Utility of end of induction bone marrow biopsy and survival outcomes in acute promyelocytic leukemia treated with fixed-dose induction regimen.

Significant variations exist related to the end of induction practices in the management of Acute Promyelocytic Leukemia (APL). These variations include all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) in fixed doses versus continuation until hematologic complete remission (CR) and performance versus omission of post-induction bone marrow biopsy to confirm morphological CR. A retrospective chart review was conducted of 61 patients (42 low/intermediate-risk and 19 high-risk) aged ≥ 18 years with newly diagnosed APL treated with fixed duration ATRA-ATO +/- cytoreduction at a tertiary medical center from December 2012 through March 2020. Of the 54 patients with post-induction bone marrow biopsy results, 52 (96%) demonstrated no morphologic evidence of APL while the remaining were equivocal. After 2.6 years median follow-up, no relapses occurred. The estimated 2-year overall survival rate of 95% suggests excellent outcomes with a fixed ATO induction regimen and safe omission of post-induction bone marrow biopsy irrespective of hematologic parameters.

Best Practices in CD30 Immunohistochemistry Testing, Interpretation, and Reporting: An Expert Panel Consensus.

CONTEXT.­: Although CD30 testing is an established tool in the diagnostic workup of lymphomas, it is also emerging as a predictive biomarker that informs treatment. The current definition of CD30 positivity by immunohistochemistry is descriptive and based on reactivity in lymphomas that are defined by their universal strong expression of CD30, rather than any established threshold. Challenges include inconsistencies with preanalytic variables, tissue processing, pathologist readout, and with the pathologist and oncologist interpretation of reported results. OBJECTIVE.­: To develop and propose general best practice recommendations for reporting CD30 expression by immunohistochemistry in lymphoma biopsies to harmonize practices across institutions and facilitate assessment of its significance in clinical decision-making. DESIGN.­: Following literature review and group discussion, the panel of 14 academic hematopathologists and 2 clinical/academic hematologists/oncologists divided into 3 working groups. Each working group was tasked with assessing CD30 testing by immunohistochemistry, CD30 expression readout, or CD30 expression interpretation. RESULTS.­: Panel recommendations were reviewed and discussed. An online survey was conducted to confirm the consensus recommendations. CONCLUSIONS.­: CD30 immunohistochemistry is required for all patients in whom classic Hodgkin lymphoma and any lymphoma within the spectrum of peripheral T-cell lymphoma are differential diagnostic considerations. The panel reinforced and summarized that immunohistochemistry is the preferred methodology and any degree of CD30 expression should be reported. For diagnostic purposes, the interpretation of CD30 expression should follow published guidelines. To inform therapeutic decisions, report estimated percent positive expression in tumor cells (or total cells where applicable) and record descriptively if nontumor cells are positive.

Developing 3D Organoid Raft Cultures from Patient-Derived Xenografts as Rapid Models to Screen Efficacy of Experimental Therapeutics.

Reliable preclinical models are needed for screening new cancer drugs. Thus, we developed an improved 3D tumor organoid model termed "organoid raft cultures" (ORCs). Development of ORCs involved culturing tumors ex vivo on collagen beds (boats) with grid supports to maintain their morphological structure. The ORCs were developed from patient-derived xenografts (PDXs) of colon cancers excised from immune-deficient mice (NOD/SCID/IL2Rgammanull). We utilized these new models to evaluate the efficacy of an investigational drug, Navitoclax (ABT-263). We tested the efficacy of ABT-263, an inhibitor of BCL-2 family proteins, in these ORCs derived from a PDX that showed high expression of antiapoptotic BCL2 family proteins (BCL-2, BCL-XL, and BCL-W). Hematoxylin and eosin staining evaluation of PDXs and corresponding ORCs indicated the retention of morphological and other histological integrity of ORCs. ORCs treated with ABT-263 showed decreased expression of antiapoptotic proteins (BCL2, BCL-XL and BCL-W) and increased proapoptotic proteins (BAX and PUMA), with concomitant activation of caspase 3. These studies support the usefulness of the ORCs, developed from PDXs, as an alternative to PDXs and as faster screening models.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.

