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A life-threatening complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is acute respiratory distress syndrome. Our understanding of the pathologic changes in coronavirus disease 2019 (COVID-19) is based almost exclusively on post-mortem analyses of adults. These studies established several hallmarks of SARS-CoV-2 lung infection, including diffuse alveolar damage, microvascular thrombi, and acute bronchopneumonia. We describe a fatal example of COVID pneumonia in a 9-year-old girl who presented with fever 10 months following the diagnosis of ALK-positive anaplastic large cell lymphoma (ALCL). A chest computed tomography scan revealed left upper lobe lung consolidation and nodular airspace disease, and an initial SARS-CoV-2 nasopharyngeal swab (RT-PCR) was negative. A subsequent lung biopsy performed due to concern for relapsed ALCL demonstrated sheets of intra-alveolar and interstitial macrophages, and macrophage-rich fibrinous exudates. Immunohistochemical and in-situ hybridization stains confirmed these macrophages as the predominant SARS-CoV-2-infected cell type. Subsequent RT-PCR testing of upper and lower respiratory tract samples was positive for SARS-CoV-2 infection. Whole genome sequencing confirmed the presence of the B.1.617.2 (Delta) variant. This biopsy illustrates the histopathologic features of early COVID pneumonia in antemortem lung tissue from a pediatric patient, and establishes macrophages as a potential source of SARS-CoV-2 amplification., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Peripheral blood involvement by MF/SS has significant implications for prognosis and treatment. Flow cytometry is commonly used to assess MF/SS by analyzing the ratio of CD26- and/or CD7-CD4 + T cells and assessment of immunophenotypic abnormalities. However, distinguishing normal from abnormal cells is not always easy. In this study, we aimed to establish quantitative thresholds to better distinguish normal CD4 + T cells from neoplastic CD4 + T cells. A retrospective analysis of flow cytometry data was performed on 30 MF/SS patients with a detectable abnormal T cell population (positive), 63 patients with suspected or confirmed cutaneous involvement without a detectable abnormal T cell population (negative), and 60 healthy controls (control). CD3 and CD4 median fluorescence intensity (MFI) was normalized to internal control subsets. Among the positive cases, 50% had CD3 expression outside ± 2 SD from the mean of the negative and control group in the CD4 + CD26- subset. The corresponding specificity of this threshold was 94%. The ± 2 SD threshold showed a sensitivity of 57% and a specificity of 94% for the CD3 intensity among the CD7-negative subset. For CD4 intensity, the ± 2 SD threshold had a sensitivity of 33.3% and specificity of 95% for the CD26-negative subset and a sensitivity of 37% and specificity of 95% for the CD7-negative subset. In our study, although changes in CD3 and CD4 intensity greater than ± 2 SD were specific for MF/SS, more subtle differences in the intensity of CD3 and CD4 should not be used as the sole abnormality to make a diagnosis of circulating MF/SS., Competing Interests: Declarations. Ethical approval: For this type of study, formal consent is not required. Informed consent: This study has obtained IRB approval and the need for informed consent was waived. Consent for publication: For this type of study, consent for publication is not required. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Ancillary testing on cytopathology and other small biopsy specimens is crucial for diagnosis and provides critical information to clinicians. Testing is dependent on preanalytic factors and would benefit from standardization of specimen collection protocols across laboratories. To assess institutional practices and areas of need for evidence-based standards, we surveyed current practices across cytopathology laboratories., Materials and Methods: A twelve-question electronic survey was distributed to American Society of Cytopathology (ASC) members through email, social media, and the ASC from January 8, 2024 to March 1, 2024. Survey responses were tabulated., Results: Of 294 respondents, 257 (87%) completed at least 10/12 questions. Formalin-fixed, paraffin-embedded cell blocks (CBs) are utilized for immunohistochemistry, molecular testing, and in situ hybridization by 89%, 84%, and 71% of respondents, respectively. For fine needle aspirations, no collection medium is utilized by a majority of respondents. In contrast, 61% utilize no collection medium for fluids; 64% predominantly utilize liquid-based preservatives for other exfoliative specimens. For CB preparation, 58% of respondents use coagulating agent; 67% use no fixative before formalin. The two most significant factors limiting clinical utility of ancillary testing in cytology specimens are low cellularity and lack of validation (49% and 23% of respondents, respectively)., Conclusions: There is wide variation in current practices among laboratories, reflecting lack of consensus. Although laboratories utilize different collection media for different specimen types, for CB utilization, current survey results are similar to those reported previously. ASC has convened a task force to facilitate specimen standardization and minimize variability among preanalytic factors., (Copyright © 2024 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53-mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC., Methods: We retrospectively identified 28 pre- and posttherapy bone marrow biopsy specimens from 9 patients with TP53+ AML/MDS and a p53 overexpressor phenotype by IHC (strong 3+ staining at initial diagnosis). Next-generation sequencing and/or MRD-FC results were collected for each specimen., Results: Using a threshold of more than ten 2-3+ cells in any one 400× field, p53 IHC detected residual disease with a sensitivity of 94% and a specificity of 89%. The threshold used in this study showed a high degree of concordance among 6 blinded pathologists (Fleiss κ = 0.97)., Conclusions: Our study suggests that p53 IHC can be used as a rapid tool (within 24 hours) to aid in the detection of residual disease that may complement MRD-FC or NGS in cases in which the flow cytometry immunophenotype is equivocal and/or the bone marrow aspirate is suboptimal., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2 , or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies., Methods: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens., Results: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement., Discussion: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2 , or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Menke, Aypar, Bangs, Cook, Gupta, Hasserjian, Kong, Lin, Long, Ly, Menke, Natkunam, Ruiz-Cordero, Spiteri, Ye, Zadeh and Gratzinger.)

