CD30 Positivity Research Articles

DOP133 Spatiotemporal analysis of Crohn’s disease reveals PECAM2 signaling at the basis of inflammation-to-fibrosis transition

Abstract Background Crohn’s disease is a chronic inflammatory disease of the bowel often complicated by fibrotic strictures(1,2,3). Medical treatment is lacking, and surgery is commonly required(3). The mechanisms underlying the progression from chronic inflammation to fibrosis are not yet defined. We aim to unravel Crohn’s disease pathogenesis using cutting-edge computational and bioinformatics tools (Figure 1). Methods Spatial transcriptomics was performed on 13 surgical specimens of inflamed and fibrotic Crohn’s disease and healthy controls. Spatial transcriptomics results were integrated with single-cell data to track the cellular and molecular evolution from healthy intestine to fibrosis by employing CellChat(4) and pseudotime analysis. Computational data were confirmed by immunostaining of tissues from an independent cohort of Crohn’s patients. Results We demonstrated that intestinal cytoarchitecture was rearranged while chronic inflammation progressed. Crohn’s disease-associated fibrosis evolved within the mesenchymal compartment, driven by PECAM2 signaling through PECAM1-CD38 interaction. Notably, CD38 positivity was found in the mesenchymal compartment in an independent cohort of Crohn’s disease patients. In parallel, ApoA signaling, particularly APOA1-ABCA interaction, emerged as relevant for maintaining epithelial and stromal homeostasis, while its downregulation was associated with fibrosis development (Figure 2). Conclusion Our results provide insights into CD38-driven fibrosis and suggest that PECAM2 signaling blockade could reduce the development of strictures in patients with Crohn’s disease, potentially offering a new treatment target.

Recent Advances in Understanding the Clinical Responses of Brentuximab Vedotin in Lymphoma and the Correlation with CD30 Expression.

Brentuximab vedotin (BV) is an antibody-drug conjugate that combines the CD30 monoclonal antibody with the microtubule-disrupting agent, monomethyl auristatin E, which induces apoptosis in the tumor cell upon its release from the conjugate. The safety and efficacy of BV have been assessed in several studies in patients with T- and B-cell lymphomas. This article reviews the currently available data on the distribution of CD30 expression in T- and B-cell lymphomas, as well as the various levels of CD30 positivity cutoff used in the literature. It also analyzes the relationship between CD30 expression levels and the clinical response to BV in clinical trials for both T- and B-cell lymphomas and investigates BV efficacy in patients with low or undetectable levels of CD30 and examines potential mechanisms by which BV exerts its effect on these patients. This review contributes to the growing evidence suggesting that CD30 expression levels do not predict the clinical benefit of BV as the drug demonstrated substantial efficacy in patients across a wide range of CD30 expression levels while suggesting that the antitumor activity was not associated with CD30 expression levels. Furthermore, the potential of BV as a targeted approach along with its mechanism of action is also summarized to explain its key role in the future treatments of lymphomas, especially for CD30-expressing lymphomas.

Molecular profiling of acute myeloid leukemia with Runx1-Runx1t1 fusion

ABSTRACT Introduction Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of immature myeloid cells. Among the genetic alterations in AML, the RUNX1- RUNX1T1 fusion, resulting from the t (8; 21) (q22; q22.1) translocation, is common and linked with a favorable prognosis. However, the complete mutational profile contributing to leukemogenesis remains unclear. This study characterizes the mutational profile of the RUNX1-RUNX1T1 fusion in AML using Next-Generation Sequencing (NGS). Methods Twenty-four newly diagnosed AML patients were selected. DNA and RNA were extracted from bone marrow aspirate samples, and libraries were prepared using the Ion AmpliSeq™ Library Kit. Sequencing was performed on the Ion S5™ system, and data were analyzed using Torrent Suite™ and Ion Reporter™ Software. Variants were annotated, and their clinical significance was assessed via ClinVar. In silico prediction tools, including SIFT and PolyPhen-2, were used for functional impact assessment. Results Patients with RUNX1-RUNX1T1 fusion (n = 3) demonstrated higher initial peripheral blood and bone marrow blast counts and a pronounced prevalence of CD56 and CD19 positivity. The average number of mutations in KIT and NF1 was higher in the fusion group (p = 0.021 and p = 0.049, respectively). In total, 228 genetic variants were identified, with most associated with transcription/kinase signaling pathways (36.8%). Epigenetic regulators were the next most common category (21.5%). ClinVar data revealed pathogenic variants predominantly in the KIT gene, including two missense mutations, p.Asp816Val and p.Asp816Ala, at exon 17. Unique variants were identified exclusively in RUNX1-RUNX1T1 patients, including eight non-reported variants. Among these, a TET2 variant (p.Pro1367Leu) was predicted to have deleterious effects based on in silico tools. Conclusion The molecular profiling of RUNX1-RUNX1T1 fusion offers crucial insights into AML’s genetic landscape. Identifying therapeutic targets and novel variants broadens our understanding of mutations, presenting new research opportunities and potential interventions.

