BACKGROUND AND OBJECTIVES

Non-Hodgkin Lymphoma (NHL) ranks 11th in cancer incidence and mortality in the Philippines with the combination chemotherapy composed of Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) being commonly used as treatment. However, the addition of Rituximab to CHOP (R-CHOP) has been shown to exhibit higher response rates and longer remissions, potentially improving quality of life. Currently, there is conflicting evidence on the cost-utility of CHOP versus R-CHOP. The study aimed to describe the patient- and country-specific factors, and treatment modalities used for NHL and systematically review cost-utility evidence of R-CHOP versus CHOP in adult NHL patients.

A systematic literature search of cost-utility studies on R-CHOP versus CHOP for NHL treatment was performed on eight databases: PubMed/MEDLINE, Scopus, Web of Science, EBSCOHost, Cochrane, York Research Database, Centre for Reviews and Dissemination Database, and HERDIN, where 607 studies were identified. Upon screening using an eligibility criteria, 10 studies were included and critically assessed using four appraisal tools: CHEERS, Drummond, Cooper, and ECOBIAS. These were performed independently by two authors with a third author assisting to help reach a consensus.

All studies from high-income countries (HICs) (n=8) and low-middle-income country (LMIC) (n=1) suggested that R-CHOP was more cost-effective for NHL treatment than CHOP in terms of utility outcomes. The study conducted in a low-income country (LIC) (n=1) suggested the opposite, favoring CHOP over R-CHOP. Methodological differences such as perspective, discount rate, willingness-to-pay (WTP), time horizon, and economic model were observed. Methodological limitations include completeness of data reported and credibility of sources used.

The results of this review shall be interpreted with caution as those favoring R-CHOP over CHOP for NHL treatment in terms of cost-utility were concentrated in HICs. More economic evaluations from LICs, LMICs, and upper-middle income countries (UMICs) are needed for a robust conclusion. Additionally, establishing a universally recognized guideline for economic evaluations is essential to guide researchers effectively.

Introduction: Arginine vasopressin (AVP) deficiency is an uncommon but important presentation of infiltrative hypothalamic– pituitary disorders. In adults, isolated AVP deficiency with pituitary stalk thickening is diagnostically challenging, especially in the absence of systemic disease. Langerhans cell histiocytosis (LCH) is a rare cause and may precede systemic involvement by several years. Case: We report a 42-year-old male who presented in 2017 with polyuria and polydipsia, with urine output of up to 10 L/ day. AVP deficiency was confirmed by the water deprivation test, and desmopressin was initiated. Initial pituitary magnetic resonance imaging (MRI) was normal, baseline anterior pituitary hormonal evaluation was unremarkable, and contrast-enhanced computed tomography (CECT) of the thorax and abdomen showed no abnormalities. Repeat pituitary MRI 1 year later demonstrated loss of the posterior pituitary bright spot with pituitary stalk thickening. In the absence of systemic involvement, a presumptive diagnosis of lymphocytic hypophysitis was made, and pituitary biopsy was deferred due to the high procedural risk. Serial pituitary MRIs over the following years showed persistent infundibular thickening and continued absence of the posterior pituitary bright spot, without interval progression or development of additional hormonal deficiencies. The patient remained clinically stable until June 2024, when new-onset left hip pain prompted MRI, revealing a heterogeneous mass involving the femoral neck and intertrochanteric region with a pathological fracture. Histopathological examination following wide resection confirmed LCH, with negative BRAF V600 mutation. Postoperative PET scan revealed a multisystem disease involving the skeleton, lymph nodes, spine, and gastrointestinal tract, with no bone marrow involvement. He subsequently completed six cycles of intravenous methotrexate and cytarabine. Conclusion Adult-onset AVP deficiency may be the earliest manifestation of occult multisystem Langerhans cell histiocytosis. This case highlights the importance of longterm follow-up and reconsideration of the initial diagnosis when new systemic features emerge.
Histiocytosis, Langerhans-Cell