Background: Few studies have evaluated diagnostic yield of small volume biopsies (SVB) for the diagnosis and management of follicular lymphoma (FL)., Methods: The authors performed a multi-institutional retrospective analysis of SVBs including fine-needle aspiration (FNA) and needle core biopsy (NCB) for initial FL diagnosis and suspected recurrence or transformation of FL. A total of 676 workups beginning with SVB were assessed for the mean number of biopsies per workup, the proportion of workups requiring multiple biopsies, and the proportion with a complete diagnosis including grade, on initial biopsy., Results: Compared to workups performed for question transformation/recurrence, those done for initial FL diagnosis were significantly more likely to require multiple biopsies (p < .01), had a higher mean number of biopsies per workup (1.7 vs. 1.1, absolute standardized difference = 1.1), and a lower complete diagnosis rate at initial biopsy (39% vs. 56%). At initial FL diagnosis, NCB +/- FNA was associated with fewer biopsies per workup compared to FNA +/- CB (1.2 vs. 1.9), fewer workups requiring multiple biopsies (23% vs. 83%), and a higher complete diagnosis rate (71% vs. 18%). In contrast, during assessment for transformation/recurrence, NCB and FNA showed a similar mean number of biopsies per workup (1.2 vs. 1.2) and few workups required multiple biopsies (6% vs. 19%)., Conclusions: SVB at initial FL diagnosis often required additional biopsies to establish a complete diagnosis. In contrast, when assessing for transformed/recurrent FL, additional biopsies were generally not obtained regardless of SVB type, suggesting that in these clinical settings SVB may be sufficient for clinical decision-making., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Small-volume biopsies (SVBs) including fine-needle aspiration (FNA), cell block, and needle core biopsies (NCB) are increasingly utilized to diagnose and guide the clinical management of lymphoma. We established a multi-institutional interdisciplinary collaboration of cytopathologists, hematopathologists, and oncologists focused on the role of SVB in the management of patients with follicular lymphoma (FL). To assess the performance characteristics of SVB in this setting, we evaluated all consecutive SVBs performed for clinical indications of initial diagnosis, recurrence, or transformation of FL over a 5-year period and focused on the 182 that had at least one subsequent biopsy within 3 months as part of the same clinical work-up. The most common outcome of a subsequent biopsy as part of the same clinical work-up was a more specific diagnosis usually assigning the pathologic grade (111/182, 61%), followed by a complete agreement with the SVB (24/182, 13%), and change from nondiagnostic on initial biopsy to diagnostic on subsequent biopsy (21/182, 12%). A minority resulted in a diagnostic change from benign to lymphoma (17/182, 9%), a change in FL grade (5/182, 3%), or change in the lymphoma diagnostic category (4/182, 2%). There were no cases where an initial diagnosis of lymphoma was overturned. The distribution of discrepancies was similar across initial SVB types (FNA, FNA + cell block, NCB with or without FNA). Tissue limitations were noted in a minority of cases (53/182, 29%) and were enriched among initially nondiagnostic biopsies (16/21, 76%). Flow cytometry immunophenotyping was performed in the majority of cases both at the first and last biopsy (147/182, 81%). SVB can be a powerful method to detect FL in various clinical indications, with discrepant cases mostly resulting from a refinement in the initial diagnosis., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Epstein-Barr virus (EBV; human herpesvirus 4; HHV-4) and Kaposi sarcoma-associated herpesvirus (KSHV; human herpesvirus 8; HHV-8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV-8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms. Interestingly, these viruses can also infect epithelial cells causing carcinomas and, in the case of KSHV, endothelial cells, causing sarcoma. EBV is associated with Burkitt lymphoma, classic Hodgkin lymphoma, nasopharyngeal carcinoma, plasmablastic lymphoma, lymphomatoid granulomatosis, leiomyosarcoma, and subsets of diffuse large B-cell lymphoma, post-transplant lymphoproliferative disorder, and gastric carcinoma. KSHV is implicated in Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease, and KSHV-positive diffuse large B-cell lymphoma. Pathogenesis by these two herpesviruses is intrinsically linked to viral proteins expressed during the lytic and latent lifecycles. This comprehensive review intends to provide an overview of the EBV and KSHV viral cycles, viral proteins that contribute to oncogenesis, and the current understanding of the pathogenesis and clinicopathology of their related neoplastic entities., (© 2021 Federation of European Biochemical Societies.)