CD23 expression in lymphoplasmacytic lymphoma: Clinical-pathological and biological correlations.

The diagnosis of lymphoplasmacytic lymphoma (LPL) in the bone marrow (BM) is challenged by aberrant phenotypes and by overlapping histological features with marginal zone lymphoma (MZL). To address these issues, we (i) assessed LPL immunophenotype on a large series of BM samples, (ii) drew possible correlations between LPL phenotype and clinical/molecular data and (iii) investigated the role of new phenotypical markers in the differential diagnosis between LPL and MZL. The study retrospectively considered 81 clinically annotated LPL diagnosed at Padua University Hospital (Padua, Italy) during a 5-year period. BM findings were correlated with clinical laboratory findings and with MYD88 and CXCR4 mutational status. The obtained results were compared with a series of 77 MZL in the BM, including 46 splenic MZL (SMZL), 14 nodal MZL (NMZL) and 17 extra-nodal MZL (EMZL). The LPL cohort included 52 males and 29 females (median age at diagnosis=71 years). Aberrant CD10 and CD5 positivity was documented in 3 of 81 (3.7%) and 13 of 81 (16.1%) cases, respectively. CD23 positivity occurred in 56 of 81 (69.1%) cases, being usually partial/focal. CD23 expression did not correlate with any specific clinical-pathological parameter. Comparison with SMZL, NMZL and EMZL highlighted less frequent splenomegaly, higher serum paraprotein, higher CD23 expression and fewer follicular dendritic cell networks in LPL. A combined clinical-pathological score supported the differential diagnosis between LPL and MZL of any type. The highest diagnostic yield was obtained for the differential diagnosis between LPL and SMZL. Partial positivity for CD23 is a common feature of LPL in the BM. Together with other clinical and histological parameters, CD23 expression supports the differential diagnosis between LPL and MZL.

An Isolated Cutaneous Relapse in a Known Case of Systemic ALK-Positive Anaplastic Large Cell Lymphoma: A Rare Case Report with Review of Literature

AbstractAmong non-Hodgkin's lymphomas (NHLs), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a relatively uncommon subtype that accounts for 3% of all adult NHLs. It typically affects young males, with a prevalence of three to one. Most cases present with nodal disease at the time of presentation. An extranodal involvement is seen in 60% of cases and skin involvement is seen in only 8 to 21% of cases. Cutaneous involvement in ALCL can manifest as primary cutaneous ALCL or secondary to systemic ALCL, and while CD30 positivity is common to both, ALK is not expressed by the former. A secondary skin involvement is usually associated with a poorer prognosis.We report a rare case of an isolated cutaneous relapse of systemic ALK-positive ALCL in a 62-year-old woman following the second cycle of chemotherapy. The acute febrile, widespread papulonodular eruption clinically resembled mycosis fungoides and lymphomatoid papulosis. With the introduction of oral crizotinib, a drastic improvement in the skin lesions and an exceptional response on positron emission tomography-computed tomography were noted.

Clinically assessed mycosis fungoides tumor burden index as a prognostic marker in tumor-stage mycosis fungoides: a retrospective cohort study.

