A p-value less than 0.05 was taken as significant. RESULTS: The results showed that improvement was occurred in both groups after treatment. The DEXAscan median values after treatment were changed to 3.00 (0) for group 1 (exercises and medication) and 2.00 (1) for group 2 (medication). CONCLUSION: The physical activity along with medication play vital role in the treatment of post-menopausal osteoporosis than medication alone.

Severe Cytomegalovirus Gastritis During Natalizumab-Mediated Immunosuppression.

We report a 35-year-old female receiving natalizumab as monotherapy for multiple sclerosis who subsequently developed severe cytomegalovirus gastritis. As cytomegalovirus gastritis has not been previously described during natalizumab treatment, we discuss the biological plausibility of this potential association and avenues for further study.

PRDM1 expression levels in marginal zone lymphoma and lymphoplasmacytic lymphoma.

PRDM1 (BLIMP1) is a transcription repressor protein shown to be involved in B-cell differentiation into plasma cells. Marginal zone lymphomas (MZL) and lymphoplasmacytic lymphomas (LPL) are B cell lymphomas that both show some degree of plasmacytic differentiation and thus can sometimes constitute a difficult differential diagnosis. In this study, we investigated if MZL and LPL have abnormalities in the expression of PRDM1 beta and if there are any differences in expression between these two entities. After interrogating 42 samples (15 marginal zone lymphomas, 9 lymphoplasmacytic lymphomas, 3 follicular lymphomas, and 13 normal/control samples), we have found that a significant percentage of MZL and LPL cases harbor abnormalities (67% and 44%, respectively) involving the PRDM1-ß transcript (P=0.004). By immunohistochemistry, PRDM1 positive staining (>5%) was more common in MZL. We conclude that PRDM1-ß may play a role in the pathogenesis of these low-grade lymphomas with plasmacytic differentiation.

CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential.

CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4(+) DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively.

The role of amniotic fluid index in the management of postdate pregnancy.

OBJECTIVE: To evaluate the role of amniotic fluid index as a reliable fetal surveillance test in the management of postdate pregnancy. DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Hamdard University Hospital from May 2000 till May 2003. MATERIALS AND METHODS: A total of 210 patients were studied. The antenatal fetal surveillance in these patients was based on ultrasound assessment of AFI twice weekly after 41 weeks. An abnormal AFI was defined as 6 cm , between 6 - 8 cm as equivocal and more than or equal to 8 as normal. Delivery outcome and early neonatal complications were main outcomes. RESULTS: Rate of caesarean section (35.8%) in the women with AFI 6 cm was found significantly higher than 8.9% rate of caesarean section of the women having AFI > 6 cm (p = 0.001). Proportion of early neonatal complications was also significantly higher in the women with AFI 6 cm (p = 0.03). Out of a total 210 fetuses, 38 (18.1%) neonates were found with early complications, of these, 24 (63.2%) neonates were those whose AFI was 6 cm. Sensitivity of AFI was 63.2% while specificity was 83.1% as the power of reliable fetal surveillance. CONCLUSION: AFI is a reliable fetal surveillance test. It may allow the conservative approach till 42 weeks to reduce the caesarean section rate due to failed induction of labour as well as perinatal morbidity and mortality.

A comparison of oral misoprostol tablets and vaginal prostaglandin E2 pessary in induction of labour at term.

OBJECTIVE: To compare the cost-effectiveness, mode of delivery, fetal and maternal outcome of oral Misoprostol and vaginal prostaglandin E2 pessary in induction of labour at term. DESIGN: Randomized clinical trial. PLACE AND DURATION OF STUDY: Hamdard University Hospital, Imam Clinic and General Hospital from February 2002 to January 2003. PATIENTS AND METHODS: The trial was conducted over two groups of patient for labour induction such that Group A received 50 microg oral Misoprostol 4 hourly to a maximum of four doses. Group B received prostaglandin E2 vaginal pessary at 6 hourly intervals upto two doses. Labour induction, number of doses, need of augmentation, induction to delivery time interval, mode of delivery and neonatal outcome were the main outcomes. Test of proportions was used to compare the significance between both managements. RESULTS: Out of a total of 214 women, 106 received oral Misoprostol and 108 received PGE2 vaginal pessary. Ninety-three percent women in misoprostol group were successfully induced compared with 91% in PGE2 group. A significant response of labour induction with the minimal dose (58%, p = 0.001) and earlier induction to vaginal delivery (74%, p = 0.01) was observed in Misoprostol group. Rate of operative delivery was also less (16%, p = 0.16) compared with PGE2 group (25%). CONCLUSION: Oral Misoprostol administration was more efficient and cost-effective than PGE2 vaginal pessary for induction of labour due to earlier response with minimal dose and less number of operative deliveries.

Clinical presentation, progression, and outcome of patients with clonal B-cell counts of less than 5 × 10(9)/l, 5 to 10 × 10(9)/l, and more than 10 × 10(9)/l and chronic lymphocytic leukemia immunophenotype.

OBJECTIVES: The flow cytometric evaluation of peripheral lymphocytosis has led to a dramatic increase in the diagnosis of early stage chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL). Few studies exist to better delineate the natural history and differences between MBL and CLL. METHODS: Applying the recently updated B-lymphocyte threshold of 5 × 10(9) B lymphocytes/L for the diagnosis of CLL, we evaluated the differences in initial presentation, disease progression, time to treatment (TTT), and 10-year overall survival rates between patients with less than 5 × 10 × 10(9)/L, 5 to 10 × 10(9)/L, and more than 10 × 10(9)/L B cells. These clinical/treatment parameters were also compared among the MBL, 5 to 10 CLL Rai stage 0, and more than 10 CLL Rai stage 0 groups. RESULTS: In total, 310 patients were included, with 67 in the less than 5, 75 in the 5 to 10, and 168 in the more than 10 B-cell groups. Statistically significant differences were seen when comparing the 5 to 10 and more than 10 B-cell groups regarding anemia (P = .021 for median hemoglobin; P = .028 for anemia <11 g/dL), platelet count (P = .041 for median platelet count), splenomegaly (P = .013), initial management plan (P = .012 for observation; P = .0021 for treatment with chemotherapy), and TTT (P = .0033). No statistically significant difference was seen among the MBL, 5 to 10, and more than 10 CLL Rai stage 0 groups regarding TTT and 10-year overall survival. CONCLUSIONS: Findings suggest that patients with B-cell counts of 5 to 10 × 10(9)/L behave clinically more similar to patients with B-cell counts of less than 5 × 10(9)/L.

Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps.

Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target beta-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low. The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation. A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett's esophagus, were included in this study. Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P<0.001). However, immunostaining failed to show aberrant nuclear localization of beta-catenin, a protein regulated by APC, in any of the polyps, irrespective of syndromic or sporadic types. Instead, positive membranous staining for beta-catenin was observed in all the cases. In addition, the expression characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been reported to be transcriptionally regulated by the APC/beta-catenin pathway, were similar in these two types of polyps. Furthermore, all cases, including those harboring dysplasia, showed negative nuclear staining for p53 and positive nuclear staining for retinoblastoma (RB). Taken together, these data show a lack of dysregulation in the APC/beta-catenin signaling pathway and in the expression of p53 and RB in fundic gland polyps despite a high frequency of somatic mutations of the APC and beta-catenin genes reported in these polyps. These findings may explain at least in part why fundic gland polyps show a negligible malignant potential even in the presence of dysplasia.