Introduction: Pediatric-type follicular lymphoma (PTFL) is a rare and recently recognized subtype of nodal follicular B-cell lymphoma. While significant recent progress has been made in understanding the morphologic, immunophenotypic, and molecular findings, there are only rare case reports describing the cytomorphologic features of PTFL., Materials and Methods: Four cases of PTFL initially evaluated on fine needle aspiration (FNA) biopsy were retrieved from our institutions' databases. The cytologic and subsequent surgical excision specimens were compared in terms of cytology, histology, immunophenotype, and molecular findings., Results: A constellation of cytologic features for PTFL are able to distinguish it from other cytomorphologic entities in the differential including: 1) the presence of large blastoid cells with fine chromatin and irregular nuclear membranes, 2) small/intermediate-sized lymphocytes with subtle nuclear membrane irregularities, 3) near complete absence of cytoplasmic vacuoles in lymphoid cells, 4) tingible body macrophages, 5) mitotic figures, 6) absence of a diffuse large cell component, 7) and no significant plasma cell population., Conclusions: We present four cases of PTFL initially evaluated on FNA biopsy and define the cytomorphologic features of PTFL. FNA biopsy is presented as a practical tool for initial evaluation of this rare entity as part of a multimodal diagnostic approach, for which increased awareness among cytopathologists can ensure the appropriate triage of specimen studies necessary for the diagnosis. Additionally, we comprehensively review the current literature on PTFL and discuss the differential diagnosis on cytology, including potential pitfalls., (Published by Elsevier Inc.)