Prognostic markers are needed for tumor-stage mycosis fungoides (MF) because of their variable prognosis. The objectives of this study were to explore prognostic markers for tumor-stage MF and assess the prognostic significance of clinically assessed MF tumor burden index (MTBI). MTBI was devised to consider the tumor size ≥ 2cm, number ≥ 5, ulcers, and body surface area ≥ 50%. The prognostic value of MTBI and other potential markers derived from blood tests and skin biopsy were evaluated retrospectively using a tertiary medical center database. We included 38 cases of tumor-stage MF. The mean age was 52.1 years, and the male-to-female ratio was 2.5:1. In multivariable analysis, MTBI ≥ 3 (adjusted hazard ratio, 9.41; 95% confidence interval, 1.13-78.15) was significantly associated with worse disease-specific survival. Ulcers were the only MTBI constituent significantly associated with survival. Among other markers, elevated lactate dehydrogenase level was associated with a worse disease-specific survival. Neutrophil-lymphocyte-ratio, pan-inflammation-value, CD30 positivity, Ki-67 index, large cell transformation, and monoclonal T-cell receptor gene rearrangement were not associated with prognosis. In conclusion, MTBI is useful and promising prognostic marker for tumor-stage MF.

An Unusual Case of Lymphoplasmacytic Variant of Multiple Myeloma

Abstract Introduction/Objective Multiple myeloma is characterized by unregulated growth of monoclonal plasma cells with overt production of nonfunctional intact immunoglobulins or immunoglobulin chains. Immunohistochemically, the plasma cells are positive for CD138 and CD38, and are rarely positive for CD20 or cyclin D1. CD20 positivity and plasmacytoid morphology in our case pointed towards a lymphoplasmacytic variant of multiple myeloma. The translocation t(11;14) has been detected in this variant, which can explain the positive cyclin D1 immunostaining. The differential diagnosis of this myeloma variant includes lymphoplasmacytic lymphoma. Methods/Case Report We present a case of a 75-year-old female with no significant past medical history who suffered a fall and hesitated to get evaluated until her pain persisted. Initial ER evaluation revealed she had a compression fracture of the T10 and T11 vertebrae with no other abnormality identified. Subsequently, she underwent kyphoplasty, and bone biopsies were performed. The biopsies showed prominent monotonous lymphocytes and some plasmacytoid cell proliferation. Immunostains showed the tumor cells were positive for CD20, Pax-5, Bcl-2, cyclin D1, CD138, and kappa light chain, weakly positive for CD23; and negative for CD5, CD3, CD10, Sox11, and lambda light chain. Based on the morphology and immunoprofile, current findings were considered suggestive of a low-grade B cell lymphoplasmacytic proliferation with cyclin D1 expression. The differential diagnosis includes a lymphoplasmacytic lymphoma or lymphoplasmacytic variant of multiple myeloma. This case was forwarded to a higher-level care facility for consultation and the diagnosis of plasmacytoma, kappa light chain restricted, was rendered. Results (if a Case Study enter NA) NA Conclusion Misdiagnosis of lymphoma can be made in lesions showing classic plasma cells, numerous lymphoplasmacytic cells, and cyclin-D1 positivity on immunohistochemistry if additional testing is not performed. We recommended further testing, including but not limited to bone marrow biopsy, molecular testing, FISH, and genetic testing for a definitive diagnosis.

Navigating Uncharted Territory: High-Grade B-Cell Lymphoma Coexisting with Warthin Tumor – Lessons Learned from an Unusual Encounter

Abstract Introduction/Objective High-grade B-cell lymphomas (HGBCL) coexisting with Warthin tumors (WT) are infrequently encountered, yet each case offers valuable insights. This introduction sets the stage by highlighting the rarity of such occurrences and emphasizing the importance of thorough evaluation in diagnosing and managing salivary gland neoplasms. Methods/Case Report We present the case of a 78-year-old man with longstanding bilateral parotid gland masses, initially presumed to be benign WT based on prior biopsies. However, surgical intervention unmasked a surprising twist – concurrent presence of HGBCL within the WT. This rare juxtaposition posed a diagnostic and management conundrum, underscoring the importance of thorough evaluation and consideration of atypical presentations. Pathological examination revealed a landscape of large-sized cells with aberrant expression profiles, including CD20, Pax-5, BCL2, and MUM-1 positivity, along with a MYC rearrangement. Despite the rarity of this phenomenon, the case serves as a poignant reminder of the necessity for comprehensive assessment in seemingly benign conditions. Results (if a Case Study enter NA) N/A Conclusion By dissecting this unique encounter, we glean invaluable lessons in diagnostic vigilance, emphasizing the need for heightened awareness and multidisciplinary collaboration in the management of salivary gland neoplasms. This case underscores the significance of recognizing unusual presentations and leveraging them to refine diagnostic and therapeutic approaches, ultimately enhancing patient outcomes and guiding future clinical practice.

