Conventional Chemotherapy Regimens Research Articles

Prognostic value of different radiation-related cell death genes in patients with lung adenocarcinoma

Background and aimsRadiotherapy is widely applied for lung adenocarcinoma (LUAD), while individualized differences led to different outcomes. This study aimed to establish a multi-gene risk scoring model to predict the benefits of LUAD patients from radiotherapy, based on different types of cell death respectively. ResultsOther than autophagy, pyroptosis, ferroptosis and Immunogenic cell death (ICD), the LUAD prognostic model based on apoptosis had the best performance, and the area under curves (AUCs) of the receiver operating curve (ROC) for 1-, 3-, and 5-year OS were 0.700,0.736,0.723,respectively. Such genes were involved as SLC7A5, EXO1, ABAT, NLRP1 and GAR1. Then patients were divided into high and low risk groups by the median apoptosis-LUAD risk score. For patients in the high-risk group, i.e., the radiotherapy-tolerant group, we screened adjuvant chemotherapy and found that besides the conventional first-line chemotherapy regimen, drugs such as Fludarabine, Pevonedistat, and Podophyllotoxin Bromide may also have potential therapeutic value. ConclusionThe multi-gene risk scoring model based on apoptosis might predict the radiotherapy benefits of LUAD patients and for those radioresistant patients classified by the model we also provided effective adjuvant chemicals, which would be used to guide clinical treatment.

Abstract 4671: Efficacy and mechanism of mebendazole for ovarian cancer therapy

Abstract Introduction: Ovarian cancer (OvCa) is the most lethal gynecological malignancy. Although most OvCa patients initially respond to frontline platinum-based therapies with approximately 80% of patients experiencing remission, approximately 75% of those women experience a recurrence with only approximately 50% of patients alive 5 years following diagnosis. There is a critical need to develop novel therapeutic agents or methods to overcome chemoresistance and toxicities experienced with conventional chemotherapy regimens used for OvCa patients. Repurposing drugs is a promising strategy to safely and more rapidly evaluate potentially effective treatment regimens. Over the past two decades, Mebendazole (MBZ), an anti-parasitic drug, has gained much attention in oncology due to its favorable biosafety profile and potent anti-cancerous activity seen in several human malignancies. Therefore, we examined the efficiency and mechanism of MBZ against OvCa. Methods: The in vitro efficacy of MBZ was evaluated in cisplatin-resistant (CPR) and parent (WT/sensitive) OVCAR-8 cell lines as well as in ascites samples collected from chemo-resistant OvCa patients by using 2D and/or 3D cell viability assay and invasion assay. The in vivo efficacy of MBZ was assessed in orthotopic animal models, utilizing CPR-OVCAR8 spheroids, and patient-derived xenograft (PDX) animal models with specimens from chemo-resistant ovarian cancer patients. Molecular mechanisms were investigated through western blot and immunofluorescence analysis. Result: Our results confirmed that MBZ efficiently decreased cell viability, spheroid size, and the invasion ability of OvCa cell lines and ascites samples. OvCa cells treated with MBZ demonstrated downregulation of proliferation markers and upregulation of apoptosis markers indicating inhibition of cell proliferation and induction of apoptosis. Mechanistically, MBZ inhibited the Wnt/β-catenin signaling pathway by downregulating the expression and nuclear localization of β-catenin and epithelial-mesenchymal transition (EMT) markers. Preclinical studies showed that MBZ at 50 mg/kg/day dose for 28 days significantly reduced tumor growth in PDXs and orthotopic tumor models without any evidence of toxicity. Conclusion: Collectively, our study strongly supports the therapeutic potential of MBZ against OvCa particularly, which warrants further clinical studies. Citation Format: Rajani Rai, Dhanamjai Penta, Debasish Dey, Doris M Benbrook, Lin Wang, Magdalena Bieniasz, Lauren E Dockery. Efficacy and mechanism of mebendazole for ovarian cancer therapy [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 4671.

CCT2 prevented β-catenin proteasomal degradation to sustain cancer stem cell traits and promote tumor progression in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is featured by rapid progression and dismal outcomes clinically. Chaperonin Containing TCP1 Subunit 2 (CCT2) was identified as a crucial regulator for tumor progression, however, its exact role in EOC remained largely unknown. CCT2 expression and prognostic value in EOC samples were assessed according to TCGA dataset. Proliferation and mobility potentials were assessed by CCK8, colony-formation, wound healing, and Transwell assays. Cancer stem cell (CSC) traits were evaluated by RT-PCR, WB assays, sphere-forming assay and chemoresistance analysis. Bioinformatic analysis, co-IP assays and ubiquitin assays were performed to explore the mechanisms of CCT2 on EOC cells. CCT2 highly expressed in EOC tissues and predicted poor prognosis of EOC patients by TCGA analysis. Silencing CCT2 significantly restrained cell proliferation, migration, and invasion. Moreover, CCT2 could effectively trigger epithelial-mesenchymal transition to confer extensive invasion potentials to EOC cells, Importantly, CCT2 positively correlated with CSC markers in EOC, and CCT2 knockdown impaired CSC traits and sensitize EOC cells to conventional chemotherapy regimens. Contrarily, overexpressing CCT2 achieved opposite results. Mechanistically, CCT2 exerted its pro-oncogene function by triggering Wnt/β-catenin signaling. Specifically, CCT2 could recruit HSP105-PP2A complex, a well-established dephosphorylation complex, to β-catenin via direct physical interaction to prevent phosphorylation-induced proteasomal degradation of β-catenin, resulting in intracellular accumulation of active β-catenin and increased signaling activity. CCT2 was a novel promotor for EOC progression and a crucial sustainer for CSC traits mainly by preventing β-catenin degradation. Targeting CCT2 may represent a promising therapeutic strategy for EOC.

Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment.

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

Royal jelly induces ROS-mediated apoptosis in acute lymphoblastic leukemia (ALL)-derived Nalm-6 cells: Shedding light on novel therapeutic approaches for ALL.

Until recently, a conventional chemotherapy regimen for Acute lymphoblastic leukemia (ALL) is considered an efficient therapeutic method in children. However, suboptimal long-term survival rates in adults, disease relapse, and drug-induced toxicities require novel therapeutic agents for ALL treatments. Today, natural products with pharmacological benefits play a significant role in treating different cancers. Among the most valued natural products, honey bees' royal jelly (RJ) is one of the most appreciated which has revealed anti-tumor activity against different human cancers. This study aimed to evaluate anti-leukemic properties and the molecular mechanisms of RJ cytotoxicity on ALL-derived Nalm-6 cells. The metabolic activity was measured by MTT assay. Apoptosis, cell distribution in the cell cycle, and intracellular reactive oxygen species (ROS) level were investigated using flow cytometry analysis. Moreover, quantitative real-time PCR (qRT-PCR) was performed to scrutinize the expression of various regulatory genes. RJ significantly decreased the viability of Nalm-6 cells but had no cytotoxic effect on normal cells. In addition, RJ induced ROS-mediated apoptosis by up-regulating pro-apoptotic genes while decreasing anti-apoptotic gene expression. The results outlined that ROS-dependent up-regulation of FOXO4 and Sirt1 inhibits the cells' transition to the S phase of the cell cycle through p21 up-regulation. The qRT-PCR analysis of autophagy-related gene expression also demonstrated that RJ induced BECN1 mediated autophagy in Naml-6 cells. Taken together, this study showed that RJ can be utilized as a potent natural substance to induce ALL cells' programmed cell death. However, further studies are required to examine this compound's pharmaceutical application.

Sclerosing epithelioid fibrosarcoma associated with WRN gene variant presenting as chronic dyspnea and pathologic cervical fracture: a case report and review of the literature

BackgroundSclerosing epithelioid fibrosarcoma is an aggressive sarcoma subtype with poor prognosis and limited response to conventional chemotherapy regimens. Diagnosis can be difficult owing to its variable presentation, and cases of sclerosing epithelioid fibrosarcoma are rare. Sclerosing epithelioid fibrosarcoma typically affects middle-aged individuals, with studies inconsistently citing gender predominance. Sclerosing epithelioid fibrosarcoma typically arises from the bones and soft tissues and often has local recurrence after resection and late metastases. Immunohistochemical staining typically is positive for mucin-4. Werner syndrome is due to an autosomal recessive mutation in the WRN gene and predisposes patients to malignancy.Case presentationA 37-year-old Caucasian female presented to the emergency department with 4 months of dyspnea and back pain. She had been treated for pneumonia but had persistent symptoms. A chest, abdomen, and pelvis computed tomography showed near-complete right upper lobe collapse and consolidation, mediastinal lymphadenopathy, lytic spinal lesions, and a single 15-mm hypodense liver nodule. The patient underwent a transthoracic right upper lobe biopsy, bronchoscopy, endobronchial ultrasound with transbronchial lymph node sampling, and bronchoalveolar lavage of the right upper lobe. The bronchoalveolar lavage cytology was positive for malignant cells compatible with poorly differentiated non-small cell carcinoma; however, the cell block materials were insufficient to run immunostains for further investigation of the bronchoalveolar lavage results. Consequently, the patient also underwent a liver biopsy of the liver nodule, which later confirmed a diagnosis of sclerosing epithelioid fibrosarcoma. Next-generation sequencing revealed a variant of unknown significance in the WRN gene. She was subsequently started on doxorubicin.ConclusionSclerosing epithelioid fibrosarcoma is a very rare entity, only cited approximately 100 times in literature to date. Physicians should be aware of this disease entity and consider it in their differential diagnosis. Though pulmonary involvement has been described in the context of sclerosing epithelioid fibrosarcoma, this malignancy may affect many organ systems, warranting extensive investigation. Through our diagnostic workup, we suggest a possible link between sclerosing epithelioid fibrosarcoma and the WRN gene. Further study is needed to advance our understanding of sclerosing epithelioid fibrosarcoma and its clinical associations as it is an exceedingly rare diagnosis.

