Splenic histiocytic sarcoma: Disease progression from the perspective of pathophysiology

BackgroundLocalized splenic histiocytic sarcoma (HS) in dogs is a poorly understood disease, and could have longer survival times than disseminated or hemophagocytic HS. Understanding the clinical behavior of localized splenic HS can refine treatment recommendations.ObjectiveTo describe the clinical characteristics and outcomes of dogs with localized splenic HS.AnimalsFourteen client‐owned dogs with histologically confirmed splenic HS that received splenectomy.MethodsMulti‐institutional retrospective case series—medical records of dogs with splenic HS were reviewed. Dog signalment, clinicopathologic data, primary and adjuvant treatments, and outcomes were obtained. Survival data were calculated using Kaplan‐Meier analysis. Dog variables such as age, weight, platelet counts were reported using descriptive statistics. The Cox proportional hazards regression method was used to determine whether potential risk factors (weight, age, albumin level, hematocrit, and platelet count) were associated with PFI.ResultsMedian survival time for the dogs in this study was 427 days. Twelve dogs received adjuvant lomustine‐based chemotherapy. Five dogs (35.7%) were suspected or confirmed to have developed metastatic disease. Eleven dogs died of disease, 1 dog died of unrelated cause, and 2 dogs were alive at final follow‐up.Conclusions and Clinical SignificanceHistiocytic sarcoma in dogs can manifest as a localized form in the spleen. Dogs with localized splenic HS treated with surgery ± chemotherapy can experience survival times over a year.

SummaryBackgroundPatients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited.MethodsWe investigated the feasibility and clinical impact of multiparametric, single-cell, drug-response profiling in patient biopsies by immunofluorescence, automated microscopy, and image analysis, an approach we call pharmacoscopy. First, the ability of pharmacoscopy to separate responders from non-responders was evaluated retrospectively for a cohort of 20 newly diagnosed and previously untreated patients with acute myeloid leukaemia. Next, 48 patients with aggressive haematological malignancies were prospectively evaluated for pharmacoscopy-guided treatment, of whom 17 could receive the treatment. The primary endpoint was progression-free survival in pharmacoscopy-treated patients, as compared with their own progression-free survival for the most recent regimen on which they had progressive disease. This trial is ongoing and registered with ClinicalTrials.gov, number NCT03096821.FindingsPharmacoscopy retrospectively predicted the clinical response of 20 acute myeloid leukaemia patients to initial therapy with 88·1% accuracy. In this interim analysis, 15 (88%) of 17 patients receiving pharmacoscopy-guided treatment had an overall response compared with four (24%) of 17 patients with their most recent regimen (odds ratio 24·38 [95% CI 3·99–125·4], p=0·0013). 12 (71%) of 17 patients had a progression-free survival ratio of 1·3 or higher, and median progression-free survival increased by four times, from 5·7 (95% CI 4·1–12·1) weeks to 22·6 (7·4–34·0) weeks (hazard ratio 3·14 [95% CI 1·37–7·22], p=0·0075).InterpretationRoutine clinical integration of pharmacoscopy for treatment selection is technically feasible, and led to improved treatment of patients with aggressive refractory haematological malignancies in an initial patient cohort, warranting further investigation.FundingAustrian Academy of Sciences; European Research Council; Austrian Science Fund; Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Anniversary Fund of the Austrian National Bank; MPN Research Foundation; European Molecular Biology Organization; and Swiss National Science Foundation.

Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically "cold" to "hot" tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.

We report three patients with histiocytic sarcoma of the spleen associated with severe hypoalbuminemia, hypo y-globulinemia and thrombocytopenia. After the clinical diagnosis of splenic tumor of unknown origin was made, all three patients underwent splenectomy. The histiocytic origin of the tumor was confirmed histopathologically and immunohistochemically using a panel of antibodies. In contrast to malignant histiocytosis (MH), which typically reveals severe generalized clinical manifestations and a rapidly fatal course caused by the disseminated proliferation of neoplastic histiocytes, these patients were asymptomatic or showed only mild clinical symptoms for a long period of time until the recurrence was detected by which time the tumor cells had already spread to other organs. All three cases were characteristically associated with hypoalbuminemia, hypo γ-globulinemia and thrombocytopenia, which returned to normal after splenectomy. Splenic histiocytic sarcoma with the features described here may represent a unique clinical entity, distinct from MH.