Diffuse Large B-cell Lymphoma (DLBCL) involving the Uterine Corpus presenting with Abnormal Uterine Bleeding: A Rare Case Report

Abstract Introduction/Objective Diffuse Large B-cell Lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. Lymphomas affecting the female genital system are extremely rare, accounting for about 1% of extra-nodal lymphomas, with DLBCL being the most common type. We present a rare case of uterine lymphoma presenting with abnormal uterine bleeding. Methods/Case Report A 50-year-old female presented with abnormal uterine bleeding and fatigue for the past three weeks. Laboratory work-up showed hemoglobin level of 5.5 g/dL. Pelvic ultrasound revealed thickening of the endometrium and a 1.6 cm hypoechoic uterine lesion along with multiple enlarged bilateral adnexal lymph nodes. Histological examination of the endometrial biopsy demonstrated endometrial fragments with diffuse subepithelial proliferation of large, poorly differentiated cells with round nuclear contours, finely dispersed chromatin, relatively inconspicuous nucleoli and moderate amount of cytoplasm. Many scattered mitoses and apoptotic bodies were present. Primary set of immunohistochemical stains were performed to rule out primary uterine epithelial or mesenchymal tumors. The tumor cells were negative for pan-keratin, high and low molecular weight keratins and positive for CD45. Further work-up demonstrated CD20 positivity. It was diagnosed as DLBCL with a non-germinal center, double expressor phenotype and a high Ki-67 proliferation. Fluorescence in-situ hybridization studies were negative for MYC and BCL6 gene rearrangements and IGH-BCL2 translocation. Further radiological workup revealed diffuse lymphadenopathy with multiple pulmonary and renal nodules consistent with Stage IV DLBCL. She was treated with six cycles of R-CHOP regimen, and complete metabolic response was achieved. Results (if a Case Study enter NA) NA Conclusion Uterine lymphomas are very rare and on small biopsies may histologically mimic poorly differentiated uterine malignancies such as dedifferentiated/undifferentiated carcinomas. Adding lymphoma lineage markers to poorly differentiated tumors is recommended to avoid missing such a rare entity.

Prevalence and Prognostication of CD5+ Mature T-Cell Lymphomas

Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) (p = 0.00004). Older age at diagnosis (p = 0.001), stage III or IV disease (p = 0.05), and bone marrow involvement (p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL (p = 0.04) and CD5+ ATLL (p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.

Evaluation of CD56 and CD117 Double-Positivity as a Predictor of Poor Prognosis in Multiple Myeloma Patients: A Retrospective Analysis

Despite advancements in treatment, multiple myeloma (MM) remains a challenging hematologic malignancy. It is crucial to stratify risk and perform prognostic assessment with various markers, including the expression of cluster of differentiation 56 (CD56) and cluster of differentiation 117 (CD117). However, the relationship of these markers with MM-related survival remains unclear. In this context, the objective of this study was to investigate the prognostic implications of CD56 and CD117 expression and associated clinical features in MM patients. The population of this retrospective single-center study consisted of adult MM patients whose CD56 and CD117 expression levels were analyzed. Patients were divided into four groups according to their immunophenotypes: CD56+CD117-, CD56-CD117+, CD56+CD117+, and CD56-CD117-. These groups were compared in terms of demographic and clinical characteristics, response to treatment, and survival outcomes. Of the 168 MM patients included in the study, CD56 positivity, CD117 positivity, CD56 and CD117 double positivity, and CD56 and CD117 double negativity were observed in 57.1%, 38.1%, 21.4%, and 26.2%, respectively. Patients with double positivity had significantly higher cytogenetic risk and significantly lower overall response rate (ORR) compared to other patients (p<0.001 for both). ORR and overall survival (OS) were significantly lower in CD56-positive patients than in CD56-negative patients (p=0.017 and p=0.004, respectively). Mortality rates were significantly higher in CD56-positive and CD117-positive patients than in double-negative patients (p<0.001 and p=0.002, respectively). Double-negative patients had significantly lower ORR and OS and higher mortality than others (p=0.001, p=0.002, and p<0.001, respectively). High cytogenetic risk was found to be an independent predictor of shorter OS (p>0.001). This study’s findings revealed that MM patients with CD56 and CD117 double positivity had poorer prognosis, lower ORR, shorter OS, and higher mortality.