Discordance Between Immunohistochemistry and In Situ Hybridization to Detect HER2 Overexpression/Gene Amplification in Breast Cancer in the Modern Age: A Single Institution Experience and Pooled Literature Review Study.

BACKGROUND: Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12% to 25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status because its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported. METHODS: We determined the frequency of HER2 IHC/ISH discordance in these patients and also performed a pooled literature review analysis. RESULTS: Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC-/ISH+ and 17 IHC+/ISH-, representing 1.6% and 11.9% of IHC- and IHC+ cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43,468 cases with IHC and ISH performed. The IHC-/ISH+ and IHC+/ISH- discordances were seen in all antibody clones and ISH methods used. The IHC+/ISH- discordance was significantly higher than IHC-/ISH+ (13.8% vs. 3%, P < .0001). The overall discordance constituted 4% of all cases and 5.4% of those with an unequivocal IHC status. Significantly lower incongruities for both IHC-/ISH+ and IHC+/ISH- were found in those published after 2018. The discordances probably reflect altered biology of HER2 oncogene/oncoprotein. Routinely performing both IHC and ISH may uncover such cases to prevent denial of potentially beneficial targeted therapy.

Secondary primary malignancies in patients with multiple myeloma: A single institution experience.

The purpose of our study is to highlight the demographic characteristics, pathological features, and clinical course of multiple myeloma (MM) patients with secondary primary malignancies (SPM). A retrospective chart review was performed from January 2009 to February 2020. Patients' demographic, pathologic and cytogenetic features, treatment characteristics and clinical outcomes were collected. We identified 871 MM patients including 40 patients who developed SPM. Among the 40 patients with SPM, 17 patients developed hematological SPM and 23 patients developed solid SPM. The median time from diagnosis of MM to the occurrence of hematological SPM was 6.85 versus 3.91 years in solid SPM, with a median overall survival (OS) after diagnosis of SPM of 120 and 880 days, respectively. Interestingly, we observed that there was no significant difference in OS between MM patients with or without SPM. Multivariable analysis showed that age and autologous stem cell transplantation were independent factors associated with patients' clinical outcomes. Our study highlights the importance of understanding the etiology, biology, clinical outcome and management in MM patients with SPM.

The Interpretation of Sequence Variants in Myeloid Neoplasms.

OBJECTIVES: To provide an overview of the challenges encountered during the interpretation of sequence variants detected by next-generation sequencing (NGS) in myeloid neoplasms, as well as the limitations of the technology with the goal of preventing the over- or undercalling of alterations that may have a significant effect on patient management. METHODS: Review of the peer-reviewed literature on the interpretation, reporting, and technical challenges of NGS assays for myeloid neoplasms. RESULTS: NGS has been integrated widely and rapidly into the standard evaluating of myeloid neoplasms. Review of the literature reveals that myeloid sequence variants are challenging to detect and interpret. Large insertions and guanine-cytosine-heavy areas prove technically challenging while frameshift and truncating alterations may be classified as variants of uncertain significance by tertiary analysis informatics pipelines due to their absence in the literature and databases. CONCLUSIONS: The analysis and interpretation of NGS results in myeloid neoplasia are challenging due to the varied number of detectable gene alterations. Familiarity with the genomic landscape of myeloid malignancies and knowledge of the tools available for the interpretation of sequence variants are essential to facilitate translation into clinical and therapy decisions.

EBV Positive Mucocutaneous Ulcer (EBVMCU): Single Center Series of Three Cases and Review of Literature.