Objectives: Small-volume biopsy-fine-needle aspiration biopsy (FNAB) with or without core biopsy-is in increasing use in diagnosis and management of lymphoma patients. Our objective was to survey the current practice in small-volume biopsy diagnosis of lymphoma, focusing on the interaction among hematopathologists and cytopathologists and the integration of FNAB, core biopsy, and flow cytometry studies at sign-out., Methods: This study used a cross-sectional survey design employing the RedCap database distributed via nine pathology professional society email listservs. The survey consisted of 25 multiple-choice questions and several free text fields. In total, 128 pathologists participated., Results: Most respondents indicated that FNAB specimens in which lymphoma is a diagnostic consideration (FNAB-L) are seen daily or weekly (68/116; 58.6%). However, most institutions have separate hematopathology and cytopathology services (72/116; 62.1%) with inconsistent communication. When communication occurred, respondents were frequently inclined to reconsider their original diagnoses. Barriers identified included lack of communication, inadequate access to diagnostic studies, no formal subspecialty training, and various opinions regarding FNAB in diagnosing lymphoma., Conclusions: This survey showed that FNAB-L specimens are common, with a lack of uniformity in how complementary fine-needle aspiration and core biopsy specimens or flow immunophenotyping results are shared across hematopathology and cytopathology services., (© American Society for Clinical Pathology, 2021. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Diagnosis of histologic transformation (HT) of follicular lymphoma (FL) requires tissue biopsy. While surgical biopsy represents the gold standard, less invasive procedures such as fine-needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are frequently performed. In this retrospective multi-institutional study including 269 patients with FL and suspected HT, the median time from initial clinical suspicion to final diagnostic biopsy was similar whether the workup began with FNAB, CNB, or surgical biopsy (4, 9, and 6 days, respectively; p =.27), despite more subsequent biopsies performed following initial FNAB. Periprocedural complications were uniformly minimal. Biopsy-proven HT was more common in the initial surgery group and in workups including positron emission tomography/computed tomography (PET/CT). Our findings, derived from US academic centers with specialized procedural and pathology expertise, suggest that FNAB, CNB, and surgical biopsy are all viable initial diagnostic procedures that can inform clinical decision-making in select FL patients with suspected HT.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) represents approximately 5% of Hodgkin lymphoma and typically affects children and young adults. Although the overall prognosis is favorable, variant growth patterns in NLPHL correlate with disease recurrence and progression to T-cell/histiocyte-rich large B-cell lymphoma or frank diffuse large B-cell lymphoma (DLBCL). The diagnostic boundary between NLPHL and DLBCL can be difficult to discern, especially in the presence of variant histologies. Both diagnoses are established using morphology and immunophenotype and share similarities, including the infrequent large tumor B-cells and the lymphocyte and histiocyte-rich microenvironment. NLPHL also shows overlap with other lymphomas, particularly, classic Hodgkin lymphoma and T-cell lymphomas. Similarly, there is overlap with non-neoplastic conditions, such as the progressive transformation of germinal centers. Given the significant clinical differences among these entities, it is imperative that NLPHL and its variants are carefully separated from other lymphomas and their mimics. In this article, the characteristic features of NLPHL and its diagnostic boundaries and pitfalls are discussed. The current understanding of genetic features and immune microenvironment will be addressed, such that a framework to better understand biological behavior and customize patient care is provided.

Context.—: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma., Objective.—: To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution., Design.—: A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted., Results.—: Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naïve, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease., Conclusions.—: NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyte-rich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation.

Histiocytic sarcoma (HS) is a rare aggressive malignancy with a dismal prognosis and no agreed-upon standard treatment. Classically, the diagnosis of HS has been difficult to confirm and has relied on inaccurate, crude techniques. Therapy often involves intensive chemotherapeutic regimens, surgery, and/or radiotherapy, which are poorly tolerated with variable response rates. Patients often die of diffusely metastatic disease. Modern diagnostic techniques are helping to slowly uncover more uniquely customized therapeutic approaches in this enigmatic disease. We present a review of the current literature regarding HS diagnosis, treatment, and outcomes. Additionally, we describe the first reported case of HS transdifferentiated from follicular lymphoma that had a dramatic and durable response to rituximab/bendamustine alone as initial treatment. Unlike traditional chemotherapy regimens, this treatment was well tolerated and had a good toxicity profile. The combination of rituximab and bendamustine warrants further investigation in the treatment of HS, especially those originating from prior follicular lymphoma. Modern immunohistochemical and molecular profiling techniques are beginning to reveal heterogeneity among HS tumors and potentially therapeutic targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