Introduction: Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of langerin-positive histiocytes. Endocrine involvement most frequently manifests as central diabetes insipidus or secondary hypothyroidism, caused by infiltration of the hypothalamic-pituitary axis. Conversely, direct infiltration of the thyroid gland leading to primary hypothyroidism is an exceptionally rare clinical entity, particularly when presenting concurrently with central disease. Case: A 21-year-old female with known right otic and multisystem LCH presented with septic shock secondary to a right ear abscess accompanied by polyuria and polydipsia. Physical examination revealed a palpable goiter. Clinical and biochemical evaluation confirmed central diabetes insipidus with associated anterior hypopituitarism (low adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone). However, concurrent thyroid function tests demonstrated overt primary hypothyroidism, evidenced by an appropriately elevated thyroid-stimulating hormone (26.19 mIU/L) and low free T4 (5.47 pmol/L), rather than the anticipated secondary hypothyroidism. Neck ultrasound showed diffuse thyroid enlargement with heterogeneous echotexture. Crucially, anti-thyroid peroxidase and anti-thyroglobulin antibodies were both negative, rendering Hashimoto’s thyroiditis highly unlikely. Although the patient declined confirmatory fine-needle aspiration, the constellation of a palpable goiter, characteristic ultrasonographic findings, negative autoimmunity, and active multisystem disease strongly supported a diagnosis of direct histiocytic infiltration of the thyroid gland. She was initiated on appropriate glucocorticoid coverage and subsequent levothyroxine replacement, alongside systemic intravenous cytarabine. Conclusion This case highlights a rare, mixed endocrine profile in multisystem LCH, demonstrating that pituitary and direct end-organ infiltration can coexist. Hypothyroidism in LCH patients with established central diabetes insipidus should not be reflexively assumed to be central in origin. A comprehensive diagnostic workup, including autoantibody screening, ultrasound, and ideally histopathological confirmation, is essential to accurately identify primary endocrine failure and guide appropriate clinical management in these complex cases.
Histiocytosis, Langerhans-Cell ; Hypothyroidism ; Pituitary Gland

Introduction: Ovarian lymphoma is rare and often misdiagnosed, as its clinical presentation can be similar to other more frequent tumors. It accounts for <1% of all non-Hodgkin lymphomas, with high-grade B-cell lymphoma being the most frequently implicated subtype. Case Description: A 48-year-old woman presented with bilateral ovarian masses, elevated CA-125, and extensive abdominal and thoracic lymphadenopathy. She was managed as advanced ovarian cancer and underwent TAHBSO. Grossly, both ovaries were enlarged and nodular. Histology showed a round cell neoplasm composed predominantly of medium-sized, cleaved lymphocytes, admixed with scattered larger atypical cells. Initial immunohistochemistry panel demonstrated diffuse CD45 positivity and negativity for AE1/AE3, Inhibin, SALL4, Desmin, and Calretinin. Subsequently, CD20 and PAX5 showed diffuse reactivity. CD10, BCL2, and BCL6 highlighted neoplastic follicles. CD3 was negative. High-grade B-cell lymphoma was considered; however, the Ki-67 proliferative index was 38%, and c-MYC expression was low (5%). A final diagnosis of follicular lymphoma involving both ovaries was rendered. Discussion: The clinical presentation strongly suggested advanced ovarian carcinoma. However, histologic and immunophenotypic evaluation established lymphoma. Although aggressive subtypes are more common in advanced cases, indolent entities such as follicular lymphoma should also be considered, particularly in resource-limited settings where delays in diagnosis occur. Distinguishing lymphoma from carcinoma is critical, as management differs significantly and misclassification may lead to overtreatment. Conclusion Recognition of ovarian lymphoma is critical, as accurate diagnosis alters management and prevents unnecessary radical surgery.
CA-125 Antigen ; Immunohistochemistry ; Lymphoma, Follicular ; Ovarian Neoplasms

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by extreme immune activation, resulting in pathologic inflammation that may be life-threatening. Early recognition is crucial since survival largely depends on early initiation of treatment which utilizes a combination of chemotherapy, immunotherapy and in some cases even bone marrow transplantation. OBJECTIVES: This study aims to describe the clinical characteristics, treatment received and outcome of patients diagnosed with HLH at the Philippine Children’s Medical Center from 2004 to 2017. MATERIALS AND METHODS: A retrospective analysis of records of children 0-18 years of age diagnosed with HLH from January 2004 to December 2017 was done. RESULTS: A total of 39 patients were included in the study which gave an incidence of 1.22 per 3000 patients admitted under 18 years of age. There were 29 males (74.4%) and 10 females (25.6%) with a male to female ratio of 2.9:1 Mean age was 6.12 ± 3.89 years. The average time from initial presentation to diagnosis was 6 weeks and 2 days. The most commonly seen clinical and laboratory features observed in these patients were fever (100%), splenomegaly (71.8%), anemia (87.17%), thrombocytopenia (79.48%) and hypertriglyceridemia (69.23%). Only 5 patients were confirmed to be familial HLH with 3 having XLP gene mutation, and one each having syntaxin and perforin gene mutations. Majority of patients received a combination of treatment based on the HLH 2004 regimen while almost one third only received antibiotics. Only 23% of patients survived during the study period and all but one of these patients received drug combinations based on the HLH 2004 protocol. CONCLUSIONS AND RECOMMENDATIONS HLH is a rare but important condition that must be recognized early and treated appropriately to optimize survival. The mortality rate of 39 patients seen in this institution is high. There is a need to better utilize the diagnostic criteria of the disease and to employ a more uniform treatment strategy. Increasing awareness among health care personnel can also improve case finding, characterization and treatment.
Human ; Male ; Female ; Adolescent: 13-18 Yrs Old ; Lymphohistiocytosis, Hemophagocytic ; Philippines

BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

A 4-year-old boy was admitted to the hospital with a 3-day history of rash and intermittent abdominal pain, during which abnormal results from routine blood tests were discovered. Initially, he presented with acute jaundice hepatitis and pancytopenia. The patient's condition progressed rapidly, with recurrent fever, worsening jaundice of the skin and sclera, and progressively worsening hepatosplenomegaly. Liver function impairment and bone marrow failure continued to deteriorate, while cytokine levels continued to rise. After excluding infections, autoimmune diseases, tumors, genetic metabolic disorders, and toxicities, the patient was diagnosed with hepatitis-associated aplastic anemia (HAAA) complicated by hemophagocytic lymphohistiocytosis (HLH). Following treatment with corticosteroids, plasma exchange, intravenous immunoglobulin, and liver protection therapy, the patient's symptoms partially alleviated. Aplastic anemia complicated by HLH is relatively uncommon, and HAAA complicated by HLH is even rarer, often presenting insidiously and severely. This paper presents a case of HAAA complicated by HLH and summarizes previously reported cases in the literature, providing references for the early diagnosis and treatment of this condition.
Humans ; Lymphohistiocytosis, Hemophagocytic/therapy* ; Male ; Anemia, Aplastic/complications* ; Child, Preschool ; Hepatitis/complications*

OBJECTIVES: To study the clinical characteristics, efficacy, and prognosis of pediatric Langerhans cell histiocytosis (LCH). METHODS: A retrospective analysis was conducted on 72 children with newly diagnosed LCH. RESULTS: The median age of the 72 children was 5 years (range: 0-14 years), with skull involvement being the most common (56 cases, 77.8%). The BRAF-V600E mutation was not associated with clinical characteristics, efficacy, or prognosis (P>0.05). The 5-year overall survival rate was 91.6%±4.2%, and the 5-year event-free survival (EFS) rate was 67.5%±5.8%. The 6-week chemotherapy response rate and 5-year EFS rate were lower in the risk organ involvement group compared to the no risk organ involvement group (P<0.05). The five-year overall survival rates for the group with multi-system involvement and the group with platelet count ≥450×10⁹/L were respectively lower than those for the single-system involvement group and the group with platelet count <450×10⁹/L (P<0.05). Risk organ involvement is an independent risk factor for 5-year EFS (P<0.05). CONCLUSIONS Skull is the most commonly affected site in pediatric LCH. The BRAF-V600E mutation is not related to clinical characteristics, efficacy, or prognosis. Elevated platelet count, risk organ involvement, and multisystem involvement are associated with poor prognosis, with risk organ involvement being an independent risk factor for 5-year EFS.
Humans ; Histiocytosis, Langerhans-Cell/therapy* ; Child, Preschool ; Child ; Male ; Infant ; Female ; Adolescent ; Retrospective Studies ; Proto-Oncogene Proteins B-raf/genetics* ; Prognosis ; Infant, Newborn ; Mutation

The patient was a girl, aged 10 years, who was admitted due to fever for 5 days and pancytopenia in peripheral blood for 2 days. Bone marrow examination showed the presence of phagocytic activity, and peripheral blood tests showed pancytopenia, an increase in ferritin, a reduction in fibrinogen, increases in triglyceride and sCD25, and a reduction in natural killer cell activity, which led to the diagnosis of hemophagocytic lymphohistiocytosis (HLH). On the day of admission, the child developed convulsions and rapidly progressed to refractory status epilepticus, which was consistent with the manifestations of febrile infection-related epilepsy syndrome. HLH was controlled after active immunotherapy, with the sequela of refractory epilepsy, and her cognitive function was essentially within normal limits. This article reports the condition of febrile infection-related epilepsy syndrome caused by HLH for the first time in China, in order to improve the awareness of this disease among clinicians.
Humans ; Lymphohistiocytosis, Hemophagocytic/complications* ; Female ; Child ; Epilepsy/etiology* ; Fever/etiology* ; Epileptic Syndromes/etiology*

RAS-associated autoimmune lymphoproliferative disorder (RALD) is a rare congenital immunodeficiency disorder caused by somatic mutations in NRAS or KRAS. Its main pathological feature is immune dysregulation-induced hematologic destruction, presenting with symptoms resembling autoimmune diseases. RALD exhibits significant clinical heterogeneity, with manifestations including autoimmune phenomena, hepatosplenomegaly, lymphadenopathy, monocytosis, and increased susceptibility to infections. Owing to its rarity and its unclear nature, a standardized therapeutic regimen for RALD is currently lacking. This review summarizes the latest advances in the pathogenesis, clinical manifestations, differential diagnosis, and treatment of RALD, aiming to provide new insights and reference for the understanding and management of this disorder.
Humans ; Lymphoproliferative Disorders/etiology* ; Autoimmune Diseases/etiology* ; Autoimmune Lymphoproliferative Syndrome/genetics* ; GTP Phosphohydrolases/genetics* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Mutation ; Membrane Proteins