EBV positive mucocutaneous ulcer (EBVMCU) is a newly recognized clinicopathologic entity in the 2017 World Health Organization (WHO) classification. Patients frequently present with an isolated ulcerative lesion in mucosal and cutaneous sites with immunosuppression as the main risk factor. The disease typically follows an indolent clinical course. Herein we describe a series of three patients diagnosed with EBVMCU. Histopathologic examination of these cases shows ulceration in mucosal or cutaneous surface with a substantial number of large atypical transformed cells in the background of dense polymorphous infiltrates. One patient regressed spontaneously with no treatment, one patient needed Rutiximab, and one patient had persistent EBVMCU process with possible transformation to large B cell lymphoma. The aim of the present case series is to highlight the pathologic, diagnostic and clinical features of patients with EBVMCU.

Co-Occurrence of Familial Hemophagocytic Lymphohistiocytosis Type 2 and Chronic Active Epstein-Barr Virus in Adulthood.

We report, to the best of our best knowledge, the oldest individual to ever be diagnosed with Familial Hemophagocytic Lymphohistiocytosis (FHL) Type 2 from homozygous c.1349C>T (p.T450M) missense variants in the PRF1 gene. This rare case advanced in complexity with a simultaneous diagnosis of Chronic Active Epstein-Barr Virus (CAEBV) - a distinct clinical entity from acute EBV infections and a well-described trigger of Hemophagocytic Lymphohistiocytosis (HLH). This is, to the best of our knowledge, the only individual to ever be diagnosed with CAEBV in the setting of this specific variant and the oldest to be diagnosed with a coexisting perforin variant. This case provides understanding of EBV, human genetics, and lymphoproliferative disorders while adding a unique differential diagnosis to adults who present with fever of unknown origin and diffuse lymphadenopathy without evidence of malignancy. This report explores the diagnosis and treatment of both HLH and CAEBV, encouraging discussion regarding current clinical management and future research needs.

Monomorphic Epitheliotropic Intestinal T-cell Lymphoma: A Study of Four Cases and Review of Literature.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary and highly aggressive intestinal T-cell lymphoma derived from intraepithelial lymphocytes. MEITL is previously designated as type II enteropathy-associated T cell lymphoma (EATL). Unlike to classic form of EATL, MEITL is not associated with celiac disease. The diagnosis of MEITL is very challenging and the clinical outcome of patients with MEITL is very poor. Herein we describe a series of four patients diagnosed with MEITL identified upon a 10-year institutional retrospective review. Histopathologic examination of these cases revealed monotonous population of medium sized cells infiltrating intestinal mucosa, positive for CD3, CD8 and CD56 in all four cases. Two patients had the combination chemotherapy; however, the average survival time was only 7.5 months for these two patients after diagnosis. The aim of the present case series is to highlight the pathology, diagnosis and clinical course of the patients with MEITL based on the current literature.

The Outcome Analysis and Complication Rates of Tracheostomy Tube Insertion in Critically Ill Neurosurgical Patients; A Data Mining Study.

OBJECTIVES: To assess the impact, timing, the intra and early post-operative complications and the survival outcome of tracheostomy in critically ill neurosurgery patients. METHODS: This study was a retrospective data mining where data was collected from hospital records from 175 consecutive patients who underwent tracheostomy in the department of Neurosurgery at the Narayna Medical College Hospital, Nellore, India from Jan 2016 to April 2018. A proforma was used to note down the details on the patient status before and after tracheostomy: Glasgow coma scale (GCS), procedure and intra and post-operative complications, type of tracheostomy cannula, details of decannulation, respiration difficulties, and problems with wound, swallowing difficulties, and voice difficulties, stay in intensive care unit (ICU) and hospital and survival status of the patient. RESULTS: In our series, mean age of TBI cases was 47.42±16.62; mean hospital stay and ICU stay was 18.81±10.22 and 12.58±7.36 days respectively. In all age groups, more tracheostomy was needed in cranial injury cases and surgery was major intervention. Commoner complications were mucous deposition (6.86%), blockage of tracheostomy canula (6.29%), bleeding from multiple attempts (6.06%), excessive bleeding (2.94%). Cranial injury needed tracheostomy more in all age groups and more done at operation theatre without significant improvement of GCS score. Survival was statistically higher after tracheostomy irrespective of GCS status or venue of intervention. CONCLUSION: Tracheostomy should be considered as soon as the need for airway access is identified during intervention of the critically ill neurosurgical patients.