High-grade gliomas (World Health Organization grade III-IV) are highly lethal primary brain tumors. Imaging modalities, including MRI and FDG PET, provide a limited ability to differentiate treatment effects (such as radiation necrosis) from recurrent or residual tumor. As the first step in validating the applicability of prostate-specific membrane antigen (PSMA)-targeted imaging in high-grade gliomas, we evaluated the ability of the PSMA-targeted small molecule [F]DCFPyL (2-(3-(1carboxy-5-(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid) to image high-grade gliomas in a series of 3 prospectively recruited patients. We found [F]DCFPyL binds PSMA in the neovasculature of glioblastoma multiforme and tumor cells of anaplastic astrocytoma.

Mantle cell lymphoma (MCL) is typically characterized by t(11;14), which places the IGH@ enhancer elements upstream of CCND1. This fusion results in up-regulation of CCND1 and consequently its protein product cyclin D1. Recent studies have shown that in MCL, mutations or translocations occurring within the 3' untranslated region (UTR) of the CCND1 gene can result in a truncated mRNA transcript that is more stable and associated with more aggressive disease. We identified a case of MCL showing cyclin D1 overexpression by immunohistochemistry and a t(11;12)(q13;p11.2) by conventional cytogenetic studies. Next-generation genomic sequencing indicated a chromosomal break through the CCND1 3'-UTR and fusion with a non-coding region of chromosome 12. We suggest that, in the absence of the typical CCND1/IGH@ fusion, this rearrangement promotes MCL pathogenesis by eliminating miRNA interaction elements within the 3'-UTR of the CCND1 mRNA transcript consequently resulting in CCND1 overexpression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Wood-degrading brown rot fungi are essential recyclers of plant biomass in forest ecosystems. Their efficient cellulolytic systems, which have potential biotechnological applications, apparently depend on a combination of two mechanisms: lignocellulose oxidation (LOX) by reactive oxygen species (ROS) and polysaccharide hydrolysis by a limited set of glycoside hydrolases (GHs). Given that ROS are strongly oxidizing and nonselective, these two steps are likely segregated. A common hypothesis has been that brown rot fungi use a concentration gradient of chelated metal ions to confine ROS generation inside wood cell walls before enzymes can infiltrate. We examined an alternative: that LOX components involved in ROS production are differentially expressed by brown rot fungi ahead of GH components. We used spatial mapping to resolve a temporal sequence in Postia placenta, sectioning thin wood wafers colonized directionally. Among sections, we measured gene expression by whole-transcriptome shotgun sequencing (RNA-seq) and assayed relevant enzyme activities. We found a marked pattern of LOX up-regulation in a narrow (5-mm, 48-h) zone at the hyphal front, which included many genes likely involved in ROS generation. Up-regulation of GH5 endoglucanases and many other GHs clearly occurred later, behind the hyphal front, with the notable exceptions of two likely expansins and a GH28 pectinase. Our results support a staggered mechanism for brown rot that is controlled by differential expression rather than microenvironmental gradients. This mechanism likely results in an oxidative pretreatment of lignocellulose, possibly facilitated by expansin- and pectinase-assisted cell wall swelling, before cellulases and hemicellulases are deployed for polysaccharide depolymerization., Competing Interests: The authors declare no conflict of interest.

Based upon the antimalarial activities demonstrated by compounds I and II a series of amino ethers represented by structures III-VI was synthesized. These structures incorporated several modifications of compound II. The compounds prepared displayed no activity in either the Rane P. berghei mouse screen or the Rane P. gallinaceum sporozoite-induced chick test.

Primaquine (I) has been extensively used in combination with other drugs in the radical cure of relapsing malaria as well as for prophylaxis or the interruption of transmission. This, coupled with the activity data reported for 4-methylprimaquine (II), has led to the synthesis of a series of 14 4-substituted analogues of I. In addition, three side-chain analogues of II were prepared. The compounds were tested for suppressive antimalarial activity against Plasmodium berghei in the Rane mouse screen and for radical curative activity against Plasmodium cynomolgi in the rhesus monkey. Four of the 17 compounds prepared (1a, 9c, 15, and 17) exhibited activity in at least one of the test systems.