A 67-year-old Japanese female was followed up due to prolonged idiopathic thrombocytopenia with non-response to steroid therapy for 4 years, but recent progressive pancytopenia, hypo-albuminemia, and hypo-γ-globulinemia were presented. An abdominal CT scan revealed heterogeneously enhanced splenomegaly without any nodular lesions. A splenectomy was performed, and gross examination showed markedly hyperemic red pulp, weighing 760 g, accompanied by multiple foci of peripheral anemic infarction. Surprisingly, microscopic findings exhibited a diffuse proliferation of medium-sized to large tumor cells having pleomorphic nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm, predominantly within the sinuses and cords of the red pulp, which occasionally displayed conspicuous hemophagocytosis and vascular permeation. In immunohistochemistry, these atypical cells were specifically positive for CD68 (KP-1), CD163, and lysozyme, which was consistent with histiocytic sarcoma (HS) of the spleen. Subsequently, section from the aspiration of bone marrow showed infiltration of the neoplastic cells associated with erythrophagocytosis 2 months after the operation, but never before it. Therefore, primary splenic HS presenting with secondary bone marrow involvement was conclusively diagnosed. Since early diagnosis and treatment are necessary for the HS patients with poor outcomes, splenic HS should be considered as a differential diagnosis in cases with chronic thrombocytopenia and splenomegaly.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1009474924812827

Primary histiocytic sarcoma of the spleen is a rare but potentially lethal condition. It can remain asymptomatic or only mildly symptomatic for a long time. An 81-year-old woman presented with an extremely enlarged spleen. She suffered from progressive anemia and required a red blood cell transfusion once a month. Although computed tomography, ultrasonography, and magnetic resonance imaging were performed for diagnosis, a confirmed diagnosis was not obtained. Her enlarged spleen compressed her stomach, and she suffered from gastritis and a sense of gastric fullness just after meals. She underwent laparoscopic splenectomy for therapeutic and diagnostic purposes. Her post-operative course was uneventful. After surgery, her red blood cell and platelet counts increased markedly. The tumor was diagnosed as splenic histiocytic sarcoma. Post-surgical chemotherapy was not performed, and the patient died of liver failure due to liver metastasis 5 mo after surgery. Laparoscopic splenectomy is minimally invasive and useful for the relief of symptoms related to hematological disorders. However, in cases of an enlarged spleen, optimal views and working space are limited. In such cases, splenic artery ligation can markedly reduce the size of the spleen, thus facilitating the procedure. The case reported herein suggests that laparoscopic splenectomy may be useful for the treatment of splenic malignancy.

We present an unusual association of mediastinal germ cell tumor containing seminoma and angiosarcoma components and splenic histiocytic sarcoma. A 15-year-old boy presented with chest pain. Histopathologically, an anterior mediastinal mass contained typical seminoma, immature teratoma, embryonal carcinoma, angiosarcoma, yolk sac tumor, and polyembryoma. An abdominal ultrasonogram revealed a huge splenomegaly with multiple ill-defined low echogenic nodules, 1 month after the second cycle of chemotherapy. Histopathologically, large, round-to-oval tumor cells with abundant eosinophilic cytoplasm often contained eccentrically placed nuclei with vesicular chromatin and an irregular nuclear membrane. The tumor cells were immunoreactive for CD68, CD31, and CD4. The cytogenetic results showed deletion of the long arm of chromosome 5 and trisomy 8. This lesion might have been on the pathway of multistep tumorigenesis toward a final leukemia.

BackgroundHistiocytic sarcoma is a very rare monocyte/macrophage‐derived hematopoietic system tumor with a poor prognosis whose diagnosis is pathologically challenging due to its extreme rarity and histological overlap with various mimicking entities in which histiocytes also predominate.CaseWe report the case of a 33‐year‐old male patient with hemophagocytic lymphohistiocytosis, purpuric syndrome, and significant splenomegaly. The patient underwent splenectomy; subsequent macroscopic examination revealed a spleen weighing 2065 grams with hyperemic red pulp and multiple infarcts at the periphery. The histological and immunohistochemical study established a diagnosis of primary splenic histiocytic sarcoma with frequent hemophagocytosis. Next‐generation sequencing demonstrated mutations in FLT3, NOTCH2, and KMT2A, microsatellite stability, and a tumor mutational burden of 2 mut/Mb. The patient's condition deteriorated clinically from the appearance of the first symptoms and he died 6 months later from multi‐organ failure.ConclusionPrimary splenic histiocytic sarcoma is one of the rarest tumors of the hematopoietic system. We report the first case with mutations in FLT3, NOTCH2, and KMT2A, and associated hemophagocytic lymphohistiocytosis.