Wilson Disease Presenting With Acute on Chronic Liver Failure: A Single-Center Experience of Outcome and Predictors of Mortality in 68 Patients.

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is an emerging entity whose unique pathogenesis, presentation, and outcome are different from those with decompensated cirrhosis. Patients with Wilson disease (WD) often present with ACLF. The outcome in this setting and predictors of mortality have not been well delineated. We describe the clinical features, laboratory characteristics, and prognostic factors in patients with WD with ACLF. We compared the outcome in those without criteria for ACLF. PATIENTS AND METHODS: We analyzed the admission characteristics of 68 patients with WD presenting with features of ACLF among a cohort of WD patients from 1997 to 2017. WD was diagnosed as per European association for the study of the liver (EASL)/Leipzig criteria and ACLF by the Asia-Pacific Association of Study of Liver and World Gastroenterology Organization consensus criteria. Factors associated with mortality were analyzed by univariate followed by multivariate analysis and receiver operating characteristic curve. RESULTS: Of the 272 patients with WD, 68 fulfilled criteria for ACLF. The mean age was 14.4 years (Range 5-42 years). Males constituted 38/68 (56%). Acute viral or drug induced hepatitis as precipitating factors was seen in 11.7%. Forty-nine patients (49/67; 73%) died including 30/32 (93.8%) with encephalopathy and 45/62 (72.6%) with ascites. Prognostic factors on univariate analysis significant for mortality included encephalopathy, international normalized ratio, white blood cell count and model for end-stage liver disease (MELD) score. On multivariate analysis, only encephalopathy was significant with 82% accuracy in differentiating survivors versus non-survivors. Post mortem liver biopsy in 21 patients and explant biopsy in 2 patients showed features of cirrhosis in all. CONCLUSIONS: WD with ACLF is associated with a high mortality Precipitating factors such as viral and drug-induced hepatitis was seen in 11.7% patients. Liver histology in patients subjected to biopsy showed cirrhosis in all. Only encephalopathy is a prognostic marker of non-survival with an accuracy of 82%.

Acute promyelocytic leukemia during pregnancy: A case report and 10-year institutional review of hematologic malignancies during pregnancy.

Acute promyelocytic leukemia (APL) manifesting during pregnancy is a very rare but highly challenging gestational complication in part due to its associated profound coagulopathy. We present the case of a 23-year-old Gravida 3 Para 2002 woman admitted to our hospital at 26 weeks of gestation for severe pre-eclampsia with documentation of intrauterine fetal demise (IUFD), thrombocytopenia, and placental abruption. A peripheral blood smear revealed promyelocytes with azure granules, highly concerning for APL. Additional peripheral blood studies confirmed APL. Placental examination also revealed circulating blasts in decidual vessels and scattered blast entrapment in diffuse perivillous fibrinoid deposits, but none in the chorionic villi. Treatment for APL was initiated immediately and she is in complete molecular remission. Our case underscores the importance of close collaboration among obstetric, hematology, and pathology teams in the care of patients with pre-eclampsia, thrombocytopenia, and postpartum coagulopathy. We also describe five additional cases of gestations complicated by hematologic malignancies identified upon a 10-year institutional retrospective review.

Chronic myelomonocytic leukemia associated with myeloid sarcomas and NPM1 mutation: a case report and literature review.

We present a case of chronic myelomonocytic leukemia (CMML) associated with myeloid sarcomas. The CMML also harbored a NPM1 mutation, which is uncommonly described outside the context of acute myeloid leukemia (AML). We describe our treatment strategy, which involved remission-induction chemotherapy that led to rapid resolution of myeloid sarcomas, and we present a literature review highlighting the treatment challenges that similar cases pose.