Myelodysplastic Syndrome Associated Hemophagocytic Lymphohistiocytosis: A Retrospective Study of 15 Cases in a Single Center

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by excessive cytokine secretion, resulting in hyperinflammation and multiorgan dysfunction. It is classified into primary HLH, which is mainly caused by genetic defects, and secondary HLH, triggered by various underlying conditions. Malignancy-associated HLH (M-HLH) is a secondary form commonly observed in patients with hematological malignancies, such as lymphomas, T/NK-cell disorders, acute leukemias, lymphoproliferative diseases, and myelodysplastic syndrome (MDS). M-HLH can occur in up to 1% of patients with hematologic malignancies, with lymphoma being the most frequently associated malignancy. HLH initiated by MDS is a rare entity with only a few cases reported, leading to limited knowledge regarding its pathogenesis, diagnosis and optimal treatment strategies. Methods: In this retrospective study, we analyzed a consecutive series of MDS-HLH patients admitted to our center between March 1, 2019, and March 1, 2023. Bio-clinical data related with MDS and HLH were collected at diagnosis of MDS-HLH. Additional observational indicators encompassed the following: basic clinical characteristics of the patients (age at onset, gender, duration of MDS prior to HLH), correlation between the onset of HLH and MDS, treatment and response, and genetic defects associated with HLH and MDS. MDS risk classification was according to the Revised International Prognosis Scoring System (IPSS-R) and the WHO classification-based Prognosis Scoring System, while patients were categorized into two groups as higher-risk and lower-risk MDS-HLH group. The follow-up period started at the time of MDS-HLH diagnosis and ended at the date of death or last examination. Overall survival (OS) was calculated from the time of HLH diagnosis to the date of death from any cause. Results: A total of 15 patients diagnosed with MDS-HLH were included in the study, with a median age of 66 years (range, 33-83 years). The majority of patients (10/15, 67%) were over 60 years old. All patients exhibited typical features of aggressive HLH: fever, cytopenia and elevated serum ferritin in all patients, hepatomegaly/splenomegaly in 87% (13/15), hypofibrinogenemia/hypertriglyceridemia in 73% (11/15), hemophagocytosis in 73% (11/15), low NK-cell activity in 21% (3/14), and elevated levels of sCD25 in 93% of patients (14/15). Additionally, four patients (27%) had concurrent Epstein-Barr virus (EBV) infection. Further analysis comparing the lower-risk and higher-risk MDS-HLH groups revealed interesting findings. In the lower-risk group, all patients developed HLH concurrently with the diagnosis of MDS. However, in the higher-risk group, the majority of patients (6/8, 62.5%) experienced HLH onset during MDS progression or relapse (p=0.014). Among the 15 patients, 8 patients (53.3%) achieved remission of HLH. During the study period, 8 deaths occurred, all directly attributed to HLH or its complications. The majority of deaths (75%, 6/8) occurred within the first two months after HLH diagnosis. The median overall survival was 12.3 weeks (95%CI, 1.1-23.5). Patients who achieved complete or partial response had significantly prolonged overall survival compared to those who did not respond to treatment (p=0.002). In the multivariate analysis of prognosis, the remission status of HLH was the only factor which was significantly associated with survival (p=0.018, Exp(B)=0.003). Conclusion: This is the first comprehensive study focusing specifically on MDS-HLH, providing valuable insights into the clinical characteristics, treatment outcomes, and prognosis of MDS-HLH. The findings emphasize the need of considering revision of diagnostic criteria specially for MDS-HLH. The pathogenesis of HLH in MDS-HLH differs based on the risk classification of MDS, with higher-risk cases driven by malignancy and lower-risk cases associated with immune dysfunction. The prognosis of MDS-HLH is generally poor. Achieving remission of HLH is crucial for improving the prognosis of MDS-HLH patients. Conventional chemotherapy regimens, including etoposide, have shown limited efficacy and safety in this context. Chemotherapy-free regimens should be preferred considering the features of ineffective hematopoiesis in MDS. The role of EBV infection in MDS-HLH development should be recognized.

Restoration of LAT Signaling in CD33-Directed CAR T Cells Improves Potency and Persistence Against Acute Myeloid Leukemia

Despite the development of novel therapies, the majority of patients with acute myeloid leukemia (AML) will not achieve long-term remissions. Patients with relapsed/refractory (r/r) AML have particularly poor outcomes, as conventional chemotherapy regimens are often unable to elicit long-term remissions. Allogeneic hematopoietic stem cell transplant (HSCT) is potentially curative in eligible patients, however, bridging therapies which can induce deep remissions prior to HSCT are needed. Second generation chimeric antigen receptor (CAR) T cells targeting lineage-restricted antigens, such as CD19, have induced remissions in up to 80 - 90% of pediatric patients with r/r B-lineage acute lymphoblastic leukemia (ALL), however, post-CAR relapses are common and only ~50% of treated patients achieve durable remissions. Similar strategies targeting myeloid-restricted antigens with 2 nd generation CAR T cells in AML have not replicated the success seen in ALL. As clinical experience has highlighted the impact of CAR T cell potency, persistence, and antigen-sensitivity to long-term efficacy in ALL, strategies to boost these properties in myeloid-directed CAR T cells are necessary to extend the clinical benefit of this therapy to patients with AML. Utilizing a global phosphoproteomics screen, we recently identified that inefficient phosphorylation of the Linker for activation of T cells (LAT) and the subsequent decrease in the downstream signaling pathways results in suboptimal CAR T cell activation. To overcome inefficient LAT activation, we developed a novel bicistronic CAR platform, consisting of a 2 nd generation CAR along with an Adjunctive LAT-Activating CAR (ALA-CART) which improved sensitivity to low-antigen leukemia cells, increased in vivo potency, and enhanced persistence in xenograft models of ALL. We hypothesized that the restoration of LAT signaling via the ALA-CART platform would also improve potency and persistence in pre-clinical models of AML. We found that while CD33 ALA-CART cells responded to CD33+ AML cells in vitro, they were less cytotoxic and produced lower levels of cytokines than CD33-28z or CD33-BBz 2 ndgeneration CAR T cells. However, CD33 ALA-CART cells demonstrated increased potency in xenograft models, eradicating AML cells at much lower doses than CD33-28z and CD33-BBz CAR T cells (Fig. 1A, p<0.0001). This in vivo potency correlated with an enrichment of T stem cell memory cells in the ALA-CART product, resulting in increased persistence of CD33 ALA-CART cells after leukemia clearance (Fig. 1B, p=0.0139). The ALA-CART platform was associated with increased mitochondrial mass and function, suggesting that the increased signaling through LAT results in an enhanced capacity for oxidative phosphorylation, potentially contributing to the increased persistence of CD33 ALA-CART cells in vivo. Thus, the ALA-CART platform, designed to restore LAT signaling in CAR T cells, demonstrates that CAR molecules can be rationally designed to enhance both in vivo potency and persistence, and represents a promising strategy for the development for more effective AML-directed CAR T cells.