Resectable pancreatic cancer: The role for neoadjuvant/preoperative therapy

17122 Background: Hepatic metastases are a common manifestation of primary lung malignancies; the primary and other extrahepatic sites are often less responsive to systemic therapy. A new method of regional therapy for hepatic metastases, called SIR-Spheres, a 32μ resin sphere incorporating a pure Beta emitter, Yttrium - 90, has advantages to older forms of regional hepatic therapy, used to treat colorectal liver metastases. The effectiveness and relatively response durability suggests a favorable alternative to chemotherapy for patients with liver-dominant metastatic lung cancers. We report our experience using SIR-Spheres in this setting. Methods: 6 patients (2 well differentiated carcinoid, 2 well & 1 poorly differentiated adenocarcinoma, 1 poorly differentiated small cell carcinoma) with unresectable hepatic metastases were treated with 8 infusions of SIR-Spheres after failing systemic chemotherapy, radiofrequency ablation or arterial embolization were included in the study. SIR-Spheres were administered as 2nd-6th line therapy. Median interval from diagnosis to SIR-Spheres treatment was 20.5 months (6–51 m). Results: Abdominal visceral arteriography demonstrated vasculature conducive for SIR-Spheres delivery in all patients. The median dose of 36.1 mCi (12.9–54 mCi) was delivered. SPECT - CT fusion Bremsstrahlung scans post therapy confirmed preferential deposition of SIR-Spheres within metastases. Responses to therapy included a decrease in the size of the hepatic metastases in one patient and stable disease in two patients. One patient had a mixed response and two patients had progression of disease. One Gr. III and one Gr. IV hepatic toxicity occurred. All patients experienced transient Gr. 1 or 2 fatigue. Time to progression of liver disease ranged from 3 to 9 months. Conclusion: SIR-Spheres is a feasible alternative to systemic therapy for patients with liver dominant metastases from lung cancers. Although serious hepatotoxicity was noted in patients with advanced liver metastases, the treatment was tolerated with only reversible fatigue in the majority of patients. When the treatment was effective, the duration of local disease control after one treatment equaled or exceeded what would be expected with chemotherapy. [Table: see text]

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, typically presenting with systemic symptoms and mediastinal involvement. Leukemia cutis (LC) and renal infiltration are rare, especially at disease onset. A 27-year-old man presented with a solitary scalp lesion without systemic symptoms or hematologic abnormalities. Histopathology revealed a blastoid lymphoid infiltrate with a T-ALL immunophenotype. Two weeks later, laboratory tests showed leukocytosis, lymphocytosis, and renal dysfunction. Imaging revealed a large mediastinal mass, scalp soft tissue involvement, and bilateral renal infiltration. Bone marrow biopsy confirmed T-ALL with a mature phenotype. FISH identified TRAD:NKX2 rearrangement and CDKN2AB deletion. The patient received three cycles of pediatric-inspired chemotherapy, achieving complete molecular remission and resolution of extramedullary disease. He subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling. Post-transplant complications included febrile neutropenia and mucositis. On day +100, he remained in minimal residual disease (MRD)-negative remission. This case illustrates a rare presentation of T-ALL with isolated skin involvement and renal infiltration at diagnosis, highlighting the importance of early biopsy and immunophenotyping of atypical skin lesions. Intensive chemotherapy followed by HSCT represents a viable strategy for young adults with high-risk T-ALL and extramedullary disease.

The salivary and GCF AGE/sRAGE-IL-17 axis in periodontitis and diabetes: A pathophysiological perspective on disease progression and inflammation.

Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e.g., non-involved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, non-involved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells.

Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: A phase I study

e19015 Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy, with particularly dismal prognosis in the relapsed or refractory (R/R) setting, with a median overall survival of approximately 6 months. There has been increasing interest in novel therapeutic approaches to intelligently harness cellular pathways to improve outcomes in this difficult to treat population. Pevonedistat, a first-in-class NEDD8 inhibitor, and Belinostat a HDAC inhibitor work synergistically in AML cells and human xenograft AML models supporting the clinical rationale for this Phase I study. Methods: A Phase I dose-escalation study with a 3+3 design was performed to assess safety and tolerability of pevonedistat plus belinostat. Beliniostat (D1-5) and Pevonedistat(D1,3,5) were administered in a 21 day cycle until disease progression or unacceptable toxicity. Primary endpoint was identification of MTD/RP2D, secondary endpoints included toxicity, efficacy, pharmacokinetic interactions, and pharmacodynamic studies. Results: 18 patients (67% female; median age 67.5 (41-74)), 16 of whom had AML, were treated at 5 dose levels (belinostat 800-1000mg/m2, pevonedistat 20-50mg/m2), no dose limiting toxicities were noted. Average number of prior lines of therapy was 3. Most Grade 3 or 4 toxicities were hematologic (Table). Maximum number of cycles reached was 8. Best response was stable disease in four patients, and CR in one patient. The remainder had progressive disease or were not evaluable. Most common reason for discontinuation was disease progression (67%), 11% treatment ended per protocol criteria, 6% pursued alternative therapy, 6% due to side effects. The patient achieving CR was a 54 year old female with BRAF and TET2 mutation, primarily refractory to 7+3 and also unresponsive to second line azacitidine and venetoclax. After CR, she received an allogeneic stem cell transplant and remains in remission with 2 years of follow up. Conclusions: The combination of pevonedistat plus belinostat is safe in adult R/R AML with a manageable, primarily hematologic profile, and modest but notable activity in this heavily treated population. This regimen may be effective as a bridge to transplant in some patients. MTD was not reached in this study. Clinical trial information: NCT03772925 . [Table: see text]