Central Nervous System Double Relapse of Acute Promyelocytic Leukemia and Acute Myelomonocytic Leukemia.

Relapse of acute promyelocytic leukemia (APL) and non-M3-acute myeloid leukemia in the central nervous system (CNS) are rare events. Here, we describe a case of simultaneous relapses of APL and acute myelomonocytic leukemia on the CNS of a patient after allogeneic bone marrow transplant. This extremely unusual case highlights the difficulties that CNS leukemia relapses pose in the post-transplant setting.

Optimization of Laboratory Ordering Practices for Complete Blood Count With Differential.

Objectives: To investigate the utilization of CBC and CBC with differential (CBC w/diff) tests at University of Alabama at Birmingham Hospital, and to determine if a reduction in CBC w/diff tests could be achieved without negatively impacting patient care. Methods: The quantity of testing and distribution of repeated tests before, during, and after an educational intervention were compared. Results: CBC w/diff tests were ordered 10-fold more frequently than CBC tests. The trauma burn intensive care unit ordered the most CBC w/diff tests, with repeat tests done every 4 or 12 hours. The educational intervention reduced the number of CBC w/diff tests ordered and tests repeated every 12 hours. Conclusions: The educational intervention changed the ordering practices of CBC w/diff and CBC tests. This was sustained after the intervention and no negative effects on patient care were noted. Similar interventions may lead to optimization of ordering practices of other laboratory tests.

Primary Bone Marrow Diffuse Large B-cell Lymphoma Presenting as Transverse Myelitis.

Primary bone marrow diffuse large B-cell lymphoma (BM-DLBCL) is uncommon, with prior reports largely limited to small case series. Here we report the case of a patient who presented with neurologic deficits consistent with acute transverse myelitis and was found to have DLBCL isolated to the bone marrow. We follow this case with a review of the literature summarizing 107 reported cases of BM-DLBCL. Consistent with our case, literature review indicates that BM-DLBCL is characterized by (1) frequent presentation with cytopenias and B symptoms (2) predominant non-germinal center phenotype and (3) aggressive disease with high International Prognostic Index score and low overall survival, with a median survival of 10.0 months in our cohort.

Arthritis in sarcoidosis: A multicentric study from India.

INTRODUCTION: Ten to 15% of patients with sarcoidosis have associated arthritis. Chronic arthritis is fairly uncommon. There is a paucity of data on articular manifestations of the disease from India. METHODS: Case records of adult patients with sarcoidosis presenting to 11 rheumatology centers from 2005 to 2017 were retrospectively reviewed. Joint involvement was assessed clinically, classified as acute or chronic depending on duration of symptoms less or greater than 6 months, respectively. RESULTS: A total of 117 patients with sarcoid arthritis were reviewed. Forty-five patients were classified as having Lofgren's syndrome. The pattern of joint involvement revealed the ankle to be most commonly affected in both the groups. Shoulder, wrist, metacarpophalangeal, proximal interphalangeal joints of hands and knee joint involvement were significantly more common in chronic sarcoid arthritis. Peripheral lymphadenopathy and uveitis were significantly more frequent in chronic sarcoid arthritis. Forty out of 49 patients with acute arthritis followed up over a median of 1.8 years had achieved complete remission. Twelve out of 16 chronic sarcoid arthritis (median follow up 2.5 years) had achieved complete remission with 15, 12 and five patients on steroids, methotrexate and hydroxychloroquine, respectively. One patient with acute sarcoid arthritis with concomitant interstitial lung disease had died due to lung infection. CONCLUSION: Acute oligoarthritis was the commonest presentation with the ankle being the most commonly affected joint. Upper limb joint (predominantly distal) and knee involvement were more common as reported in our largest series worldwide of chronic sarcoid arthritis in adults. Hilar adenopathy and erythema nodosum were common extra-articular features in both acute and chronic sarcoid arthritis. A limitation of the study was the retrospective nature of the analysis.