Clinical Predilection Features of Middle Ear Adenomatous Neuroendocrine Tumors: A Review of 10 Patients and a Special Case Is Attached.

Introduction: Middle ear adenomatous neuroendocrine tumors (MEANTs) are rare middle ear lesions characterized by nonspecific symptoms, signs, and imaging findings. Diagnosis typically relies on postoperative pathological assessment. This study investigated the diagnostic utility of the predilection sites and clinical characteristics of MEANTs. Methods: A retrospective analysis was conducted on clinical data from 10 patients with histologically confirmed MEANTs, admitted to Eye & ENT Hospital of Fudan University between March 2016 and March 2023. Results: The median age of the patients at diagnosis was 39.3 years. Hearing loss (n = 8) and ear pain (n = 6) were the most prevalent clinical symptoms in the patients diagnosed with MEANTs. Endoscopic examination revealed diverse symptoms, predominantly presenting as non-pulsatile masses with distinct boundaries and quasi-circular shapes within the external auditory canal, often accompanied by abundant blood vessels (n = 4). Tumors were typically confined to the middle/lower tympanic chambers or eustachian tube and were frequently associated with tympanic sclerosis, particularly around the pharyngeal tube (n = 3). Pathologically, MEANTs exhibited CD56 positivity or weak positivity, along with positive staining for CKpan and Syn, negativity for S100, and Ki67 ≤3%. Personalized surgical interventions were chosen by all the patients based on lesion severity, with no subsequent radiotherapy or chemotherapy administered postoperatively. No tumor progression was noted during the postoperative follow-up. In addition, a noteworthy case was presented in which MEANT initially manifested in the middle or lower tympanic cavity and eustachian tubes. Over 2 years, the tumor progressively grew, invading the middle tympanum and surrounding ossicles, ultimately achieving complete resection with no recurrence observed during subsequent follow-up. Conclusions: A possible diagnosis of middle ear adenoma should be considered when encountering non-pulsatile tumors with clearly demarcated inner boundaries within the external auditory canal accompanied by abundant quasi-circular vessels and the presence of new bone or neoplasm at the pharyngeal tympanic canal orifice observed during preoperative examinations or surgical procedures.

Successful outcome achieved with adjuvant chemotherapy with irinotecan plus cisplatin in rectal neuroendocrine carcinoma: a case report

BackgroundRectal neuroendocrine carcinomas (NECs) are rare and associated with poorer prognoses compared to conventional adenocarcinomas. The efficacy of adjuvant chemotherapy for resectable rectal NECs remains uncertain. Herein, we present a case of rectal NEC successfully treated with postoperative chemotherapy using irinotecan plus cisplatin.Case presentationA 48-year-old woman with a history of endometrial cancer presented with an intramural rectal tumour detected on follow-up imaging. Colonoscopy revealed a 30 mm submucosal tumour, and laparoscopic low anterior resection was performed. Histopathological examination showed poorly differentiated atypical cells with solid growth patterns. Metastasis from the uterine cancer was ruled out due to histological differences between the primary uterine tumour and the rectal lesion, as well as the absence of hormone receptor immunohistochemical expression. Further immunohistochemical analysis revealed diffuse CD56 positivity, a high mitotic rate (> 20/10 high power fields) and a Ki-67 labelling index exceeding 70%. Based on these findings, a diagnosis of rectal NEC, T3N0M0, Stage IIB (UICC 8th edition), was established. Given the aggressive nature of the tumour evidenced by a high Ki-67 labelling index, adjuvant chemotherapy comprising six cycles of irinotecan plus cisplatin was administered to mitigate the risk of recurrence. At the 3-year follow-up, the patient was free of disease recurrence.ConclusionThis case highlights the importance of multidisciplinary surgical interventions followed by adjuvant chemotherapy in managing rectal NECs.

Histologic, Phenotypic, and Molecular Characterization of Feline Hodgkin-Like Lymphoma With Classical Reed-Sternberg Cells.