Update Analysis of Central Nervous System Multiple Myeloma Prognosis and Survival: A Real-World Multi-Institutional Study of the Greek Myeloma Study Group

Central Nervous System Multiple Myeloma (CNS-MM) is a rare but aggressive complication of MM, and its treatment remains an unmet clinical need. Herein we present a real-world national analysis of incidence, characteristics, prognostic factors and outcome of a large cohort of patients with CNS-MM. We evaluated 53 patients with CNS-MM (M/F: 23/30; median age: 59, range: 20-96 years; IgG: 27, IgA: 10, light-chain: 11, non-secretory: 4, IgD: 1; ISS1: 22, ISS2: 13, ISS3: 18; RISS1: 15, RISS2: 22, RISS3: 16) out of 4352 MM patients (1.2%), who were treated within the Greek Myeloma Study Group centers from 2000 to 2022 (23% of patients were diagnosed after 2016). A control group of MM patients matched for age, gender, and stage (ISS/RISS) who were treated during the same period was used for comparisons. Presence of soft tissue plasmacytomas (STP) and/or plasma cell leukemia (PCL; circulating plasma cells, cPCs: ≥5%) was determined and analyzed as extramedullary involvement (EMI). Median time to CNS-MM from MM diagnosis was 28 months (range 0-149 months); 6/53 (11.3%) patients experienced CNS-MM at initial MM diagnosis. Clinical manifestations of CNS-MM included visual disturbances/diplopia: 32%, paresis/paraplegia: 22%, lethargy/confusion: 37%, headache: 22%, cranial nerve palsy: 13% and dysarthria: 11%. PCL was present in 16/53 (30%) CNS-MM patients, while 29/53 (54.7%) CNS-MM patients had bone and/or STP vs. 13/53 matched controls (p=0.001); EMI was found in 24/53 (45%) patients with CNS-MM vs. 4/53 (7%) in controls (p<0.001). 35/53 (66%) CNS-MM patients had leptomeningeal infiltration (LMI) and 34% had intraparenchymal lesions. Median number of cells in the cerebrospinal fluid (CSF) was 60/μL (range 10-2550) and almost all of them (80%, range: 20-100%) were clonal plasma cells. Out of 53 CNS-MM patients, 14 (26.4%) had only CNS involvement without marrow infiltration by PCs; 51% had ≥1 high-risk molecular features (i.e., del17p, t4:14, t14:16, 1q+), and this was marginally higher vs. controls (36%; p=0.15). CD56 negative marrow PCs did not differ between groups (33% vs. 37%). A binary logistic regression analysis demonstrated that EMI was the strongest prognostic factor for the development of CNS-MM (p=0.01; HzR: 5.7). Median number of lines of treatment before the development of CNS-MM was 2 (range 0-9). First line anti-myeloma treatment in patients who developed CNS-MM included conventional chemotherapy (CT) or thalidomide-based regimens in 19 patients, bortezomib-based triplets in 27 and daratumumab-based regimens (DBR) in 7; this did not differ from controls. Overall response rate (ORR) in first-line therapy was similar between CNS-MM and controls (85% for both groups; CR 41% vs. 36%, respectively). After a median follow-up of 150 months post-MM diagnosis (95% CI: 107-192), 46 CNS-MM patients (87%) deceased (MM progression: 34, infection/sepsis: 10, cerebral hemorrhage: 2). Median overall survival (OS) of CNS-MM patients vs. matched controls from initial MM diagnosis was 43 months (95% CI: 31-54) vs 60 months (95% CI: 34-86) (p=0.002; Figure). Regarding CNS-MM therapy, 17 patients received IMiD-based regimens and 26 received PI-based regimens, 6 received CT and 4 received DBR. Patients with CNS-MM and marrow infiltration by PCs displayed an ORR of 31% only; CNS symptoms improved in 74% of all patients. Median OS of CNS-MM patients from the time of CNS involvement was 4 months (95% CI: 2.6-5.3), and it was longer in 12 patients treated after 2016 [18 months (95% CI: 7-29) vs. 2 months (95% CI: 1-3)]. Cerebrospinal fluid (CSF) infusions were performed in 28 patients (53%); 9 patients (19%) underwent radiotherapy. A multivariate analysis showed that EMI, either at diagnosis or during MM course, was the strongest negative predictor for post CNS-MM OS (p=0.008; HR: 3.4 95% CI: 1.4-8.0). Moreover, LMI was a negative predictor (p=0.02; HR: 2.7, 95% CI: 1.2-6.3) for OS, whereas treatment after 2016 had a positive impact (p=0.02; HR: 0.28, 95% CI: 0.12-0.8); CSF infusions did not affect OS. In conclusion, our analysis representing one of the largest real-world series of CNS MM patients after 2016, showed that, OS of CNS-MM remains poor however, there is a positive impact of treatment after 2016, reflecting the efficacy of modern anti-myeloma therapy; EMI strongly predicts for CNS-MM and induces a 3-fold increase in the probability of post CNS-MM death indicating a potential need for CNS prophylaxis in these patients.