Hodgkin-like lymphoma (HLL) is a rare neoplasm in cats that shares characteristics with the human disease. The hallmark of HLL is the presence of Reed-Sternberg (RS) cells expressing CD30 and CD20. This study aimed to elucidate the clinicopathologic features, immunophenotype and clonality patterns of feline HLL. A comprehensive retrospective review of clinicopathologic and molecular data of nodal lymphomas over a 6-year period was conducted in MyLav laboratory. Twenty-four cases were identified. All cats presented with submandibular or retropharyngeal lymphadenopathy. Histopathologic examination revealed a multifocal to diffuse proliferation of medium-to-large lymphoid cells with low mitotic activity, interspersed RS cells, and a heterogeneous inflammatory infiltrate comprising T-cells, plasma cells and neutrophils. In addition, extensive necrosis was a consistent finding. Immunohistochemistry showed a variable membranous CD20 and nuclear PAX5 expression in neoplastic cells, while RS cells displayed only mild to moderate CD20 positivity and were negative to PAX5. In 21/24 cases (87.5%), RS cells were diffusely CD30-positive. PARR analysis demonstrated clonal B-cell expansion in 60% of cases, with the remaining 40% exhibiting polyclonality. For the 10 cats with available follow-up, the prognosis was generally favourable, with only two cats succumbing to progressive disease. In conclusion, diagnosing feline HLL is challenging. The expression of CD30 and CD20 by RS cells should be considered a hallmark of the disease, but only after excluding differential diagnoses such as anaplastic B-cell lymphoma and granulomatous lymphadenopathy.

Outcome of the Modified St. Jude Total XV Protocol in Turkish Children with Newly Diagnosed Acute Lymphoblastic Leukemia: A Single-Center Retrospective Analysis

The prognostic factors and outcomes of Turkish children with newly diagnosed acute lymphoblastic leukemia (ALL), treated with the Modified St. Jude Total XV Protocol, which was adjusted by adding high-dose methylprednisolone (HDMP) before induction in the original protocol, were assessed in this study. The Modified St. Jude Total XV Protocol was administered to 183 newly diagnosed ALL patients, aged 1-18 years, between 1 January 2008 and 30 January 2016. HDMP was applied at doses of either 10 mg/kg/day (Group A) or 20 mg/kg/day (Group B) for 7 days before induction and then tapered over the next 7 days to 5 or 10 mg/kg/day, and continued at 2 mg/kg/day for 2 weeks during the induction phase. Absolute blast count (ABC) in peripheral blood and minimal residual disease (MRD) in bone marrow were assessed at the end of the initial 7-day HDMP treatment. MRD in the bone marrow was evaluated on day 15 and at the end of the induction period. The follow-up for these patients ended on 15 July 2019. The 5-year event-free (EFS) and overall survival (OS) rates for all patients were 85.6±2.6% and 89.2±2.3%, respectively. The rate of good response to steroids (defined as ABC in peripheral blood of less than 1000/mm3 on day 7) was 88% and 97% of children achieved complete remission after induction. The survival rate and infection frequency did not show statistically significant differences between Group A and B. EFS and OS correlated with initial leukocyte count, age of 10-18 years at diagnosis, CD20 positivity at diagnosis, and gram-negative bacterial infection during remission induction. The remarkable response rates on days 7 and 15, along with the promising EFS and OS results in childhood ALL patients treated with the Modified St. Jude Total XV Protocol, highlight the early and substantial response effect of HDMP. At the onset of induction, short-term HDMP can be initiated, preferably at 10 mg/kg/day for the first 7 days, to minimize potential side effects.

Association of CD38+ Immunophenotyping Biomarker With a Better Prognosis in Elderly Acute Myeloid Leukemia Patients.

The relevance of cytogenetic markers as prognostic risk factors has been demonstrated in a vast number of studies, with many prognostication tools utilizing these factors to determine treatment approaches. Patients aged above 60 years represent an important subgroup of acute myeloid leukemia (AML) patients, especially because they usually exhibit a poorer cytogenetic landscape and are less suitable for intensive treatments. The importance of evaluating prognostic parameters in AML, especially in low-income countries, prompted an investigation into CD38 expression and its effects. Medical records of AML patients aged above 60 years from three hospitals in Brazil's northwest region were analyzed. A total of 67 patients were evaluated in terms of overall survival and factors predicting worse outcomes. The risk stratification was performed based on the European LeukemiaNet 2022 guidelines. The analysis of immunophenotyping markers was conducted using multi-parametric flow cytometry. The overall survival of CD38-positive AML patients was higher than that of patients with CD38-negative AML, with survival rates of 15.6 months versus 4 months, respectively (p-value=0.026). The impact of CD38 positivity was relevant also in multivariable Cox proportional hazards regression, demonstrating a positive effect on overall survival, with a hazard ratio of 0.33 (95%CI=0.13-0.79; p-value=0.014). Expression of CD38 in patients with AML was associated with better overall survival and serves as a relevant predictor of improved outcome in patients aged above 60 years.

A disease warranting attention from neurosurgeons: primary central nervous system post-transplant lymphoproliferative disorder.

Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with histological biopsy essential for diagnosis. Standardized treatment protocols are lacking. This disease requires urgent attention due to the increasing number of organ transplant surgeries and the use of immunosuppressive agents. From 2020 to 2023, our center diagnosed five patients with PCNS-PTLD. We reviewed their clinical records and conducted a comprehensive analysis of 22 literatures on PCNS-PTLD cases following renal transplantation or allogeneic hematopoietic stem cell transplantation (HSCT). Four patients had previously received a kidney transplant, one had undergone allogeneic HSCT. The median time from the last transplant surgery to the diagnosis of PCNS-PTLD differs between kidney transplant (21.5 years) and allogeneic HSCT (9 months). Common symptoms included motor weakness (n = 4), headache (n = 2), confusion (n = 2), and nausea (n = 2), with ring-enhancing (n = 5), typically solitary (n = 3) and supratentorial (n = 3) lesions on imaging. Diagnosis involved robot-assisted stereotactic brain biopsy (n = 4) or craniotomy (n = 1), all showing Epstein-Barr virus and CD20 positivity. Most cases (n = 4) were monomorphic diffuse large B-cell lymphoma. Treatment included rituximab (n = 3), surgical resection (n = 2), zanubrutinib (n = 1), whole-brain radiation (n = 1), and methotrexate (n = 1). At the last follow-up, the median duration of follow-up for all patients was 19 months. During this time, 3 patients had died and 2 patients were still alive. In patients with a history of kidney transplantation or allogeneic HSCT who are on long-term immunosuppressive therapy, any neurological symptoms, particularly the presence of supratentorial ring-enhancing masses in the brain on imaging, whether solitary or multiple, should raise high suspicion for this disease, warranting a timely brain biopsy. Additionally, we found that besides reducing immunosuppressants, zanubrutinib may be a potential, safe, and effective treatment for this condition. Moreover, post-surgical administration of rituximab in conjunction with whole-brain radiotherapy also appears to be a potentially safe and effective approach.

May 2024 Imaging Case of the Month: Nothing Is Guaranteed

No abstract available. Article truncated after 150 words. Clinical History: A 68-year-old man with mantle cell lymphoma diagnosed 5 years earlier presents with weight loss and abdominal distension. HIs lymphoma presented as lymphadenopathy in the neck, chest, and abdomen (Figure 1A), the diagnosis established by percutaneous needle biopsy of enlarged lymph nodes in the neck (Figure 1B); the lymph nodes showed CD5 positivity. Peripheral flow cytometry revealed leukemic involvement as well. The patient underwent hyper-CVAD therapy (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride [aka, Adriamycin], and dexamethasone), with rituximab, with a good response (Figure 1C). Radiotherapy was also performed for the left neck and supraclavicular lymphadenopathy. PMH, SH, FH: The patient’s past medical history was otherwise unremarkable and he had no previous surgical history. The patient had no known allergies and denied alcohol use. He was former smoker, having quit at a young age. Physical Exam: The patient’s physical examination showed a blood pressure of 130 / 76 mmHg, pulse …

Phase II single-arm study of a combination of obinutuzumab and venetoclax in early relapsed or refractory diffuse large B-cell lymphoma—final results of the AGMT NHL15B study