Chemotherapy Response and Toxicities in Older Adults with Hodgkin Lymphoma

INTRODUCTION Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by high-rate responses to conventional chemotherapy (CT). However, older adults are usually undertreated and develop poor outcomes, mainly due to their limited functional status, comorbidities and toxicities concerns. We evaluated the characteristics and outcomes of patients with HL older than 65 years in a real-life limited setting. METHODS We performed a retrospective study based on medical records review of newly diagnosed HL between 2004 and 2019 at Instituto Nacional de Enfermedades Neoplasicas (INEN, Lima- Peru). The initial treatment options were classified into three categories: (1) Curative CT regimen, (2) palliative treatment, or (3) no treatment. The staging was done according to Ann Arbor Staging Classification and response were defined by RECIST criteria in patients who received at least 3 courses of CT. RESULTS 73 patients were included. Median age was 73 years (range 65- 88y). Among the patients, 61% were male, and the remaining 39% were female. Majority of the patients (61%) presented B symptoms. The details of the presentation features are shown in Table 1. The most common histology was classic HL mixed cellularity (46%); although it could not be determined in 19% of patients. At diagnosis, 86% (n=63) of patients had an ECOG performance status of 0-2. Bulky disease was present in 20% of patients (n=15), and 15% (n=11) had visceral involvement. 26% were classified as early-stage (stage I-II), while 74% had advanced disease (stage III-IV). Regarding treatment, 67.1% (n=49) of the patients received curative CT with ABVD or AVD regimen. A smaller proportion, 4.1% (n= 3), received palliative treatment, and 28.7% (n=28) did not receive any treatment. In patients who received curative CT, 13 patients only received 1 or 2 courses of CT and were subsequently excluded from the analysis. 47% (17/36 patients) achieved complete response, 41.6% partial response (15/36 patients) and 11.1% had progression disease (4/36 patients). In this group of patients, the most common adverse effects observed were hematologic toxicity (22.2%). Additionally, one patient presented pneumonia, and three patients developed pneumonitis. Two patients who presented pneumonitis experienced treatment-related mortality (Table 2). CONCLUSIONS In conclusion, this study provided insights into the characteristics and treatment outcomes of older adults with classic Hodgkin lymphoma. The results suggest that curative chemotherapy with ABVD or AVD regimen is the most common treatment approach, with a significant proportion of patients achieving complete response. However, treatment-related adverse effects, particularly pneumonitis, were noted, warranting careful monitoring and management during the treatment process. Further research and careful assessment of treatment protocols are necessary to improve the outcomes and quality of life for this patient population.

Induction therapy choices and responses in a third world country: A single center study from Pakistan

BackgroundLeukaemia accounts for approximately 2.5% of all new cancer incidence and 3.1% of cancer-related mortality with a significant number of the total presenting as Acute Lymphocytic Leukemia. Acute Lymphocytic Leukemia (ALL) poses a healthcare burden in the majority of the countries of the world but is more so a case in resource-limited countries where access to comprehensive healthcare is often limited and scarcely available. This article tries to highlight the challenges in ALL treatments in one such region by presenting the facts regarding treatments employed and patient outcomes seen. MethodThis was a retrospective single-institution study in a tertiary care setup examining Ph neg ALL patient data from Jan 2019 to Dec 2020. It was stratified according to various parameters ranging from presentation to mode of diagnosis as well as treatment strategies and responses achieved after induction including mortality. Conventional chemotherapy regimens for ALL treatment were used with corticosteroids, vincristine, anthracyclines, asparaginase, cytosar, and MTX being the backbone of ALL induction. Cytogenetics were not possible due to resource constraints. ResultsData showed 85 patients being managed during the mentioned time period. 65 percent were males and 68 percent were between the age 15 to 30 years. Approximately 80 percent had no co-morbid condition including diabetes, hypertension, ischemic heart disease or Hep B/C positivity. Around 60 percent were diagnosed on immunophenotyping by flowcytometry and 62 percent used HyperCVAD as the induction protocol. Patients who achieved CR were 62 percent after single induction and most were assessed after count recovery on (3-4 weeks) or after 6 weeks with the percentages being 32 and 41 respectively. Duration of admission was for 1-3 weeks for almost 70 percent of the patients and those alive at the end of induction were around 90 percent. ConclusionIn conclusion, the treatment of Acute Lymphocytic Leukemia in resource-limited countries remains a formidable task,sometimes requiring innovative and sustainable approaches. Due to limited resources, a resource stratified rather than risk-stratified treatment approach is often utilized to tailor therapy. This approach ensures that relatively better resourced patients receive more intensive treatment others are spared unnecessary toxicity. While the challenges in resource-limited settings are significant, the treatment strategies and chemotherapy protocols, if modified as per need and implemented effectively, hold promise in improving outcomes for patients with Ph negative Acute Lymphocytic Leukemia in regions which have limited resources at their disposal.