BackgroundPatients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis. We therefore initiated a study with obinutuzumab and venetoclax.Study design and methodsTwenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression, and CD20 positivity were included in this prospective single-arm study between 2016 and 2021. Obinutuzumab was administered i.v. at a dose of 1,000 mg on days 1, 8, and 15 in cycle 1 and on day 1 of each of the following 21-day cycles. Venetoclax was given at 800 mg daily p.o. continuously. Treatment was repeated for up to three cycles. Eligible patients were planned to either proceed to cellular therapies or receive up to nine cycles of maintenance. The primary endpoint was objective response rate (ORR) after three cycles (Eudract Nr. 2016-001760-10 and NCT02987400).ResultsTwenty-one patients (median age, 64 years) with refractory or early relapsed DLBCL after one (N = 11) to four previous lines of therapy were included. The majority of patients received three cycles of obinutuzumab/venetoclax (range, 1–8). The regimen was well tolerated with manageable cytopenias and infections. Severe adverse events related to treatment were observed in 9.5%. The ORR was 38.1% (8/21 patients) with a best response of five complete remissions (CRs; 23.8%) and three partial remissions (PRs; 14.2%). The primary endpoint (45% ORR) was not met. Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and a median overall survival of 169.1 weeks. All deaths were due to underlying disease. Seven patients became eligible for autologous transplant. Overall, nine patients (42.8%) received 11 cellular therapies (5 ASCT and 6 CAR-T). Three patients went directly from obinutuzumab/venetoclax to CAR-T therapy. All patients had successful peripheral stem cell or T-cell harvests. Characteristics of responders include relapsed disease (response rate, 6 of 11 = 54%), very good or good R-IPI (7 of 8), and low number of previous therapies (median = 1).ConclusionObinutuzumab/venetoclax represents an effective chemo-free relapse regimen with low toxicity that can be followed by cellular therapies, particularly CAR-T cells.

Abstract 541: Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance

Abstract Introduction: Inotuzumab Ozogamicin (IO) is a humanized anti-CD22 monoclonal antibody conjugated with chalicheamicin, which causes single- and double-strand DNA breaks. Although IO shows a high CR/CRi rate in relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia (ALL), the duration of remission is short due to early acquisition of resistance. Therefore, the present study attempted to enhance the cytotoxicity of IO by focusing on polyadenosine diphosphate-ribose polymerase (PARP) inhibition. Furthermore, IO-resistant cell lines were newly established to investigate the mechanism of IO resistance. Methods: Reh cell line derived from Ph-negative B-ALL cells was used. To establish IO-resistant cell lines, Reh cells were long-term exposed to IO, followed by limiting dilution. FACS analysis evaluated the CD22 positivity and the induction of apoptosis. WTS assay determined the cell growth inhibition effects. The Comet assay quantitatively assessed DNA damage. Gene expression profiles were determined by using DNA microarray. Results: The 50%-inhibitory concentration (IC50) of IO was 2.1 ng/mL in Reh cells. Reh cells were synergistically sensitized to IO by the addition of non-toxic concentrations of PARP inhibitors, olaparib or talazoparib, with the Combination Index of 0.19 and 0.42, respectively. Moreover, these combinations augmented the induction of apoptosis (23.5% in IO alone, 51.7% in IO + olaparib, 66.1% in IO + talazoparib). The Comet assay demonstrated that DNA strand breaks observed 1h after IO administration were repaired 6h later. In the combination of IO with olaparib or talazoparib, DNA damage remained even at 6h, suggesting the inhibition of DNA repair by PARP inhibitors. Next, six IO-resistant cell lines were established with IC50 more than 60-fold that of parental cells. All these cell lines kept CD22 expression. These cell lines were also resistant to apoptosis induced by IO. In addition of olaparib or talazoparib to IO, the IC50 of IO decreased by 40% to 70% in 6 IO-resistant cells. These combinations also augmented the induction of apoptosis (24.2% in IO alone, 45.3% in IO+olaparib, and 56.8% in IO+talazoparib). DNA microarray was performed to compare gene expression profiles between parental and IO-resistant cell lines. ABCB1 (p-gp), a drug efflux pump that causes multi-drug resistance, was overexpressed in resistant cell lines. Moreover, the addition of p-gp inhibitor, PSC-833, to IO enhanced the cell growth inhibition and induction of apoptosis due to more DNA strand break. Conclusion: The present study demonstrated that the combination of IO with PARP inhibitors exerted synergistic cytotoxicity via the inhibition of DNA repair. In addition, it was suggested that overexpression of p-gp caused IO resistance, which was partially reversed with the combination of PARP inhibitors or a p-gp inhibitor. Citation Format: Naoko Ida, Miyuki Okura, Naoko Hosono, Takahiro Yamauchi. Establishment of Inotuzumab ozogamicin resistant leukemia cell lines; Focusing on p-gp and DNA damage repair for overcoming drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 541.