Identification an innovative classification and nomogram for predicting the prognosis of thyroid carcinoma patients and providing therapeutic schedules.

Thyroid carcinoma (THCA) represents a prevalent form of cancer globally, with its incidence demonstrating an upward trend in recent years. Accumulating evidence has indicated that programmed cell death (PCD) patterns exert a vital influence on tumor progression. Nevertheless, the association between PCD and the prognosis of patients with papillary thyroid carcinoma remains to be elucidated. The current study endeavors to examine the link between PCD and the prognosis of thyroid cancer while concurrently developing a prognostic index based on PCD genes. Programmed cell death patterns were employed to construct the model and define clusters. Gene expression profile genomics and clinical data pertaining to 568 patients with thyroid cancer were sourced from the TCGA database. In addition, single-cell transcriptome data GSE184362 were procured from the Gene Expression Omnibus (GEO) database for subsequent analysis. The study harnessed six machine learning algorithms to create a programmed cell death signature (PCDS). Ultimately, the model developed via SVM was chosen as the optimal model, boasting the highest C-index. Moreover, the application of non-negative matrix factorization (NMF) led to the identification of two molecular subtypes of THCA, each characterized by distinct vital biological processes and drug sensitivities. The investigation revealed that PCDS is linked to chemokines, interleukins, interferons, and checkpoint genes, as well as pivotal components of the tumor microenvironment, as determined through a comprehensive analysis of bulk and single-cell transcriptomes. Patients with THCA and elevated PCDS values are more inclined to exhibit resistance to conventional chemotherapy regimens, yet may display heightened responsiveness to targeted therapeutic agents. Finally, we established a nomogram model based on multivariable cox and logistic regression analyses to predict the overall survival of THCA patients. This research sheds new light on the role of programmed cell death (PCD) patterns in THCA. By conducting an in-depth analysis of various cell death patterns, a novel PCD model has been devised, capable of accurately predicting the clinical prognosis and drug sensitivity of patients with THCA.

Efficacy and safety of immunochemotherapy, immunotherapy, chemotherapy, and targeted therapy as first-line treatment for advanced and metastatic esophageal cancer: a systematic review and network meta-analysis

The treatment of esophageal cancer has entered a new phase with the development of immunotherapy. The current investigation purpose is to investigate and contrast the efficacy and safety of immunotherapy, immunochemotherapy, chemotherapy, and targeted therapy as first-line treatment for individuals suffering from advanced and metastatic esophageal cancer. Within the framework of this systematic review and network meta-analysis, clinical trials published or reported in English up until 01 May, 2022, were retrieved from Embase, PubMed, Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov databases, ESMO, and ASCO. The analysis incorporated randomized controlled trials (RCTs) from phase 2 to 3 that evaluated a minimum of two first-line therapeutic regimens for metastatic esophageal cancer were included in the analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary clinical outcomes included the incidence of objective response rate (ORR), and adverse events (AEs) of any grade and ≥3 grade. Relative summary data were extracted from included studies by GZ, HS, WS, and TD. For clear statistical analysis, chemotherapy was divided into two categories of fluorouracil-based chemotherapy (FbCT) and fluorouracil-free chemotherapy (FfCT). Bayesian frequentist approach was employed to conduct the network meta-analysis. The indirect intercomparison between regimens was presented with league tables (HRs and 95% CI for OS and PFS, ORs and 95% CI for ORR and AEs). A greater surface value under the cumulative ranking (SUCRA) indicates a higher potential ranking for the corresponding treatment. A further calculation of relative results about esophageal squamous cell cancer was performed in the subgroup analysis. The current protocol for the systematic review has been properly registered on PROSPERO (registration number: CRD42021241145). The final analysis comprised 17 trials that involved 9128 patients and 19 distinct treatment regimens. Within the scope of investigated immunotherapy (IO) combinations, toripalimab+FfCT (tori+FfCT) demonstrated the best OS advantages (tori+FfCT vs. FbCT, HR 0.57, 95% CI 0.38-0.85; tori+FfCT vs. FfCT, HR 0.58, 95% CI 0.43-0.78). In terms of PFS, camrelizumab+FfCT (cam+FfCT) demonstrated the best PFS advantages (FbCT vs. cam+FfCT, HR 1.79, 95% CI 1.22-2.63; FfCT vs. cam+FfCT, HR 1.79, 95% CI 1.47-2.17). Nivolumab+FbCT (nivo+FbCT vs. FfCT, OR 3.29, 95% CI 1.43-7.56) showed the best objective responses. Compared to the conventional chemotherapy regimen, the toxicity was observed to be the slightest for the tori+FfCT (FbCT vs. tori+FfCT, OR 3.07, 95% CI 1.22-7.7) and sintilimab+FfCT (FbCT vs. sin+FfCT, OR 2.93, 95% CI 1.16-7.37). The results in this study were evaluated as having a low heterogeneity since the I2 value was ≤25% in all analyses. Compared to foreign IO combinations, sin+FfCT, tori+FfCT, cam+FfCT, and tisle+FbCT are superior first-line treatment options for patients with advanced and metastatic esophageal cancer. Although foreign IO combinations, such as pembro+FbCT and nivo+FbCT obtained better objective response rates than other IO combinations, the addition of chemotherapy to IO worsens the safety profiles. Our findings could provide complementary evidence for current guideline recommendations. This work was supported by a grant from the Science and Technology Program of Guangzhou, China (202206010103); and Natural Science Foundation of Guangdong Province (2022A1515012469).

Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies.

Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.

Retracted: Efficacy, Safety, and Tumor Marker Inhibition of Apatinib Combined with Conventional Chemotherapy Regimens for Patients with Advanced Triple-Negative Breast Cancer.

[This retracts the article DOI: 10.1155/2021/8720679.].

Diffuse Large B-Cell Lymphoma in the HIV Setting.

Despite the widespread use of combined antiretroviral therapy (cART) and the subsequent decrease in AIDS-defining cancers, HIV-related lymphomas remain a leading cause of morbidity and mortality in people with HIV (PWH). Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in PWH. This lymphoma is a heterogeneous disease including morphological variants and molecular subtypes according to the cell of origin or the mutation profile. In the pre-cART era, treatment with standard-dose chemotherapy induced high rates of toxicity and outcomes were very poor. The introduction of cART and the incorporation of infection prophylaxis allowed the use of conventional intensive chemotherapy regimens used in the general population, such as R-CHOP or R-EPOCH. The use of cART during chemotherapy treatment was initially controversial due to the potential risk of adverse drug-drug interactions. However, the availability of current cART regimens with less potential to cause drug interactions and evidence that cART improves survival rates in NHL strongly support the use of cART in PWH with DLBCL. Consequently, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PWH with NHL.

The conundrum of metaplastic breast cancer: a single Egyptian institution retrospective 10-year experience (2011–2020)

BackgroundMetaplastic breast cancer (MetBC) still represents a conundrum owing to its peculiar histogenesis and molecular drivers that render it extremely resistant to standard chemotherapy with ultimate dismal survival.AimDescribe the Egyptian National Cancer Institute’s (NCI-E) experience with MetBC regarding its clinicopathologic features, treatment, and survival outcomes.Patients and methodsBetween 2011 and 2020, all MetBC patients presented to NCI-E were retrospectively evaluated. Original clinicopathologic data, therapeutic modalities, pathologic response to neoadjuvant chemotherapy (NACT), recurrence, and date of last follow-up/death were obtained from archived charts.ResultsA cohort of 135 females, the median age was 52 years, and median follow-up period was 40 months (range: 2.6–130.8). Two-thirds were triple negative (TN). Squamous carcinoma was prevalent in 74.8% followed by carcinoma with osseous/chondroid differentiation, spindle cell, and low-grade adenosquamous carcinoma encountered in 13.3, 7.4, and 4.5%, respectively. Modified radical mastectomy was done in 59.3%, and positive nodes (pN+) were depicted in 37.7%. Median Ki-67 was 45% (range: 10–88); grade III and lymphovascular invasion (LVI) were observed in 83.7 and 43.7%, respectively. Stage II was the most common (49%), whereas initial stage IV was encountered in 8.1%. Anthracyclines/taxane combinations were rampant in adjuvant/neoadjuvant settings. The latter was employed in 41 patients, with only 3 cases (7.3%) achieving pathologic complete response (pCR), while moderate/significant residual tumor burden was found in 83%. The 5-year DFS and OS were 56.4 and 57.6%, respectively. Spindle cell carcinoma showed the worst survival parameters in univariate analysis. On the multivariate level, higher tumor stage (pT3 & 4), Ki-67 ≥ 45%, and TN subtype were independent variables for worse DFS and OS; age ≥ 52 years and the presence of LVI were independent features for worse DFS, whereas pN+ was an independent parameter for worse OS.ConclusionsThis study further solidifies the dreadful response of MetBC to conventional chemotherapy regimens employed in common non-metaplastic pathologies. A radical shift in treatment standards tailored to combat the molecular landscape of this distinctive tumor is urgently needed. Immunotherapy and molecularly targeted agents demonstrated promising results in phase I and II trials with hopeful sooner implementation in phase III studies.

Efficacy of Tyrosine Kinase Inhibitor Combined with Decitabine, Homoharringtonine, Interferon in the Maintenance Therapy of Blast Phase Chronic Myeloid Leukemia

To explore the efficacy of tyrosine kinase inhibitor (TKI) combined with decitabine, homoharringtonine, and interferon regimen as maintenance therapy for blast phase chronic myeloid leukemia (CML-BP). The clinical data of CML-BP patients who received the first major hematological response after induction therapy at The Affiliated Cancer Hospital of Zhengzhou University from June 2015 to December 2021 were analyzed retrospectively. The event-free survival, duration of remission, and overall survival of patients in TKI combined with decitabine, homoharringtonine, interferon group(n=18) and TKI combined with conventional chemotherapy group(n=10) were compared by log-rank test. A total of 28 patients were included, with a median age of 46 (24-58) years old. Kaplan-Meier survival analysis showed that patients in TKI combined with decitabine, homoharringtonine, interferon group had longer event-free survival (7.4 vs 4.3 months, P=0.043, HR＝0.44, 95% CI: 0.17-1.14), duration of overall remission (16.1 vs 6.6 months, P=0.005, HR＝0.32, 95% CI: 0.11-0.89), overall survival (34.3 vs 13.5 months, P=0.006, HR＝0.29, 95% CI: 0.10-0.82) compared with patients in TKI combined with conventional chemotherapy group. The TKI combined with decitabine, homoharringtonine and interferon regimen can significantly prolong the survival of CML-BP patients who obtained the major hematological response compared with TKI combined with conventional chemotherapy regimen.

Effect of upfront HSCT on patients with T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma at high risk of relapse: Single center retrospective observational study on minority rich population.

e19014 Background: T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/TLBL) is an aggressive neoplasm of lymphoid tissue. It comprises 15-25% of all cases of ALL. Given the rarity of the disease, data regarding its optimal management remains limited. Hematopoietic stem cell transplant (HSCT) is usually recommended for patients with T-ALL in second or later complete remission (CR). The data on upfront use of HSCT in ethnic minority rich population is rare. Methods: We conducted a single-center retrospective observational study in patients diagnosed with T-ALL who were followed at our center from 2004-2022. We collected and analyzed data on demographics, race, treatment regimens including HSCT, and survival outcomes. Overall survival (OS) was compared using the Kaplan-Meier curve and log-rank test. P-values < 0.05 were considered as statistically significant. Cox proportional hazards regression model was used for the statistical analysis of prognostic factors and analyses were performed using R software. Results: We identified 59 unique records with this diagnosis (78% males, 22% females). The median age at diagnosis was 20 years (range 1-48 years). Sixty one percent were ethnic minority (32% African American, 29% Hispanic), 17% were white, and 14% were of other ethnicities. Patients were treated at diagnosis with conventional chemotherapy regimens. Our transplant cohort had 10 patients, eight of whom received an allogeneic graft (2 matched related donor, 4 matched unrelated, 1 haploidentical, and 1 cord blood transplant) and 2 an autologous graft. Eight out of 10 patients received HSCT in CR1, 1/10 patient in CR2 (remission data-not available 1/10 patient). The OS of patients transplanted in CR1 did not differ significantly from the patients not receiving HSCT in CR1 (p = 0.5) with OS rates at 12, 24, and 36 months of 87.5% vs 83%, 75% vs 77%, 60%vs 77% respectively. However in the patients who eventually relapsed (n = 13), OS was significantly higher in patients receiving upfront HSCT in CR1 (n = 8) vs patients receiving chemotherapy only (p = 0.013). Furthermore, the OS from the transplant date compared between patients of age (at the time of transplant) < / = 20 years vs > 20 years didn’t differ significantly with p values of 0.29. Conclusions: Our study in T-ALL patients from a mainly minority urban population in NYC showed OS was not significantly different when transplant patients were compared to patients receiving only chemotherapy. For patients who eventually relapsed, the OS for patients receiving upfront HSCT was significantly higher than patients receiving chemotherapy only. Hence, patients at high risk of relapse might benefit from upfront HSCT. However, due to small sample size, evaluation of the effects of confounders was limited in our study.

Phytochemicals and bioactive compounds effective against acute myeloid leukemia: A systematic review.

This systematic review identified various bioactive compounds which have the potential to serve as novel drugs or leads against acute myeloid leukemia. Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy that arises from the dysregulation of cell differentiation, proliferation, and cell death. The risk factors associated with the onset of AML include long-term exposure to radiation and chemicals such as benzene, smoking, genetic disorders, blood disorders, advancement in age, and others. Although novel strategies to manage AML, including a refinement of the conventional chemotherapy regimens, hypomethylating agents, and molecular targeted drugs, have been developed in recent years, resistance and relapse remain the main clinical problems. In this study, three databases, PubMed/MEDLINE, ScienceDirect, and Google Scholar, were systematically searched to identify various bioactive compounds with antileukemic properties. A total of 518 articles were identified, out of which 59 were viewed as eligible for the current report. From the data extracted, over 60 bioactive compounds were identified and divided into five major groups: flavonoids, alkaloids, organosulfur compounds, terpenes, and terpenoids, and other known and emerging bioactive compounds. The mechanism of actions of the analyzed individual bioactive molecules differs remarkably and includes disrupting chromatin structure, upregulating the synthesis of certain DNA repair proteins, inducing cell cycle arrest and apoptosis, and inhibiting/regulating Hsp90 activities, DNA methyltransferase 1, and histone deacetylase 1.